Professor David Russell-Jones

Aims/hypothesis Glycaemic control and clinical outcomes in diabetes are improved by continuous subcutaneous insulin infusion (CSII). Atmospheric pressure changes during flights may affect insulin delivery from pumps and cause unintended metabolic consequences, including hypoglycaemia, in people with type 1 diabetes. The present report evaluates both hypobaric flight simulation and real-world data in pilots using insulin pumps while flying. Methods In the flight simulation part of this study, an in vitro study of insulin pumps was conducted in a hypobaric chamber, de-pressurised to 550 mmHg to mimic the atmospheric pressure changes in airliner cabins during commercial flights. Insulin delivery rates and bubble formation were recorded for standard flight protocol. Insulin infusion sets, without pumps, were tested in a simulated rapid decompression scenario. The real-world observational study was a 7.5-year retrospective cohort study in which pre- and in-flight self-monitored blood glucose (SMBG) values were monitored in pilots with insulin-treated diabetes. Commercial and private pilots granted a medical certificate to fly within the European Union Aviation Safety Agency approved protocol and receiving insulin either by pump or multiple daily injections (MDI) were included. Results In the flight simulation study, full cartridges over-delivered 0.60 U of insulin during a 20 min ascent and under-delivered by 0.51 U during descent compared with ground-level performance. During emergency rapid decompression, 5.6 U of excess insulin was delivered. In the real-world study, seven pilots using CSII recorded 4656 SMBG values during 2345 h of flying across 1081 flights. Only 33 (0.7%) values were outside an acceptable safe range (5.0–15.0 mmol/l [90–270 mg/dl]). No clinically significant fall in the median SMBG concentration was observed after aircraft ascent and no in-flight SMBG values were within the hypoglycaemic range (

Two populations of Fijian Melanesians over 40 years of age were compared. The first population was located in a remote rural area and the other in an urban environment. There was no significant difference between the two populations in age, height and diastolic blood pressure. Highly significant differences were observed in mean weight, body mass index, prevalence of impaired glucose tolerance, prevalence of diabetes, mean glycosolated haemoglobin, mean systolic blood pressure, fasting cholesterol, immunological albumin, immunological transferrin, and Al and B apolipoproteins. The higher value was associated with urban living. Thus urban living is associated with obesity, impaired glucose tolerance, diabetes, higher systolic blood pressure, higher levels of fasting lipids and increased risk factors for cardiovascular disease.

A blind painful eye may harbor an unsuspected malignant melanoma. We report a cause of ocular melanoma that presented with confusion owing to direct extension via the optic nerve into the anterior cranial fossa.

Aim To summarise, in a narrative review, published data on hypoglycaemia occurrence with basal insulin therapy in adults with type 1 diabetes treated with basal‐bolus insulin regimens in treat‐to‐target randomised controlled trials. Methods Data were included from 21 eligible trials, which mainly used self‐measured blood glucose or plasma glucose to detect hypoglycaemia. Results All‐day self‐measured blood glucose or plasma glucose level 2 (glucose threshold of 3.1 or 3.0 mmol/L) and level 3 (severe, requiring assistance) hypoglycaemic events were reported, respectively, by a range of 69.0%–97.5% and 0%–13.4% adults when receiving basal‐bolus insulin therapy, with rates of 10.6–68.1 and 0.0–0.4 events per patient‐year of exposure, respectively. Hypoglycaemia rates measured using continuous glucose monitoring (three studies) were numerically, yet consistently, higher than with either other method, except when limiting to symptomatic events. Nocturnal hypoglycaemia rates were generally less than 30% of the equivalent all‐day rates. Conclusions Differences across the studies in design (e.g., titration targets) and participant characteristics hindered comparison of hypoglycaemia rates by insulin formulation. Consequently, few trends were identified by insulin formulation, study methodology or individuals' characteristics, suggesting that further research is required to identify treatment strategies that facilitate development of individualised recommendations to lower hypoglycaemia risk. These findings are useful to understand hypoglycaemia risk with available basal insulin therapies when used in a multiple daily injection regimen, as well as to provide context for the results of ongoing and future clinical trials, including those for two once‐weekly basal insulins, insulin icodec and basal insulin Fc.

Aim/hypothesis Pilots with type 1 diabetes are required to perform capillary glucose monitoring regularly during flights. Continuous glucose monitoring (CGM) may be an effective and more practical alternative. This study aimed to assess the accuracy of CGM systems against self-monitoring of blood glucose (SMBG) during a hypobaric flight simulation. Methods Twelve insulin pump users with type 1 diabetes were studied using two simulation protocols. Protocol A consisted of a ground phase, ascent, a 190 min cruise with ingestion of a liquid meal, descent and then ground. Protocol B consisted of a ground phase, ascent, a 60 min cruise while fasting, descent, a 20 min ground phase, ascent, a second flight of 120 min with ingestion of a meal, followed by descent and ground. Insulin was administered with or before the meal according to the participants’ carbohydrate-counting regimen during both protocols. In Protocol A, capillary, interstitial and plasma glucose were measured during flight and at ground, while in Protocol B, glucose and oxygen were measured. Measurements from three CGM brands and two SMBG devices were recorded during the flight simulations. Findings at cabin pressures during flight (550 mmHg) and ground (750 mmHg) were compared. Fasted and postprandial glucose measurements were analysed using Spearman’s correlations and mean absolute relative differences (MARDs). Results Eleven men and one woman (n=6 men in Protocol A; n=5 men and n=1 woman in Protocol B) were studied. A total of 1533 data points were recorded. During flight vs ground level, Spearman’s correlations for CGM system- and SMBG-derived glucose values were very strong in both Protocol A (r=0.96 during flight vs r=0.94 at ground) and Protocol B (r=0.85 during flight vs r=0.69 at ground). The differences in aggregated CGM MARDs during flight vs ground level were minimal across Protocol A (11.85%; 95% CI [9.78, 13.92] vs 9.08%; 95% CI [7.02, 11.14]) and Protocol B (12.01%; 95% CI [3.34, 20.69] vs 12.97%; 95% CI [4.30, 21.65]). Conclusions/interpretation The performance of CGM systems and SMBG are comparable during flight-associated atmospheric pressure changes. All tested measurement devices for CGM and SMBG were suitable for diabetes-care-based decisions during flight simulation.

INTRODUCTION: With the increasing use of aeromedical transport for critically ill patients, it is essential to understand the impact of pressure changes on drug infusion delivery systems. As airplanes ascend and descend, gases/bubbles are released from solutions when ambient pressure decreases and dissolves when pressure increases. This may affect mechanical fluid delivery systems and cause clinically significant changes, especially within a critical care setting. We aimed to evaluate the impact of pressure changes on volumetric pumps and syringe drivers. METHODS: An in vitro study of six volumetric pumps and eight syringe drivers was conducted in a hypobaric chamber to mimic pressure changes during flights. Infusion devices were set to deliver water at 0.2 ml ⋅ h−1 and infused volumes were measured. There were 15 open-ended syringes also studied. RESULTS: During ascent, syringe drivers and volumetric pumps over-delivered 173 µL and 38 µL of fluid. During descent, syringe drivers under-delivered by 166 µL, whereas volumetric pumps under-delivered by 9 µL. Syringe drivers experienced statistically significant changes in fluid delivery during both ascent and descent. In volumetric pumps, only the descent phase infusion differed significantly from other phases. The volume of fluid expansion is dependent on volume and the mechanical properties of the fluid. DISCUSSION: Decreasing ambient pressure causes bubble formation, which displaces fluid, and increasing ambient pressure causes bubble reabsorption in mechanical infusion devices. Hence, atmospheric pressure changes during air travel may alter fluid delivery from medical fluid delivery systems and affect critically ill patients who require both aeromedical evacuation and accurate infusion of drugs.

In common with global trends, the number of individuals with type 2 diabetes in the UK is rising, driven largely by obesity. The increasing prevalence of younger individuals with type 2 diabetes is of particular concern because of the accelerated course of diabetes‐related complications that is observed in this population. The importance of good glycaemic control in the prevention of microvascular complications of diabetes is widely accepted, and there is a growing body of evidence to support a benefit in the reduction of cardiovascular events in the long term. Despite the importance of maintaining a healthy weight for the prevention of type 2 diabetes, the results from trials of lifestyle intervention strategies to reduce body weight have been disappointing. New glucose‐lowering agents offer some promise in this regard, offering an opportunity to combat the dual burden of hyperglycaemia and obesity simultaneously. The timing and appropriate choice of glucose‐lowering therapy has never been more complex as a result of rising prevalence of obesity in the young, concomitant obesity in some 90% of adults with type 2 diabetes and an ever‐increasing range of therapeutic options. The present review evaluates performance measures specific to weight and glycaemic control in type 2 diabetes in the UK using data from the Q uality and O utcomes F ramework in E ngland and W ales, and the S cottish D iabetes S urvey. Potential barriers to improvement in standards of care for people with type 2 diabetes are considered, including patient factors, clinical inertia and the difficulties in translating therapeutic guidelines into everyday clinical practice.

