Professor A. Margot Umpleby


Diabetes & Metabolic Medicine Research
+44 (0)1483 688579
21 PG 00

Academic and research departments

School of Biosciences.

About

Areas of specialism

Stable isotope techniques in the study of human metabolism

My qualifications

1976
BA Natural Sciences
Cambridge
1982
PhD Medicine
University of London

Affiliations and memberships

Department of Nutritional Sciences

Research

Research interests

Publications

Aryati Ahmad, Cheryl Isherwood, Margot Umpleby, Bruce Griffin (2020)Effects of High and Low Sugar Diets on Cardiovascular Disease Risk Factors, In: Journal of nutritional science and vitaminology66(Supplement)S18pp. S18-S24

It has been proposed that a high sugar intake was associated with cardiovascular disease (CVD) risk and metabolic syndrome depending on the amount of carbohydrate (CHO), other nutrients in foods, and underlying metabolic disturbances. This study aimed to investigate the effects of high (HS) and low sugar (LS) diets on metabolic profiles in 25 middle-aged men at increased CVD risk in a 12-week randomised cross-over intervention study. An isocaloric dietary exchanged model consisted of HS (24% energy from sugar) and LS (6% energy from sugar) with comparable total CHO, fat and fibre composition in normal foods was used. Anthropometric, blood pressure and plasma lipid profile were measured pre- and post-intervention. Body weight, waist circumference and fat mass increased and decreased significantly after HS (by 0.7±0.3 kg, 1.4±1.0 cm and 0.5±0.3 kg) and LS (by 2.1±0.5 kg, 2.0±0.8 cm and 1.4±0.3 kg) (p

Olah Hakim, Oluwatoyosi Bello, Meera Ladwa, Janet L. Peacock, A. Margot Umpleby, Geoffrey Charles-Edwards, Stephanie A. Amiel, Louise M. Goff (2020)The Link between Obesity and Inflammatory Markers in the Development of Type 2 Diabetes in Men of Black African and White European Ethnicity, In: Nutrients12(12)3796pp. 1-15 Mdpi

In this study, we aimed to assess ethnic differences in visceral (VAT), deep subcutaneous (dSAT), and superficial subcutaneous (sSAT) adipose tissue and their relationships with inflammatory markers between white European (WE) and black West African (BWA) men with normal glucose tolerance (NGT) and type 2 diabetes (T2D). Forty-two WE (23 NGT/19 T2D) and 43 BWA (23 NGT/20 T2D) men underwent assessment of plasma inflammatory markers using immunoassays alongside Dixon magnetic resonance imaging to quantify L4-5 VAT, dSAT and sSAT. Despite no ethnic differences in sSAT and dSAT, BWA men exhibited lower VAT (p = 0.002) and dSAT:sSAT (p = 0.047) than WE men. Adiponectin was inversely associated with sSAT in WE (p = 0.041) but positively associated in BWA (p = 0.031) men with T2D. Interleukin-6 (IL-6) was associated with VAT in WE but not in BWA men with NGT (WE: p = 0.009, BWA: p = 0.137) and T2D (WE: p = 0.070, BWA: p = 0.175). IL-6 was associated with dSAT in only WE men with NGT (WE: p = 0.030, BWA: p = 0.833). The only significant ethnicity interaction present was for the relationship between adiponectin and sSAT (P-interaction = 0.003). The favourable adipose tissue distribution and the weaker relationships between adiposity and inflammation in BWA men suggest that adipose tissue inflammation may play a lesser role in T2D in BWA than WE men.

Roselle A. Herring, Fariba Shojaee-Moradie, Robert Garesse, Mary Stevenage, Nicola Jackson, Barbara A. Fielding, Agampodi Mendis, Sigurd Johnsen, A. Margot Umpleby, Melanie Davies, David L. Russell-Jones (2020)Metabolic Effects of an SGLT2 Inhibitor (Dapagliflozin) During a Period of Acute Insulin Withdrawal and Development of Ketoacidosis in People With Type 1 Diabetes, In: Diabetes care43(9)2128pp. 2128-2136 Amer Diabetes Assoc

OBJECTIVE To determine the effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketone body concentrations during insulin withdrawal in people with type 1 diabetes. RESEARCH DESIGN AND METHODS A double-blind, placebo-controlled crossover study with a 4-week washout period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the glucose R-a, R-d, and lipolysis. At isotopic steady state, insulin was withdrawn, and the study was terminated after 600 min or earlier if blood glucose reached 18 mmol/L, bicarbonate 27 and

Roselle A. Herring, Fariba Shojaee-Moradie, Robert Garesse, Mary Stevenage, Nicola Jackson, Barbara A. Fielding, Agampodi Mendis, Sigurd Johnsen, A. Margot Umpleby, Melanie Davies, David L. Russell-Jones (2021)RESPONSE TO COMMENT ON HERRING ET AL. Metabolic Effects of an SGLT2 Inhibitor (Dapagliflozin) During a Period of Acute Insulin Withdrawal and Development of Ketoacidosis in People With Type 1 Diabetes. Diabetes Care 2020;43:2128-2136, In: Diabetes care44(3)pp. E61-E61 Amer Diabetes Assoc
Roselle A. Herring, Iain Parsons, Fariba Shojaee-Moradie, Mary Stevenage, Nicola Jackson, Ralph Manders, A. Margot Umpleby, Barbara A. Fielding, Melanie Davies, David L. Russell-Jones (2023)Effect of Dapagliflozin on Cardiac Function and Metabolic and Hormonal Responses to Exercise, In: The journal of clinical endocrinology and metabolism108(4)pp. 888-896 Endocrine Soc

Objective This work aimed to investigate the effect of the SGLT(2) inhibitor, dapagliflozin (DAPA), on cardiac function and the metabolic and hormonal response to moderate exercise in people with type 2 diabetes. Methods This was a double-blind, placebo-controlled crossover study with a 4-week washout period. Nine participants were randomly assigned to receive either 4 weeks of DAPA or 4 weeks of placebo. After each treatment, they underwent an exercise protocol with 2 consecutive 10-minute stages at a constant load corresponding to 40% and 70% maximal oxygen consumption (VO2max), coupled with hormonal and metabolic analysis. A blinded transthoracic echocardiogram was performed 3 days later. Results During the exercise protocol, glucose and lactate were lower (P < .0001 and P < .05, respectively) and beta-hydroxybutyrate (BOBH) and growth hormone (GH) were higher (P < .0005 and P = .01) following DAPA treatment compared to placebo. There was a trend for lower insulin with DAPA. Adrenalin, noradrenalin, and glucagon were not different. Following DAPA participants demonstrated an increased mean peak diastolic mitral annular velocity (e') in comparison to placebo (P = .03). The indexed left atrial volume and right ventricular e" were reduced following DAPA compared with placebo (P = .045 and P = .042, respectively). Arterial stiffness was not different between treatments (DAPA 9.35 +/- 0.60 m/s; placebo 9.07 +/- 0.72 m/s). Conclusion During exercise, GH may be more important than catecholamines in driving the shift from glucose to fatty acid metabolism by SGLT(2) inhibitors. The 4-week crossover design showed changes in cardiac function were rapid in onset and reversible.

Ann Kristin Hjelle de Soysa, Mette Langaas, Anida Jakic, Fariba Shojaee-Moradie, A. Margot Umpleby, Valdemar Grill, Ingrid Lovold Mostad (2021)The fat mass and obesity-associated (FTO) gene allele rs9939609 and glucose tolerance, hepatic and total insulin sensitivity, in adults with obesity, In: PloS one16(3)0248247pp. e0248247-e0248247 Public Library Science

The objective of the study was to assess associations of the rs9939609 FTO allele to glucose tolerance, hepatic and total insulin sensitivity (IS) in individuals with obesity. From a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer, hepatic IS was assessed by rates of basal and suppressed glucose appearance (Ra), a measure of endogenous glucose production (EGP), and the hepatic insulin resistance index (HIR). Total IS was assessed by rates of glucose infusion (GIR), disappearance (Rd), and metabolic clearance (MCR). From a meal test we assessed IS by the Matsuda index and glucose tolerance by glucose and insulin measurements in the fasted state and postprandially for 2.5 h. The meal test was performed in 97 healthy individuals with BMI >= 35 in similar-sized risk-allele groups (n = 32 T/T, 31 NT, and 34 NA), and 79 of them performed the clamp. We analyzed out-comes separately for males and females, and adjusted glucose Ra, Rd, MCR, GIR, and HIR for fat mass. We did not find genotype effects on EGP. Among males, genotype NA was associated with a significantly lower glucose Rd, MCR, and Matsuda index score relative to genotype T/T. Glucose tolerance was significantly lower in males with genotype NT vs. T/T and NA. For females, there were no genotype effects on hepatic or total IS, or on glucose tolerance. Independently of genotypes, females displayed a significantly better hepatic and total IS, and better glucose tolerance than males. We conclude that in subjects with similar obesity we did not register any FTO risk-allele effect on hepatic IS. A FTO risk-allele effect on total IS was registered in males only, findings which need to be reproduced in further studies. Results confirm marked differences in IS between the biological sexes and extend present knowledge by demonstrating a lower endogenous glucose production in females vs. males in uniformly obese individuals.

Meera Ladwa, Oluwatoyosi Bello, Olah Hakim, Maria Linda Boselli, Fariba Shojaee-Moradie, A Margot Umpleby, Janet Peacock, Stephanie A Amiel, Riccardo C Bonadonna, Louise M Goff (2022)Exploring the determinants of ethnic differences in insulin clearance between men of Black African and White European ethnicity, In: Acta diabetologica59(3)329pp. 329-337

People of Black African ancestry, who are known to be at disproportionately high risk of type 2 diabetes (T2D), typically exhibit lower hepatic insulin clearance compared with White Europeans. However, the mechanisms underlying this metabolic characteristic are poorly understood. We explored whether low insulin clearance in Black African (BA) men could be explained by insulin resistance, subclinical inflammation or adiponectin concentrations. BA and White European (WE) men, categorised as either normal glucose tolerant (NGT) or with T2D, were recruited to undergo the following: a mixed meal tolerance test with C-peptide modelling to determine endogenous insulin clearance; fasting serum adiponectin and cytokine profiles; a hyperinsulinaemic-euglycaemic clamp to measure whole-body insulin sensitivity; and magnetic resonance imaging to quantify visceral adipose tissue. Forty BA (20 NGT and 20 T2D) and 41 WE (23 NGT and 18 T2D) men were studied. BA men had significantly lower insulin clearance (P = 0.011) and lower plasma adiponectin (P = 0.031) compared with WE men. In multiple regression analysis, ethnicity, insulin sensitivity and plasma adiponectin were independent predictors of insulin clearance, while age, visceral adiposity and tumour necrosis factor alpha (TNF-α) did not significantly contribute to the variation. These data suggest that adiponectin may play a direct role in the upregulation of insulin clearance beyond its insulin-sensitising properties.

Olah Hakim, Oluwatoyosi Bello, Meera Ladwa, Fariba Shojaee-Moradie, Nicola Jackson, Janet L. Peacock, A. Margot Umpleby, Geoffrey Charles-Edwards, Stephanie A. Amiel, Louise M. Goff (2021)Adiponectin is associated with insulin sensitivity in white European men but not black African men, In: Diabetic medicine38(8)14571pp. e14571-n/a Wiley

Aims We aimed to assess ethnic differences in inflammatory markers and their relationships with insulin sensitivity and regional adiposity between white European and black African men. Methods A total of 53 white European and 53 black African men underwent assessment of inflammatory markers alongside Dixon-magnetic resonance imaging to quantify subcutaneous and visceral adipose tissue and intrahepatic lipid. A hyperinsulinaemic-euglycaemic clamp was used to measure whole-body and adipose tissue insulin sensitivity. To assess ethnic differences in relationships, the statistical significance of an interaction term between adipokines and ethnic group was tested in multivariable regression models. Results The black African men exhibited significantly lower adiponectin and tumour necrosis factor-alpha (TNF-alpha) and greater interleukin-10 (IL-10) compared to white European men (all p < 0.05). There were no statistically significant ethnic differences in leptin, resistin, IL-6, interferon-gamma, IL-13, IL-1 beta, IL-8 and vascular endothelial growth factor. Several relationships differed significantly by ethnicity such that they were stronger in white European than black African men including IL-6 with visceral adipose tissue; adiponectin with subcutaneous adipose tissue; leptin with intrahepatic lipid; adiponectin, IL-6 and TNF-alpha with whole-body insulin sensitivity and TNF-alpha with adipose tissue insulin sensitivity (all pinteraction

Emily Brown, Moon M. Wilton, Victoria S. Sprung, Joanne A. Harrold, Jason C. G. Halford, Andrej Stancak, Malcolm Burgess, Elaine Howarth, A. Margot Umpleby, Graham J. Kemp, John P. H. Wilding, Daniel J. Cuthbertson (2021)A randomised, controlled, double blind study to assess mechanistic effects of combination therapy of dapagliflozin with exenatide QW versus dapagliflozin alone in obese patients with type 2 diabetes mellitus (RESILIENT): study protocol, In: BMJ open11(7)045663pp. e045663-e045663 Bmj Publishing Group

Introduction The newer glucose-lowering therapies for type 2 diabetes (T2D), the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), have additional clinical benefits beyond improving glycaemic control; promoting weight loss, addressing associated cardiovascular risk factors and reducing macrovascular and microvascular complications. Considering their independent mechanisms of actions, there is a potential for significant synergy with combination therapy, yet limited data exist. This 32-week randomised, double-blind, placebo-controlled trial will gain mechanistic insight into the effects of coadministration of exenatide QW, a weekly subcutaneous GLP1-RA, with dapagliflozin, a once daily oral SGLT2i, on the dynamic, adaptive changes in energy balance, total, regional and organ-specific fat mass and multiorgan insulin sensitivity. Methods and analysis 110 obese patients with diagnosed T2D (glycated haemoglobin, HbA(1c) >= 48 mmol/mol) will be treated for 32 weeks with dapagliflozin (10 mg once daily either alone or in combination with exenatide QW (2 mg once weekly); active treatments will be compared with a control group (placebo tablet and sham injection). The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). Secondary outcome measures include changes in (1) energy balance (energy intake and energy expenditure measured by indirect calorimetry); (2) appetite (between and within meals) and satiety quotient; (3) body composition including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include metabolic changes in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp), central nervous system responses to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and changes in cardiovascular function (using transthoracic echocardiography, cardiac MR and duplex ultrasonography). Ethics and dissemination This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1147) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice. Results from the study will be published in peer-reviewed scientific and open access journals and/or presented at scientific conferences and summarised for distribution to the participants. Trial sponsor University of Liverpool.

Meera Ladwa, Oluwatoyosi Bello, Olah Hakim, Fariba Shojaee-Moradie, Linda Boselli, Geoff Charles-Edwards, Marietta Stadler, Janet L. Peacock, Anne Margot Umpleby, Stephanie A. Amiel, Riccardo C. Bonadonna, Louise M. Goff (2020)Insulin clearance as the major player in the hyperinsulinaemia of black African men without diabetes, In: Diabetes, obesity & metabolism22(10)pp. 1808-1817 Wiley

Aim To investigate relationships between insulin clearance, insulin secretion, hepatic fat accumulation and insulin sensitivity in black African (BA) and white European (WE) men. Methods Twenty-three BA and twenty-three WE men with normal glucose tolerance, matched for age and body mass index, underwent a hyperglycaemic clamp to measure insulin secretion and clearance, hyperinsulinaemic-euglycaemic clamp with stable glucose isotope infusion to measure whole-body and hepatic-specific insulin sensitivity, and magnetic resonance imaging to quantify intrahepatic lipid (IHL). Results BA men had higher glucose-stimulated peripheral insulin levels (48.1 [35.5, 65.2] x 10(3)vs. 29.9 [23.3, 38.4] x 10(3)pmol L-1 x min,P= .017) and lower endogeneous insulin clearance (771.6 [227.8] vs. 1381 [534.3] mL m(-2)body surface area min(-1),P < .001) compared with WE men. There were no ethnic differences in beta-cell insulin secretion or beta-cell responsivity to glucose, even after adjustment for prevailing insulin sensitivity. In WE men, endogenous insulin clearance was correlated with whole-body insulin sensitivity (r = 0.691,P= .001) and inversely correlated with IHL (r = -0.674,P= .001). These associations were not found in BA men. Conclusions While normally glucose-tolerant BA men have similar insulin secretory responses to their WE counterparts, they have markedly lower insulin clearance, which does not appear to be explained by either insulin resistance or hepatic fat accumulation. Low insulin clearance may be the primary mechanism of hyperinsulinaemia in populations of African origin.

Laura J. McCreight, Andrea Mari, Lucy Coppin, Nicola Jackson, A. Margot Umpleby, Ewan R. Pearson (2020)Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals, In: Diabetologia63(2)pp. 444-447 Springer Berlin Heidelberg
Martin Brunel Whyte, Prashanth R. J. Vas, Anne M. Umpleby (2021)Could Exogenous Insulin Ameliorate the Metabolic Dysfunction Induced by Glucocorticoids and COVID-19?, In: Frontiers in endocrinology (Lausanne)12649405pp. 649405-649405 Frontiers Media Sa

The finding that high-dose dexamethasone improves survival in those requiring critical care due to COVID-19 will mean much greater usage of glucocorticoids in the subsequent waves of coronavirus infection. Furthermore, the consistent finding of adverse outcomes from COVID-19 in individuals with obesity, hypertension and diabetes has focussed attention on the metabolic dysfunction that may arise with critical illness. The SARS coronavirus itself may promote relative insulin deficiency, ketogenesis and hyperglycaemia in susceptible individuals. In conjunction with prolonged critical care, these components will promote a catabolic state. Insulin infusion is the mainstay of therapy for treatment of hyperglycaemia in acute illness but what is the effect of insulin on the admixture of glucocorticoids and COVID-19? This article reviews the evidence for the effect of insulin on clinical outcomes and intermediary metabolism in critical illness.

