Total adiponectin in indigenous Melanesians on Kitava.

OBJECTIVES: Experimental and small human studies have indicated that high total adiponectin levels have beneficial cardiometabolic effects. In contrast, however, high total adiponectin levels are also associated with higher all-cause and cardiovascular mortality in thoroughly adjusted epidemiological studies. To gain further insight into these seemingly contradictory results, we report results on total adiponectin from the indigenous Melanesian population of Kitava, Trobriand Islands, Papua New Guinea, where an apparent absence of cardiometabolic disease has been previously reported. METHODS: Fasting levels of serum total adiponectin were measured cross-sectionally in ≥40-year-old Kitavans (n = 102) and Swedish controls matched for age and sex (n = 108). Multivariable linear regression was used for the analysis of associations with total adiponectin when controlled for group, sex, smoking, hypertension and/or type 2 diabetes, age, and body mass index. RESULTS: Total adiponectin was lower for Kitavans compared to Swedish controls (Median [Mdn] 4.6 µg/mL, range 1.0-206 µg/mL and Mdn 9.7 µg/mL, range 3.1-104 µg/mL, respectively, r = .64, p < .001). Lower total adiponectin was associated with Kitavan group, male sex (only in Swedish controls), smoking (only in Kitavans and Swedish controls combined), younger age (not in Swedish controls), higher BMI, lower total, low-density lipoprotein, high-density lipoprotein (HDL) (only in Kitavans and Swedish controls combined), and non-HDL cholesterol, and higher anti-PC IgG (only in Kitavans and Swedish controls combined). CONCLUSION: Total adiponectin in Kitavans was significantly lower than in Swedish controls.

Gut hormone-based pharmacology: novel formulations and future possibilities for metabolic disease therapy.

Glucagon-like peptide-1 (GLP-1) receptor agonists are established pharmaceutical therapies for the treatment of type 2 diabetes and obesity. They mimic the action of GLP-1 to reduce glucose levels through stimulation of insulin secretion and inhibition of glucagon secretion. They also reduce body weight by inducing satiety through central actions. The GLP-1 receptor agonists used clinically are based on exendin-4 and native GLP-1 and are available as formulations for daily or weekly s.c. or oral administration. GLP-1 receptor agonism is also achieved by inhibitors of dipeptidyl peptidase-4 (DPP-4), which prevent the inactivation of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), thereby prolonging their raised levels after meal ingestion. Other developments in GLP-1 receptor agonism include the formation of small orally available agonists and compounds with the potential to pharmaceutically stimulate GLP-1 secretion from the gut. In addition, GLP-1/glucagon and GLP-1/GIP dual receptor agonists and GLP-1/GIP/glucagon triple receptor agonists have shown the potential to reduce blood glucose levels and body weight through their effects on islets and peripheral tissues, improving beta cell function and stimulating energy expenditure. This review summarises developments in gut hormone-based therapies and presents the future outlook for their use in type 2 diabetes and obesity.

Persistent whole day meal effects of three dipeptidyl peptidase-4 inhibitors on glycaemia and hormonal responses in metformin-treated type 2 diabetes.

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibition has effects on both fasting and postprandial glucose. However, the extent of this effect over the whole day and whether different DPP-4 inhibitors have the same effects have not been established. We therefore explored the whole day effects of three different DPP-4 inhibitors versus placebo on glucose, islet and incretin hormones after ingestion of breakfast, lunch and dinner in subjects with metformin-treated and well-controlled type 2 diabetes. METHODS: The study was single-centre and crossover designed, involving 24 subjects [12 men, 12 women, mean age 63 years, body mass index 31.0 kg/m2 , glycated haemoglobin 44.7 mmol/mol (6.2%)], who underwent four test days in random order. Each whole day test included ingestion of standardized breakfast (525 kcal), lunch (780 kcal) and dinner (560 kcal) after intake of sitagliptin (100 mg) or vildagliptin (50 mg twice), or saxagliptin (5 mg) or placebo. RESULTS: Compared with placebo, DPP-4 inhibition reduced glucose levels, increased beta-cell function (insulin secretory rate in relation to glucose), suppressed glucagon, increased intact glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) but suppressed total GLP-1 and GIP after all three meals. The effects were sustained throughout the daytime period with similar changes after each meal and did not differ between the DPP-4 inhibitors. CONCLUSIONS: DPP-4 inhibition has persistent daytime effects on glucose, islet and incretin hormones with no difference between three different DPP-4 inhibitors.