The diabetogenic action of pituitary extracts containing growth hormone has been recognised for more than 60 years and the importance of growth hormone in the development and progression of diabetic retinopathy for more than 30 years. Hypophysectomy was the first effective treatment for retinopathy but was discontinued because of the risk of severe hypoglycaemia that it produced and the development of an alternative, less dangerous therapy - photocoagulation. The precise role and significance of growth hormone in diabetes care, however, remains to this day a mystery. The fact that modem, highly purified biosynthetic preparations of growth hormone still retain full diabetogenic potency and the fact that diabetes develops in up to 25% of patients with acromegaly indicate growth hormone's potential for involvement in the aetiology of diabetes mellitus, although most will agree that this is not likely to be an important factor in the large majority of 'idiopathic' cases. There is strong evidence to indicate a substantial hypersecretion of growth hormone in 'idiopathic' diabetes mellitus (particularly insulin-dependent cases and those with retinopathy), which appears to be more related to residual pancreatic insulin secretion than to metabolic control. Since the advent of biosynthetic growth hormone in sufficient quantity to perform trials in adults, we are more aware of growth hormone's considerable potency in the regulation of body composition, growth factor production and intermediary metabolism. In this article, we review the literature and, from this and our own work, propose a new hypothesis which links the hypersecretion of growth hormone to reduced hepatic secretion of insulin-like growth-factor I (IGF-1) as a direct result of reduced portal insulin levels in diabetes mellitus. The hypersecretion of growth hormone exposes peripheral organs such as the retina and kidney to conditions favouring the expression of growth-hormone-dependent growth factors such as IGF-I which may contribute to the development of diabetic microvascular disease by autocrine and/or paracrine effects. If this hypothesis proves to be true, it offers new opportunities for the prevention of diabetic microvascular complications through suppression of growth hormone secretion which in turn will increase insulin sensitivity and facilitate good glycaemic control.

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 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.

There is evidence that the hormonal control of hepatic IGF-I production is mediated by GH and insulin. To elucidate the role of these hormones further we administered s.c. or i.p. insulin (at 2.5 and 5.0 IU/day) and/or GH (0.8 IU/day) to rats made diabetic with streptozotocin 16 days previously. Hepatic IGF-I production was then assessed by quantifying hepatic IGF-I mRNA levels by autoradiography of Northern blots. Diabetes resulted in a fivefold reduction in hepatic IGF-I mRNA levels (optical density (OD) of the 0.7-1.1 kb band: controls, 1.3 +/- 0.09; diabetics, 0.28 +/- 0.08; P < 0.01), which was not significantly changed by treatment with s.c. insulin (OD: low dose, 0.55 +/- 0.05; high dose, 0.58 +/- 0.05) or low dose i.p. insulin (OD: 0.40 +/- 0.03). High dose i.p. insulin enhanced hepatic IGF-I mRNA levels (OD: 0.93 +/- 0.23) compared with diabetic rats (P < 0.01) and those given high dose s.c. insulin (P < 0.04), despite the blood glucose values being similar in the treated groups (i.p., 4.72 +/- 0.29 mmol/l; s.c., 3.32 +/- 0.03 mmol/l). Administration of GH alone partially restored the hepatic IGF-I mRNA level (OD: GH-treated, 1.00 +/- 0.05; diabetic, 0.28 +/- 0.08; P < 0.01), whilst having no effect on blood glucose values (diabetic, 36.35 +/- 0.45 mmol/l; GH-treated, 38.65 +/- 2.39 mmol/l). Additional administration of s.c. insulin completely restored IGF-I mRNA levels to those of controls (OD: low dose, 1.35 +/- 0.14; high dose, 1.27 +/- 0.18).

We report the case of a 7 year old girl who developed central hypoventilation following pertussis and who was treated by negative pressure ventilation using a new portable tank respirator. We believe this is the first reported case of central hypoventilation following pertussis successfully treated by intermittent negative pressure ventilation.

The purpose of this trial was to compare the effects of QD basal insulin replacement using insulin detemir versus neutral protamine Hagedorn (NPH) insulin in basal-bolus therapy in combination with regular human insulin (HI) in patients with type 1 diabetes mellitus (DM). This was a 6-month, prospective, randomized, open-label, controlled, parallel-group trial conducted at 92 sites in Europe and Australia. The trial population included men and women with type 1 DM for at least 1 year aged > or = 18 years with glycosylated hemoglobin (HbA(1c))

To compare the efficacy and safety of self- versus physician-managed titration of insulin glargine 300 U/mL (Gla-300) in people with inadequately controlled type 2 diabetes. Take Control (EudraCT number: 2015-001626-42) was a 24-week, multi-national, open-label, controlled, two-arm, parallel-group study in insulin-naïve and pre-treated participants, randomized 1:1 to a self- or physician-managed titration of Gla-300. The fasting self-monitored plasma glucose (SMPG) target was 4.4 to 7.2 mmol/L. The primary outcome was non-inferiority of glycated haemoglobin (HbA1c) change from baseline to week 24. Secondary outcomes included SMPG target achievement without hypoglycaemia, hypoglycaemia incidence, adverse events and participant-reported outcomes (PROs). At week 24, the least squares (LS) mean HbA1c reduction was 0.97% (10.6 mmol/mol) and 0.84% (9.2 mmol/mol) in the self- and physician-managed groups, respectively, with an LS mean difference of -0.13% [95% confidence interval -0.2619 to -0.0004] (-1.4 mmol/mol [-2.863 to -0.004]), demonstrating non-inferiority (P 

The anabolic actions of GH in GH-deficient adults and children are well documented. Replacement with GH in such individuals promotes protein synthesis and reduces irreversible loss of protein through oxidation. Although GH is known to be self-administered by athletes, its protein metabolic effects in this context are unknown. This study was designed to determine whether 4 wk of high dose recombinant human GH (r-hGH) administration altered whole body leucine kinetics in endurance-trained athletes at rest and during and after 30 min of exercise at 60% of maximal oxygen uptake. Eleven endurance-trained male athletes were studied, six randomized to receive r-hGH (0.067 mg/kg·d), and five to receive placebo. Whole body leucine turnover was measured at rest and during and after exercise, using a 5-h primed constant infusion of 1-[13C]leucine, from which rates of leucine appearance (an index of protein breakdown), leucine oxidation, and nonoxidative leucine disposal (an index of protein synthesis) were estimated. Under resting conditions, r-hGH administration increased rate of leucine appearance and nonoxidative leucine disposal, and reduced leucine oxidation (P < 0.01). This effect was apparent after 1 wk, and was accentuated after 4 wk, of r-hGH administration (P < 0.05). During and after exercise, GH attenuated the exercise-induced increase in leucine oxidation (P < 0.05). There were no changes observed in placebo-treated subjects compared with the baseline study. We conclude that GH administration to endurance-trained male athletes has a net anabolic effect on whole body protein metabolism at rest and during and after exercise.

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.

Background Results of an exploratory phase 2 study showed that insulin degludec, a basal insulin with an action profile of longer than 42 h, provided similar glycaemic control when injected three times a week (IDeg 3TW) to once-daily insulin glargine (IGlar OD). To provide further evidence, we did two phase 3 trials to compare the efficacy and safety of IDeg 3TW with IGlar OD in insulin-naive patients with type 2 diabetes. Methods In two 26 week, randomised, open-label, parallel group, non-inferiority trials IDeg was injected Monday, Wednesday, and Friday before breakfast (IDeg 3TW(AM)) in the AM trial (94 sites in seven countries) or with the evening meal (IDeg 3TW(PM)) in the PM trial (89 sites in seven countries), and compared with IGlar OD. Adults with type 2 diabetes (HbA(1c) 7.0-10.0%; body-mass index

GH is an important regulator of fat metabolism at rest, but it is not known whether it regulates fat metabolism during exercise. To determine whether physiologic concentrations of GH influence fat metabolism during exercise, we randomized 16 GH-deficient adults, receiving long-term (mean duration, 5 yr) GH replacement, to either continue GH (n = 8) or receive identical placebo (n = 8) for a 3-month period. Metabolic studies, at rest, during and following exhaustive exercise were carried out at baseline and at the end of the 3 months. The rate of appearance of glycerol (glycerol Ra, an index of lipolysis) and free fatty acids (FFA, FFA Ra) and the rate of disappearance of FFA (FFA Rd) in the plasma were measured using infusions of 2H5-glycerol and 1-13C-palmitic acid. Changes in body composition were assessed using dual-energy x-ray absorptiometry scanning and anthropometric measurements. In the baseline studies, exercise resulted in an increase in plasma glycerol and FFA concentrations, glycerol Ra, FFA Ra, and FFA Rd (P < 0.001). Three months of GH withdrawal resulted in reductions in plasma glycerol and FFA, glycerol Ra, FFA Ra, and FFA Rd at rest (P < 0.05 vs. baseline) and during exercise (P < 0.05 vs. baseline and vs. GH treated). Lean body mass decreased after 3 months of GH withdrawal, but total body fat, trunk fat, waist circumference, and the sum of skinfold thicknesses increased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). Fasting insulin and homeostasis model assessment of insulin resistance decreased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). In summary, GH withdrawal for 3 months resulted in reductions in release of glycerol and FFA into the circulation and uptake of FFA into the tissues during intense exercise. These changes were accompanied by reduced lean body mass and increased total body and trunk fat. Further studies are required to determine whether reduced mobilization of fat during exercise contributes to reduced exercise capacity and increased body fat in GH-deficient adults.