Meera Ladwa, Oluwatoyosi Bello, Olah Hakim, Fariba Shojaee-Moradie, Maria Linda Boselli, Geoff Charles-Edwards, Janet Peacock, A Margot Umpleby, Stephanie A Amiel, Riccardo C Bonadonna, Louise M Goff (2021)Ethnic differences in beta cell function occur independently of insulin sensitivity and pancreatic fat in black and white men, In: BMJ open diabetes research & care9(1)e002034

IntroductionIt is increasingly recognized that type 2 diabetes (T2D) is a heterogenous disease with ethnic variations. Differences in insulin secretion, insulin resistance and ectopic fat are thought to contribute to these variations. Therefore, we aimed to compare postprandial insulin secretion and the relationships between insulin secretion, insulin sensitivity and pancreatic fat in men of black West African (BA) and white European (WE) ancestry.Research design and methodsA cross-sectional, observational study in which 23 WE and 23 BA men with normal glucose tolerance, matched for body mass index, underwent a mixed meal tolerance test with C peptide modeling to measure beta cell insulin secretion, an MRI to quantify intrapancreatic lipid (IPL), and a hyperinsulinemic-euglycemic clamp to measure whole-body insulin sensitivity.ResultsPostprandial insulin secretion was lower in BA versus WE men following adjustment for insulin sensitivity (estimated marginal means, BA vs WE: 40.5 (95% CI 31.8 to 49.2) × 103 vs 56.4 (95% CI 48.9 to 63.8) × 103 pmol/m2 body surface area × 180 min, p=0.008). There was a significantly different relationship by ethnicity between IPL and insulin secretion, with a stronger relationship in WE than in BA (r=0.59 vs r=0.39, interaction p=0.036); however, IPL was not a predictor of insulin secretion in either ethnic group following adjustment for insulin sensitivity.ConclusionsEthnicity is an independent determinant of beta cell function in black and white men. In response to a meal, healthy BA men exhibit lower insulin secretion compared with their WE counterparts for their given insulin sensitivity. Ethnic differences in beta cell function may contribute to the greater risk of T2D in populations of African ancestry.

D Elleri, JM Allen, M Biagioni, K Kumareswaran, L Leelarathna, K Caldwell, M Nodale, ME Wilinska, A Haidar, P Calhoun, C Kollman, MA Umpleby, CL Acerini, DB Dunger, R Hovorka (2012)Efficacy and safety of reduced prandial boluses during closed-loop insulin delivery in adolescents with type 1 diabetes, In: DIABETOLOGIA55pp. S86-S87 SPRINGER
Roselle A. Herring, Fariba Shojaee-Moradie, Robert Garesse, Mary Stevenage, Nicola Jackson, Barbara Fielding, Agampodi Mendis, Sigurd Johnsen, Margot Umpleby, Melanie Davies, David L. Russell-Jones (2020)Full Title Metabolic effects of an SGLT2 inhibitor (dapagliflozin) during a period of acute insulin withdrawal and development of ketoacidosis in people with type 1 diabetes., In: Diabetes Care American Diabetes Association

Objective: To determine the effect of SGLT2 inhibitor dapagliflozin on glucose flux, lipolysis and ketone body concentrations during insulin withdrawal in people with type 1 diabetes. Research Design and Methods: A double-blind placebo controlled crossover study with a 4-week wash out period was performed in 12 people with type 1 diabetes using insulin pump therapy. Participants received dapagliflozin or placebo in random order for 7 days. Stable isotopes were infused to measure the rate of glucose production (Ra), disappearance (Rd) and lipolysis. At isotopic steady state insulin was withdrawn and the study terminated after 600 minutes or earlier if blood glucose reached 18mmol/L, bicarbonate 27 and

Alexander Dimitri Miras, Anna Kamocka, Belen Perez-Pevida, Sanjay Purkayastha, Krishna Moorthy, Ameet Patel, Harvinder Chahal, Gary Frost, Paul Bassett, Lidia Castagnetto-Gissey, Lucy Coppin, Nicola Jackson, A. Margot Umpleby, Stephen Robert Bloom, Tricia Tan, Ahmed Rashid Ahmed, Francesco Rubino (2021)The Effect of Standard Versus Longer Intestinal Bypass on GLP-1 Regulation and Glucose Metabolism in Patients With Type 2 Diabetes Undergoing Roux-en-Y Gastric Bypass: The Long-Limb Study, In: Diabetes care44(5)1082pp. 1082-1090 Amer Diabetes Assoc

OBJECTIVE Roux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass. RESEARCH DESIGN AND METHODS A total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery. RESULTS Both groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity. CONCLUSIONS The findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP- 1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.

F Shojaee-Moradie, DJ Cuthbertson, M Barrett, NC Jackson, R Herring, EL Thomas, J Bell, GJ Kemp, J Wright, M Umpleby (2016)Exercise training reduces liver fat and increases rates of VLDL clearance, but not VLDL production in NAFLD, In: Journal of Clinical Endocrinology and Metabolism101(11) Oxford University Press (OUP)

Context Randomised controlled trials in non-alcoholic fatty liver disease (NAFLD) have shown that regular exercise, even without calorie restriction, reduces liver steatosis. A previous study has shown that 16 weeks supervised exercise training in NAFLD did not affect total VLDL kinetics. Objective To determine the effect of exercise training on intrahepatocellular fat (IHCL) and the kinetics of large triglyceride-(TG)-rich VLDL1 and smaller denser VLDL2 which has a lower TG content. Design A 16 week randomised controlled trial. Patients 27 sedentary patients with NAFLD. Intervention Supervised exercise with moderate-intensity aerobic exercise or conventional lifestyle advice (control). Main outcome Very low density lipoprotein1 (VLDL1) and VLDL2-TG and apolipoproteinB (apoB) kinetics investigated using stable isotopes before and after the intervention. Results In the exercise group VO2max increased by 31±6% (mean±SEM) and IHCL decreased from 19.6% (14.8, 30.0) to 8.9% (5.4, 17.3) (median (IQR)) with no significant change in VO2max or IHCL in the control group (change between groups p

D Elleri, M Biagioni, JM Allen, K Kumareswaran, L Leelarathna, K Caldwell, M Nodale, ME Wilinska, A Haidar, P Calhoun, C Kollman, NC Jackson, AM Umpleby, CL Acerini, DB Dunger, R Hovorka (2015)Safety, efficacy and glucose turnover of reduced prandial boluses during closed-loop therapy in adolescents with type 1 diabetes: a randomized clinical trial, In: DIABETES OBESITY & METABOLISM17(12)pp. 1173-1179 WILEY-BLACKWELL
R Dobson, MI Burgess, VS Sprung, A Irwin, M Hamer, J Jones, C Daousi, V Adams, GJ Kemp, F Shojaee-Moradie, M Umpleby, DJ Cuthbertson (2016)Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity, In: INTERNATIONAL JOURNAL OF OBESITY40(1)pp. 153-161 NATURE PUBLISHING GROUP
CJA Pugh, VS Sprung, GJ Kemp, P Richardson, F Shojaee-Moradie, AM Umpleby, DJ Green, NT Cable, H Jones, DJ Cuthbertson (2014)Exercise training reverses endothelial dysfunction in nonalcoholic fatty liver disease, In: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY307(9)pp. H1298-H1306 AMER PHYSIOLOGICAL SOC
Simon Steenson, Fariba Shojaee-Moradie, Martin Whyte, Kim G. Jackson, Julie A. Lovegrove, Barbara Fielding, Margot Umpleby (2020)The effect of fructose feeding on intestinal triacylglycerol production and de novo fatty acid synthesis in humans, In: Nutrients MDPI

A high fructose intake exacerbates postprandial plasma triacylglycerol (TAG) concentration, an independent risk factor for cardiovascular disease, although it is unclear whether this is due to increased production or impaired clearance of triacylglycerol (TAG)-rich lipoproteins. We determined the in vivo acute effect of fructose on postprandial intestinal and hepatic lipoprotein TAG kinetics and de novo lipogenesis (DNL). Five overweight men were studied twice, 4 weeks apart. They consumed hourly mixed-nutrient drinks that were high-fructose (30% energy) or low-fructose (

A Ahmad, C Isherwood, BA Fielding, JD Bell, EL Thomas, G Frost, F Shojaee-Moradie, M Umpleby, BA Griffin (2012)Individuals with moderately raised liver fat show a greater increase in liver fat in response to a high sugar diet, In: PROCEEDINGS OF THE NUTRITION SOCIETY71(OCE2)pp. E31-E31 CAMBRIDGE UNIV PRESS
HR Murphy, D Elleri, JM Allen, J Harris, D Simmons, G Rayman, RC Temple, AM Umpleby, DB Dunger, A Haidar, M Nodale, ME Wilinska, R Hovorka (2012)Pathophysiology of postprandial hyperglycaemia in women with type 1 diabetes during pregnancy., In: Diabetologia55(2)pp. 282-293

Although maternal hyperglycaemia is associated with increased risk of adverse pregnancy outcome, the mechanisms of postprandial hyperglycaemia during pregnancy are poorly understood. We aimed to describe glucose turnover in pregnant women with type 1 diabetes, according to stage of gestation (early vs late gestation).

M Boothby, KC McGee, JW Tomlinson, LL Gathercole, PG McTernan, F Shojaee-Moradie, AM Umpleby, P Nightingale, M Shahmanesh (2009)Adipocyte differentiation, mitochondrial gene expression and fat distribution: differences between zidovudine and tenofovir after 6 months, In: ANTIVIRAL THERAPY14(8)pp. 1089-1100 INT MEDICAL PRESS LTD
F Smeeton, F Shojaee Moradie, RH Jones, L Westergaard, H Haahr, AM Umpleby, DL Russell-Jones (2009)Differential effects of insulin detemir and neutral protamine Hagedorn (NPH) insulin on hepatic glucose production and peripheral glucose uptake during hypoglycaemia in type 1 diabetes., In: Diabetologia52(11)pp. 2317-2323

We compared the symptoms of hypoglycaemia induced by insulin detemir (NN304) (B29Lys(epsilon-tetradecanoyl),desB30 human insulin) and equally effective doses of neutral protamine Hagedorn (NPH) insulin in relation to possible differential effects on hepatic glucose production and peripheral glucose uptake.

D Elleri, JM Allen, J Harris, K Kumareswaran, M Nodale, L Leelarathna, CL Acerini, A Haidar, ME Wilinska, N Jackson, AM Umpleby, ML Evans, DB Dunger, R Hovorka (2013)Absorption patterns of meals containing complex carbohydrates in type 1 diabetes., In: Diabetologia56(5)pp. 1108-1117

Successful postprandial glycaemia management requires understanding of absorption patterns after meals containing variable complex carbohydrates. We studied eight young participants with type 1 diabetes to investigate a large low-glycaemic-load (LG) meal and another eight participants to investigate a high-glycaemic-load (HG) meal matched for carbohydrates (121 g).

HL Simpson, NC Jackson, F Shojaee-Moradie, RH Jones, DL Russell-Jones, PH Sonksen, DB Dunger, AM Umpleby (2004)Insulin-like growth factor I has a direct effect on glucose and protein metabolism, but no effect on lipid metabolism in type 1 diabetes, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM89(1)pp. 425-432 ENDOCRINE SOC
Martin B Whyte, Fariba Shojaee-Moradie, Sharaf E Sharaf, Nicola Jackson, Barbara Fielding, Roman Hovorka, Jeewaka Mendis, David Russell-Jones, A Margot Umpleby (2018)Lixisenatide reduces chylomicron triacylglycerol due to increased clearance, In: The Journal of Clinical Endocrinology & Metabolism104(2)pp. 359-368 Oxford University Press (OUP)

Context GLP-1 agonists control postprandial glucose and lipid excursion in type 2 diabetes; however the mechanism(s) are unclear. Objective To determine the mechanism(s) of postprandial lipid and glucose control with lixisenatide (GLP-1 analogue) in type 2 diabetes. Design Randomised, double-blind, cross-over study. Setting Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, UK Patients Eight obese men with type 2 diabetes (57.3±1.9yrs; BMI 30.3±1.0kg/m2, HbA1C 66.5±2.6mmol/mol, [8.2±0.3%]). Interventions Two metabolic studies, four-weeks after lixisenatide or placebo; with cross-over and repetition of studies. Main outcome measures Study one: very-low density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with iv bolus of [2H5]glycerol in a 12h study, with hourly feeding. Oral [13C]triolein, in a single meal, labelled enterally-derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable iv [6,6-2H2]glucose infusion. Results Study one: CM-TAG (but not VLDL-TAG) pool-size, was lower with lixisenatide (P=0.046). Lixisenatide reduced CM [13C]oleate AUC60-480min concentration (P=0.048) and increased CM-TAG clearance; with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0-240min were reduced with lixisenatide (P=0.0051, P˂0.05). Total glucose production rate (Ra) (P=0.015), Rameal (P=0.0098) and acetaminophen AUC0-360min (P=0.006) were lower with lixisenatide than placebo. Conclusions Lixisenatide reduced [13C]oleate concentration, derived from a single meal in CM-TAG, as well as glucose Rameal, through delayed gastric emptying. However day-long CM production, measured with repeated meal-feeding, was not reduced by lixisenatide and decreased CM-TAG concentration was due to increased CM-TAG clearance.

DJ Cuthbertson, MO Weickert, D Lythgoe, VS Sprung, R Dobson, F Shoajee-Moradie, M Umpleby, AFH Pfeiffer, EL Thomas, JD Bell, H Jones, GJ Kemp (2014)External validation of the fatty liver index and lipid accumulation product indices, using H-1-magnetic resonance spectroscopy, to identify hepatic steatosis in healthy controls and obese, insulin-resistant individuals, In: EUROPEAN JOURNAL OF ENDOCRINOLOGY171(5)pp. 561-569 BIOSCIENTIFICA LTD
CL Bodinham, L Smith, EL Thomas, JD Bell, JR Swann, A Costabile, D Russell-Jones, AM Umpleby, MD Robertson (2014)Efficacy of increased resistant starch consumption in human type 2 diabetes, In: ENDOCRINE CONNECTIONS3(2)pp. 75-84 BIOSCIENTIFICA LTD
P Lee, V Birzniece, AM Umpleby, A Poljak, KKY Ho (2015)Formoterol, a Highly beta(2)-Selective Agonist, Induces Gender-Dimorphic Whole Body Leucine Metabolism in Humans, In: METABOLISM-CLINICAL AND EXPERIMENTAL64(4)pp. 506-512 W B SAUNDERS CO-ELSEVIER INC
AH Sam, ML Sleeth, EL Thomas, NA Ismail, NM Daud, E Chambers, F Shojaee-Moradie, M Umpleby, AP Goldstone, CW Le Roux, P Bech, M Busbridge, R Laurie, DJ Cuthbertson, A Buckley, MA Ghatei, SR Bloom, GS Frost, JD Bell, KG Murphy (2015)Circulating Pancreatic Polypeptide Concentrations Predict Visceral and Liver Fat Content, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM100(3)pp. 1048-1052 ENDOCRINE SOC
I Sarac, K Backhouse, F Shojaee-Moradie, M Stolinski, MD Robertson, JD Bell, EL Thomas, R Hovorka, J Wright, AM Umpleby (2012)Gender Differences in VLDL1 and VLDL2 Triglyceride Kinetics and Fatty Acid Kinetics in Obese Postmenopausal Women and Obese Men., In: J Clin Endocrinol Metab97(7)pp. 2475-2481 The Endocrine Society

Context:High plasma triglycerides (TG) have been shown to be independent and better predictors of cardiovascular disease than low-density lipoprotein (LDL) cholesterol in women. This may be due to gender differences in very-low-density lipoprotein 1 (VLDL(1))- and VLDL(2)-TG and fatty acid kinetics.Objective:Our objective was to investigate whether there are differences in VLDL(1)- and VLDL(2)-TG and fatty acid kinetics in obese men and postmenopausal women, a high risk group for cardiovascular disease.Research Design and Methods:Stable isotopes techniques were used to measure fasting palmitate rate of appearance, metabolic clearance rate, oxidation rate, and nonoxidative disposal rate, VLDL(1)-TG and VLDL(2)-TG fractional catabolic rate (FCR) and production rate (PR). Whole-body fat distribution was measured by magnetic resonance imaging.Participants:Participants included 10 postmenopausal obese women and eight obese men matched for age, body mass index, and fasting plasma TG.Results:The women had lower visceral fat and higher sc fat than the men (P < 0.001 and P < 0.002). Palmitate rate of appearance, metabolic clearance rate, nonoxidative disposal rate, and oxidation rate corrected for resting energy expenditure were greater in the women than the men (all P < 0.03). VLDL(2)-TG PR corrected for fat-free mass was higher in the women (P < 0.001). VLDL(2)-TG and VLDL(2)-cholesterol pools were higher in the women (P < 0.001 and P < 0.008). VLDL(1)-TG FCR and PR and VLDL(2)-TG FCR were not different between genders.Conclusion:Fatty acid and VLDL(2)-TG flux is higher in postmenopausal obese women than in obese men matched for fasting plasma TG levels.