Glucagon and insulin secretion, insulin clearance, and fasting glucose in GIP receptor and GLP-1 receptor knockout mice.

It is not known whether GIP receptor and GLP-1 receptor knockout (KO) mice have perturbations in glucagon secretion or insulin clearance, and studies on impact on fasting glycemia have previously been inconsistent in these mice. We therefore studied glucagon secretion after oral whey protein (60 mg) and intravenous arginine (6.25 mg), insulin clearance after intravenous glucose (0.35 g/kg) and fasting glucose, insulin, and glucagon levels after standardized 5-h fasting in female GIP receptor and GLP-1 receptor KO mice and their wild-type (WT) littermates. Compared with WT controls, GIP receptor KO mice had normal glucagon responses to oral protein and intravenous arginine, except for an enhanced 1-min response to arginine, whereas glucagon levels after oral protein and intravenous arginine were enhanced in GLP-1 receptor KO mice. Furthermore, the intravenous glucose test revealed normal insulin clearance in both GIP receptor and GLP-1 receptor KO mice, whereas ß-cell glucose sensitivity was enhanced in GIP receptor KO mice and reduced in GLP-1 receptor KO mice. Finally, GIP receptor KO mice had reduced fasting glucose (6.7 ± 0.1, n = 56, vs. 7.4 ± 0.1 mmol/l, n = 59, P = 0.001), whereas GLP-1 receptor KO mice had increased fasting glucose (9.1 ± 0.2, n = 44, vs. 7.7 ± 0.1 mmol/l, n = 41, P < 0.001). We therefore suggest that GIP has a limited role for glucagon secretion in mice, whereas GLP-1 is of importance for glucagon regulation, that GIP and GLP-1 are of importance for the regulation of ß-cell function beyond their role as incretin hormones, and that they are both of importance for fasting glucose.

Increased insulin clearance in mice with double deletion of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors.

To establish whether incretin hormones affect insulin clearance, the aim of this study was to assess insulin clearance in mice with genetic deletion of receptors for both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), so called double incretin receptor knockout mice (DIRKO). DIRKO ( n = 31) and wild-type (WT) C57BL6J mice ( n = 45) were intravenously injected with d-glucose (0.35 g/kg). Blood was sampled for 50 min and assayed for glucose, insulin, and C-peptide. Data were modeled to calculate insulin clearance; C-peptide kinetics was established after human C-peptide injection. Assessment of C-peptide kinetics revealed that C-peptide clearance was 1.66 ± 0.10 10-3 1/min. After intravenous glucose administration, insulin clearance during first phase insulin secretion was markedly higher in DIRKO than in WT mice (0.68 ± 0.06 10-3 l/min in DIRKO mice vs. 0.54 ± 0.03 10-3 1/min in WT mice, P = 0.02). In contrast, there was no difference between the two groups in insulin clearance during second phase insulin secretion ( P = 0.18). In conclusion, this study evaluated C-peptide kinetics in the mouse and exploited a mathematical model to estimate insulin clearance. Results showed that DIRKO mice have higher insulin clearance than WT mice, following intravenous injection of glucose. This suggests that incretin hormones reduce insulin clearance at physiological, nonstimulated levels.

Different glucagon effects during DPP-4 inhibition versus SGLT-2 inhibition in metformin-treated type 2 diabetes patients.