This multicenter, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus conventional insulin aspart (IAsp) in adults with type 1 diabetes. The primary end point was change from baseline in HbA after 26 weeks. After an 8-week run-in, subjects were randomized (1:1:1) to double-blind mealtime faster aspart ( = 381), IAsp ( = 380), or open-label postmeal faster aspart ( = 382)-each with insulin detemir. HbA was reduced in both treatment groups, and noninferiority to IAsp was confirmed for both mealtime and postmeal faster aspart (estimated treatment difference [ETD] faster aspart-IAsp, mealtime, -0.15% [95% CI -0.23; -0.07], and postmeal, 0.04% [-0.04; 0.12]); mealtime faster aspart statistically significantly reduced HbA versus IAsp ( = 0.0003). Postprandial plasma glucose (PPG) increments were statistically significantly lower with mealtime faster aspart at 1 h (ETD -1.18 mmol/L [95% CI -1.65; -0.71], -21.21 mg/dL [-29.65; -12.77];< 0.0001) and 2 h (-0.67 mmol/L [-1.29; -0.04], -12.01 mg/dL [-23.33; -0.70]; = 0.0375) after the meal test; superiority to IAsp for the 2-h PPG increment was confirmed. The overall rate of severe or blood glucose-confirmed (plasma glucose

To assess the impact of faster aspart vs insulin aspart on long-term clinical outcomes and costs for patients with type 1 diabetes mellitus (T1DM) in the UK setting. The QuintilesIMS CORE Diabetes Model was used to project clinical outcomes and costs over patient lifetimes in a cohort with data on baseline characteristics from the "onset 1" trial. Treatment effects were taken from the 26-week main phase of the onset 1 trial, with costs and utilities based on literature review. Future costs and clinical benefits were discounted at 3.5% annually. Projections indicated that faster aspart was associated with improved discounted quality-adjusted life expectancy (by 0.13 quality-adjusted life-years) vs insulin aspart. Improved clinical outcomes resulted from fewer diabetes-related complications and a delayed time to their onset with faster aspart. Faster aspart was found to be associated with reduced costs vs insulin aspart (cost savings of £1715), resulting from diabetes-related complications avoided and reduced treatment costs. Faster aspart was associated with improved clinical outcomes and cost savings vs insulin aspart for patients with T1DM in the UK setting.

Poor glycaemic control in type 2 diabetes (T2D) is a global problem despite the availability of numerous glucose‐lowering therapies and clear guidelines for T2D management. Tackling clinical or therapeutic inertia, where the person with diabetes and/or their healthcare providers do not intensify treatment regimens despite this being appropriate, is key to improving patients’ long‐term outcomes. This gap between best practice and current level of care is most pronounced when considering insulin regimens, with studies showing that insulin initiation/intensification is frequently and inappropriately delayed for several years. Patient‐ and physician‐related factors both contribute to this resistance at the stages of insulin initiation, titration and intensification, impeding achievement of optimal glycaemic control. The present review evaluates the evidence and reasons for this delay, together with available methods for facilitation of insulin initiation or intensification.

The prevalence of type 2 diabetes in the UK has increased enormously over recent years and is closely associated with obesity and other risk factors for cardiovascular disease. The incretin system, which contributes significantly to the insulin response in healthy individuals, but is impaired in individuals with diabetes, offers a target for the development of agents that address many aspects of diabetes. These agents are broadly split into two categories — the glucagon-like polypeptide-1 (GLP-1) receptor agonists and the dipeptidyl peptidase-4 (DPP-4) inhibitors. The DPP-4 inhibitors sitagliptin and vildagliptin, along with the GLP-1 receptor agonists exenatide and liraglutide are currently approved for use and offer effective glycaemic control with a low risk of hypoglycaemia. GLP-1 receptor agonists may offer further benefits over both DPP-4 inhibitors and conventional therapies, such as reductions in body weight and blood pressure. Here we review the incretin system (with particular reference to GLP-1) and consider the development of these two classes of antidiabetic therapy, discussing the safety and efficacy of some of the latest available GLP-1 receptor agonists and DPP-4 inhibitors.

The aim of this review is to summarize the clinical efficacy, tolerability and safety data of insulin detemir, and compare its use with that of neutral protamine Hagedorn (NPH) insulin in randomized controlled trials in people with type 1 or type 2 diabetes. A literature search was conducted with PubMed using predefined search terms. Studies were included if they met the following criteria: randomized, controlled trial, comparison of insulin detemir with NPH insulin, non-hospitalized adults aged 18years with either type 1 or type 2 diabetes, and study duration of 12weeks. The following types of studies were excluded: non-randomized controlled trials, studies of mixed cohorts of patients with type 1 or type 2 diabetes that did not report results separately, pharmacokinetic/pharmacodynamic studies, reviews, pooled or meta-analyses or health-economic analyses. Fourteen publications met the inclusion criteria. Nine studies in people with type 1 diabetes and three studies in people with type 2 diabetes, using insulin detemir in a basal-bolus regimen were included. Two studies were in people with type 2 diabetes using insulin detemir with oral antidiabetes medicines. In 14 studies of people with type 1 or type 2 diabetes, insulin detemir treatment provided similar or better glycaemic control, lower within-subject variability, similar or lower frequency of hypoglycaemia and less weight gain when compared with NPH insulin.

Background: Serum sialic acid (TSA) has been shown to be a cardiovascular risk factor and an acute phase reactant, with elevated concentrations associated with increased cardiovascular mortality and to precede the onset of type 2 diabetes. Aim: The purpose of this present study was to test the hypothesis that serum TSA may be related to serum leptin concentrations in healthy individuals. Methods: Thirty Fijian individuals were studied (8 males and 22 females). They were urban Melanesians living in Raiwaga, a suburb of Suva in Fiji. Results: Serum TSA significantly correlated with subject body mass index (BMI, ρ 0.39, P

The importance of strict glycaemic control in reducing diabetes-related outcomes is well recognised. Yet, despite the range of available treatment options, clinical experience suggests that individuals with diabetes frequently fail to achieve good glucose control. Instead, patients often have poorly controlled, unpredictable blood glucose levels. In insulin-treated patients, one of the reasons for this may be the inherently variable action of exogenously injected insulin. For example, the currently available longer-lasting insulin preparations that aim to provide a continuous basal level of circulating insulin are associated with markedly variable action both between and within subjects. Unpredictable insulin action contributes to variable blood glucose control, which in addition to increasing the risk of hypoglycaemia has also been shown to be an independent risk factor for mortality. It is hoped that advances in longer-lasting insulin preparations will provide significant benefits to patients, improving control and reducing variability. A new, long-lasting analogue, insulin detemir, has been shown to be significantly less variable than other basal insulin preparations in pharmacological and clinical studies. The improved predictability in insulin response offered by insulin detemir may be associated with a number of clinical benefits including a reduction in hypoglycaemia and weight gain.

Insulin detemir is a soluble long-acting basal insulin analog designed to overcome the limitations of conventional basal insulin formulations. Accordingly, insulin detemir has been compared with NPH insulin with respect to glycemic control (HbA1c, prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration. People with type 1 diabetes (n = 408) were randomized in an open-label, parallel-group trial of 16-week treatment duration using either insulin detemir or NPH insulin. Insulin detemir was administered twice daily using two different regimens, either before breakfast and at bedtime (IDet(morn+bed)) or at a 12-h interval (IDet(12h)). NPH insulin was administered before breakfast and at bedtime. Mealtime insulin was given as the rapid-acting insulin analog insulin aspart. With both insulin detemir groups, clinic fasting plasma glucose was lower than with NPH insulin (IDet(12h) vs. NPH, -1.5 mmol/l [95% CI -2.51 to -0.48], P = 0.004; IDet(morn+bed) vs. NPH, -2.3 mmol/l (-3.32 to -1.29), P < 0.001), as was self-measured prebreakfast plasma glucose (P = 0.006 and P = 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P = 0.046; 32%, P = 0.002; respectively) compared with NPH insulin in the last 12 weeks of treatment, this being mainly attributable to a 53% reduction in nocturnal hypoglycemia in the IDet(morn+bed) group (P < 0.001). Although HbA1c for each insulin detemir group was not different from the NPH group, HbA1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference -0.18% [-0.34 to -0.02], P = 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P < 0.001). The NPH group gained weight during the study, but there was no change in weight in either of the insulin detemir groups (IDet(12h) vs. NPH, -0.8 kg [-1.44 to -0.24], P = 0.006; IDet(morn+bed) vs. NPH, -0.6 kg [-1.23 to -0.03], P = 0.040). Overall glycemic control with insulin detemir was improved compared with NPH insulin. The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person's needs.