M Stolinski, S Alam, NC Jackson, F Shojaee-Moradie, C Pentecost, W Jefferson, ER Christ, RH Jones, AM Umpleby (2008)Effect of 6-month supervised exercise on low-density lipoprotein apolipoprotein B kinetics in patients with type 2 diabetes mellitus, In: METABOLISM-CLINICAL AND EXPERIMENTAL57(11)pp. 1608-1614 W B SAUNDERS CO-ELSEVIER INC
A Thankamony, PH Tossavainen, A Sleigh, C Acerini, D Elleri, RN Dalton, NC Jackson, AM Umpleby, RM Williams, DB Dunger (2013)Short-term administration of pegvisomant improves hepatic insulin sensitivity and reduces soleus muscle intramyocellular lipid content in young adults with type 1 diabetes., In: J Clin Endocrinol Metabpp. jc20133264-?

Context: Data on metabolic effects of Growth Hormone (GH) derived from studies using GH suppression by pharmacological agents may not reflect selective actions. Objective: To evaluate the effects of GH antagonism on glucose and lipid metabolism using pegvisomant, a selective GH receptor antagonist in patients with type 1 diabetes (T1D). Design & participants: In a randomised, placebo-controlled, crossover study, 10 young adults with T1D were evaluated at baseline, and after 4 weeks of treatment with either 10mg of pegvisomant or placebo. The assessments included an overnight euglycaemic steady state followed by a hyperinsulinaemic euglycaemic clamp, and employed glucose and glycerol cold stable isotopes. Outcome measures: Hepatic and peripheral insulin sensitivity (IS), lipid turnover and intramyocellular lipid (IMCL) Results: Compared with placebo, pegvisomant treatment resulted in lower IGF-I levels (p

MG Giannoulis, N Jackson, F Shojaee-Moradie, PH Sonksen, FC Martin, AM Umpleby (2006)Effects of growth hormone and/or testosterone on very low density lipoprotein apolipoprotein B100 kinetics and plasma lipids in healthy elderly men: A randomised controlled trial, In: GROWTH HORMONE & IGF RESEARCH16(5-6)pp. 308-317 CHURCHILL LIVINGSTONE
PV Carroll, NC Jackson, DL Russell-Jones, DF Treacher, PH Sönksen, AM Umpleby (2004)Combined growth hormone/insulin-like growth factor I in addition to glutamine-supplemented TPN results in net protein anabolism in critical illness., In: Am J Physiol Endocrinol Metab286(1)pp. E151-E157

Protein loss leading to reduced lean body mass is recognized to contribute to the high levels of morbidity and mortality seen in critical illness. This prospective, randomized, controlled study compared the effects of conventional parenteral nutrition (TPN), glutamine-supplemented (0.4 g.kg-1.day-1) TPN (TPNGLN), and TPNGLN with combined growth hormone (GH, 0.2 IU.kg-1.day-1) and IGF-I (160 microg.kg-1.day-1) on protein metabolism in critical illness. Nineteen mechanically ventilated subjects [64 +/- 3 yr, body mass index (BMI) 23.8 +/- 1.3, kg/m2] were initially studied in the fasting state (study 1) and subsequently after 3 days of nutritional with/without hormonal support (study 2). All had recently been admitted to the ICU and the majority were postemergency abdominal surgery (APACHE II 17.5 +/- 1.0). Protein metabolism was assessed using a primed constant infusion of [1-13C]leucine. Conventional TPN contained mixed amino acids, Intralipid, and 50% dextrose. TPNGLN, unlike TPN alone, resulted in an increase in plasma glutamine concentration ( approximately 50%, P < 0.05). Both TPN and TPNGLN decreased the rate of protein breakdown (TPN 15%, P < 0.002; TPNGLN 16%, P < 0.05), but during these treatments the patients remained in a net negative protein balance. Combined treatment with TPNGLN + GH/IGF-I increased plasma IGF-I levels (10.3 +/- 0.8 vs. 48.1 +/- 9.1 nmol/l, study 1 vs. study 2, P < 0.05), and in contrast to therapy with nutrition alone, resulted in net protein gain (-0.75 +/- 0.14 vs. 0.33 +/- 0.12 g protein.kg-1.day-1, study 1 vs. study 2, P < 0.05). Therapy with GH/IGF-I + TPNGLN, unlike nutrition alone, resulted in net positive protein balance in a group of critically ill patients.

Margot Umpleby, F Shojaee-Moradie, Barbara Fielding, X Li, A Marino, N Alsini, Cheryl Isherwood, N Jackson, A Ahmad, M Stolinski, JA Lovegrove, Sigurd Johnsen, Agampodi Mendis, John Wright, ME Wilinska, R Hovorka, JD Bell, EL Thomas, GS Frost, Bruce Griffin (2017)Impact of liver fat on the differential partitioning of hepatic triacylglycerol into VLDL subclasses on high and low sugar diets, In: Clinical Science131(21)pp. 2561-2573 Portland Press

Dietary sugars are linked to the development of non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia, but it is unknown if NAFLD itself influences the effects of sugars on plasma lipoproteins. To study this further, men with NAFLD (n=11) and low liver fat ‘controls’ (n= 14) were fed two iso-energetic diets, high or low in sugars (26% or 6% total energy) for 12 weeks, in a randomised, cross-over design. Fasting plasma lipid and lipoprotein kinetics were measured after each diet by stable isotope trace-labelling. There were significant differences in the production and catabolic rates of VLDL subclasses between men with NAFLD and controls, in response to the high and low sugar diets. Men with NAFLD had higher plasma concentrations of VLDL1-triacylglycerol (TAG) after the high (P

SB Bowes, M Umpleby, MH Cummings, NC Jackson, PV Carroll, C Lowy, PH Sonksen, DL RussellJones (1997)The effect of recombinant human growth hormone on glucose and leucine metabolism in Cushing's syndrome, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM82(1)pp. 243-246 ENDOCRINE SOC
F Sun, M Stolinski, F Shojaee-Moradie, S Lou, Y Ma, R Hovorka, AM Umpleby (2013)A novel method for measuring intestinal and hepatic triacylglycerol kinetics., In: Am J Physiol Endocrinol Metab

The study aimed to 1] develop a method which completely separated hepatic (VLDL1, VLDL2) and intestinal (chylomicron, CM) lipoproteins and 2] use the method to measure triacylglycerol (TAG) kinetics in these lipoproteins in the fed and fasting state in healthy subjects using intravenous (2)H5-glycerol as the tracer. An immunoaffinity method which completely separated hepatic and intestinal particles using sequential binding to three antibodies to apolipoprotein B100 (apoB100) was established and validated. Six healthy volunteers were studied in a fasted and continuous feeding study (study 1). Five additional healthy volunteers were studied in a continuous feeding study which included an oral (13)C3-glycerol tripalmitin tracer (study 2). In both studies an intravenous bolus of (2)H5-glycerol was administered to label TAG in hepatic and intestinal lipoproteins. In both feeding studies there was sufficient incorporation of the glycerol tracer into the exogenous lipoproteins to enable isotopic enrichment to be measured. In study 2 the oral tracer enrichment in VLDL1 was

A Brackenridge, ER Pearson, F Shojaee-Moradie, AT Hattersley, D Russell-Jones, AM Umpleby (2006)Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1 beta and -1 alpha mutations, In: DIABETES55(2)pp. 405-411 AMER DIABETES ASSOC
DJ Cuthbertson, A Irwin, VS Sprung, H Jones, CJA Pugh, C Daousi, VL Adams, WE Bimson, F Shojaee Moradie, P Richardson, AM Umpleby, JP Wilding, GJ Kemp (2014)Ectopic lipid storage in non-alcoholic fatty liver disease is not mediated by impaired mitochondrial oxidative capacity in skeletal muscle, In: CLINICAL SCIENCE127(11-12)pp. 655-663 PORTLAND PRESS LTD
GF WATTS, MH CUMMINGS, M UMPLEBY, J QUINEY, R NAOUMOVA, GR THOMPSON, PH SONKSEN (1995)SIMVASTATIN DECREASES THE HEPATIC SECRETION OF VERY-LOW-DENSITY LIPOPROTEIN APOLIPOPROTEIN B-100 IN HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA - PATHOPHYSIOLOGICAL AND THERAPEUTIC IMPLICATIONS, In: EUROPEAN JOURNAL OF CLINICAL INVESTIGATION25(8)pp. 559-567 BLACKWELL SCIENCE LTD
Simon Steenson, Margot Umpleby, JA Lovegrove, KG Jackson, Barbara Fielding (2017)Role of the enterocyte in fructose-induced hypertriglyceridaemia, In: Nutrients9(4)349 MDPI AG

Abstract: Dietary fructose has been linked to an increased post-prandial triglyceride (TG) level, which is an established independent risk factor for cardiovascular disease. Although much research has focused on the effects of fructose consumption on liver-derived very-low density lipoprotein (VLDL), emerging evidence also suggests that fructose may raise post-prandial TG levels by affecting the metabolism of enterocytes of the small intestine. Enterocytes have become well recognised for their ability to transiently store lipids following a meal and to thus control post-prandial TG levels according to the rate of chylomicron (CM) lipoprotein synthesis and secretion. The influence of fructose consumption on several aspects of enterocyte lipid metabolism are discussed, including de novo lipogenesis, apolipoprotein B48 and CM-TG production, based on the findings of animal and human isotopic tracer studies. Methodological issues affecting the interpretation of fructose studies conducted to date are highlighted, including the accurate separation of CM and VLDL. Although the available evidence to date is limited, disruption of enterocyte lipid metabolism may make a meaningful contribution to the hypertriglyceridaemia often associated with fructose consumption.

S Das, M Shahmanesh, M Stolinski, F Shojaee-Moradie, W Jefferson, NC Jackson, M Cobbold, P Nightingale, AM Umpleby (2006)In treatment-naive and antiretroviral-treated subjects with HIV, reduced plasma adiponectin is associated with a reduced fractional clearance rate of VLDL, IDL and LDL apolipoprotein B-100, In: DIABETOLOGIA49(3)pp. 538-542 SPRINGER
C Sibbons, L Boyle, GC Burdge, M Umpleby, KA Lilycrop, CA Hartwick, S Lanham-New, K Hart, BA Fielding (2015)Evaluation of fatty acid status in children of different nationalities, In: PROCEEDINGS OF THE NUTRITION SOCIETY74(OCE1)pp. E94-E94 CAMBRIDGE UNIV PRESS
MG Burt, G Johannsson, AM Umpleby, DJ Chisholm, KKY Ho (2008)Impact of growth hormone and dehydroepiandrosterone on protein metabolism in glucocorticoid-treated patients, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM93(3)pp. 688-695 ENDOCRINE SOC
A Haidar, E Potocka, B Boulet, AM Umpleby, R Hovorka (2012)Estimating postprandial glucose fluxes using hierarchical Bayes modelling., In: Comput Methods Programs Biomed

A new stochastic computational method was developed to estimate the endogenous glucose production, the meal-related glucose appearance rate (R(a meal)), and the glucose disposal (R(d)) during the meal tolerance test. A prior probability distribution was adopted which assumes smooth glucose fluxes with individualized smoothness level within the context of a Bayes hierarchical model. The new method was contrasted with the maximum likelihood method using data collected in 18 subjects with type 2 diabetes who ingested a mixed meal containing [U-(13)C]glucose. Primed [6,6-(2)H(2)]glucose was infused in a manner that mimicked the expected endogenous glucose production. The mean endogenous glucose production, R(a meal), and R(d) calculated by the new method and maximum likelihood method were nearly identical. However, the maximum likelihood gave constant, nonphysiological postprandial endogenous glucose production in two subjects whilst the new method gave plausible estimates of endogenous glucose production in all subjects. Additionally, the two methods were compared using a simulated triple-tracer experiment in 12 virtual subjects. The accuracy of the estimates of the endogenous glucose production and R(a meal) profiles was similar [root mean square error (RMSE) 1.0±0.3 vs. 1.4±0.7μmol/kg/min for EGP and 2.6±1.0 vs. 2.9±0.9μmol/kg/min for R(a meal); new method vs. maximum likelihood method; P=NS, paired t-test]. The accuracy of R(d) estimates was significantly increased by the new method (RMSE 5.3±1.9 vs. 4.2±1.3; new method vs. ML method; P

ML Healy, J Gibney, C Pentecost, P Croos, DL Russell-Jones, PH Sonken, AM Umpleby (2006)Effects of high-dose growth hormone on glucose and glycerol metabolism at rest and during exercise in endurance-trained athletes, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM91(1)pp. 320-327 ENDOCRINE SOC
V Birzniece, UJ Meinhardt, MA Umpleby, DJ Handelsman, KKY Ho (2011)Interaction between testosterone and growth hormone on whole-body protein anabolism occurs in the liver, In: Journal of Clinical Endocrinology and Metabolism96(4)pp. 1060-1067
CE Higham, S Rowles, D Russell-Jones, AM Umpleby, PJ Trainer (2009)Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly., In: J Clin Endocrinol Metab94(7)pp. 2459-2463

Acromegaly is complicated by an increased incidence of diabetes mellitus caused by impaired insulin sensitivity and reduced beta-cell function. Pegvisomant blocks activity at GH receptors, normalizing IGF-I in over 90% of patients and improving insulin sensitivity. The mechanisms for this increase in insulin sensitivity are not fully determined. We used stable isotope techniques to investigate the effects of pegvisomant on glucose and lipid metabolism in acromegaly.

CJ Pugh, DJ Cuthbertson, VS Sprung, GJ Kemp, P Richardson, A Margot Umpleby, DJ Green, N Timothy Cable, H Jones (2013)Exercise training improves cutaneous microvascular function in nonalcoholic fatty liver disease., In: Am J Physiol Endocrinol Metab305(1)pp. E50-E58

The leading causes of mortality in nonalcoholic fatty liver disease (NAFLD) relate to cardiovascular disease (CVD). The contribution of nitric oxide (NO) to endothelial function, a surrogate of CVD risk, is currently unknown in NAFLD. We hypothesize that NO-mediated cutaneous microvessel function would be impaired in NAFLD compared with controls and that exercise would enhance microvessel function compared with conventional care. Thirteen NAFLD patients (aged 50 ± 3 yr, BMI 31 ± 1 kg/m(2)) and seven controls (48 ± 4 yr, 30 ± 2 kg/m(2)) were studied. NAFLD patients were randomized to either 16 wk of exercise or conventional care. Cutaneous microvessel function was examined using laser Doppler flowmetry combined with intradermal microdialysis of N(G)-monomethyl-l-arginine to assay the NO dilator response to local forearm heating. Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively, and cardiorespiratory fitness was assessed. Differences in NO contribution to cutaneous blood flow between NAFLD and control individuals and between interventions were analyzed using general linear modeling. NO contribution to cutaneous blood flow was similar between NAFLD and controls (P = 0.47). Cardiorespiratory fitness was greater following exercise training compared with conventional care. NO contribution to cutaneous blood flow in response to heating at 42°C was 20.4% CVCmax (95% CI = 4.4, 36.4) greater following exercise training compared with conventional care (P = 0.02). Exercise training improves cutaneous microvascular NO function in NAFLD patients. The benefit of exercise training compared with conventional care strongly supports a role for exercise in the prevention of CVD in NAFLD.

AM Umpleby (2015)HORMONE MEASUREMENT GUIDELINES Tracing lipid metabolism: the value of stable isotopes, In: JOURNAL OF ENDOCRINOLOGY226(3)pp. G1-G10 BIOSCIENTIFICA LTD
MG Burt, J Gibney, DM Hoffman, AM Umpleby, KKY Ho (2008)Relationship between GH-induced metabolic changes and changes in body composition: A dose and time course study in GH-deficient adults, In: GROWTH HORMONE & IGF RESEARCH18(1)pp. 55-64 CHURCHILL LIVINGSTONE
RM Williams, R Amin, F Shojaee-Moradie, AM Umpleby, CL Acerini, DB Dunger (2003)The effects of a specific growth hormone antagonist on overnight insulin requirements and insulin sensitivity in young adults with Type 1 diabetes mellitus, In: DIABETOLOGIA46(9)pp. 1203-1210 SPRINGER-VERLAG
A Haidar, D Elleri, JM Allen, J Harris, K Kumareswaran, M Nodale, CL Acerini, ME Wilinska, N Jackson, AM Umpleby, ML Evans, DB Dunger, R Hovorka (2012)Validity of triple- and dual-tracer techniques to estimate glucose appearance., In: Am J Physiol Endocrinol Metab302(12)pp. E1493-E1501

The triple-tracer (TT) dilution technique has been proposed to be the gold standard method to measure postprandial glucose appearance. However, validation against an independent standard has been missing. We addressed this issue and also validated the simpler dual-tracer (DT) technique. Sixteen young subjects with type 1 diabetes (age 19.5 ± 3.8 yr, BMI 23.4 ± 1.5 kg/m(2), HbA(1c) 8.7 ± 1.7%, diabetes duration 9.0 ± 6.9 yr, total daily insulin 0.9 ± 0.2 U·kg(-1)·day(-1), mean ± SD) received a variable intravenous 20% dextrose infusion enriched with [U-(13)C]glucose over 8 h to achieve postprandial-resembling glucose excursions while intravenous insulin was administered to achieve postprandial-resembling levels of plasma insulin. Primed [6,6-(2)H(2)]glucose was infused in a manner that mimicked the expected endogenous glucose production and [U-(13)C; 1,2,3,4,5,6,6-(2)H(7)]glucose was infused in a manner that mimicked the expected glucose appearance from a standard meal. Plasma glucose enrichment was measured by gas chromatography-mass spectrometry. The intravenous dextrose infusion served as an independent standard and was reconstructed using the TT and DT techniques with the two-compartment Radziuk/Mari model and an advanced stochastic computational method. The difference between the infused and reconstructed dextrose profile was similar for the two methods (root mean square error 6.6 ± 1.9 vs. 8.0 ± 3.5 μmol·kg(-1)·min(-1), TT vs. DT, P = NS, paired t-test). The TT technique was more accurate in recovering the overall dextrose infusion (100 ± 9 and 92 ± 12%; P = 0.02). The root mean square error associated with the mean dextrose infusion profile was 2.5 and 3.3 μmol·kg(-1)·min(-1) for the TT and DT techniques, respectively. We conclude that the TT and DT techniques combined with the advanced computational method can measure accurately exogenous glucose appearance. The TT technique tends to outperform slightly the DT technique, but the latter benefits from reduced experimental and computational complexity.