AIMS: Previous studies have shown that dipeptidyl peptidase (DPP)-4 inhibition lowers glucagon levels whereas sodium-glucose co-transporter 2 (SGLT-2) inhibition increases them. This study evaluated the extent of these opposite effects in a direct comparative head-to-head study. METHODS: In a single-centre, randomized study with a cross-over design, 28 metformin-treated patients with type 2 diabetes (T2D) (mean age, 63 years; baseline HbA1c, 6.8%) were treated with vildagliptin (50 mg twice daily) or dapagliflozin (10 mg once daily) for 2 weeks, with a 4-week wash-out period between the two separate treatments. After each treatment period, a meal test was undertaken, with measurements of islet and incretin hormones and 4-hour area under the curve (AUC) levels were estimated. RESULTS: Fasting glucagon (35.6 ± 2.5 vs 39.4 ± 3.4 pmoL/L; P = .032) and postprandial glucagon (4-hour AUCglucagon , 32.1 ± 2.3 vs 37.5 ± 2.7 nmoL/L min; P = .001) were ~15% lower after vildagliptin compared to dapagliflozin treatment. This was associated with stronger early (15 minute) C-peptide response and higher 4-hour AUCC-peptide (P < .010), higher 4-hour AUC of the intact form of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) (P < .001) and lower 4-hour AUC of total GIP and GLP-1 (P < .001). CONCLUSION: Treatment with DPP-4 inhibition with vildagliptin results in 15% lower fasting and postprandial glucagon levels compared to SGLT-2 inhibition with dapagliflozin. DPP-4 inhibition also induces more rapid insulin secretion and higher levels of intact incretin hormones, resulting in stronger feedback inhibition of incretin hormone secretion than SGLT-2 inhibition.

Effects on the glucagon response to hypoglycaemia during DPP-4 inhibition in elderly subjects with type 2 diabetes: A randomized, placebo-controlled study.

AIMS: Maintainance of glucagon response to hypoglycaemia is important as a safeguard against hypoglycaemia during glucose-lowering therapy in type 2 diabetes. During recent years, DPP-4 (dipeptidyl peptidase-4) inhibition has become more commonly used in elderly patients. However, whether DPP-4 inhibition affects the glucagon response to hypoglycaemia in the elderly is not known and was the aim of this study. METHODS: In a single-centre, double-blind, randomized, placebo-controlled crossover study, 28 subjects with metformin-treated type 2 diabetes (17 male, 11 female; mean age, 74 years [range 65-86]; mean HbA1c, 51.5 mmol/mol [6.9%]) received sitagliptin (100 mg once daily) as add-on therapy or placebo for 4 weeks with a 4-week washout period in between. After each treatment period, the subjects underwent a standard breakfast test, followed by a 2-step hyperinsulinaemic hypoglycaemic clamp (target 3.5 and 3.0 mmol/L), followed by lunch. RESULTS: Glucagon levels after breakfast and lunch, and the glucagon response at 3.5 mmol/L, were lower after sitagliptin than after placebo. However, the glucagon response to hypoglycaemia at 3.1 mmol/L did not differ significantly between the two. Similarly, the noradrenaline, adrenaline and cortisol responses were lower with sitagliptin than with placebo at 3.5 mmol/L, but not at 3.1 mmol/L glucose. Responses in pancreatic polypeptide did not differ between the two. CONCLUSIONS: Elderly subjects with metformin-treated type 2 diabetes have lower glucagon levels at 3.5 mmol/L glucose, but maintain the glucagon response to hypoglycaemia at 3.1 mmol/L during DPP-4 inhibition, which safeguards against hypoglycaemia and may contribute to decreasing the risk of hypoglycaemia by DPP-4 inhibition in this age group.

Effect of single-dose DPP-4 inhibitor sitagliptin on ß-cell function and incretin hormone secretion after meal ingestion in healthy volunteers and drug-naïve, well-controlled type 2 diabetes subjects.

To explore the effects of a single dose of the DPP-4 inhibitor sitagliptin on glucose-standardized insulin secretion and ß-cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug-naïve, well-controlled type 2 diabetes (T2D) subjects (mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100 mg) or placebo before a meal (525 kcal). ß-cell function was measured as the insulin secretory rate at a standardized glucose concentration and the ß-cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing ß-cell glucose sensitivity. Sitagliptin also increased active glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and reduced total (reflecting the secretion) GIP, but not total GLP-1 levels. We conclude that a single dose of DPP-4 inhibition induces dissociated effects on different aspects of ß-cell function and incretin hormones after meal ingestion in both healthy and well-controlled T2D subjects.

Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials.

AIMS: To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3-6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established. MATERIALS AND METHODS: Subjects with inadequately controlled type 2 diabetes (drug-naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects. RESULTS: Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects). CONCLUSIONS: In SUSTAIN 1 to 5, semaglutide-induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor.