Background: Acromegalic patients have slow colonic transit, increased rates of deoxycholic acid formation, and an increased prevalence of cholesterol gall stones, especially during long term octreotide treatment. However, the effects of this prolonged large bowel transit time on the numbers of faecal anaerobes and the activities of the enzyme systems which biotransform conjugated cholic acid into unconjugated deoxycholic acid (cholylglycine hydrolase and 7α-dehydroxylase) are unknown. Methods: Therefore, in 10 non-acromegalic controls, 11 acromegalic patients not treated with octreotide, and 11 acromegalics on long term (8–48 months) octreotide (100–200 μg three times daily subcutaneously), we measured large bowel transit time and, in freshly voided faeces, the activities of the two bile acid metabolising enzymes, and related the results to the proportion of deoxycholic acid in fasting serum. Moreover, in patients with acromegaly, we measured quantitative bacteriology in faeces. Results: Mean large bowel transit time in acromegalics not treated with octreotide (35 (SEM 6.5) hours) was 66% longer than that in non-acromegalic controls (21 (3.1) hours; NS) and became further prolonged during octreotide treatment (48 (6.6) hours; p

Abnormal lipid metabolism may be related to the increased cardiovascular risk in type 1 diabetes. Secretion and clearance rates of very low density lipoprotein (VLDL) apolipoprotein B100 (apoB) determine plasma lipid concentrations. Type 1 diabetes is characterized by increased growth hormone (GH) secretion and decreased insulin-like growth factor (IGF) I concentrations. High-dose IGF-I therapy improves the lipid profile in type 1 diabetes. This study examined the effect of low-dose (40 μg · kg −1 · day −1 ) IGF-I therapy on VLDL apoB metabolism, VLDL composition, and the GH-IGF-I axis during euglycemia in type 1 diabetes. Using a stable isotope technique, VLDL apoB kinetics were estimated before and after 1 wk of IGF-I therapy in 12 patients with type 1 diabetes in a double-blind, placebo-controlled trial. Fasting plasma triglyceride ( P < 0.03), VLDL-triglyceride concentrations ( P < 0.05), and the VLDL-triglyceride-to-VLDL apoB ratio ( P < 0.002) significantly decreased after IGF-I therapy, whereas VLDL apoB kinetics were not significantly affected by IGF-I therapy. IGF-I therapy resulted in a significant increase in IGF-I and a significant reduction in GH concentrations. The mean overnight insulin concentrations during euglycemia decreased by 25% after IGF-I therapy. These results indicate that low-dose IGF-I therapy restores the GH-IGF-I axis in type 1 diabetes. IGF-I therapy changes fasting triglyceride concentrations and VLDL composition probably because of an increase in insulin sensitivity.

In this post hoc analysis of the randomized controlled LixiLan-O trial in insulin-naive patients with type 2 diabetes mellitus (T2DM) not controlled with metformin, with or without a second oral antihyperglycaemic drug (OAD), the efficacy and safety of the fixed-ratio combination, iGlarLixi (insulin glargine 100 U [iGlar] and lixisenatide [Lixi]), compared to its individual components was assessed in two patient subgroups: group 1) baseline HbA1c ≥9% (n = 134); group 2) inadequate control (HbA1c ≥7.0% and ≤9.0%) despite administration of two OADs at screening (n = 725). Treatment with iGlarLixi resulted in significantly greater reduction in least squares mean HbA1c compared to treatment with iGlar or Lixi alone in both subgroups (group 1: 2.9%, 2.5%, 1.7% and group 2: 1.5%, 1.2%, 0.7%, respectively). Target HbA1c less than 7% was achieved in more than 70% of patients using iGlarLixi in both subgroups, while mitigating the weight gain observed with use of iGlar alone. Rates of hypoglycaemic events were low overall. These results suggest that treatment with iGlarLixi achieves superior glycaemic control compared to treatment with iGlar or Lixi alone in T2DM patients with HbA1c ≥9% or in those inadequately controlled with two OADs.

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/ΔTTR, where u is the infusion rate of (stable label) leucine tracer and ΔTTR 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/m 2 ] who received a primed (7.58 μmol/kg) constant intravenous infusion (7.58 μmol ⋅ kg −1 ⋅ h −1 ) ofl-[1- 13 C]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 μmol/l), TTR of leucine (9.0 ± 1.5%), and TTR of α-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 μmol ⋅ kg −1 ⋅ min −1 ; the rate of leucine appearance due to proteolysis was 1.93 ± 0.24 μmol ⋅ 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.

Adult growth hormone (GH) deficiency is associated with a lipid profile known to be related to atherosclerosis. GH replacement therapy improves the lipid profile with the exception of lipoprotein (a) concentrations, which tend to increase after GH therapy. Plasma lipid concentrations depend on its plasma carriers, the lipoproteins. Possible mechanisms involved in the dyslipidaemia of GH-deficient patients and the effects of GH replacement therapy are discussed with a special focus on hepatic lipoprotein metabolism.

Background Serum total sialic acid (TSA) has been shown to be a strong cardiovascular risk factor with increased concentrations being associated with increased mortality. Serum TSA is also elevated in patients with type 2 diabetes including those with micro- and macrovascular complications. We wished, therefore, to test the hypothesis that serum TSA may be abnormal in individuals with impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), in Fijian Melanesians. Method Twenty-one subjects with IGT (17 women and four men) were recruited along with 20 subjects with IFG (14 women and six men) and 22 normal subjects (12 women and 10 men). Serum TSA was 2.18 +/- 0.027 mmol/L, 2.19 +/- 0.033 mmol/L and 2.24 +/- 0.042 mmol/L in the three groups, respectively, which was not statistically different. Both systolic and diastolic blood pressure were, however, higher in the IGT group compared with the IFG and normal groups (P < 0.04). Conclusion Serum TSA is not elevated in Fijian Melanesians with IGT and IFG although it is reported to be elevated in type 2 diabetes mellitus in other populations. Further research is needed to establish why serum TSA is a potent independent cardiovascular risk factor and is elevated in type 2 diabetes mellitus in some populations.

Despite early evidence from studies performed soon after its discovery, the role of human growth hormone (GH) in metabolic processes during adulthood has, until recently, been largely ignored. The importance of GH in the regulation of body composition in the adult is clearly demonstrated by the abnormalities seen in "nature's experiments', i.e. acromegaly and GH deficiency. Body composition has been shown to change favourably following successful treatment of acromegaly. Formal replacement studies in adult GH-deficient patients, made possible by the recent advent of recombinant GH, have also shown dramatic changes in body composition, with increases in lean body mass and reductions in fat mass towards normality and associated improvements in physical performance. Thus, adult GH deficiency, like acromegaly, has become widely accepted as a distinct clinical entity warranting treatment.

GH replacement therapy has been shown to improve the dyslipidemic condition in a substantial proportion of patients with adult GH deficiency. The mechanisms are not yet fully elucidated. Low-density lipoprotein (LDL) apolipoprotein B100 (apoB) formation and catabolism are important determinants of plasma cholesterol concentrations. This study examined the effect of GH replacement therapy on LDL apoB metabolism using a stable isotope turnover technique. LDL apoB kinetics was determined in 13 adult patients with GH deficiency before and after 3 months GH/placebo treatment in a randomized, double-blind, placebo-controlled study. LDL apoB 13C-leucine enrichment was determined by isotope-ratio mass spectrometry. Plasma volume was assessed by standardized radionuclide dilution technique.GH replacement therapy significantly decreased LDL cholesterol, LDL apoB concentrations, and LDL apoB pool size compared with placebo. Compared with baseline, GH replacement therapy resulted in a significant increase in plasma volume and fractional catabolic rate, whereas LDL formation rate remained unchanged. LDL lipid content did not significantly change after GH and placebo.This study suggests that short-term GH replacement therapy decreases the LDL apoB pool by increasing removal of LDL particles without changing LDL composition or LDL apoB production rate. In addition, it is possible that the beneficial effects of GH on the cardiovascular system contribute to these findings.

There have been many advances in insulin with a realistic possibility of mimicking nature to improve insulin replacement, with a view to achieving improved metabolic control. Lessons can be learnt from the evolution of insulin, insulin development, and new advances in technology. This may lead to fewer side effects of therapy resulting in a lower risk of hypoglycaemia and less weight gain, which could in turn could reduce long-term complications for people with diabetes.