L Bhatia, E Scorletti, F Shojaee-Moradie, M Umpleby, A Fletcher, A Bateman, NP Curzen, GF Clough, P Calder, CD Byrne (2013)Peripheral and hepatic insulin resistance are key determinants of progression of non-alcoholic fatty liver disease severity independent of body fat percentage, In: DIABETIC MEDICINE30pp. 60-60 WILEY-BLACKWELL
MG Giannoulis, PH Sonksen, M Umpleby, L Breen, C Pentecost, M Whyte, CV McMillan, C Bradley, FC Martin (2006)The effects of growth hormone and/or testosterone in healthy elderly men: a randomized controlled trial, In: The Journal of Clinical Endocrinology & Metabolism91(2)pp. 477-484

CONTEXT: Declines in GH and testosterone (Te) secretion may contribute to the detrimental aging changes of elderly men. OBJECTIVE: To assess the effects of near-physiological GH with/without Te administration on lean body mass, total body fat, midthigh muscle cross-section area, muscle strength, aerobic capacity, condition-specific quality of life (Age-Related Hormone Deficiency-Dependent Quality of Life questionnaire), and generic health status (36-Item Short-Form Health Survey) of older men. DESIGN, SETTINGS, AND PARTICIPANTS: A 6-month, randomized, double-blind, placebo-controlled trial was performed on 80 healthy, community-dwelling, older men (age, 65-80 yr). INTERVENTIONS: Participants were randomized to receive 1) placebo GH or placebo Te, 2) recombinant human GH (rhGH) and placebo Te (GH), 3) Te and placebo rhGH (Te), or 4) rhGH and Te (GHTe). GH doses were titrated over 8 wk to produce IGF-I levels in the upper half of the age-specific reference range. A fixed dose of Te (5 mg) was given by transdermal patches. RESULTS: Lean body mass increased with GHTe (P = 0.008) and GH (P = 0.004), compared with placebo. Total body fat decreased with GHTe only (P = 0.02). Midthigh muscle (P = 0.006) and aerobic capacity (P < 0.001) increased only after GHTe. Muscle strength changes were variable; one of six measures significantly increased with GHTe. Significant treatment group by time interactions indicated an improved Age-Related Hormone Deficiency-Dependent Quality of Life questionnaire score (P = 0.007) in the GH and GHTe groups. Bodily pain increased with GH alone, as determined by the Short-Form Health Survey (P = 0.003). There were no major adverse effects. CONCLUSION: Coadministration of low dose GH with Te resulted in beneficial changes being observed more often than with either GH or Te alone.

Martin B. Whyte, Fariba Shojaee-Moradie, Sharaf E. Sharaf, Daniel J. Cuthbertson, Graham J. Kemp, Mark Barrett, Nicola C. Jackson, Roselle A. Herring, John Wright, E. Louise Thomas, Jimmy Bell, A. Margot Umpleby (2020)HDL-apoA-I kinetics in response to 16 wk of exercise training in men with nonalcoholic fatty liver disease, In: American Journal of Physiology-Endocrinology and Metabolism318(6)pp. E839-E847 American Physiological Society

Nonalcoholic fatty liver disease (NAFLD) is characterized by low-circulating concentration of high-density lipoprotein cholesterol (HDL-C) and raised triacylglycerol (TAG). Exercise reduces hepatic fat content, improves insulin resistance and increases clearance of very-low-density lipoprotein-1 (VLDL1). However, the effect of exercise on TAG and HDL-C metabolism is unknown. We randomized male participants to 16 wk of supervised, moderate-intensity aerobic exercise (n = 15), or conventional lifestyle advice (n = 12). Apolipoprotein A-I (apoA-I) and VLDL-TAG and apolipoprotein B (apoB) kinetics were investigated using stable isotopes (1-[13C]-leucine and 1,1,2,3,3-2H5 glycerol) pre- and postintervention. Participants underwent MRI/spectroscopy to assess changes in visceral fat. Results are means ± SD. At baseline, there were no differences between exercise and control groups for age (52.4 ± 7.5 vs. 52.8 ± 10.3 yr), body mass index (BMI: 31.6 ± 3.2 vs. 31.7 ± 3.6 kg/m2), and waist circumference (109.3 ± 7.5 vs. 110.0 ± 13.6 cm). Percentage of liver fat was 23.8 (interquartile range 9.8–32.5%). Exercise reduced body weight (101.3 ± 10.2 to 97.9 ± 12.2 kg; P ˂ 0.001) and hepatic fat content [from 19.6%, interquartile range (IQR) 14.6–36.1% to 8.9% (4.4–17.8%); P = 0.001] and increased the fraction HDL-C concentration (measured following ultracentrifugation) and apoA-I pool size with no change in the control group. However, plasma and VLDL1-TAG concentrations and HDL-apoA-I fractional catabolic rate (FCR) and production rate (PR) did not change significantly with exercise. Both at baseline (all participants) and after exercise there was an inverse correlation between apoA-I pool size and VLDL-TAG and -apoB pool size. The modest effect of exercise on HDL metabolism may be explained by the lack of effect on plasma and VLDL1-TAG.

FM Regan, RM Williams, A McDonald, AM Umpleby, CL Acerini, S O'Rahilly, R Hovorka, RK Semple, DB Dunger (2010)Treatment with Recombinant Human Insulin-Like Growth Factor (rhIGF)-I/rhIGF Binding Protein-3 Complex Improves Metabolic Control in Subjects with Severe Insulin Resistance, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM95(5)pp. 2113-2122 ENDOCRINE SOC
F Shojaee-Moradie, NC Jackson, RH Jones, AI Mallet, R Hovorka, AM Umpleby (1996)Quantitative measurement of 3-O-methyl-D-glucose by gas chromatography-mass spectrometry as a measure of glucose transport in vivo., In: J Mass Spectrom31(9)pp. 961-966

Existing methods of measuring glucose kinetics are subject to errors. There is considerable interest in improved methods of measuring glucose kinetics to allow the development of new regimes for the treatment of diabetes mellitus. 3-O-Methyl-D-glucose is transported but not metabolized and therefore allows independent estimation of transport parameters. We describe a method by which 3-O-methyl-D-glucose in plasma samples can be measured in protocols during which glucose flux is assessed with simultaneous use of two isotopically labeled glucoses to quantitate and validate measurements of the rate of glucose appearance and disappearance. Quantitative gas chromatographic/mass spectrometric (GC/MS) analysis of 3-O-methyl-D-glucose, D-glucose, D-[U-13C] glucose and D-[6,6-2H2] glucose in human plasma using methoxime-trimethylsilyl ether derivatives is described. Measurements of all four derivatives were performed together in a small sample volume (50 microliters) with high precision. The intra-assay (inter-assay) coefficients of variation at an isotope content of 0.25 atom% excess for D-[6,6-2H2] glucose, D-[U-13C] glucose and 3-O-methyl-D-glucose were 0.8% (1.0%), 0.5% (4.0%) and 0.1% (3.7%), respectively. This method provides the basis for quantitative estimation of parameters of glucose kinetics in man and the rates of glucose flux across the cell membrane.

MG Burt, G Johannsson, AM Umpleby, DJ Chisholm, KKY Ho (2007)Impact of acute and chronic low-dose glucocorticoids on protein metabolism, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM92(10)pp. 3923-3929 ENDOCRINE SOC
MH CUMMINGS, GF WATTS, M UMPLEBY, TR HENNESSY, J QUINEY, PH SONKSEN (1995)INCREASED HEPATIC SECRETION OF VERY-LOW-DENSITY-LIPOPROTEIN APOLIPOPROTEIN B-100 IN HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA - A STABLE-ISOTOPE STUDY, In: ATHEROSCLEROSIS113(1)pp. 79-89 ELSEVIER SCI PUBL IRELAND LTD
F Shojaee-Moradie, KC Baynes, C Pentecost, JD Bell, EL Thomas, NC Jackson, M Stolinski, M Whyte, D Lovell, SB Bowes, J Gibney, RH Jones, AM Umpleby (2007)Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism, In: Diabetologia50(2)pp. 404-413 Springer-Verlag

AIMS/HYPOTHESIS: It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables. SUBJECTS AND METHODS: We randomised 17 sedentary overweight male subjects (age 50 +/- 2.6 years, BMI 27.6 +/- 0.5 kg/m(2)) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic-euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg(-1) min(-1)]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning. RESULTS: After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group. CONCLUSIONS/INTERPRETATION: Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise.

MB Whyte, NC Jackson, F Shojaee-Moradie, DF Treacher, RJ Beale, RH Jones, AM Umpleby (2010)Metabolic effects of intensive insulin therapy in critically ill patients, In: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM298(3)pp. E697-E705 AMER PHYSIOLOGICAL SOC
MG Giannoulis, FC Martin, KS Nair, AM Umpleby, P Sonksen (2012)Hormone replacement therapy and physical function in healthy older men. Time to talk hormones?, In: Endocr Rev33(3)pp. 314-377

Improving physical function and mobility in a continuously expanding elderly population emerges as a high priority of medicine today. Muscle mass, strength/power, and maximal exercise capacity are major determinants of physical function, and all decline with aging. This contributes to the incidence of frailty and disability observed in older men. Furthermore, it facilitates the accumulation of body fat and development of insulin resistance. Muscle adaptation to exercise is strongly influenced by anabolic endocrine hormones and local load-sensitive autocrine/paracrine growth factors. GH, IGF-I, and testosterone (T) are directly involved in muscle adaptation to exercise because they promote muscle protein synthesis, whereas T and locally expressed IGF-I have been reported to activate muscle stem cells. Although exercise programs improve physical function, in the long-term most older men fail to comply. The GH/IGF-I axis and T levels decline markedly with aging, whereas accumulating evidence supports their indispensable role in maintaining physical function integrity. Several studies have reported that the administration of T improves lean body mass and maximal voluntary strength in healthy older men. On the other hand, most studies have shown that administration of GH alone failed to improve muscle strength despite amelioration of the detrimental somatic changes of aging. Both GH and T are anabolic agents that promote muscle protein synthesis and hypertrophy but work through separate mechanisms, and the combined administration of GH and T, albeit in only a few studies, has resulted in greater efficacy than either hormone alone. Although it is clear that this combined approach is effective, this review concludes that further studies are needed to assess the long-term efficacy and safety of combined hormone replacement therapy in older men before the medical rationale of prescribing hormone replacement therapy for combating the sarcopenia of aging can be established.

R Murphy, J Baptista, J Holly, AM Umpleby, S Ellard, LW Harries, J Crolla, T Cundy, AT Hattersley (2008)Severe Intrauterine Growth Retardation and Atypical Diabetes Associated with a Translocation Breakpoint Disrupting Regulation of the Insulin-Like Growth Factor 2 Gene, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM93(11)pp. 4373-4380 ENDOCRINE SOC
J Wee, C Charlton, H Simpson, NC Jackson, F Shojaee-Moradie, M Stolinski, C Pentecost, AM Umpleby (2005)GH secretion in acute exercise may result in post-exercise lipolysis, In: GROWTH HORMONE & IGF RESEARCH15(6)pp. 397-404 CHURCHILL LIVINGSTONE
S Zachariah, A Brackenridge, F Shojaee-Moradie, C Camuncho-Hubner, AM Umpleby, D Russell-Jones (2007)The mechanism of non-islet cell hypoglycaemia caused by tumour-produced IGF-II, In: CLINICAL ENDOCRINOLOGY67(4)pp. 637-638 BLACKWELL PUBLISHING
R Herring, F Shojaee-Moradie, N Jackson, R Jones, AM Umpleby, DL Russell-Jones (2013)The effects of subcutaneous neutral protamine Hagedorn (NPH) insulin on glucose metabolism following a period of insulin withdrawal in patients with Type 1 diabetes, In: DIABETIC MEDICINE30pp. 15-16 WILEY-BLACKWELL
F Shojaee-Moradie, Y Ma, S Lou, R Hovorka, AM Umpleby (2013)Prandial Hypertriglyceridemia in Metabolic Syndrome Is Due to an Overproduction of Both Chylomicron and VLDL Triacylglycerol., In: Diabetes62(12)pp. 4063-4069

The aim was to determine whether fed VLDL and chylomicron (CM) triacylglycerol (TAG) production rates are elevated in metabolic syndrome (MetS). Eight men with MetS (BMI 29.7 ± 1.1) and eight lean age-matched healthy men (BMI 23.1 ± 0.4) were studied using a frequent feeding protocol. After 4 h of feeding, an intravenous bolus of (2)H5-glycerol was administered to label VLDL1, VLDL2, and TAG. (13)C-glycerol tripalmitin was administered orally as an independent measure of CM TAG metabolism. Hepatic and intestinal lipoproteins were separated by an immunoaffinity method. In MetS, fed TAG and the increment in TAG from fasting to feeding were higher (P = 0.03 and P = 0.04, respectively) than in lean men. Fed CM, VLDL1, and VLDL2 TAG pool sizes were higher (P = 0.006, P = 0.03, and P < 0.02, respectively), and CM, VLDL1, and VLDL2 TAG production rates were higher (P < 0.002, P < 0.05, and P = 0.06, respectively) than in lean men. VLDL1, VLDL2, and CM TAG clearance rates were not different between groups. In conclusion, prandial hypertriglyceridemia in men with MetS was due to an increased production rate of both VLDL and CM TAG. Since both groups received identical meals, this suggests that in MetS the intestine is synthesizing more TAG de novo for export in CMs.

PV Carroll, M Umpleby, GS Ward, S Imuere, E Alexander, D Dunger, PH Sonksen, DL RussellJones (1997)rhIGF-I administration reduces insulin requirements, decreases growth hormone secretion, and improves the lipid profile in adults with IDDM, In: DIABETES46(9)pp. 1453-1458 AMER DIABETES ASSOC
S Zachariah, B Sheldon, F Shojaee-Moradie, NC Jackson, K Backhouse, S Johnsen, RH Jones, AM Umpleby, DL Russell-Jones (2011)Insulin detemir reduces weight gain as a result of reduced food intake in patients with type 1 diabetes., In: Diabetes Care34(7)pp. 1487-1491 American Diabetes Association

Insulin detemir lacks the usual propensity for insulin to cause weight gain. We investigated whether this effect was a result of reduced energy intake and/or increased energy expenditure.

SVM Hordern, JE Wright, AM Umpleby, F Shojaee-Moradie, J Amiss, DL Russell-Jones (2005)Comparison of the effects on glucose and lipid metabolism of equipotent doses of insulin detemir and NPH insulin with a 16-h euglycaemic clamp, In: DIABETOLOGIA48(3)pp. 420-426 SPRINGER
J Gibney, T Wolthers, MG Burt, K-C Leung, AM Umpleby, KKY Ho (2007)Protein metabolism in acromegaly: Differential effects of short- and long-term treatment, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM92(4)pp. 1479-1484 ENDOCRINE SOC
SJ Clark, F Shojaee-Moradie, P Croos, PT Seed, AM Umpleby, JA Wendon, J Miell (2001)Temporal changes in insulin sensitivity following the development of acute liver failure secondary to acetaminophen, In: HEPATOLOGY34(1)pp. 109-115 W B SAUNDERS CO
OA Hakim, F Shojaee-Moradie, K Hart, JL Berry, R Eastell, F Gossiel, R Hannon, AM Umpleby, BA Griffin, SA Lanham-New (2011)Vitamin D deficiency, poor bone health and the risk of CVD in Caucasian and South Asian women: analysis from the D-FINES study, In: PROCEEDINGS OF THE NUTRITION SOCIETY70(OCE3)pp. E100-E100 CAMBRIDGE UNIV PRESS
KC McGee, M Shahmanesh, M Boothby, P Nightingale, LL Gathercole, G Tripathi, AL Harte, F Shojaee-Moradie, AM Umpleby, S Das, NM Al-Daghri, PG McTernan, JW Tomlinson (2012)Evidence for a shift to anaerobic metabolism in adipose tissue in efavirenz-containing regimens for HIV with different nucleoside backbones., In: Antivir Ther17(3)pp. 495-507

Antiretroviral (ARV) treatment has been associated with abnormalities in lipid and mitochondrial metabolism. We compared patterns of gene expression in the subcutaneous adipose tissue (SAT) of HIV-positive subjects before and after 18-24 months of ARV therapy with HIV-negative controls.

