Professor David Russell-Jones

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.

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.

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.

To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes.

To assess whether the introduction of a management of raised glucose clinical decision tool could improve assessment of patients with hyperglycaemia by non-specialist physicians, leading to early discharge and improved quality of inpatient care.

Liraglutide is a new glucagon-like peptide-1 (GLP-1) receptor agonist and a true GLP-1 analogue. After successful phase 2 studies, liraglutide was assessed in a series of phase 3 trials [(Liraglutide Effect and Action in Diabetes (LEAD)] designed to demonstrate efficacy and safety across the continuum of type 2 diabetes antihyperglycaemic care, both as monotherapy and in combination with commonly used oral antidiabetic drugs (OADs). The LEAD programme also compared liraglutide with other OADs. As a monotherapy, liraglutide demonstrated significant improvements in glycaemic control in comparison with glimepiride. When combined with one or two OADs, reductions in haemoglobin A1c, fasting plasma glucose and postprandial glucose were generally greater with liraglutide than with comparators. Throughout the trials, liraglutide was associated with weight reduction; in most instances, the reduction from baseline was significantly greater than that seen with comparators. Improvements in assessments of beta-cell function were consistently shown with liraglutide treatment across all trials. Furthermore, reductions in systolic blood pressure were reported. Liraglutide was associated with a low risk of hypoglycaemia and was generally well tolerated. The majority of adverse effects were gastrointestinal, the most frequent of which was nausea.

Type 2 diabetes (T2D) has been linked with increased intestinal permeability, but the clinical significance of this phenomenon is unknown. The objective of this study was to investigate the potential link between glucose control, intestinal permeability, diet and intestinal microbiota in patients with T2D. Thirty-two males with well-controlled T2D and 30 age-matched male controls without diabetes were enrolled in a case-control study. Metabolic parameters, inflammatory markers, endotoxaemia and intestinal microbiota in individuals subdivided into high (HP) and normal (LP) colonic permeability groups, were the main outcomes. In T2D, the HP group had significantly higher fasting glucose (P = 40 0.034) and plasma non-esterified fatty acid levels (P = 0.05) compared with the LP group. Increased colonic permeability was also linked with altered abundances of selected microbial taxa. The microbiota of both T2D and control HP groups was enriched with Enterobacteriales. In conclusion, high intestinal permeability was associated with poorer fasting glucose control in T2D patients and changes in some microbial taxa in both T2D patients and non-diabetic controls. Therefore, enrichment in the gram- negative order Enterobacteriales may characterise impaired colonic permeability prior to/independently from a disruption in glucose tolerance.

Incretin-based therapies represent a new and innovative treatment modality in the management of Type 2 diabetes. Their therapeutic actions address many of the key metabolic defects in the pathophysiology of diabetes. Incretin hormones augment insulin secretion in a glucose-dependent manner. They have a low risk of inducing hypoglycemia, unlike many other antidiabetic medications. They also have the beneficial effect of being associated with early satiety, decreased caloric intake and weight loss. Exenatide was the first incretin-based therapy to be licensed for use and has now been developed in a once-weekly preparation. We review the evidence base for the use of exenatide and discuss the implications for the management of diabetes. © 2012 Expert Reviews Ltd.

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.

People with diabetes, particularly those with type 2 diabetes, may be at an increased risk of cancer. Furthermore, their cancer risk may be modified by treatment choices. In this respect, metformin may be protective, whereas insulin and insulin analogues can function as growth factors and therefore have theoretical potential to promote tumour proliferation. Analogues causing inappropriate prolonged stimulation of the insulin receptor, or excess stimulation of the IGF-1 receptor, are the most likely to show mitogenic properties in laboratory studies. Some recent epidemiological studies appear to be consistent with these experimental findings, suggesting that there could be different relative risks for cancer associated with different insulins, although these studies have attracted some methodological criticism. However, it is biologically plausible that hormonal factors that influence neoplasia could begin to manifest their effects in surprisingly short timescales (within 2 years) and hence these epidemiological studies justify further research. Even if future research were to document an increase in cancer risk among insulin users, this would be unlikely to significantly diminish the favourable benefit-risk ratio for patients requiring insulin therapy. There is a need for further population studies and for the development of new laboratory models that are more sophisticated than previous experimental methods employed to assess potential tumour growth-promoting properties of insulins.

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.

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

The global burden of type 2 diabetes is growing. Traditional therapies are suboptimal and there is a clear unmet need for treatments that offer effective glucose control while addressing the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease, without the fear of hypoglycaemia. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors offer a novel way of reducing hyperglycaemia by targeting the incretin system. This review provides an overview of the development of incretin-based therapies and explains their differing modes of action compared with traditional interventions. A comparison of the clinical profiles of current glucagon-like peptide-1 receptor agonists [liraglutide and exenatide (twice-daily and once-weekly)] and dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, vildagliptin and linagliptin) is performed alongside a discussion of the placement of incretin-based therapies in treatment guidelines. Further improvements in this class are expected, and we will examine some of the novel glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors currently under development.