While all the hormones described have regulatory effects on the rates of protein synthesis and breakdown there is a complex interaction between them in this control process. Insulin, GH and IGF-I play a dominant role in the day-to-day regulation of protein metabolism. In humans insulin appears to act primarily to inhibit proteolysis while GH stimulates protein synthesis. In the post-absorptive state IGF-I has acute insulin-like effects on proteolysis but in the fed state, or when substrate is provided for protein synthesis in the form of an amino acid infusion, IGF-I has been shown to stimulate protein synthesis. Growth hormone and testosterone have an important role during growth but continue to be required to maintain body protein during adulthood. Thyroid hormones are also required for normal growth and development. The hormones glucagon, glucocorticoids and adrenaline are all increased in catabolic states and may work in concert to increase protein breakdown in muscle tissue and to increase amino acid uptake in liver for gluconeogenesis. While increased glucocorticoids result in reduced muscle mass the effects of glucagon may be predominantly in the liver resulting in increased uptake of amino acids. In contrast to the catabolic effect of adrenaline on glucose and lipid metabolism, studies to date suggest that adrenaline may have an anti-catabolic effect on protein metabolism. Despite this adrenaline increases the production of the gluconeogenic amino acid alanine by muscle and its uptake by the splanchnic bed. There is considerable interest in the use of anabolic hormones, either alone or in combination, in the treatment of catabolic states. GH combined with insulin has been shown to improve whole-body and skeletal muscle kinetics while GH combined with IGF-I has a greater positive effect on protein metabolism in catabolic states than either hormone alone. If catabolic states are to be treated successfully a greater understanding of the role of the catabolic hormones in these states and the possible treatment of these states with anabolic hormones is required.

With the introduction of insulin detemir (Levemir ® [Novo Nordisk A/S, Bagsvaerd, Denmark]), a long-acting basal insulin analog, it is an opportune moment to reevaluate the use of basal insulin therapy and consider current treatment strategies, including the use of insulin detemir. This review examines the need for effective treatment options for diabetes and the economic burden of this disease. The importance of achieving glycemic control targets and the role of basal insulin therapy are discussed. Finally, the use of insulin detemir is briefly reviewed with a look at its clinical pharmacology, its use in basal insulin therapy, and its cost-effectiveness.

AimsThe goal of this study was to compare the long-term safety and efficacy of the basal insulin analogue, insulin degludec with insulin glargine (both with insulin aspart) in Type1 diabetes, over a 2-year time period. MethodsThis open-label trial comprised a 1-year main trial and a 1-year extension. Patients were randomized to once-daily insulin degludec or insulin glargine and titrated to pre-breakfast plasma glucose values of 3.9-4.9mmol/l. ResultsThe rate of nocturnal confirmed hypoglycaemia was 25% lower with insulin degludec than with insulin glargine (P=0.02). Rates of confirmed hypoglycaemia, severe hypoglycaemia and adverse events, and reductions in glycated haemoglobin and fasting plasma glucose were similar between groups. Despite achieving similar glycaemic control, insulin degludec-treated patients used 12% less basal and 9% less total daily insulin than did insulin glargine-treated patients (P

Although diabetes is a heterogeneous condition, IGF-I has been shown to improve glycaemic control and reduce insulin requirements in both IDDM and NIDDM. In IDDM, the therapeutic rationale for IGF-I is as a replacement therapy "topping up" low circulating IGF-I levels. There is now convincing evidence that this is associated with a reduction in GH secretion resulting in an improvement in insulin sensitivity and glycaemic control. The mechanism may simply be reduced GH-secretion, but pre- and post-receptor effects on insulin sensitivity are also likely. It is not clear what effect IGF-I treatment has on IGF binding proteins, but with the restoration of a more normal GH/IGF-I axis they are likely to be restored to normal concentrations which may in turn have a direct effect on glucose metabolism. In NIDDM, the mechanism of action of IGF-I remains unclear. At high doses, IGF-I may mimic insulin, but at levels resulting in unacceptable "acromegalic" IGF-I levels and side-effects. The most exciting data concerning IGF-I is with a low dose where IGF-I improves insulin sensitivity by an unknown mechanism. This may be mediated via the IGF-I receptor, by cross-reactivity with the insulin receptor, or by activation of hybrid receptors. The exact mechanism and interaction remains to be elucidated. In severe insulin-resistant states, IGF-I-treatment appears to be effective, and may be the only realistic therapeutic measure in the near future, and warrants further investigation. Detailed genetic characterization of these syndromes following treatment with IGF-I may also help to characterize the mechanism of action of IGF-I and its interactions with the insulin receptor. Thus, IGF-I appears to have a future as a therapeutic agent in treating diabetes, but long-term studies addressing safety and short-term studies addressing mechanisms are essential. With only a few pharmaceutical companies having the capability to produce IGF-I for scientific and therapeutic investigation, it is important that short-term marketing strategy does not prevent the proper exploration of this exciting peptide hormone as a therapeutic agent for all types of diabetes.

AimsThe recent type 2 diabetes American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) position statement suggested insulin is the most effective glucose-lowering therapy, especially when glycated haemoglobin (HbA1c) is very high. However, randomized studies comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide once-weekly [OW; DURATION-3 (Diabetes therapy Utilization: Researching changes in A1c, weight, and other factors Through Intervention with exenatide ONce-Weekly)] and liraglutide once-daily [OD; LEAD-5 (Liraglutide Effect and Action in Diabetes)] with insulin glargine documented greater HbA1c reduction with GLP-1RAs, from baseline HbA1c approximate to 8.3% (67mmol/mol). This post hoc analysis of DURATION-3 and LEAD-5 examined changes in HbA1c, fasting glucose and weight with exenatide OW or liraglutide and glargine, by baseline HbA1c quartile. MethodsDescriptive statistics were provided for change in HbA1c, fasting glucose, weight, and insulin dose, and subjects (%) achieving HbA1c

Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 μg/kg and 20 μg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 pm to 8:00 am) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU · kg −1 · min −1 from 8 to 10 am and 1.5 mU · kg −1 · min −1 from 10 am to 12 noon) incorporating [6,6 2H 2]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean ± SEM) increased (40 μg/kg, 655 ± 90 ng/mL, P < .001; 20 μg/kg, 472 ± 67 ng/mL, P < .001; placebo, 258 ± 51 ng/mL). Dose-related reductions in insulin were observed during the period of steady-state euglycemia (1 am to 8 am) (40 μg/kg, 48 ± 5 pmol/L, P = .01; 20 μg/kg, 58 ± 8 pmol/L, P = .03; placebo, 72 ± 8 pmol/L). The mean overnight GH level (40 μg/kg, 9.1 ± 1.4 mU/L, P = .04; 20 μg/kg, 9.6 ± 2.0 mU/L, P = .12; placebo, 11.3 ± 1.7 mU/L) and GH pulse amplitude (40 μg/kg, 18.8 ± 2.9 mU/L, P = .04; 20 μg/kg, 17.0 ± 3.4 mU/L, P > .05; placebo, 23.0 ± 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or β-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 μg/kg ( P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH suppression, although a direct effect by rhIGF-I cannot be entirely discounted.

Aims: To compare, in a double-blind, randomized, multi-national study, 52- or 78-week treatment with basal insulin peglispro or insulin glargine, added to pre-study oral antihyperglycaemic medications, in insulin-naive adults with type 2 diabetes. Material and methods: The primary outcome was non-inferiority of peglispro to glargine with regard to glycated haemoglobin (HbA1c) reduction (margin = 0.4%). Six gated secondary objectives with statistical multiplicity adjustments focused on other measures of glycaemic control and safety. Liver fat content was measured using MRI, in a subset of patients. Results: Peglispro was non-inferior to glargine in HbA1c reduction [least-squares (LS) mean difference: -0.29%, 95% confidence interval (CI) -0.40, -0.19], and had a lower nocturnal hypoglycaemia rate [relative rate 0.74 (95% CI 0.60, 0.91); p=.005), more patients achieving HbA1c

The long term effects of GH replacement in adult GH-deficient (GHD) patients have not yet been clarified. We studied 21 GHD adults who originally took part in a randomized, double blind, placebo-controlled trial of GH treatment in 1987. After completion of that trial, 10 patients received continuous GH replacement for the subsequent 10 yr, whereas 11 did not. A group of 11 age- and sex-matched normal controls were also studied in 1987 and 1997. Lean body mass, as assessed by total body potassium measurement and computed tomography scanning of the dominant thigh, increased in the GH-treated group (P < 0.01 for both) only (P < 0.05 between groups for total body potassium). Low density lipoprotein cholesterol decreased in the GH-treated group (P < 0.05) only. Carotid intima media thickness was significantly greater (P < 0.05) in the untreated group than in the GH-treated group. Assessment of psychological well-being using the Nottingham Health Profile revealed improvement in overall score, energy levels, and emotional reaction in the GH-treated group compared with those in the untreated group (P < 0.02). In conclusion, GH treatment for 10 yr in GHD adults resulted in increased lean body and muscle mass, a less atherogenic lipid profile, reduced carotid intima media thickness, and improved psychological well-being.

Insulin therapy is often associated with adverse weight gain. This is attributable, at least in part, to changes in energy balance and insulin's anabolic effects. Adverse weight gain increases the risk of poor macrovascular outcomes in people with diabetes and should therefore be mitigated if possible. Clinical studies have shown that insulin detemir, a basal insulin analogue, exerts a unique weight-sparing effect compared with other basal insulins. To understand this property, several hypotheses have been proposed. These explore the interplay of efferent and afferent signals between the muscles, brain, liver, renal and adipose tissues in response to insulin detemir and comparator basal insulins. The following models have been proposed: insulin detemir may reduce food intake through direct or indirect effects on the central nervous system (CNS); it may have favourable actions on hepatic glucose metabolism through a selective effect on the liver, or it may influence fluid homeostasis through renal effects. Studies have consistently shown that insulin detemir reduces energy intake, and moreover, it is clear that this shift in energy balance is not a consequence of reduced hypoglycaemia. CNS effects may be mediated by direct action, by indirect stimulation by peripheral mediators and/or via a more physiological counter-regulatory response to insulin through restoration of the hepatic-peripheral insulin gradient. Although the precise mechanism remains unclear, it is likely that the weight-sparing effect of insulin detemir can be explained by a combination of mechanisms. The evidence for each hypothesis is considered in this review.