A Ahmad, C Isherwood, JD Bell, EL Thomas, G Frost, M Umpleby, BA Griffin (2011)Impact of liver fat on the response of plasma triacylglycerol to diets high and low in extrinsic sugars, In: PROCEEDINGS OF THE NUTRITION SOCIETY70(OCE6)pp. E364-E364 CAMBRIDGE UNIV PRESS
DL Russell-Jones, AM Umpleby, F Shojaee-Moradie, MA Boroujerdi, RH Jones, RC Baxter, PH Sonksen (1997)The effect of an intravenous infusion of IGF-I and insulin on IGFBP-1, IGFBP-3, acid labile subunit, free and bound IGF-I, catecholamines and potassium in normal volunteers during an amino acid and glucose clamp, In: CLINICAL ENDOCRINOLOGY47(6)pp. 685-691 BLACKWELL SCIENCE LTD
KCR Baynes, MD Nicholas, F Shojaee-Moradie, AM Umpleby, MG Giannoulis (2006)Acute regulation of plasma leptin by isoprenaline in lean and obese fasted subjects, In: DIABETES OBES METAB8(4)pp. 412-418 BLACKWELL PUBLISHING
Margaret Robertson, David Russell-Jones, A Umpleby, Derk-Jan Dijk (2013)Effects of three weeks of mild sleep restriction implemented in the home environment on multiple metabolic and endocrine markers in healthy young men, In: Metabolism: Clinical and Experimental62(2)pp. 204-211 Elsevier

Objectives: Evidence for a causal relationship between sleep-loss and metabolism is derived primarily from short-term sleep deprivation studies in the laboratory. The objective of this study was to investigate whether small changes in sleep duration over a three week period while participants are living in their normal environment lead to changes in insulin sensitivity and other metabolic parameters. Methods: Nineteen healthy, young, normal-weight men were randomised to either sleep restriction (habitual bedtime minus 1.5 h) or a control condition (habitual bedtime) for three weeks. Weekly assessments of insulin sensitivity by hyperinsulinaemic-euglycaemic clamp, anthropometry, vascular function, leptin and adiponectin were made. Sleep was assessed continuously using actigraphy and diaries. Results: Assessment of sleep by actigraphy confirmed that the intervention reduced daily sleep duration by 01:19 ± 00:15 (SE; p < 0.001). Sleep restriction led to changes in insulin sensitivity, body weight and plasma concentrations of leptin which varied during the three week period. There was no effect on plasma adiponectin or vascular function. Conclusions: Even minor reductions in sleep duration lead to changes in insulin sensitivity, body weight and other metabolic parameters which vary during the exposure period. Larger and longer longitudinal studies of sleep restriction and sleep extension are warranted. © 2013 Elsevier Inc.

MG Giannoulis, N Jackson, F Shojaee-Moradie, KS Nair, PH Sonksen, FC Martin, AM Umpleby (2008)The effects of growth hormone and/or testosterone on whole body protein kinetics and skeletal muscle gene expression in healthy elderly men: A randomized controlled trial, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM93(8)pp. 3066-3074 ENDOCRINE SOC
MD Robertson, JW Wright, E Loizon, C Debard, H Vidal, F Shojaee-Moradie, D Russell-Jones, AM Umpleby (2012)Insulin-sensitizing effects on muscle and adipose tissue after dietary fiber intake in men and women with metabolic syndrome., In: J Clin Endocrinol Metab97(9)pp. 3326-3332 The Endocrine Society

Context: Dietary fibers have been associated with a reduced incidence of type 2 diabetes mellitus in epidemiological studies; however, the precise mechanisms are unknown. Objective: The objective of the study was to evaluate the efficacy and site of action of an insoluble dietary fiber derived from maize (HAM-RS2) in improving insulin resistance in subjects at increased risk of type 2 diabetes mellitus. Design: This study was a randomized, controlled crossover, dietary intervention study. Setting: The study was conducted at the Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Participants: Fifteen men and women with insulin resistance participated in the study. Intervention: The intervention included 40 g/d HAM-RS2 compared with a matched placebo for 8 wk. Main Outcome Measures: After each supplement, participants underwent a two-step hyperinsulinemic-euglycemic clamp study with the addition of glucose tracers; a meal tolerance test; arteriovenous sampling across forearm muscle tissue; and a sc adipose tissue biopsy for assessment of gene expression. Results: There was enhanced uptake of glucose into the forearm muscle measured by arteriovenous sampling (65 ± 15% increase after resistant starch; P < 0.001). Adipose tissue function was also affected, with enhanced fatty acid suppression after HAM-RS2 treatment and an increase in gene expression for hormone sensitive lipase (P = 0.005), perilipin (P = 0.011), lipoprotein lipase (P = 0.014), and adipose triglyceride lipase (P = 0.03) in biopsy samples. There was no effect on the insulin sensitivity of hepatic glucose production or plasma lipids after HAM-RS2. Conclusion: HAM-RS2 improved peripheral but not hepatic insulin resistance and requires further study as an intervention in patients with or at risk for type 2 diabetes.

DJ Cuthbertson, F Shojaee-Moradie, VS Sprung, H Jones, CJ Pugh, P Richardson, GJ Kemp, M Barrett, NC Jackson, EL Thomas, JD Bell, AM Umpleby (2015)Dissociation between exercise-induced reduction in liver fat and changes in hepatic and peripheral glucose homoeostasis in obese patients with non-alcoholic fatty liver disease., In: Clinical Science130(2)pp. 93-104

Non-alcoholic fatty liver disease (NAFLD) is associated with multi-organ (hepatic, skeletal muscle, adipose tissue) insulin resistance (IR). Exercise is an effective treatment for lowering liver fat but its effect on IR in NAFLD is unknown. We aimed to determine whether supervised exercise in NAFLD would reduce liver fat and improve hepatic and peripheral (skeletal muscle and adipose tissue) insulin sensitivity. Sixty nine NAFLD patients were randomized to 16 weeks exercise supervision (n=38) or counselling (n=31) without dietary modification. All participants underwent MRI/spectroscopy to assess changes in body fat and in liver and skeletal muscle triglyceride, before and following exercise/counselling. To quantify changes in hepatic and peripheral insulin sensitivity, a pre-determined subset (n=12 per group) underwent a two-stage hyperinsulinaemic euglycaemic clamp pre- and post-intervention. Results are shown as mean [95% confidence interval (CI)]. Fifty participants (30 exercise, 20 counselling), 51 years (IQR 40, 56), body mass index (BMI) 31 kg/m(2) (IQR 29, 35) with baseline liver fat/water % of 18.8% (IQR 10.7, 34.6) completed the study (12/12 exercise and 7/12 counselling completed the clamp studies). Supervised exercise mediated a greater reduction in liver fat/water percentage than counselling [Δ mean change 4.7% (0.01, 9.4); P

AL Brackenridge, N Jackson, W Jefferson, M Stolinski, F Shojaee-Moradie, R Hovorka, AM Umpleby, D Russell-Jones (2009)Effects of rosiglitazone and pioglitazone on lipoprotein metabolism in patients with Type 2 diabetes and normal lipids, In: DIABETIC MEDICINE26(5)pp. 532-539 WILEY-BLACKWELL PUBLISHING, INC
C Isherwood, A Ahmad, JA Lovegrove, GS Frost, AM Umpleby, BA Griffin (2011)Dietary exchange model to investigate the metabolic effects of extrinsic sugars on an atherogenic lipoprotein phenotype, In: PROCEEDINGS OF THE NUTRITION SOCIETY70(OCE4)pp. E221-E221 CAMBRIDGE UNIV PRESS
HB Holt, SH Wild, N Wareham, U Ekelund, M Umpleby, F Shojaee-Moradie, RIG Holt, DI Phillips, CD Byrne (2007)Differential effects of fatness, fitness and physical activity energy expenditure on whole-body, liver and fat insulin sensitivity, In: DIABETOLOGIA50(8)pp. 1698-1706 SPRINGER
K Backhouse, I Sarac, F Shojaee-Moradie, M Stolinski, MD Robertson, GS Frost, JD Bell, EL Thomas, JW Wright, D Russell-Jones, AM Umpleby (2012)Fatty acid flux and oxidation is increased by rimonabant in obese women, In: Metabolism-Clinical and Experimental
R Hovorka, F Shojaee-Moradie, PV Carroll, LJ Chassin, IJ Gowrie, NC Jackson, RS Tudor, AM Umpleby, RH Jones (2002)Partitioning glucose distribution/transport, disposal, and endogenous production during IVGTT, In: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM282(5)pp. E992-E1007 AMER PHYSIOLOGICAL SOC
ER Christ, MH Cummings, M Stolinski, N Jackson, PJ Lumb, AS Wierzbicki, PH Sonksen, DL Russell-Jones, AM Umpleby (2006)Low-density lipoprotein apolipoprotein B100 turnover in hypopituitary patients with GH deficiency: a stable isotope study, In: EUROPEAN JOURNAL OF ENDOCRINOLOGY154(3)pp. 459-466 BIO SCIENTIFICA LTD
PV Carroll, M Umpleby, EL Alexander, VA Egel, KV Callison, PH Sonksen, DL Russell-Jones (1998)Recombinant human insulin-like growth factor-I (rhIGF-I) therapy in adults with type 1 diabetes mellitus: effects on IGFs, IGF-binding proteins, glucose levels and insulin treatment, In: CLINICAL ENDOCRINOLOGY49(6)pp. 739-746 BLACKWELL SCIENCE LTD
HB Holt, SH Wild, AD Postle, J Zhang, G Koster, M Umpleby, F Shojaee-Moradie, K Dewbury, PJ Wood, DI Phillips, CD Byrne (2007)Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men, In: DIABETOLOGIA50(5)pp. 1024-1032 SPRINGER
M Shahmanesh, S Das, M Stolinski, F Shojaee-Moradie, NC Jackson, W Jefferson, R Cramb, P Nightingale, AM Umpleby (2005)Antiretroviral treatment reduces very-low-density lipoprotein and intermediate-density lipoprotein apolipoprotein B fractional catabolic rate in human immunodeficiency virus-infected patients with mild dyslipidemia, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM90(2)pp. 755-760 ENDOCRINE SOC
R Herring, R Knight, F Shojaee-Moradie, S Johnsen, AM Umpleby, N Jackson, R Jones, DJ Dijk, DL Russell-Jones (2015)Effect of Subcutaneous Insulin Detemir on Glucose Flux, Lipolysis and Electroencephalography in Type 1 Diabetes., In: Diabetes Obes Metab Wiley

To investigate the effects of subcutaneous detemir on glucose flux, lipid metabolism and brain function, twelve people with type 1 diabetes received in random order 0.5Units/kgBW detemir or NPH insulin. Glucose concentration was clamped at 5mmol/L then increased to 10mmol/L. Glucose production rate (glucose Ra), glucose uptake (glucose Rd) and glycerol production (glycerol Ra) were measured with a constant iv infusion of [6,6(2) H2 ]glucose and [(2) H5 ]glycerol. Electroencephalography direct (DC) and alternating (AC) current potentials were measured. While detemir induced comparable effects on glucose Ra, glucose Rd and glycerol Ra during euglycaemia, compared with NPH, it triggered a distinct negative shift in DC-potentials, with significant treatment effect in frontal cerebrocortical channels (p

T Saukkonen, F Shojaee-Moradie, RM Williams, R Amin, KC Yuen, A Watts, CL Acerini, AM Umpleby, DB Dunger (2006)Effects of recombinant human IGF-I/IGF-binding protein-3 complex on glucose and glycerol metabolism in type 1 diabetes, In: DIABETES55(8)pp. 2365-2370 AMER DIABETES ASSOC
H Thabit, K Kumareswaran, A Haidar, L Leelarathna, K Caldwell, D Elleri, JM Allen, M Nodale, ME Wilinska, NC Jackson, AM Umpleby, ML Evans, R Hovorka (2014)Glucose Turnover After Replacement of Usual Therapy by Insulin in Insulin-naive Type 2 Diabetes Subjects, In: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM99(6)pp. 2225-2232 ENDOCRINE SOC
V Birzniece, MA Umpleby, A Poljak, DJ Handelsman, KK Ho (2013)Oral low-dose testosterone administration induces whole-body protein anabolism in postmenopausal women: a novel liver-targeted therapy., In: Eur J Endocrinol169(3)pp. 321-327

OBJECTIVE: In hypopituitary men, oral delivery of unesterified testosterone in doses that result in a solely hepatic androgen effect enhances protein anabolism during GH treatment. In this study, we aimed to determine whether liver-targeted androgen supplementation induces protein anabolism in GH-replete normal women. DESIGN: Eight healthy postmenopausal women received 2-week treatment with oral testosterone at a dose of 40 mg/day (crystalline testosterone USP). This dose increases portal concentrations of testosterone, exerting androgenic effects on the liver without a spillover into the systemic circulation. OUTCOME MEASURES: The outcome measures were whole-body leucine turnover, from which leucine rate of appearance (LRa, an index of protein breakdown) and leucine oxidation (Lox, a measure of irreversible protein loss) were estimated, energy expenditure and substrate utilization. We measured the concentration of liver transaminases as well as of testosterone, SHBG and IGF1. RESULTS: Testosterone treatment significantly reduced LRa by 7.1 ± 2.5% and Lox by 14.6 ± 4.5% (P

RA Herring, F Shojaee-Moradie, AM Umpleby, R Jones, N Jackson, DL Russell-Jones (2015)Effect of subcutaneous insulin detemir on glucose flux and lipolysis during hyperglycaemia in people with type 1 diabetes, In: DIABETES OBESITY & METABOLISM17(5)pp. 459-467 WILEY-BLACKWELL
Roselle A Herring, Fariba Shojaee-Moradie, Mary Stevenage, Iain Parsons , NICOLA JACKSON, JEEWAKA MENDIS, BENITA ANNE MIDDLETON, A. Margot Umpleby , BARBARA ANN FIELDING, Melanie Davies, David L Russell-Jones (2022)The SGLT2 inhibitor, dapagliflozin increases the oxidation of ingested fatty acids to ketones in type 2 diabetes, In: Diabetes care American Diabetes Association

Objective. To investigate the mechanism for increased ketogenesis following treatment with SGLT2 inhibitor, dapagliflozin in people with type 2 diabetes. Research, Design & Methods. This was a double-blind placebo-controlled crossover study with a 4-week washout period. Participants received dapagliflozin or placebo in random order for 4 weeks. After each treatment, they ingested 30ml of olive oil containing [U-13C] palmitate to measure ketogenesis with blood sampling for 480 min. Stable isotopes of glucose and glycerol were infused to measure glucose flux and lipolysis respectively at 450-480 min. Results. Glucose excretion rate was higher and peripheral glucose uptake lower with dapagliflozin than placebo. Plasma beta-hydroxybutyrate (BOHB) concentrations and [13C2] BOHB concentrations were higher and glucose concentrations lower with dapagliflozin than placebo. Non-esterified fatty acids (NEFA) were higher with dapagliflozin at 300 and 420 min but lipolysis at 450-480 min was not different. Triacylglycerol (TAG) at all time points and endogenous glucose production rate at 450-480 min were not different between treatments. Conclusions. The increase in ketone enrichment from the ingested palmitic acid tracer suggests meal derived fatty acids contribute to the increase in ketones during treatment with dapagliflozin. The increase in BOHB concentration with dapagliflozin, occurred with only minimal changes in plasma NEFA concentration and no change in lipolysis. This suggests a metabolic switch to increase ketogenesis within the liver.

OA Hakim, A Darling, S Starkey, M Wong, F Shojaee-Moradie, K Hart, L Morgan, J Berry, A Umpleby, B Griffin, S Lanham-New (2010)POOR BONE HEALTH AND INCREASED CARDIOVASCULAR DISEASE RISK: EVIDENCE OF A LINK IN THE D-FINES STUDY POPULATION, In: OSTEOPOROSIS INTERNATIONAL21pp. 96-97
O Hakim, S Lanham-New, F Shojaee-Moradie, L Morgan, A Umpleby, B Griffin, J Berry, R Eastell, F Gossiel, R Hannon, K Hart (2010)POORER LIPID PROFILE ARE ASSOCIATED WITH INCREASED BONE RESORPTION AND PARATHYROID HORMONE: PRELIMINARY RESULTS OF THE D-FINES STUDY, In: OSTEOPOROSIS INTERNATIONAL21(Suppl)pp. S506-S507
O Hakim, K Hart, L Morgan, B Griffin, S Lanham-New, F Shojaee-Moradie, A Umpleby, J Berry (2010)(PREMIER POSTER-AWARD CANDIDATE) EVIDENCE OF A LINK BETWEEN OSTEOPOROSIS RISK AND CVD IN CAUCASIAN BUT NOT ASIAN WOMEN: RESULTS OF THE D-FINES STUDY, In: OSTEOPOROSIS INTERNATIONAL21pp. S466-S467
M Shahmanesh, S Das, M Umpleby (2009)Pre-treatment alterations in lipoprotein metabolism predict changes in blood lipids after antiretroviral therapy, In: ANTIVIRAL THERAPY14(7)pp. A56-A56
DL Russell-Jones, AT Bates, AM Umpleby, TR Hennessy, SB Bowes, KD Hopkins, N Jackson, J Kelly, F Shojaee-Moradie, RH Jones (1995)A comparison of the effects of IGF-I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers., In: Eur J Clin Invest25(6)pp. 403-411

The metabolic and cardiovascular effects of recombinant human IGF-I were compared to insulin in six normal subjects. Subjects were studied twice and intravenously received an infusion of [6,6-2H2]glucose (0-480 min) and in random order either IGF-I 20 micrograms kg-1 h-1 (43.7 pmol kg-1 min-1 or insulin 0.5 mU kg-1 min-1 (3.4 pmol kg-1 min-1) with an euglycaemic clamp. One subject was withdrawn following a serious adverse event. During the IGF-I infusion glucose appearance rate (Ra) decreased from 1.79 +/- 0.13 at baseline (150-180 min) to 0.35 +/- 0.26 mg kg-1 min-1 (P < 0.01) at 360 min, and glucose utilization rate (Rd) increased from 1.79 +/- 0.28 to 4.17 +/- 0.84 mg kg-1 min-1 (P < 0.01). There was no change in free fatty acids (FFA) and an increase (percentage change from pre-infusion mean) in cardiac output +l37.3% +/- 9% (P < 0.01), heart rate +13% +/- 2% (P < 0.01) and stroke volume +21% +/- 7% (P < 0.05). During the insulin infusion glucose Ra decreased from 1.89 +/- 0.13 to 0.34 +/- 0.33 mg kg-1 min-1 (P < 0.01) and FFA from 0.546 mmol l-1 to 0.198 mmol l-1 (P < 0.01), glucose Rd increased from 1.89 +/- 0.18 to 5.41 +/- 1.47 mg kg-1 min-1 (P < 0.01) and there were no significant changes in the cardiovascular variables.