Diurnal glucose exposure profiles of patients treated with lixisenatide before breakfast or the main meal of the day: An analysis using continuous glucose monitoring.

BACKGROUND: In the parent study of this analysis, patients with type 2 diabetes received lixisenatide before breakfast or the main meal of the day. This substudy was designed to examine the effect of lixisenatide administered before breakfast or the main meal of the day on continuously assessed 24-hour patient glucose profiles. METHODS: A subset of patients from the parent study underwent 2 14-day periods of continuous glucose monitoring (CGM) at the start and end of the 24-week study. Ambulatory glucose profile analysis was used to measure changes over time in detailed aspects of the glucose profiles. The breakfast group consumed a standardized meal during both CGM periods to determine change in 4-hour glycemic response. RESULTS: Data were available for 69 patients in the substudy, 40 from the original breakfast group and 29 from the main meal group. Between baseline and end of study, mean (standard deviation) total glucose exposure decreased from 4198.1 (652.3) to 3681.2 (699.6) mg/dL*24 h in the breakfast group (P < .0001) and from 4127.9 (876.8) to 3880.9 (1165.0) mg/dL*24 h in the main meal group (P = .0224). For patients included in the substudy, HbA1c decreased by approximately 0.6% in both groups. Mean (standard deviation) 4-hour total glucose exposure fell by 168.9 (158.4) mg/dL*4 h (P < .0001) from baseline. CONCLUSIONS: This analysis demonstrates that lixisenatide has beneficial effects on components of the 24-hour glucose profile, which endure beyond the meal at which it is administered. Continuous glucose monitoring analysis detects changes not captured using HbA1c alone.

Effects of DPP-4 inhibitor linagliptin and GLP-1 receptor agonist liraglutide on physiological response to hypoglycaemia in Japanese subjects with type 2 diabetes: A randomized, open-label, 2-arm parallel comparative, exploratory trial.

Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce the risk of hypoglycaemia, possibly through augmentation of glucose-dependent insulinotropic polypeptide (GIP) action, but not that of glucagon-like peptide-1 (GLP-1) on glucagon secretion. To examine this model in Japanese individuals with type 2 diabetes (T2D), the effects of the DPP-4 inhibitor linagliptin on glucagon and other counter-regulatory hormone responses to hypoglycaemia were evaluated and compared with those of the GLP-1 receptor agonist liraglutide in a multi-centre, randomized, open-label, 2-arm parallel comparative, exploratory trial. Three-step hypoglycaemic clamp glucose tests preceded by meal tolerance tests were performed before and after 2-week treatment with the drugs. Glucagon levels were increased during the hypoglycaemic clamp test at 2.5 mmol/L. This increase was similar in the linagliptin and liraglutide groups, both before and after the 2-week treatment. Changes in other counter-regulatory hormones (ie, growth hormone, cortisol, epinephrine and norepinephrine) were also similar between the groups, but were suppressed substantially after 2-week treatment compared to baseline. In conclusion, we confirmed that the glucagon response to hypoglycaemia was not affected by linagliptin or liraglutide treatment in Japanese individuals with T2D.

Improved glucose regulation in type 2 diabetic patients with DPP-4 inhibitors: focus on alpha and beta cell function and lipid metabolism.

Inhibition of dipeptidyl peptidase-4 (DPP-4) is an established glucose-lowering strategy for the management of type 2 diabetes mellitus. DPP-4 inhibitors reduce both fasting and postprandial plasma glucose levels, resulting in reduced HbA1c with low risk for hypoglycaemia and weight gain. They act primarily by preventing inactivation of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, thereby prolonging the enhanced endogenous levels of these hormones after meal ingestion. This in turn causes islet and extrapancreatic effects, including increased glucose sensing in islet alpha and beta cells. These effects result in increased insulin secretion and decreased glucagon secretion being more effective in hyperglycaemic states and reduced insulin secretion and increased glucagon secretion being more effective during hypoglycaemia. Other secondary pharmacological actions of DPP-4 inhibitors include mobilisation and burning of fat during meals, decrease in fat extraction from the gut, reduction of fasting lipolysis and liver fat and increase in LDL particle size. These actions contribute to the clinical effects of DPP-4 inhibition, and the reduced demand for insulin could also lead to a durability benefit. This review summarises the current knowledge of the secondary pharmacological actions of DPP-4 inhibitors that lead to improved glucose regulation in patients with type 2 diabetes, focusing on alpha and beta cell function and lipid metabolism.

CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion.

AIMS/HYPOTHESIS: Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart (-/-) mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice. METHODS: CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca(2+) oscillation patterns and exocytosis were studied in mouse islets. RESULTS: We report an important role of CART in human islet function and glucose homeostasis in mice. CART was found to be expressed in human alpha and beta cells and in a subpopulation of mouse beta cells. Notably, CART expression was several fold higher in islets of type 2 diabetic humans and rodents. CART increased insulin secretion in vivo in mice and in human and mouse islets. Furthermore, CART increased beta cell exocytosis, altered the glucose-induced Ca(2+) signalling pattern in mouse islets from fast to slow oscillations and improved synchronisation of the oscillations between different islet regions. Finally, CART reduced glucagon secretion in human and mouse islets, as well as in vivo in mice via diminished alpha cell exocytosis. CONCLUSIONS/INTERPRETATION: We conclude that CART is a regulator of glucose homeostasis and could play an important role in the pathophysiology of type 2 diabetes. Based on the ability of CART to increase insulin secretion and reduce glucagon secretion, CART-based agents could be a therapeutic modality in type 2 diabetes.

Enhanced insulin sensitivity mediated by adipose tissue browning perturbs islet morphology and hormone secretion in response to autonomic nervous activation in female mice.

Insulin resistance results in a compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin-sensitive mice, due to adipocyte-specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with insulin secretion significantly lower than that of wild-type mice; however, when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild-type mice. In response to autonomic nervous activation by 2-deoxyglucose, the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice, suggesting impaired sympathetic signaling to the islet. Basal glucagon was increased in Foxc2TG mice, but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity, which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation.

Decreased insulin secretion and glucose clearance in exocrine pancreas-insufficient pigs.

The effect of exocrine pancreatic function on the glucose-mediated insulin response and glucose utilization were studied in an exocrine pancreas-insufficient (EPI) pig model. Five 10-week-old EPI pigs after pancreatic duct ligation and 6 age-matched, non-operated control pigs were used in the study. Blood glucose, plasma insulin and C-peptide concentrations were monitored during meal (MGTT), oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. Upon post-mortem examination, the pancreatic remnants of the EPI pigs showed acinar fibrotic atrophy but normal islets and ß-cell morphology. The EPI pigs displayed increased fasting glucose concentrations compared with control animals (6.4 ± 0.4 versus 4.8 ± 0.1 mmol l(-1) , P < 0.0001) but unchanged insulin concentrations (2.4 ± 0.6 versus 2.1 ± 0.2 pmol l(-1) ). During the OGTT and IVGTT, the EPI pigs showed slower, impaired glucose utilization, with the disruption of a well-timed insulin response. Plasma C-peptide concentrations confirmed the delayed insulin response during the IVGTT in EPI pigs. Oral pancreatic enzyme supplementation (PES) of EPI pigs improved glucose clearance during IVGTT [AUC(glucose) 1295 ± 70 mmol l(-1) × (120 min) in EPI versus 1044 ± 32 mmol l(-1) × (120 min) in EPI + PES, P < 0.0001] without reinforcing the release of insulin [AUC(C-peptide) 14.4 ± 3.8 nmol l(-1) × (120 min) in EPI versus 6.4 ± 1.3 nmol l(-1) × (120 min) in EPI + PES, P < 0.002]. The results suggest the existence of an acino-insular axis regulatory communication. The presence of pancreatic enzymes in the gut facilitates glucose utilization in an insulin-independent manner, indicating the existence of a gut-derived pancreatic enzyme-dependent mechanism involved in peripheral glucose utilization.

Creative use of novel glucose-lowering drugs for type 2 diabetes: where will we head in the next 50 years?

Research conducted over the last 50 years has produced discoveries on the importance of glucose control for reducing the risk of diabetic complications, the pathophysiology of type 2 diabetes, the development and validation of mechanistic glucose-lowering targets, and the preclinical and clinical development of individual drugs. This science established the different drug classes that are clinically used today in association with lifestyle changes for lowering glucose in type 2 diabetes. For the next 50 years, we can anticipate that science will explore (1) the use of current drugs and, as they become available, newly developed drugs in early (initial) oral combinations followed by intensification with injectable combinations when glycaemia deteriorates, (2) the validation of novel mechanistic biochemical and physiological targets, including indirect effects of future antiobesity drugs, and (3) the development of true disease-modifying strategies based on knowledge of islet cell biology and replacement. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).