The aim of GH replacement therapy in GH-deficient adults is to optimize response with minimum incidence of adverse reactions, but optimal therapy regimens are still to be established. This two-arm parallel study examined effects of two GH dose algorithms in adults with GH deficiency of adult or childhood onset. Patients on low dose (LD; n = 302) received GH at 3 μg/kg per day for 3 months increasing to 6 μg/kg per day for 3 months, and those on conventional dose (CD; n = 293) started on 6 μg/kg per day for 3 months increasing to 12 μg/kg per day for 3 months. The proportion of patients completing therapy was greater for the LD group than the CD group for the first 3 months (93.0% vs. 88.1%; P = 0.037) and overall for the 6 months (90.7% vs. 84.0%; P = 0.013). Both dose groups showed significant increases in lean body mass and decreases in fat mass for all time points. Percent increase in lean body mass was less with LD than CD over the first 3 months (2.43 ± 4.33 vs. 3.58 ± 4.69%; P = 0.006) but not overall for the 6-month period (4.38% ± 5.34% vs. 5.21% ± 5.99%; P = 0.141). Percent decrease in fat mass was less with LD than CD for the first 3 months (−2.81% ± 7.81% vs. −5.53% ± 8.64%; P < 0.001) and overall for the 6-month period (−6.35% ± 9.42% vs. −9.45% ± 12.07%; P = 0.006). IGF-I sd score increased less with LD than CD for 0 to 3 and 0 to 6 months, although for IGF-binding protein-3 sd score, there was no significant difference between doses at any time. Arthralgia was the only adverse event that occurred significantly less frequently with LD than with CD. Calculated changes based on gender and onset indicated greater changes in males than females for body composition, but there was little difference in GH-related adverse events between males and females. The lower starting dose with dose titration appeared more favorable, but differences in response between genders and onset of GH deficiency need to be taken into account when setting an individual dose regimen.

IntroductionThe aim of this study was to investigate the association between baseline characteristics [HbA1c and body mass index (BMI)] and the effect of mealtime fast-acting insulin aspart (faster aspart) relative to insulin aspart (IAsp) or basal-only insulin therapy on several efficacy and safety outcomes in people with diabetes.MethodsPost hoc analysis of three randomised phase 3a trials in people with type 1 diabetes (T1D; onset 1) and type 2 diabetes (T2D; onset 2 and 3). Participants (N=1686) were stratified according to baseline BMI (

Background and aims: Basal insulin analogues have a reduced risk of hypoglycaemia compared with NPH insulin, but hypoglycaemia still remains a major impediment to achieving recommended fasting plasma glucose (FPG) targets in patients with diabetes. Insulin degludec (IDeg) is a new basal insulin that forms soluble multihexamers after subcutaneous injection resulting in an ultra-long duration of action and stable glucose-lowering effect. The aim of this analysis was to compare the effect of IDeg on FPG and nocturnal confirmed hypoglycaemia as compared to insulin glargine (IGlar). Methods and results: Data were included from seven phase 3a, randomised, open-label, treat-to-target clinical trials in which once-daily IDeg was compared with once-daily IGlar. Two trials included a total of 957 patients with type 1 diabetes (T1D) and five trials included a total of 3360 patients with type 2 diabetes (T2D); all trials were 26 or 52 weeks in duration. Confirmed hypoglycaemia was defined as plasma glucose

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- 13 C]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.

To compare the safety and efficacy of fast-acting insulin aspart (faster aspart) with conventional insulin aspart (IAsp) in adults with type 1 diabetes (T1D). onset 1 was a randomized, multicentre, treat-to-target, phase III, 52-week (initial 26 weeks + additional 26 weeks) trial conducted at 165 sites across 9 countries. Adults with T1D were randomly allocated to double-blind mealtime faster aspart or IAsp, each with once- or twice-daily insulin detemir. The primary endpoint, change in glycated haemoglobin (HbA1c) from baseline after the initial 26 weeks, has been reported previously. In the present paper, we report data from the full 52-week study period. Between August 2013 and June 2015, 381 participants were assigned to double-blind faster aspart and 380 participants to IAsp. After 52 weeks, estimated mean changes from baseline in HbA1c levels were -0.08% (faster aspart) and +0.01% (IAsp); estimated treatment difference significantly favoured faster aspart (-0.10% [95% confidence interval {CI} -0.19;-0.00]; P = .0424). Changes from baseline in 1-hour postprandial plasma glucose (PPG) increment (meal test; faster aspart -1.05 mmol/L; IAsp -0.14 mmol/L) also significantly favoured faster aspart (estimated treatment difference -0.91 mmol/L [95% CI -1.40;-0.43]; -16.48 mg/dL [95% CI -25.17;-7.80]; P = .0002). There was no difference in overall severe or blood glucose-confirmed hypoglycaemic episodes or treatment-emergent adverse events between treatments. At 52 weeks, overall glycaemic control had significantly improved with faster aspart vs IAsp, consistent with the 26-week study findings. Achieving an insulin profile closer to physiological insulin secretion with faster aspart translates into lower PPG and HbA1c levels compared with those achieved with IAsp in people with T1D.

Net protein loss and large decreases in plasma glutamine concentration are characteristics of critical illness. We have used [2- 15 N]glutamine and [1- 13 C]leucine to investigate whole body glutamine and leucine kinetics in a group of critically ill patients and matched healthy controls. Glutamine appearance rate (R a,Gln ) was similar in both groups. However, in the patients, the proportion of R a,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 R a,Gln suggest that the increase in proteolysis is insufficient to meet increased demand for glutamine in this severe catabolic state.

OBJECTIVES The object of the present study is to determine whether native (n) low-density lipoprotein (LDL) isolated from men with type II diabetes and abnormal endothelial function inhibits endothelium-dependent relaxation more than n-LDL isolated from nondiabetic control subjects. BACKGROUND Endothelium-dependent vasodilation is impaired in men with type II diabetes and this may result from qualitative rather than quantitative abnormalities of LDL. METHODS Forearm blood flow responses to brachial artery infusions of acetylcholine (endothelium-dependent vasodilator) and nitroprusside (endothelium-independent vasodilator) were measured in 10 men with uncomplicated type II diabetes and 10 nondiabetic men of similar age and with similar plasma concentrations of LDL cholesterol. Native LDL was isolated by discontinuous density gradient ultracentrifugation using EDTA to prevent oxidation. Preconstricted rabbit aortic ring bioassay was used to determine inhibitory properties of n-LDL on endothelium-dependent relaxation by measuring relaxation to acetylcholine (and nitroprusside) in the presence and absence of n-LDL. RESULTS Forearm blood flow responses to acetylcholine but not nitroprusside were significantly impaired (p < 0.01) in diabetic men compared with control subjects. Native LDL (10 and 100 μg protein/ml) from diabetic men inhibited relaxation to acetylcholine by 13.9 ± 4.8% and 61.9 ± 7.8% (mean inhibition for all doses ± SE), respectively, whereas n-LDL from control subjects inhibited relaxation by 7.3 ± 3.0% and 23.9 ± 5.7% (p < 0.01 for a difference between diabetic and control n-LDL). Relaxation to nitroprusside was not significantly inhibited by n-LDL. CONCLUSIONS A qualitative abnormality of LDL may account for endothelial dysfunction in men with type II diabetes.