C Mohandas, MI de Abreu, BM Wilson, AM Pernet, AM Umpleby, T Dew, F Shojaee-Moradie, N Jackson, KGMM Alberti, SA Amiel, LM Goff (2015)Exaggerated insulin secretory deficits in early Type 2 diabetes in men of black West African ethnicity are not corrected by enhanced incretin responses to oral glucose, In: DIABETIC MEDICINE32pp. 6-6
GF Watts, MH Cummings, M Umpleby, JR Quiney, R Naoumova, GR Thompsom, PH Sonksen (1995)Simvastatin decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: Pathophysiological and therapeutic implications (vol 25, pg 559, 1995), In: EUROPEAN JOURNAL OF CLINICAL INVESTIGATION25(12)pp. 980-980 BLACKWELL SCIENCE LTD
DL RussellJones, M Umpleby (1996)Protein anabolic action of insulin, growth hormone and insulin-like growth factor I, In: EUROPEAN JOURNAL OF ENDOCRINOLOGY135(6)pp. 631-642 SCANDINAVIAN UNIVERSITY PRESS
X Li, M Stolinski, N Jackson, M Umpleby (2009)Pre beta and alpha HDL kinetics measured by a stable isotopic and two step electrophoresis technique, In: DIABETOLOGIA52pp. S490-S490
A Haidar, D Elleri, JM Allen, J Harris, K Kumareswaran, M Nodale, CL Acerini, ME Wilinska, N Jackson, AM Umpleby, ML Evans, DB Dunger, R Hovorka (2010)Triple tracer (TT) and double tracer (DT) techniques are reliable methods to estimate glucose appearance in type 1 diabetes, In: DIABETOLOGIA53
M Whyte, N Jackson, F Shojaee-moradie, R Beale, D Treacher, P Carroll, RH Jones, M Umpleby (2004)The effect of insulin therapy on glucose production rate, glucose uptake, lipolysis and proteolysis in non-surgical ICU patients, In: Diabetologia - Volume 47, Issue 1 Supplement, August 2004 - Proceedings of the 40th EASD Annual Meeting of the European Association for the Study of Diabetes47(Issue)pp. A216-A216

Background and aims: Recent data suggest that the use of insulin to maintain intensive glycaemic control amongst surgical ICU patients can improve morbidity and mortality. The value of this procedure in non-surgical patients is not known. Current insulin therapy for non-surgical patients in many ICUs aims to keep plasma glucose below 9 mmolll. The effect of this insulin therapy protocol on the catabolic response of critical illness, characterised by increased glucose production, increased lipolysis and proteolysis is unknown. Materials and methods: A prospective study was conducted in seven critically ill non-surgical patients (6M:1F, age 64±2.72 years; BMI 24.77 ± 0.77 kg/m2) within 36 hours of their admission to the ICU. Patients with diabetes mellitus, pancreatitis, oral steroid use within 1 month of entering the ICU, or liver disease (LFTs > twice normal range), were excluded. All patients were receiving 20% dextrose intravenously to provide 25kcal.kg-lday-l. Insulin was infused at a variable rate to maintain plasma glucose below 9 mmollL. Glucose production rate (Ra) and rate of uptake (Rd), glycerol Ra (a measure oflipolysis) and leucine Ra (a measure of proteolysis) were measured with a 3 hour primed infusion of [6,6- 2H2]glucose (l70mg, 1.7mg.min-I), [2H5]glycerol (0.15mg/kg, 0.61mg· kg-lhc1) and [l-l3C]leucine (1 mg/kg, 1 mg.kg-lhcl). Steady state sampling was performed at 150 to 180 minutes. Results are compared with fasting values from an age and weight matched healthy control group. All data presented are mean ± SEM. Results: The mean APACHE II score on the day of study was 15.43 ± 1.87. Mean plasma glucose at steady state was 7.95±0.73mmol· L-l. The mean glucose infusion rate was 22.83 ± 0.74 f.lmol.kg-lmin-l. The average insulin infusion rate was 4.31 ±0.73 U.hr-l which achieved plasma insulin concentrations of 655.21 ± 181.38 pmol.L-I. Endogenous glucose Ra was decreased (2.24±3.02f.lmol.kg-lmin-l, p

LS Bhatia, E Scorletti, F Shojaee-Moradie, M Umpleby, GF Clough, NP Curzen, PC Calder, CD Byrne (2014)High-dose n-3 fatty acid treatment in non-alcoholic fatty liver disease is independently associated with reduced hepatic steatosis and improved hepatic insulin sensitivity, In: DIABETIC MEDICINE31pp. 53-53
F Sun, M Stolinski, F Shojaee-Moradie, AM Umpleby (2007)Measurement of endogenous and exogenous triacylglycerol kinetics in the fed and fasted states, In: BIOCHEMICAL SOCIETY TRANSACTIONS35pp. 482-483
T Wolthers, DM Hoffman, AG Nugent, MW Duncan, M Umpleby, KKY Ho (2001)Oral estrogen antagonizes the metabolic actions of growth hormone in growth hormone-deficient women, In: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM281(6)pp. E1191-E1196 AMER PHYSIOLOGICAL SOC

We have determined whether oral estrogen reduces the biological effects of growth hormone (GH) in GH-deficient (GHD) women compared with transdermal estrogen treatment. In two separate studies, eight GHD women randomly received either oral or transdermal estrogen for 8 wk before crossing over to the alternate route of administration. The first study assessed the effects of incremental doses of GH (0.5, 1.0, 2.0 IU/day for 1 wk each) on insulin-like growth factor I (IGF-I) levels during each estrogen treatment phase. The second study assessed the effects of GH (2 IU/day) on lipid oxidation and on protein metabolism using the whole body leucine turnover technique. Mean IGF-I level was significantly lower during oral estrogen treatment (P < 0.05) and rose dose dependently during GH administration by a lesser magnitude (P < 0.05) compared with transdermal treatment. Postprandial lipid oxidation was significantly lower with oral estrogen treatment, both before (P < 0.05) and during (P < 0.05) GH administration, compared with transdermal treatment. Protein synthesis was lower during oral estrogen both before and during GH administration (P < 0.05). Oral estrogen antagonizes several of the metabolic actions of GH. It may aggravate body composition abnormalities already present in GHD women and attenuate the beneficial effects of GH therapy. Estrogen replacement in GHD women should be administered by a nonoral route.

SB Bowes, NC Jackson, D Papachristodoulou, AM Umpleby, PH Sönksen (1996)Effect of corticosterone on protein degradation in isolated rat soleus and extensor digitorum longus muscles., In: J Endocrinol148(3)pp. 501-507

The net catabolic effect of glucocorticoids on protein metabolism is well documented but the acute and chronic effect of glucocorticoids on protein breakdown remains controversial. In the present studies protein breakdown was measured by the release of tyrosine from the isolated soleus and extensor digitorum longus (EDL) muscles of control rats and rats treated with corticosterone (10 mg/100 g body weight/day) for 5 days. The effect of corticosterone in arresting growth was confirmed since corticosterone-treated rats weighed significantly less than control rats after 2, 3, 4 and 5 days of treatment (P < 0.001). Furthermore, the weights of soleus and EDL muscles from corticosterone-treated rats were significantly reduced (P < 0.001, at least P < 0.05 respectively) compared with muscles from control rats on days 3-5. In the EDL muscle tyrosine release was significantly elevated after corticosterone treatment for 2 days (257 +/- 21 nmol/g tissue/h, P < 0.05), 3 days (205 +/- 9 nmol/g tissue/h, P < 0.01), 4 days (255 +/- 20 nmol/g tissue/h, P < 0.005) and 5 days (218 +/- 8 nmol/g tissue/h, P < 0.05) compared with EDL from control rats (192 +/- 13, 171 +/- 7, 187 +/- 7, 180 +/- 12 nmol/g tissue/h respectively). In the soleus muscle, tyrosine release was significantly elevated after corticosterone treatment for 2 days (226 +/- 14 nmol/g tissue/h, P < 0.001), 3 days (223 +/- 16 nmol/g tissue/h, P < 0.001) and 4 days (199 +/- 10 nmol/g tissue/h, P < 0.001) compared with control rats (158 +/- 7, 132 +/- 6 and 153 +/- 7 nmol/g tissue/h respectively). After 5 days there was no significant difference in tyrosine release from soleus muscle between corticosterone-treated (176 +/- 15 nmol/g tissue/h) and control rats (157 +/- 6 nmol/g tissue/h). Plasma glucose concentrations were not significantly different in rats treated with corticosterone and control rats whilst insulin levels were significantly raised in the corticosterone-treated rats on all days compared with control rats (P < 0.05 on day 1; P < 0.001 on days 2, 3, 4 and 5). It is suggested that insulin may have prevented hyperglycaemia developing in the corticosterone-treated rats. Results from these studies indicate that the acute effect of glucocorticoids is to increase muscle proteolysis but this is not maintained with longer-term treatment.

NC Jackson, PV Carroll, DL Russell-Jones, PH Sönksen, DF Treacher, AM Umpleby (1999)The metabolic consequences of critical illness: acute effects on glutamine and protein metabolism., In: Am J Physiol276(1 Pt 1)pp. E163-E170

Net protein loss and large decreases in plasma glutamine concentration are characteristics of critical illness. We have used [2-15N]glutamine and [1-13C]leucine to investigate whole body glutamine and leucine kinetics in a group of critically ill patients and matched healthy controls. Glutamine appearance rate (Ra,Gln) was similar in both groups. However, in the patients, the proportion of Ra,Gln arising from protein breakdown was higher than in the control group (43 +/- 3 vs. 32 +/- 2%, P < 0.05). Glutamine metabolic clearance rate (MCR) was 92 +/- 8% higher (P < 0.001), whereas plasma glutamine concentration was 38 +/- 5% lower (P < 0.001) than in the control group. Leucine appearance rate (whole body proteolysis) and nonoxidative leucine disposal (whole body protein synthesis) were 59 +/- 14 and 49 +/- 15% higher in the patients (P < 0.001). Leucine oxidation and MCR were increased in the patients by 104 +/- 37 and 129 +/- 39%, respectively (P < 0.05). These results demonstrate that critical illness is associated with a major increase in protein turnover. The acute decrease in plasma glutamine concentration and the unaltered plasma Ra,Gln suggest that the increase in proteolysis is insufficient to meet increased demand for glutamine in this severe catabolic state.

MH CUMMINGS, GF WATTS, C PAL, M UMPLEBY, TR HENNESSY, R NAOUMOVA, PH SONKSEN (1995)INCREASED HEPATIC SECRETION OF VERY-LOW-DENSITY LIPOPROTEIN APOLIPOPROTEIN B-100 IN OBESITY - A STABLE-ISOTOPE STUDY, In: CLINICAL SCIENCE88(2)pp. 225-233 PORTLAND PRESS
M Umpleby, F Shojaee-Moradie, B Fielding, X Li, C Isherwood, N Jackson, G Wilinska, R Hovorka, J Bell, EL Thomas, J Wright, GS Frost, B Griffin (2015)A DIET LOW IN SUGAR REDUCES THE PRODUCTION OF ATHEROGENIC LIPOPROTEINS IN MEN WITH HIGH LIVER FAT, In: ATHEROSCLEROSIS241(1)pp. E46-E46
F Shojaee-Moradie, K Backhouse, I Sarac, M Stoliniski, D Robertson, JD Bell, EL Thomas, D Russell-Jones, M Umpleby (2010)Fatty acid oxidation rate is higher in obese women than obese men, In: DIABETOLOGIA53
I Sarac, K Backhouse, F Shojaee-Moradie, D Robertson, M Stolinski, M Umpleby (2009)The effect of rimonabant on resting energy expenditure, insulin sensitivity, plasma lipids and adipokines concentrations, In: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY68(2)pp. 285-285
LM Goff, F Shojaee-Moradie, C Mohandas, MI Abreu, J Peacock, N Jackson, AM Umpleby, SA Amiel (2015)Neither hepatic nor peripheral insulin sensitivity differs between men of black West African and white European ethnicity with early Type 2 diabetes, In: DIABETIC MEDICINE32pp. 92-92
X Li, M Stolinski, F Shojaee-Moradie, N Jackson, M Umpleby (2008)DEVELOPMENT OF A METHOD TO MEASURE HIGH DENSITY LIPOPROTEIN KINETICS USING STABLE ISOTOPES, In: ATHEROSCLEROSIS SUPP9(1)pp. 28-28
S Das, M Stolinski, W Jefferson, N Jackson, G Gilleran, M O'Connor, R Cramb, M Shahmanesh, M Umpleby (2003)The relationship between fat distribution and VLDL and IDL metabolism in HIV-infected adults, In: ANTIVIRAL THERAPY8(4)pp. L52-L52
SE Joseph, N Heaton, D Potter, A Pernet, M Umpleby, SA Amiel (1998)Renal glucose production compensates for the liver during the anhepatic phase of liver transplantation., In: DIABETOLOGIA41pp. A68-A68 SPRINGER VERLAG
AL Brackenridge, N Jackson, F Shojaee-Moradie, AM Umpleby, D Russell-Jones (2005)The effect of rosiglitazone and pioglitazone on VLDL apolipoprotein B metabolism in patients with type 2 diabetes, In: DIABETES54pp. A234-A234
AL Brackenridge, ER Pearson, F Shojaee-Moradie, AT Hattersley, D Russell-Jones, AM Umpleby (2005)Subjects with HNF-1 beta mutations have isolated insulin resistance of endogenous glucose production rate in contrast to normal insulin sensitivity in subjects with HNF-1 alpha mutations, In: DIABETOLOGIA48pp. A69-A69
MH Cummings, GF Watts, AM Umpleby, TR Hennessy, JM Kelly, NC Jackson, PH Sönksen (1995)Acute hyperinsulinemia decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM., In: Diabetes44(9)pp. 1059-1065

In a randomized crossover study, we measured the hepatic secretion rate of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB) in seven patients with well-controlled non-insulin-dependent diabetes mellitus (NIDDM) (HbA1 8.4 +/- 0.4% [mean +/- SE]) on two occasions: during a 13-h hyperinsulinemic (plasma insulin concentration 586 +/- 9.7 pmol/l) euglycemic (plasma glucose concentration 5.2 +/- 0.1 mmol/l) clamp; and during a 13-h saline (control) infusion. After 5 h of the hyperinsulinemic euglycemic clamp (or saline infusion) when a new steady state of apoB turnover was reached, [1-(13)C]leucine was administered by a primed (1 mg/kg), constant 8-h infusion (1 mg.kg-1. h-1). VLDL apoB isotopic enrichment was determined with gas chromatography-mass spectrometry, and a monoexponential model was used to calculate the fractional secretion rate of VLDL apoB. VLDL apoB secretion rate was significantly reduced during the hyperinsulinemic euglycemic clamp compared with the saline study (12.2 +/- 3.6 vs. 24.5 +/- 7.1 mg.kg-1.day-1, P = 0.001), but there was no change in the fractional catabolic rate of VLDL apoB. Concomitantly, plasma concentrations of nonesterified fatty acids (NEFAs), glycerol, and triglycerides (TGs) were significantly lower during the hyperinsulinemic euglycemic clamp compared with the saline study (NEFAs, P < 0.001; glycerol, P = 0.005; TGs P = 0.004). We conclude that acute hyperinsulinemia decreases the hepatic secretion rate of VLDL apoB in NIDDM, probably in part due to reduction in the delivery of NEFA and glycerol substrate to the liver.