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.

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.

Established therapies for type-2 diabetes effectively reduce blood glucose, but are often associated with adverse effects that pose risks to patient's health or diminish adherence to treatment. Weight gain, hypoglycaemia and gastrointestinal symptoms are commonly reported and some agents may not be safe for use in patients with renal impairment or elevated cardiovascular risk. New treatments based on the action of the endogenous human hormone glucagon-like peptide-1 (GLP-1), including exenatide and liraglutide, are available. These therapies provide a novel pharmacological approach to glycaemic control via multiple mechanisms of action, and accordingly exhibit different safety and tolerability profiles than conventional treatments. GLP-1 receptor agonists stimulate insulin release only in the presence of elevated blood glucose and are therefore associated with a fairly low risk of hypoglycaemia. Gastrointestinal symptoms are common but transient, and there appears to be little potential for interaction with other drugs. GLP-1 receptor agonists are associated with weight loss rather than weight gain. As protein-based therapies, these agents have the potential to induce antibody formation, but the impact on efficacy and safety is minor. GLP-1 receptor agonists thus offer a new and potentially useful option for clinicians concerned about some of the common adverse effects of type-2 diabetes therapies.

The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride.

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

This 81-year-old man with a history of type 2 diabetes presented with a cramping right arm, trismus, stiffness in the jaw, swallowing and breathing difficulties. He developed respiratory failure shortly after admission so was intubated on the intensive therapy unit where he received tetanus immunoglobulin and a course of metronidazole. Kilic et al. compared the level of tetanus antitoxin between patients with type 2 diabetes and healthy controls. They found a statistically significant difference between the groups, with people with diabetes having lower antitoxin levels. A further study shows that serum levels of tetanus antibody significantly decrease in diabetic patients older than 50 years of age. Among patients with diabetes only 55.9% had protective levels of antitoxin when aged 50-64 compared to 73.8% of controls. Copyright © 2010 John Wiley & Sons. Copyright © 2010 John Wiley & Sons, Ltd.

The 10g monofilament test is a simple method of detecting the presence of sensory neuropathy widely used by non-specialists; and included in pay-for-performance indicators for UK primary care. However, the association with increased mortality has not previously been explored. We performed a retrospective cohort analysis to determine if the presence of sensory neuropathy can be used as a predictor for increased risk of death. We used routinely recorded electronic data from 126 primary care centres across England, who participated in the Quality Improvement in Chronic Kidney Disease (QICKD) trial to follow a cohort of people with diabetes (N=35,502) over 30 months. The presence of sensory neuropathy was defined as present or absent based on routine 10g monofilament testing during 30 months prior to the observation period. The outcome measure was all-cause mortality. Known risk factors (age, gender, smoking status, co-morbidities, and HbA1c) were adjusted for using a multilevel logistic regression model. Monofilament testing was performed in 18,748 (52.2%) people during the baseline period. Abnormal sensation was identified in 1,548 (9.0%). Abnormal sensation was associated with an increased risk of mortality during the 30 month follow-up period: odds ratio 1.70 (95% confidence interval 1.41-2.06; p < 0.001). The association between mortality and sensory neuropathy was stronger than that with elevated HbA1c (OR 1.16; 95% CI 1.01-1.34; p = 0.037), and comparable to smoking, ischaemic heart disease, heart failure, and dyslipidaemia. Failure to monitor sensation using monofilament testing was also associated with an increased risk of mortality: OR 1.23 (95% CI 1.08-1.40; p = 0.002). The receiver operating characteristic (ROC) statistic for the model was 0.84. Sensory neuropathy is an important predictor of mortality in people with diabetes; and the monofilament test may have utility in primary care. People with abnormal sensation should be targeted for aggressive diabetes management.

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.

Study Type - Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Men with prostate cancer have higher rates of non-cancer mortality and CV morbidity and some of that excess risk has been attributed to the treatment they receive. ADT is an established treatment option for men with locally-advanced and metastatic prostate cancer and, although it has been shown to confer a disease-free survival advantage, it has also been associated with an increased incidence of CV disease and the metabolic syndrome (characterized by a cluster of CV risk factors, including insulin resistance). The benefits of the insulin sensitizer metformin and lifestyle intervention for reducing the incidence of metabolic syndrome have been shown in patients with impaired glucose tolerance. At the time of writing, the present study is the first to use metformin and lifestyle intervention in men with prostate cancer with the aim of reducing the risk of developing ADT-related CV morbidity and the metabolic syndrome. The study shows that lifestyle changes and metformin may indeed reduce the complications of androgen suppression in these men. Although further investigations are needed to establish which of the two interventions may be most beneficial, the favourable effects of a combination of these interventions on patients' quality of life and the potential for improved overall survival are of clinical significance.