Objective: This study investigated the efficacy and safety of insulin degludec (IDeg) once daily (OD), varying injection timing day to day in subjects with type 1 diabetes. Research Design and Methods: This 26-week, open-label, treat-to-target, noninferiority trial compared IDeg forced flexible (Forced-Flex) OD (given in a fixed schedule with a minimum 8 and maximum 40 hours between doses) with IDeg or insulin glargine (IGlar) given at the same time daily OD. In the 26-week extension, all IDeg subjects were transferred to a free-flexible (Free-Flex) regimen, which allowed any-time-of-day dosing, and compared with subjects continued on IGlar. Results: After 26 treatment weeks, mean glycosylated hemoglobin was reduced with IDeg Forced-Flex (-0.40%), IDeg (-0.41%), and IGlar (-0.58%). IDeg Forced-Flex noninferiority was achieved. Fasting plasma glucose reductions were similar with IDeg Forced-Flex and IGlar but greater with IDeg (-2.54 mmol/L) than IDeg Forced-Flex (-1.28 mmol/L) (P = .021). At week 52, IDeg Free-Flex subjects had similar glycosylated hemoglobin but greater fasting plasma glucose reductions than IGlar subjects (- 1.07 mmol/L) (P = .005). Confirmed hypoglycemia rates (plasma glucose

Background ONWARDS 6 compared the efficacy and safety of once-weekly subcutaneous insulin icodec (icodec) and once-daily insulin degludec (degludec) in adults with type 1 diabetes. Methods This 52-week (26-week main phase plus a 26-week safety extension), randomised, open-label, treat-to-target, phase 3a trial was done at 99 sites across 12 countries. Adults with type 1 diabetes (glycated haemoglobin [HbA1c]

A preliminary study compared the use of continuous glucose monitoring (CGM) with the use of self-monitored blood glucose (SMBG) by aircraft pilots with insulin-treated diabetes in the United Kingdom, Ireland, and Austria, certified to fly commercial aircraft within the European Aviation Safety Agency ARA.MED.330 protocol. SMBG and simultaneous interstitial glucose measurements using CGM (Dexcom G6 ) were recorded during pre- and in-flight periods. Eight male pilots (seven with type 1 diabetes and one with type 3c diabetes), median age of 48.5 years and median diabetes duration of 11.5 years, participated. The correlation coefficient ( ) between 874 contemporaneously recorded SMBG and CGM values was 0.843,  

The discovery of insulin 100 years ago ranks among the greatest medical achievements ever. This sparked a revolution of scientific discovery and therapeutic intervention to treat people suffering with diabetes. A light was shone for other areas of medicine to illuminate what was possible with detailed scientific endeavour. There followed a range of firsts leading to the current time in which we now know more about this peptide hormone than almost any other protein in existence. This has allowed therapeutic advancement from a positon of knowledge leading to stunning innovation. This innovation is likely to lead to more physiological insulin replacement reducing the disease burden to individuals and society as whole.

To describe the phase 3a ONWARDS clinical development programme investigating insulin icodec (icodec), a once-weekly basal insulin, including the design and rationale for each of the ONWARDS 1-6 trials. Six randomized controlled trials have been initiated in adults with type 2 diabetes (T2D) (insulin-naive: ONWARDS 1, 3 and 5; previously insulin-treated: ONWARDS 2 and 4) and type 1 diabetes (T1D) (ONWARDS 6). Each trial will investigate icodec use in a unique clinical scenario, with consideration of long-term safety and varied comparator treatments (insulin glargine U100 or U300 or insulin degludec). ONWARDS 5 will incorporate real-world elements and a digital dose titration solution to guide icodec dosing. The primary objective for each of the trials is to compare the change in HbA1c from baseline to week 26 or week 52 between icodec and comparator arms. Secondary objectives include investigating other glycaemic control and safety parameters, such as fasting glucose, time in glycaemic range and hypoglycaemia. Patient-reported outcomes will assess treatment satisfaction. The ONWARDS 1-6 trials will evaluate the efficacy and safety of once-weekly icodec compared with currently available daily basal insulin analogues in T2D and T1D. These trials will generate comprehensive evidence of icodec use in diverse populations across the spectrum of diabetes progression and treatment experience.

Objective This work aimed to investigate the effect of the SGLT2 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 β-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 SGLT2 inhibitors. The 4-week crossover design showed changes in cardiac function were rapid in onset and reversible.

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.

Hybrid closed-loop (HCL) systems remain underexplored within aviation, and as atmospheric pressure changes can independently affect insulin pumps and continuous glucose monitoring readings, this preliminary study assessed the feasibility of HCL safety evaluation, in both fasting and post-prandial states, by using hypobaric chamber to simulate flights. Participants with type 1 diabetes and on HCL were studied: Medtronic Guardian 4-Medtronic 780G-SmartGuard (n = 4), Dexcom G6-Omnipod DASH-Android APS (n = 1), and Dexcom G6-Ypsomed Pump-CamAPS (n = 1). Flight cabin pressures of 550 mmHg and 750 mmHg were simulated in a hypobaric chamber. Seven-hundred-50 glucose measurements were taken, with glucose levels demonstrating a stable decline to 4 mmol/L during fasting. To maintain a tight fasting and post-prandial glucose range across the different pressure settings, the HCL administered insulin as expected. While not demonstrating any apparent issues, repeating flight simulation protocol with other systems, examining longer flights, and undertaking larger, powered randomised controlled trials can confirm their safety in aviation.

Managing health conditions in the aviation industry is crucial to the safe and effective operation of aircraft. With diabetes on the rise, its safety and health implications should be considered in pilots and air traffic control officers (ATCOs). The incapacitation risks of hypoglycaemia remain a leading concern for regulators, and where people with diabetes are allowed to operate, medical fitness and frequent glucose monitoring must be demonstrated. Self-Monitoring of Blood Glucose (SMBG) capillary glucose measurements is typically accepted in aviation. Continuous Glucose Monitoring (CGM) systems provide near-instant measurements of interstitial glucose levels via disposable skin sensors. As they are convenient and demonstrate comparable mean absolute relative difference to SMBG, people with diabetes generally prefer CGM. Pilots and ATCOs can benefit from the tighter glucose management associated with CGM to meet medical certification and on-duty needs without additional operational load. This study investigated the perception of pilots with diabetes on the CGM and SMBG.

Using the power of stable isotope techniques, our study explored the physiological effects of the SGLT2 inhibitor dapagliflozin on glucose flux, lipolysis, and ketone body concentration in people with acute absolute insulin withdrawal (1). The power of our study from the clinical perspective was the crossover design with each individual undergoing an identical insulin withdrawal protocol with the only difference being the presence or absence of an SGLT2 inhibitor.

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.

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.

Aims To revisit the data analysis used to inform National Institute of Health and Care Excellence (NICE) NG17 guidance for initiating basal insulin in adults with type 1 diabetes mellitus (diabetes). Methods We replicated the data, methodology and analysis used by NICE diabetes in the NG17 network meta‐analysis (NMA). We expanded this data cohort to a more contemporary data set (extended 2017 NMA) and restricted the studies included to improve the robustness of the data set (restricted 2017 NMA) and in a post hoc analysis, changed the index comparator from neutral protamine Hagedorn (NPH) insulin twice daily to insulin detemir twice daily. Results The absolute changes in HbA1c were similar to those reported in the NG17. However, all 95% credible intervals for change in HbA1c point estimates crossed the line of null effect, except for detemir twice daily (in the NICE and extended 2017 NMAs) and NPH four times daily. In the detemir twice‐daily centred post hoc analysis, the 95% credible intervals for change in HbA1c crossed the line of null effect for all basal therapies, except NPH. Conclusions In NG17, comparisons of basal insulins were based solely on efficacy of glycaemic control. Many of the trials used in this analysis were treat‐to‐target, which minimize differences in HbA1c. In the NMAs, statistical significance was severely undermined by the wide credible intervals. Despite these limitations, point estimates of HbA1c were used to rank the insulins and formed the basis of NG17 guidance. This study queries whether such analyses should be used to make specific clinical recommendations. What's new? This study found no significant differences in HbA1c reduction between twice‐daily detemir and modern basal insulin comparators in efficacy trials; the apparent wide variation in HbA1c undermines the statistical robustness and the clinical relevance of the recommendation in the current National Institute of Health and Care Excellence (NICE) guidelines for type 1 diabetes in adults (NG17). The analyses highlight the importance of the quantity and quality of data used in network meta‐analyses to allow clinically meaningful recommendations. With the lack of differentiating evidence to support twice‐daily detemir as the basal insulin of choice for type 1 diabetes, selection of basal insulin should be personalized to individual needs.

This retrospective cohort study aims to define the clinical findings and outcomes of every patient admitted to a district general hospital in Surrey with COVID-19 in March 2020, providing a snapshot of the first wave of infection in the UK. This study is the first detailed insight into the impact of frailty markers on patient outcomes and provides the infection rate among healthcare workers. Data were obtained from medical records. Outcome measures were level of oxygen therapy, discharge and death. Patients were followed up until 21 April 2020. 108 patients were included. 34 (31%) died in hospital or were discharged for palliative care. 43% of patients aged over 65 died. The commonest comorbidities were hypertension (49; 45%) and diabetes (25; 23%). Patients who died were older (mean difference ±SEM, 13.76±3.12 years; p

Sodium glucose cotransporter 2 (SGLT2) inhibitors are the latest class of oral hypoglycaemic agents approved to treat type II diabetes. Their use is increasing and as such more patients will present to critical care whilst on this treatment. However, there have been several case reports of euglycaemic diabetic ketoacidosis associated with the use of these agents. Under such circumstances the blood glucose is often normal or only moderately elevated and hence the diagnosis may be delayed resulting in inappropriate therapy. In this review we describe a case of SGLT2 mediated ketoacidosis who presented to our intensive care unit, discuss the proposed pathophysiology behind this development of ketoacidosis as well as its potential prevention, management and treatment. Crown Copyright (c) 2019 Published by Elsevier Inc. All rights reserved.

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.