FJ Smeeton, F Shojaee-Moradie, N Jackson, L Westergaard, L Endahl, H Haahr, AM Umpleby, D Russell-Jones (2007)No difference in cognitive function, symptoms or counter-regulatory responses after induced hypoglycaemia in subjects with type 1 diabetes, In: DIABETES56pp. A168-A168
AM Umpleby, PV Carroll, DL Russell-Jones, DF Treacher, NC Jackson (2002)Glutamine supplementation and GH/IGF-I treatment in critically ill patients: effects on glutamine metabolism and protein balance., In: Nutrition18(2)pp. 127-129
RM Williams, R Amin, F Shojaee-Moradie, M Umpleby, KK Ong, CL Acerini, DB Dunger (2002)The effects of the specific growth hormone antagonist Pegvisomant on the GH/IGF-I axis and insulin sensitivity in adolescents with TIDM, In: DIABETES51pp. A117-A117 AMER DIABETES ASSOC
M Umpleby, F Shojaee-Moradie, S Das, M Stolinski, W Jefferson, N Jackson, R Cramb, M Shahmanesh (2004)Adiponectin levels are reduced in HIV infection and after treatment and correlate with VLDL and IDL apolipoprotein B fractional catabolic rate, In: DIABETOLOGIA47pp. A233-A234
CDT Byrne, HB Holt, SH Wild, N Wareham, U Ekelund, M Umpleby, E Shojaee-Moradie, RIG Holt, DI Phillips (2007)Differential impact of fatness, fitness and physical activity energy expenditure on whole body, liver and fat insulin sensitivity, In: DIABETOLOGIA50pp. S255-S255
PH SONKSEN, F SALOMON, R CUNEO, M UMPLEBY, S BOWES (1991)CARDIAC CACHEXIA, In: BRITISH MEDICAL JOURNAL302(6778)pp. 725-726 BRITISH MED JOURNAL PUBL GROUP
F Salomon, M Umpleby, RC Cuneo, PH Sonksen (1997)Protein, fat and glucose metabolism during treatment with recombinant human growth hormone in adults with growth hormone deficiency. Short-and long-term effects, In: ENDOCRINOLOGY AND METABOLISM4(2)pp. 121-128 BAILLIERE TINDALL
PV Carroll, ER Christ, AM Umpleby, I Gowrie, N Jackson, SB Bowes, R Hovorka, P Croos, PH Sönksen, DL Russell-Jones (2000)IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp., In: Diabetes49(5)pp. 789-796

Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.

AM Umpleby, S Das, M Stolinski, F Shojaee-Moradie, NC Jackson, W Jefferson, N Crabtree, P Nightingale, M Shahmanesh (2005)Low density lipoprotein apolipoprotein B metabolism in treatment-naive HIV patients and patients on antiretroviral therapy, In: ANTIVIRAL THERAPY10(5)pp. 663-670 INT MEDICAL PRESS LTD
O Hakim, F Shojaee-Moradie, K Hart, J Berry, R Eastell, F Gossiel, R Hannon, M Umpleby, B Griffin, S Lanham-New (2011)Evidence of a link between poor bone health, low vitamin D status and CVD risk in caucasian and asian women, In: BONE48pp. S197-S198
P Carroll, E Christ, I Gowrie, N Jackson, R Hovorka, E Albany, S Bowes, M Umpleby, P Sonksen, D RussellJones (1997)Daily rhIGF-I augments the anabolic effect of insulin in adults with IDDM., In: DIABETES46pp. 945-945 AMER DIABETES ASSOC
M Whyte, N Jackson, F Shojaee-Moradie, R Sharma, D Treacher, R Beale, RH Jones, AM Umpleby (2005)The effect of insulin dose and level of glycaemia on catabolism in critically ill patients, In: Diabetologia - August 2005, Volume 48, Supplement 1, pp A3–A431: Proceedings of the 41th EASD Annual Meeting of the European Association for the Study of Diabetes48(Issue)pp. A219-A219

Background and Aims: Evidence suggests that tight glycaemic control in critically ill patients can improve morbidity and mortality. The mechanism( s) underlying its benefit remain speculative but might involve an amelioration of catabolism. This study was designed to differentiate the contribution of the insulin dose to the level of glycaemia achieved, on the catabolic response. Materials and Methods: A prospective study was conducted in 16 critically ill patients. Subjects with diabetes mellitus, pancreatitis, or liver disease were excluded. Patients were studied on 2 occasions, 48 hours apart. The baseline study was within 36 hours of admission to the ICU with blood glucose at 7–9 mmol/L. Patients were then randomised to one of four groups: Variable insulin with plasma glucose 4–6 mmol/L (LILG); Variable insulin with plasma glucose 7–9mmol/L (LIHG); High-dose insulin (2mU· kg–1·min–1 plus requirement from baseline) and variable dextrose to maintain glucose 4–6 mmol/L (HILG); High-dose insulin and variable dextrose to maintain glucose 7–9 mmol/L (HIHG). Glucose production rate (Ra) and leucine Ra (a measure of protein degradation) were measured with a 3-hour infusion of [6,62H2]glucose and [1-13C]leucine. Steady state sampling was performed at 150 to 180 mins. Endogenous glucose Ra was calculated by subtracting the dextrose infusion rate from total glucose Ra. Leucine oxidation rate (Ox) was calculated from CO2 enrichment and CO2 production rate.Non-oxidative leucine disposal (a measure of protein synthesis) was calculated as leucine Ra minus leucine Ox. Non-esterified fatty acid concentrations provide an estimate of lipolysis. Results: Protein turnover data (mean±SEM) was compared with 12 fasted age-matched controls. Glucose turnover data was compared to a separate control group of 8 subjects. Conclusions: Amongst non-surgical ICU admissions, the use of insulin to achieve less-stringent glycaemic targets was able to suppress glucose Ra and lipolysis and increase glucose uptake. No further suppression of glucose Ra was found with high dose insulin or with tighter glycaemic control. Leucine Ra was not decreased, even by pharmacological doses of insulin, whereas glucose Rd was significantly increased in the HILG and HIHG groups. These results suggest that the use of insulin to achieve normoglycaemia in the critical care setting does not promote whole body protein anabolism.

NC Jackson, PV Carroll, DL Russell-Jones, PH Sönksen, DF Treacher, AM Umpleby (2000)Effects of glutamine supplementation, GH, and IGF-I on glutamine metabolism in critically ill patients., In: Am J Physiol Endocrinol Metab278(2)pp. E226-E233

During critical illness glutamine deficiency may develop. Glutamine supplementation can restore plasma concentration to normal, but the effect on glutamine metabolism is unknown. The use of growth hormone (GH) and insulin-like growth factor I (IGF-I) to prevent protein catabolism in these patients may exacerbate the glutamine deficiency. We have investigated, in critically ill patients, the effects of 72 h of treatment with standard parenteral nutrition (TPN; n = 6), TPN supplemented with glutamine (TPNGLN; 0.4 g x kg(-1) x day(-1), n = 6), or TPNGLN with combined GH (0.2 IU. kg(-1). day(-1)) and IGF-I (160 microg x kg (-1) x day(-1)) (TPNGLN+GH/IGF-I; n = 5) on glutamine metabolism using [2-(15)N]glutamine. In patients receiving TPNGLN and TPNGLN+GH/IGF-I, plasma glutamine concentration was increased (338 +/- 22 vs. 461 +/- 24 micromol/l, P < 0.001, and 307 +/- 65 vs. 524 +/- 71 micromol/l, P < 0.05, respectively) and glutamine uptake was increased (5.2 +/- 0.5 vs. 7.4 +/- 0.7 micromol x kg(-1) x min(-1), P < 0.05 and 5.2 +/- 1.1 vs. 7.6 +/- 0.8 micromol x kg(-1) x min(-1), P < 0.05). Glutamine production and metabolic clearance rates were not altered by the three treatments. These results suggest that there is an increased requirement for glutamine in critically ill patients. Combined GH/IGF-I treatment with TPNGLN did not have adverse effects on glutamine metabolism.

M Boothby, AM Umpleby, F Shojaee-Moradie, JW Tomlinson, LL Gathercole, K McGee, S Das, M Shahmanesh (2008)HIV infection significantly reduces lipoprotein lipase which remains low after 6 months of antiretroviral therapy, In: ANTIVIRAL THERAPY13(8)pp. A57-A57
DL Russell-Jones, AM Umpleby, TR Hennessy, SB Bowes, F Shojaee-Moradie, KD Hopkins, NC Jackson, JM Kelly, RH Jones, PH Sonksen (1994)Use of a leucine clamp to demonstrate that IGF-I actively stimulates protein synthesis in normal humans, In: American Journal of Physiology - Endocrinology and Metabolism267(4 30-4)

Insulin-like growth factor I (IGF-I) is thought to mediate the anabolic action of growth hormone. A glucose and amino acid clamp technique was used to investigate the effects of a 3-h intravenous infusion of either 43.7 pmol · kg-1 · min-1 (20 μg · kg-1 · h-1) IGF-I or 3.4 pmol · kg-1 · min-1 (0.5 mU · kg-1 · min-1) insulin on whole body leucine turnover in five normal human volunteers. During the IGF-I infusion, IGF-I levels increased (P < 0.01; 26.6 ± 2.8 to 88.9 ± 14.2 nmol/l) and insulin levels fell (P < 0.05; 0.096 ± 0.018 to 0.043 ± 0.009 nmol/l). During the insulin infusion, insulin levels increased (P < 0.01; 0.057 ± 0.013 to 0.340 ± 0.099 nmol/l), and there was no change in IGF-I. There was no significant change in leucine production rate (R(a); a measure of protein degradation) during the IGF-I infusion (2.23 ± 0.17 to 2.13 ± 0.2 μmol · kg-1 · min-1), but there was an increase (P < 0.03) in nonoxidative leucine disposal rate (R(d); a measure of protein synthesis; 1.83 ± 0.15 to 2.05 ± 0.21 μmol · kg-1 · min-1). In contrast, insulin reduced (P < 0.02) leucine R(a) (1.81 ± 0.24 to 1.47 ± 0.24 μmol · kg-1 · min-1) and had no effect on nonoxidative leucine R(d) (1.44 ± 0.25 to 1.41 ± 0.22 μmol · kg-1 · min-1). We conclude that IGF-I under conditions of adequate substrate supply, directly increases protein synthesis in contrast to insulin, which exerts its anabolic action by reducing proteolysis.

S Zachariah, B Sheldon, E Shojaee-Moradie, N Jackson, K Backhouse, S Johnsen, M Umpleby, D Russell-Jones (2010)Mechanism for the differential effect of the long-acting insulin analog detemir on weight in patients with type 1 diabetes, In: DIABETOLOGIA53
R Williams, R Amin, F Shojaee-Moradie, M Umpleby, C Acerini, D Dunger (2003)Effects of the specific growth hormone receptor antagonist Pegvisomant on insulin sensitivity & lipid metabolism in adolescents with T1DM, In: DIABETES52pp. A334-A334
PV Carroll, AM Umpleby, E Albany, NC Jackson, JA Morgan-Hughes, PH Sonksen, DL Russell-Jones (1997)Growth hormone therapy may benefit protein metabolism in mitochondrial encephalomyopathy., In: Clin Endocrinol (Oxf)47(1)pp. 113-117

Mitochondrial encephalomyopathy is a genetic disorder for which there is at present no cure. Conventional treatment regimes may not be effective in preventing weight loss and muscle wasting in many patients. Recombinant human GH has been shown to have anabolic effects on protein metabolism and to reduce muscle wasting in various diseases. We have treated a patient known to have myoclonus, epilepsy with ragged red fibres (MERRF) with a high protein diet for 1 month followed by a high protein diet and GH therapy for 1 month. To assess the benefit of these treatments the patient underwent whole body protein turnover, myometric and body composition studies at baseline, following the high protein diet (100 g/day) and following GH therapy. Whole body protein synthesis (and protein breakdown) increased following a high protein intake and was further enhanced by treatment with GH and in a high protein diet. Body composition did not change significantly following treatment with either the high protein diet or GH but there was an improvement in muscle performance following GH treatment. Mitochondrial encephalomyopathy, a wasting disorder, may be a disease in which the known protein anabolic effect of GH may have a therapeutic benefit.

Our understanding of HDL metabolism would be enhanced by the measurement of the kinetics of preβHDL, the nascent form of HDL, since elevated levels have been reported in patients with coronary artery disease. Stable isotope methodology is an established technique that has enabled the determination of the kinetics (production and catabolism) of total HDL apoA-I in vivo. The development of separation procedures to obtain a preβHDL fraction, the isotopic enrichment of which could then be measured, would enable further understanding of the pathways in vivo for determining the fate of preβHDL and the formation of αHDL. A method was developed and optimised to separate and measure preβHDL and αHDL apoA-I enrichment. Agarose gel electrophoresis was first used to separate lipoprotein subclasses, and then a 4-10 % discontinuous SDS-PAGE used to isolate apoA-I. Measures of preβHDL enrichment in six healthy subjects were undertaken following an infusion of L-[1-13C-leucine]. After isolation of preβ and αHDL, the isotopic enrichment of apoA-I for each fraction was measured by gas chromatography-mass spectrometry. PreβHDL apoA-I enrichment was measured with a CV of 0.51 % and aHDL apoA-I with a CV of 0.34 %. The fractional catabolic rate (FCR) of preβHDL apoA-I was significantly higher than the FCR of aHDL apoA-I (p < 0.005). This methodology can be used to selectively isolate preβ and aHDL apoA-I for the measurement of apoA-I isotopic enrichment for kinetics studies of HDL subclass metabolism in a research setting. © AOCS 2012.

DL Russell-Jones, SB Bowes, SE Rees, NC Jackson, AJ Weissberger, R Hovorka, PH Sonksen, AM Umpleby (1998)Effect of growth hormone treatment on postprandial protein metabolism in growth hormone-deficient adults., In: Am J Physiol274(6 Pt 1)pp. E1050-E1056

Growth hormone (GH) treatment of GH-deficient adults increases lean body mass. To investigate this anabolic effect of GH, body composition and postabsorptive and postprandial protein metabolism were measured in 12 GH-deficient adults randomized to placebo or GH treatment. Protein metabolism was measured after an infusion of [1-13C]leucine before and after a standard meal at 0 and 2 mo. After 2 mo, there was an increase in lean body mass in the GH group (P < 0. 05) but no change in the placebo group. In the postabsorptive state, there was increased nonoxidative leucine disappearance (NOLD; a measure of protein synthesis) and leucine metabolic clearance rate and decreased leucine oxidation in the GH group (P < 0.05) but no change in the placebo group. After the meal, there was an increase in NOLD and oxidation in all studies (P < 0.05), but the increase in NOLD, measured as area under the curve, was greater in the GH group (P < 0.05). This study clearly demonstrates for the first time that the increase in protein synthesis in the postabsorptive state after GH treatment of GH-deficient adults is maintained in the postprandial state.

N Alsini, F Shojaee-Moradie, B Sheldon, MD Robertson, DL Russell-Jones, AM Umpleby, J Wright (2011)Effect of insulin detemir on adipocyte lipid metabolism in patients with type 2 diabetes, In: DIABETOLOGIA54pp. S236-S237
E Potocka, R Hovorka, RA Baughman, O Klein, SM Dellweg, AM Umpleby, PC Haworth, RJ Mills, AH Boss, PC Richardson (2010)Characterization of Metabolism Parameters Following Technosphere (R) Insulin and Insulin Lispro, In: DIABETES59pp. A413-A413
F Shojaee-Moradie, K Baynes, C Pentecost, JD Bell, EL Thomas, NC Jackson, NC Jackson, M Stolinski, M Whyte, RH Jones, AM Umpleby (2004)The effect of long term exercise on intrahepatic lipid and the insulin sensitivity of glucose and fatty acid metabolism in sedentary male subjects, In: Diabetologia - Volume 47, Issue 1 Supplement, August 2004 - Proceedings of the 40th EASD Annual Meeting of the European Association for the Study of Diabetes47(Issue)pp. A245-A245

Background and aims: Adaptive changes in fatty acid metabolism, liver and muscle fat content and adipocyte-derived cytokines may potentially explain the beneficial effects of exercise on insulin action. We investigated this in sedentary men before and after 6 weeks of supervised exercise. Materials and methods: Thirteen sedentary overweight male subjects (age 50 ± 304yr, BMI 28.2 ± 0.5) were recruited, seven were randomised to a 6 week exercise programme and six remained sedentary. After completion of the baseline (0 weeks) metabolic study and body composition measurements subjects who were allocated to the exercise group started the exercise programme. Subjects exercised at 60-85% ofV02 max for a minimum of 20 minutes at least 3 times a week for 6 weeks. Insulin sensitivity of fatty acid (NEFA) production rate (Ra), glycerol Ra, glucose Ra and glucose disposal rate (Rd) were measured with stable isotopes of palmitic acid, glycerol and glucose at 0 and 6 weeks with a 2 step hyperinsulinaemic euglycaemic clamp (step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU. kg-I. min-I). Intrahepatocellular lipid (IHCL) and intramyocellular lipid (IMCL) were measured by magnetic resonance spectroscopy and visceral fat by cross-sectional CT scanning. Results: In the exercise group V02 max increased by 20 ± 5% after 6 weeks (p

SB Bowes, TR Hennessy, AM Umpleby, JJ Benn, NC Jackson, MA Boroujerdi, PH Sönksen, C Lowy (1996)Measurement of glucose metabolism and insulin secretion during normal pregnancy and pregnancy complicated by gestational diabetes., In: Diabetologia39(8)pp. 976-983

Gestational diabetes affects 2-3% of pregnant women and is associated with foetal complications including macrosomia and an increased likelihood of developing diabetes in later life. We have therefore studied seven women with gestational diabetes and five control women both during the third trimester of pregnancy and again 2-3 months post-partum, using the minimal model analysis of the frequently sampled labelled ([6,6-2H2]-glucose) intravenous glucose tolerance test. Glucose tolerance (glucose Kd) was significantly reduced in the women with gestational diabetes compared with the normal pregnant women both in pregnancy (1.16 +/- 0.11 vs 1.78 +/- 0.23%/min; p < 0.05) and post-partum (1.47 +/- 0.22 vs 2.59 +/- 0.43%/min; p < 0.05) and increased significantly in the control women after delivery (p < 0.05). Glucose effectiveness was not significantly different between the women with gestational diabetes and the control group either during or after pregnancy. Insulin sensitivity was significantly lower during pregnancy than after delivery in the women with gestational diabetes (p < 0.05). There was no significant difference in basal insulin secretion in the two groups during pregnancy or post-partum. However, during pregnancy the control subjects significantly increased (p < 0.001) their insulin secretion over a period of 20 min in response to an intravenous glucose tolerance test (96.2 +/- 42.7 pmol/kg) compared with post-partum values (58.3 +/- 25.2 pmol/kg) while in the women with gestational diabetes insulin secretion was similar in pregnancy (65.5 +/- 9.3 pmol/kg) and after delivery (57.7 +/- 15.7 pmol/kg). These data suggest that the glucose intolerance in gestational diabetes compared to normal pregnancy is due to reduced insulin sensitivity and an impaired ability in gestational diabetes to increase insulin secretion in response to glucose.