DPP-4 inhibition contributes to the prevention of hypoglycaemia through a GIP-glucagon counterregulatory axis in mice.

AIMS/HYPOTHESIS: Glucose-lowering therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors is associated with a low risk of hypoglycaemia. We hypothesise that DPP-4 inhibition prevents hypoglycaemia via increased glucagon counterregulation through the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). METHODS: Using a hyperinsulinaemic-hypoglycaemic clamp that targeted 2.5 mmol/l we examined the effects of the DPP-4 inhibitor vildagliptin and GIP infusion on steady state glucose infusion rate (GIR) and glucagon counterregulation in mice. Following up on this, we performed a hyperinsulinaemic-hypoglycaemic clamp in mice carrying a genetic deletion of the GIP receptor (GIPR (-/-) mice) or the glucagon receptor (GCGR (-/-) mice). RESULTS: GIR was reduced by 89.0 ± 3.1% (p = 7.0 × 10(-6)) by vildagliptin and by 38.8 ± 12.6% (p = 0.040) by GIP in wild-type (wt) mice, whereas GIR was increased both in GIPR (-/-) (to 33.0 ± 6.8 from 14.0 ± 2.9 µmol kg (-1) min (-1); p = 0.017) and in GCGR (-/-) mice (to 59.4 ± 1.1 from 16.5 ± 2.4 µmol kg (-1) min (-1); p = 8.2 × 10(-7)) compared with wt. By contrast, neither vildagliptin nor GIP had any effect on GIR in GCGR (-/-) mice. Furthermore, vildagliptin increased intact GIP four- to eightfold during hypoglycaemia and the counterregulatory increase in glucagon levels during hypoglycaemia was augmented by vildagliptin (incremental AUC [iAUC] during clamp was 99.2 ± 22.5 vs 42.0 ± 4.5 pmol/l × min in controls; p = 0.039) and GIP (iAUC of fold change during clamp was 372 ± 81 vs 161 ± 40 FC × min with saline; p = 0.031). CONCLUSIONS/INTERPRETATION: Based on these results we propose that DPP-4 inhibition protects from hypoglycaemia by augmenting glucagon counterregulation through a GIP-glucagon counterregulatory axis.

High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: a randomised clinical trial.

AIMS/HYPOTHESIS: High-energy breakfast and reduced-energy dinner (Bdiet) significantly reduces postprandial glycaemia in obese non-diabetic individuals. Our objective was to test whether this meal schedule reduces postprandial hyperglycaemia (PPHG) in patients with type 2 diabetes by enhancing incretin and insulin levels when compared with high-energy dinner and reduced-energy breakfast (Ddiet). METHODS: In a randomised, open label, crossover design performed in a clinic setting, 18 individuals (aged 30-70 years with BMI 22-35 kg/m(2)) with type 2 diabetes (<10 years duration) treated with metformin and/or diet were given either Bdiet or Ddiet for 7 days. Participants were randomised by a person not involved in the study using a coin flip. Postprandial levels of plasma glucose, insulin, C-peptide and intact and total glucagon-like peptide-1 (iGLP-1 and tGLP-1) were assessed. The Bdiet included 2,946 kJ breakfast, 2,523 kJ lunch and 858 kJ dinner. The Ddiet comprised 858 kJ breakfast, 2,523 kJ lunch and 2,946 kJ dinner. RESULTS: Twenty-two individuals were randomised and 18 analysed. The AUC for glucose (AUCglucose) throughout the day was 20% lower, whereas AUCinsulin, AUCC-peptide and AUCtGLP-1 were 20% higher for the Bdiet than the Ddiet. Glucose AUC0-180min and its peak were both lower by 24%, whereas insulin AUC0-180min was 11% higher after the Bdiet than the Ddiet. This was accompanied by 30% higher tGLP-1 and 16% higher iGLP-1 levels. Despite the diets being isoenergetic, lunch resulted in lower glucose (by 21-25%) and higher insulin (by 23%) with the Bdiet vs Ddiet. CONCLUSIONS/INTERPRETATION: High energy intake at breakfast is associated with significant reduction in overall PPHG in diabetic patients over the entire day. This dietary adjustment may have a therapeutic advantage for the achievement of optimal metabolic control and may have the potential for being preventive for cardiovascular and other complications of type 2 diabetes. Trial registration ClinicalTrials.gov NCT01977833 Funding No specific funding was received for the study.