Primary care providers (PCPs) play an important role in providing medical care for patients with type 2 diabetes. Advancements in diabetes technologies can assist PCPs in providing personalised care that addresses each patient's individual needs. Diabetes technologies fall into two major categories: devices for glycaemic self-monitoring and insulin delivery systems. Monitoring technologies encompass self-measured blood glucose (SMBG), where blood glucose is intermittently measured by a finger prick blood sample, and continuous glucose monitoring (CGM) devices, which use an interstitial sensor and are capable of giving real-time information. Studies show people using real-time CGM have better glucose control compared to SMBG. CGM allows for new parameters including time in range (the time spent within the desired target glucose range), which is an increasingly relevant real-time metric of glycaemic control. Insulin pens have increased the ease of administration of insulin and connected pens that can calculate and capture data on dosing are becoming available. There are a number of websites, software programs, and applications that can help PCPs and patients to integrate diabetes technology into their diabetes management schedules. In this article, we summarise these technologies and provide practical information to inform PCPs about utility in their clinical practice. The guiding principle is that use of technology should be individualised based on a patient's needs, desires, and availability of devices. Diabetes technology can help patients improve their clinical outcomes and achieve the quality of life they desire by decreasing disease burden. KEY MESSAGES It is important to understand the role that diabetes technologies can play in primary care to help deliver high-quality care, taking into account patient and community resources. Diabetes technologies fall into two major categories: devices for glycaemic self-monitoring and insulin delivery systems. Modern self-measured blood glucose devices are simple to use and can help guide decision making for self-management plans to improve clinical outcomes, but cannot provide "live" data and may under- or overestimate blood glucose; patients' monitoring technique and compliance should be reviewed regularly. Importantly, before a patient is provided with monitoring technology, they must receive suitably structured education in its use and interpretation. Continuous glucose monitoring (CGM) is now standard of care for people with type 1 diabetes and people with type 2 diabetes on meal-time (prandial) insulin. Real-time CGM can tell both the patient and the healthcare provider when glucose is in the normal range, and when they are experiencing hyper- or hypoglycaemia. Using CGM data, changes in lifestyle, eating habits, and medications, including insulin, can help the patient to stay in a normal glycaemic range (70-180 mg/dL). Real-time CGM allows for creation of an ambulatory glucose profile and monitoring of time in range (the time spent within target blood glucose of 70-180 mg/dL), which ideally should be at least 70%; avoiding time above range (>180 mg/dL) is associated with reduced diabetes complications and avoiding time below range (

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.

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.

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.

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

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 Ra, Rd, 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

The risk of hypoglycemia in people with insulin-treated diabetes has debarred them from certain "safety-critical" occupations, including flying commercial aircraft. This report evaluates the effectiveness of a protocol enabling a large cohort of insulin-treated pilots to fly commercially. This was an observational study of pilots with insulin-treated diabetes who were granted medical certification to fly commercial and noncommercial aircraft. Clinical details, pre- and in-flight (hourly and 30 min before landing) blood glucose values were correlated against the protocol-specified ranges: green (5-15 mmol/L), amber (low, 4-4.9 mmol/L; high, 15.1-20 mmol/L), and red (low, 20 mmol/L). A total of 49 pilots with type 1 (84%) or type 2 (16%) diabetes who had been issued class 1 or class 2 certificates were studied. Median diabetes duration was 10.9 years. Mean HbA was 7.2% (55.0 mmol/mol) before certification and 7.2% (55.1 mmol/mol) after certification ( = 0.97). Blood glucose values ( = 38,621) were recorded during 22,078 flying hours. Overall, 97.69% of measurements were within the green range, 1.42% within the low amber range, and 0.75% within the high amber range. Only 0.12% of readings were within the low red range and 0.02% within the high red range. Out-of-range readings declined from 5.7% in 2013 to 1.2% in 2019. No episodes of pilot incapacitation occurred, and glycemic control did not deteriorate. The protocol is practical to implement, and no events compromising safety were reported. This study represents what is, to our knowledge, the most extensive data set from people with insulin-treated diabetes working in a "safety-critical" occupation, which may be relevant when estimating risk in other safety-critical occupations.

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.

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.

Aim To examine blood glucose measurements recorded as part of the diabetes protocol operated by the UK, Ireland and Austria, which allows commercial airline pilots with insulin-treated diabetes to fly. Methods An observational study was conducted in pilots with insulin-treated diabetes, granted medical certification to fly commercial or noncommercial aircraft, who recorded pre-flight and hourly in-flight blood glucose measurements. These values were correlated to a traffic light system (green 5.0 to 15.0 mmol/L; amber 4.0 to 4.9 mmol/L and 15.1 to 20.0 mmol/L; and red 20.0 mmol/L) and studied for trends in glucose concentrations, time course within flight and any consequences. Pilot demographics were also analysed. Results Forty-four pilots (90%) recorded one or more blood glucose value outside the green range during the 7 years of the study. Pilot age, diabetes type and duration, and follow-up period were comparable among subgroups, and mean glycated haemoglobin did not differ before and after certification in a way which would indicate poorer glycaemic control in any subgroup. A total of 892 blood glucose values (2.31%) were outside the green range, with half reported in-flight at various time intervals. There were 48 (0.12%) low red range values recorded, 14 (0.04%) of which occurred in-flight; all but four were restored to within the green range by the time of the next measurement. Appropriate corrective action was taken for all out-of-range values, with no reports of pilot incapacitation from any cause. Conclusions The traffic light system appears effective in identifying and reducing the frequency and severity of out-of-range values.

People with diabetes treated with insulin have often faced blanket bans from safety-critical occupations, largely because of fear of incapacitation due to hypoglycaemia. Recent advances in insulin therapies, modes of administration, monitoring, and noninvasive monitoring techniques have allowed stereotypical views to be challenged. The aviation sector has led the way, in allowing pilots to fly while on insulin. Recently, countries that have traditionally been opposed to this have changed their minds, largely due to the increasing evidence of safety. The purpose of this review was to gather all available information to update clinicans. The physiology and pathophysiology underpinning glucose regulation and the management of diabetes in the air allowing certain insulin-treated pilots to fly are discussed.

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.

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.

There has been 100 years of research detailing the role of insulin in glucose, protein and free fatty acid metabolism. We explore the learnings though evolution and changes in management with an understanding of how it has impacted the care of people with diabetes. The discrimination endured is described and recent advances to empower and counter this are highlighted.

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.

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.

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.

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 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.

BackgroundThe pathophysiology of COVID-19 remains poorly understood. We aimed to estimate the contribution of intrapulmonary shunting and ventilation-to-perfusion (V-A/Q) mismatch using a mathematical model to construct oxygen-haemoglobin dissociation curves (ODCs). MethodsODCs were constructed using transcutaneous pulse oximetry at two different fractions of inspired oxygen (FiO(2)). 199 patients were included from two large district general hospitals in the South East of England from 1(st) to 14(th) January 2021. The study was supported by the National Institute of Health Research (NIHR) Clinical Research Network. ResultsOverall mortality was 29%. Mean age was 68.2 years (SEM 1 center dot 2) with 46% female. Median shunt on admission was 17% (IQR 8-24.5); V-A/Q was 0.61 (IQR 0.52-0.73). Shunt was 37.5% higher in deaths (median 22%, IQR 9-29) compared to survivors (16%, 8-21; p = 0.0088) and was a predictor of mortality (OR 1.04; 95% CI 1.01-1.07). Admission oxygen saturations were more strongly predictive of mortality (OR 0.91, 95% CI 0.87-0.96). There was no difference in V-A/Q mismatch between deaths (0.60; IQR 0.50-0.73) and survivors (0.61; IQR 0.52-0.73; p = 0.63) and it was not predictive of mortality (OR 0.68; 95% CI 0.18-2.52; p = 0.55). Shunt negatively correlated with admission oxygen saturation (R -0.533; p

Introduction Specific patterns of blood test results are associated with COVID-19 infection. The aim of this study was to identify which blood tests could be used to assist in diagnosing COVID-19. Method A retrospective review was performed on consecutive patients referred to hospital with a clinical suspicion of COVID-19 over a period of four weeks. The patient's clinical presentation and severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction (SARS-CoV-2 RT-PCR) were recorded. The patients were divided by diagnosis into COVID (COVID-19 infection) or CONTROL (an alternate diagnosis). A retrospective review of consecutive patients over a further two-week period was used for the purposes of validation. Results Overall, 399 patients (53% COVID, 47% CONTROL) were analysed. White cell count, neutrophils and lymphocytes were significantly lower, while lactate dehydrogenase and ferritin were significantly higher, in the COVID group in comparison to CONTROL. Combining the white cell count, lymphocytes and ferritin results into a COVID Combined Blood Test (CCBT) had an area under the curve of 0.79. Using a threshold CCBT of -0.8 resulted in a sensitivity of 0.85 and a specificity of 0.63. Analysing this against a further retrospective review of 181 suspected COVID-19 patients, using the same CCBT threshold, resulted in a sensitivity of 0.73 and a specificity of 0.75. The sensitivity was comparable to the SARS-CoV-2 RT PCR. Discussion Mathematically combining the blood tests has the potential to assist clinical acumen allowing for rapid streaming and more accurate patient flow pending definitive diagnosis. This may be of particular use in low-resource settings.

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.

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.

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.

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.

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