E Potocka, R Hovorka, R Baughman, M Umpleby, M Diaz, R Chen, J Cassidy, A Boss, P Richardson (2009)Technosphere insulin suppresses endogenous glucose production earlier than a rapid-acting analogue (lispro) and an inhaled insulin (Exubera (R)), In: DIABETOLOGIA52pp. S374-S374
R Hovorka, PV Carroll, IJ Gowrie, NC Jackson, DL Russell-Jones, AM Umpleby (1999)A surrogate measure of whole body leucine transport across the cell membrane., In: Am J Physiol276(3 Pt 1)pp. E573-E579

Based on a mass-balance model, a surrogate measure of the whole body leucine transport into and out of cells under steady-state conditions was calculated as u/DeltaTTR, where u is the infusion rate of (stable label) leucine tracer and DeltaTTR is the difference between the tracer-to-tracee ratio of extracellular and intracellular leucine. The approach was evaluated in ten healthy subjects [8 males and 2 females; age, 31 +/- 9 (SD) yr; body mass index, 24.0 +/- 1.6 kg/m2] who received a primed (7.58 micromol/kg) constant intravenous infusion (7.58 micromol. kg-1. h-1) of L-[1-13C]leucine over 180 min (7 subjects) or 240 min (3 subjects). Five subjects were studied on two occasions >/=1 wk apart to assess reproducibility. Blood samples taken during the last 30 min of the leucine infusion were used to determine plasma leucine concentration (129 +/- 35 micromol/l), TTR of leucine (9.0 +/- 1.5%), and TTR of alpha-ketoisocaproic acid (6.7 +/- 0.8%). The latter TTR was taken as the measure of the free intracellular leucine TTR. The whole body inward and outward transport was 6.66 +/- 3.82 micromol. kg-1. min-1; the rate of leucine appearance due to proteolysis was 1.93 +/- 0.24 micromol. kg-1. min-1. A positive linear relationship between the inward transport and plasma leucine was observed (P < 0.01), indicating the presence of the mass effect of leucine on its own transport. The transport was highly variable between subjects (between-subject coefficient of variation 57%) but reproducible (within-subject coefficient of variation 17%). We conclude that reproducible estimates of whole body transport of leucine across the cell membrane can be obtained under steady-state conditions with existing experimental and analytical procedures.

F Shojaee-Moradie, AM Umpleby, MJ Thomason, NC Jackson, MA Boroujerdi, PH Sönksen, A Skottner, RH Jones (1995)A comparison of the effects of insulin-like growth factor-I, insulin and combined infusions of insulin and insulin-like growth factor-I on glucose metabolism in dogs., In: Eur J Clin Invest25(12)pp. 920-928

The effect of infusions of recombinant insulin-like growth factor-I (IGF-I) (34, 103 or 688 pmol kg-1 min-1), insulin (3.4, 10.3 or 68.8 pmol kg-1 min-1) or combined infusions (34 pmol IGF-I + 3.4 pmol kg-1 min-1 insulin or 103 pmol IGF-I + 3.4 pmol kg-1 min-1 insulin) on glucose metabolism was investigated in dogs using a [3-3H]-glucose infusion and euglycaemic clamp. All insulin doses decreased glucose production rate (Ra) in a dose-dependent manner (P < 0.05). All IGF-I doses decreased glucose Ra (P < 0.05) but this decrease was not dose dependent. The decrease in glucose Ra with the combined infusion of 34 pmol kg-1 min-1 IGF-I + 3.4 pmol kg-1 min-1 insulin was greater than 34 pmol kg-1 min-1 IGF-I (P < 0.05) but not different from 3-4 pmol kg-1 min-1 insulin. All insulin and IGF-I doses increased glucose utilization rate (Rd) in a dose-dependent manner (P < 0.01). The increase in glucose utilization was greater following both combined infusions than with either component infused alone (P < 0.05). Although at the doses selected, insulin and IGF-I had similar effects on glucose utilization with additive effects when the two peptides were combined, IGF-I was less effective than insulin in suppressing glucose production.

F Shojaee-Moradie, PV Carroll, LJ Chassin, IJ Gowrie, NC Jackson, RH Jones, RS Tudor, AM Umpleby, R Hovorka (2001)Partitioning glucose transport/distribution and disposal during euglycaemic clamp, In: DIABETOLOGIA44pp. A206-A206 SPRINGER-VERLAG
M Stolinski, X Li, A Lo, F Shojaee-Moradie, S Alam, B Wheeler, C Pentecost, N Jackson, W Jefferson, M Umpleby (2006)A supervised exercise programme increases HDL ApoA-1 production rate in type 2 diabetes, In: DIABETOLOGIA49pp. 324-324
S Das, M Stolinski, W Jefferson, N Jackson, G Gilleran, M O'Connor, R Cramb, M Umpleby, M Shahmanesh (2003)Effects of HIV infection, antiviral treatment and body fat changes on V-LDL-apolipoprotein-B metabolism, In: ANTIVIRAL THERAPY8(4)pp. L6-L7
SJ Clark, F Shojaee-Moradie, P Croos, NC Jackson, AM Umpleby, JA Wendon (1999)Development of insulin insensitivity in acute liver failure, In: HEPATOLOGY30(4)pp. 168A-168A W B SAUNDERS CO
OA Hakim, K Hart, AL Darling, F Shojaee-Moradie, JL Berry, AM Umpleby, BA Griffin, SA Lanham-New (2012)Homeostatic model assessment (HOMA) in relation to lipid profiles and vitamin D status in South Asian and Caucasian women: preliminary results from D-FINES, In: PROCEEDINGS OF THE NUTRITION SOCIETY71(OCE2)pp. E70-E70
V Hordern, J Wright, M Umpleby, L Jacobsen, D Russell-Jones (2001)Stable isotope studies show effect of insulin detemir and NPH on hepatic glucose output and peripheral glucose uptake after subcutaneous administration in healthy subjects, In: DIABETES50pp. A504-A505 AMER DIABETES ASSOC
D Elleri, JM Allen, J Harris, A Haidar, K Kumareswaran, L Leelarathna, M Nodale, ME Wilinska, J Weston, CL Acerini, N Jackson, AM Umpleby, ML Evans, DB Dunger, R Hovorka (2011)Glucose appearance of large evening meals with low and high glycaemic load in type 1 diabetes, In: DIABETOLOGIA54pp. S54-S54
D RUSSELLJONES, M UMPLEBY, T HENNESEY, SB BOWES, KD HOPKINS, NC JACKSON, J KELLY, MJ THOMASON, F SHOJAEEMORADIE, RH JONES, PH SONKSEN (1993)INTRAVENOUS INSULIN-LIKE GROWTH FACTOR-I (IGF-I) UNLIKE INSULIN INCREASES WHOLE-BODY PROTEIN-SYNTHESIS IN NORMAL VOLUNTEERS, In: DIABETES42pp. A37-A37 AMER DIABETES ASSOC
R Herring, F Shojaee-Moradie, M Umpleby, N Jackson, R Jones, D Derk-Jan, R Knight, D Russell-Jones (2014)Subcutaneous insulin detemir compared with NPH insulin increases brain potential responses with similar systemic metabolic effects in people with Type 1 diabetes, In: DIABETIC MEDICINE31pp. 62-62
DL Russell-Jones, AM Umpleby, TR Hennessy, SB Bowes, F Shojaee-Moradie, KD Hopkins, NC Jackson, JM Kelly, RH Jones, PH Sönksen (1994)Use of a leucine clamp to demonstrate that IGF-I actively stimulates protein synthesis in normal humans., In: Am J Physiol267(4 Pt 1)pp. E591-E598

Insulin-like growth factor I (IGF-I) is thought to mediate the anabolic action of growth hormone. A glucose and amino acid clamp technique was used to investigate the effects of a 3-h intravenous infusion of either 43.7 pmol.kg-1.min-1 (20 micrograms.kg-1.h-1) IGF-I or 3.4 pmol.kg-1.min-1 (0.5 mU.kg-1.min-1) insulin on whole body leucine turnover in five normal human volunteers. During the IGF-I infusion, IGF-I levels increased (P < 0.01; 26.6 +/- 2.8 to 88.9 +/- 14.2 nmol/l) and insulin levels fell (P < 0.05; 0.096 +/- 0.018 to 0.043 +/- 0.009 nmol/l). During the insulin infusion, insulin levels increased (P < 0.01; 0.057 +/- 0.013 to 0.340 +/- 0.099 nmol/l), and there was no change in IGF-I. There was no significant change in leucine production rate (Ra; a measure of protein degradation) during the IGF-I infusion (2.23 +/- 0.17 to 2.13 +/- 0.2 mumol.kg-1.min-1), but there was an increase (P < 0.03) in nonoxidative leucine disposal rate (Rd; a measure of protein synthesis; 1.83 +/- 0.15 to 2.05 +/- 0.21 mumol.kg-1.min-1). In contrast, insulin reduced (P < 0.02) leucine Ra (1.81 +/- 0.24 to 1.47 +/- 0.24 mumol.kg-1.min-1) and had no effect on nonoxidative leucine Rd (1.44 +/- 0.25 to 1.41 +/- 0.22 mumol.kg-1.min-1). We conclude that IGF-I, under conditions of adequate substrate supply, directly increases protein synthesis in contrast to insulin, which exerts its anabolic action by reducing proteolysis.

Barbara A Fielding, Bruce A Griffin, Wendy Hall, Leanne Hodson, Rona Antoni, A. Margot Umpleby, Tracey Robertson, Tom Preston, Matthew Brook, Katherine Pinnick (2020)Report of a member-led meeting: how stable isotope techniques can enhance human nutrition research, In: Proceedings of the Nutrition Society79(3)pp. 373-379 Cambridge University Press

A Nutrition Society member-led meeting was held on 9 January 2020 at The University of Surrey, UK. Sixty people registered for the event, and all were invited to participate, either through chairing a session, presenting a ‘3 min lightning talk’ or by presenting a poster. The meeting consisted of an introduction to the topic by Dr Barbara Fielding, with presentations from eight invited speakers. There were also eight lightning talks and a poster session. The meeting aimed to highlight recent research that has used stable isotope tracer techniques to understand human metabolism. Such studies have irrefutably shaped our current understanding of metabolism and yet remain a mystery to many. The meeting aimed to de-mystify their use in nutrition research.

R Hovorka, F Shojaee-Moradie, PV Carroll, LJ Chassin, IJ Gowrie, NC Jackson, RS Tudor, A Margot Umpleby, RH Jones (2002)Partitioning glucose distribution/transport, disposal, and endogenous production during IVGTT, In: American Journal of Physiology - Endocrinology and Metabolism282(5 45-5)

We have separated the effect of insulin on glucose distribution/transport, glucose disposal, and endogenous production (EGP) during an intravenous glucose tolerance test (IVGTT) by use of a dual-tracer dilution methodology. Six healthy lean male subjects (age 33 ± 3 yr, body mass index 22.7 ± 0.6 kg/m2) underwent a 4-h IVGTT (0.3 g/kg glucose enriched with 3-6% D- [U-13C] glucose and 5-10% 3-O-methyl-D-glucose) preceded by a 2-h investigation under basal conditions (5 mg/kg of D-[U-13C]glucose and 8 mg/kg of 3-O-methyl-D-glucose). A new model described the kinetics of the two glucose tracers and native glucose with the use of a two-compartment structure for glucose and a one-compartment structure for insulin effects. Insulin sensitivities of distribution/transport, disposal, and EGP were similar (11.5 ± 3.8 vs. 10.4 ± 3.9 vs. 11.1 ± 2.7 X 10-2 ml·kg-1·min-1 per Mu/1; P = nonsignificant, ANOVA). When expressed in terms of ability to lower glucose concentration, stimulation of disposal and stimulation of distribution/transport accounted each independently for 25 and 30%, respectively, of the overall effect. Suppression of EGP was more effective (P < 0.01, ANOVA) and accounted for 50% of the overall effect. EGP was suppressed by 70% (52-82%) (95% confidence interval relative to basal) within 60 min of the IVGTT; glucose distribution/transport was least responsive to insulin and was maximally activated by 62% (34-96%) above basal at 80 min compared with maximum 279% (116-565%) activation of glucose disposal at 20 min. The deactivation of glucose distribution/transport was slower than that of glucose disposal and EGP (P < 0.02) with half-times of 207 (84-510), 12 (7-22), and 29 (16-54) min, respectively. The minimal-model insulin sensitivity was tightly correlated with and linearly related to sensitivity of EGP (r = 0.96, P < 0.005) and correlated positively but nonsignificantly with distribution/transport sensitivity (r = 0.73, P = 0.10) and disposal sensitivity (r = 0.55, P = 0.26). We conclude that, in healthy subjects during an IVGTT, the two peripheral insulin effects account jointly for approximately one-half of the overall insulin-stimulated glucose lowering, each effect contributing equally. Suppression of EGP matches the effect in the periphery.

M Shahmanesh, S Das, F Shojaee-Moradie, M Stolinski, W Jefferson, N Jackson, G Gilleran, NJ Crabtree, P Nightingale, R Cramb, M Umpleby (2004)The reduction in serum adiponectin levels in HIV patients correlates with apolipoprotein-B clearance, In: ANTIVIRAL THERAPY9(6)pp. L62-L63
R Sharma, S Tigas, M Rauchhaus, PP Poole-Wilson, AJ Coats, M Umpleby, PV Carroll, SD Anker (2005)Substrate metabolism in patients with chronic heart failure with and without cachexia, In: CIRCULATION112(17)pp. U660-U660
D Elleri, J Harris, K Kumareswaran, JM Allen, A Haidar, M Nodale, A Swamy, ME Wilinska, J Weston, CL Acerini, N Jackson, AM Umpleby, ML Evans, DB Dunger, R Hovorka (2010)Glucose appearance of large slowly-absorbed evening meal containing complex carbohydrates (CHO) in type 1 diabetes (T1D), In: DIABETOLOGIA53
X Li, M Stolinski, NC Jackson, MA Umpleby (2010)A NOVEL METHOD FOR THE MEASUREMENT OF PRE beta HDL AND alpha HDL KINETICS WITH STABLE ISOTOPIC LABELLING TECHNIQUES, In: ATHEROSCLEROSIS SUPPLEMENTS11(2)pp. 7-7
AM Umpleby, S Das, M Stolinski, F Shojaee-Moradie, NC Jackson, W Jefferson, N Crabtree, P Nightingale, M Shahmanesh (2005)Low density lipoprotein apolipoprotein B metabolism in treatment-naive HIV patients and patients on antiretroviral therapy., In: Antivir Ther10(5)pp. 663-670

BACKGROUND: Dyslipidaemia and lipodystrophy have been described in treated HIV patients and in a small percentage of untreated HIV patients. Lipodystrophy in these patients has been shown to be associated with a lower expression of low density lipoprotein (LDL) receptors. METHODS: We have investigated the effect of antiretroviral treatment with either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) on body fat distribution and LDL apolipoprotein B (apoB) kinetics in 12 HIV-negative controls and 52 HIV-infected patients, including antiretroviral treatment-naive (TN) patients (n=13) and patients taking two nucleoside analogues plus either a PI (n=15) or an NNRTI (n=24). RESULTS: LDL cholesterol was not different between groups. Compared with the controls, LDL apoB absolute synthetic rate (ASR) and fractional catabolic rate (FCR) were lower and residence time (RT) was higher in the PI and NNRTI groups (P

F Shojaee-Moradie, DJ Cuthbertson, GJ Kemp, M Barrett, NC Jackson, J Batt, RA Herring, J Wright, D Russell-Jones, EL Thomas, J Bell, AM Umpleby (2015)EXERCISE TRAINING ALTERS VLDL TG AND APOB METABOLISM IN MEN WITH NON-ALCOHOLIC LIVER DISEASE (NAFLD), In: ATHEROSCLEROSIS241(1)pp. E103-E103
E Potocka, R Hovorka, RA Baughman, M Umpleby, MLM Diaz, R Chen, AH Boss, PC Richardson (2009)AFRESA (TM) Suppresses Endogenous Glucose Production Earlier Than a Rapid-Acting Analog (Lispro) and Inhaled Exubera (R), In: DIABETES58pp. A61-A61
FJ Smeeton, E Shojaee-Moradie, N Jackson, RH Jones, AM Umpleby, D Russell-Jones (2007)Is insulin detemir hepatoselective when compared to NPH insulin using stable isotope methodology at plasma glucose concentrations of less than 4 mmol/l?, In: DIABETOLOGIA50pp. S24-S25
H Thabit, K Kumareswaran, A Haidar, L Leelarathna, K Caldwell, M Nodale, ME Wilinska, AM Umpleby, ML Evans, R Hovorka (2014)ALTERATION IN GLUCOSE DYNAMICS FOLLOWING WITHDRAWAL OF USUAL THERAPY AND CLOSED-LOOP INSULIN DELIVERY IN INSULIN-NAIVE TYPE 2 DIABETES SUBJECTS, In: DIABETES TECHNOLOGY & THERAPEUTICS16pp. A24-A24