Surrogate measures of insulin sensitivity vs the hyperinsulinaemic-euglycaemic clamp: a meta-analysis.

AIMS/HYPOTHESIS: We aimed to identify which surrogate index of insulin sensitivity has the strongest correlation with the reference measurement, the hyperinsulinaemic-euglycaemic clamp (HEC), to determine which surrogate measure should be recommended for use in large-scale studies. METHODS: A literature search (1979-2012) was conducted to retrieve all articles reporting bivariate correlations between the HEC and surrogate measures of insulin sensitivity (in fasting samples or during the OGTT). We performed a random effects meta-analysis for each surrogate measure to integrate the correlation coefficients of the different studies. RESULTS: The OGTT-based surrogate measures with the strongest pooled correlations (r) to the HEC were the Stumvoll metabolic clearance rate (Stumvoll MCR; r = 0.70 [95% CI 0.61, 0.77], n = 5), oral glucose insulin sensitivity (OGIS; r = 0.70 [0.57, 0.80], n = 6), the Matsuda index (r = 0.67 [0.61, 0.73], n = 19), the Stumvoll insulin sensitivity index (Stumvoll ISI; r = 0.67 [0.60, 0.72], n = 8) and the Gutt index (r = 0.65 [0.60, 0.69], n = 6). The fasting surrogate indices that correlated most strongly with the HEC and had narrow 95% CIs were the revised QUICKI (r = 0.68 [0.58, 0.77], n = 7), the QUICKI (r = 0.61 [0.55, 0.65], n = 35), the log HOMA-IR (r = -0.60 [-0.66, -0.53], n = 22) and the computer generated HOMA of insulin sensitivity (HOMA-%S; r = 0.57 [0.46, 0.67], n = 5). CONCLUSIONS/INTERPRETATION: The revised QUICKI fasting surrogate measure appears to be as good as the OGTT-based Stumvoll MCR, OGIS, Matsuda, Stumvoll ISI and Gutt indices for estimating insulin sensitivity. It can therefore be recommended as the most appropriate index for use in large-scale clinical studies.

Glucagon clearance is regulated by nutritional state: evidence from experimental studies in mice.

AIMS/HYPOTHESIS: Given the importance of glucagon in the development of type 2 diabetes and as a potential therapeutic agent, the aim of this study was to characterise glucagon kinetics in mice and its regulation by the nutritional state. METHODS: Anaesthetised C57BL/6 mice fed normal or high-fat diets, or fasted, were injected intravenously with glucagon (0.1, 0.3, 1.0, 10.0 or 20 µg/kg); blood samples were withdrawn before injection and 1, 3, 5, 10, 20 min thereafter for glucagon assay by RIA. Glucagon kinetics were described by two-compartment models using a population analysis. RESULTS: The population mean and between-animal SD of glucagon clearance in the fed mice was 6.03 ± 2.58 ml/min, with a rapid elimination half-life of 2.92 ± 1.21 min. Fasted mice showed a slower glucagon clearance. The kinetics of glucagon in the fed and fasted group was linear across this large dose range. The mice fed a high-fat diet, however, showed non-linear kinetics with a faster terminal clearance of 20.4 ± 5.45 ml/min (p < 0.001) and a shorter elimination half-life of 1.59 ± 0.606 (p < 0.001) min relative to normal mice. CONCLUSIONS/INTERPRETATION: This first systematic dose-ranging study of glucagon kinetics produced several findings: (1) a linear two-compartment model describes glucagon in normal C57BL/6 mice; (2) fasting reduces the clearance of glucagon and (3) high-fat diet enhances the clearance of glucagon. These results may direct future studies on glucagon physiology and indicate that there are other mechanisms, not included in the current model, needed to fully explain glucagon's kinetics.