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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. (Less)

Aim Use of the glucagon-like peptide 1 receptor agonist liraglutide has been shown to reduce weight. Different types of anthropometric measurements can be used to measure adiposity. This study evaluated the effect of liraglutide on sagittal abdominal diameter, waist circumference, waist-to-hip ratio and adiponectin levels in people with type 2 diabetes (T2D) treated with multiple daily insulin injections (MDI). Materials and methods In the multicentre, double-blind, placebo-controlled MDI-liraglutide trial, 124 individuals with T2D treated with MDI were randomized to either liraglutide or placebo. Basal values of weight, waist circumference, waist-to-hip ratio, sagittal abdominal diameter and adiponectin were compared with measurements at 12 and 24 weeks after randomization. Results Baseline-adjusted mean weight loss was 3.8 +/- 2.9 kg greater in liraglutide than placebo-treated individuals (p < 0.0001). Waist circumference was reduced by 2.9 +/- 4.3 cm and 0.2 +/- 3.6 cm in the liraglutide and placebo groups, respectively, after 24 weeks (baseline-adjusted mean difference: 2.6 +/- 4.0 cm, p = 0.0005). Corresponding reductions in sagittal abdominal diameter were 1.1 +/- 1.7 cm and 0.0 +/- 1.8 cm (baseline-adjusted mean difference: 1.1 +/- 1.7 cm, p = 0.0008). Hip circumference was reduced in patients randomized to liraglutide (baseline-adjusted mean difference between treatment groups: 2.8 +/- 3.8 cm, p = 0.0001), but there was no significant difference between the groups in either waist-to-hip ratio (baseline-adjusted mean difference: 0.0 +/- 0.04 cm, p = 0.51) or adiponectin levels (baseline-adjusted mean difference: 0.8 +/- 3.3 mg L-1, p = 0.17). Lower HbA1c and mean glucose levels measured by masked continuous glucose monitoring at baseline were associated with greater effects of liraglutide on reductions in waist circumference and sagittal abdominal diameter. Conclusions In patients with T2D, adding liraglutide to MDI may reduce abdominal and hip obesity to a similar extent, suggesting an effect on both visceral and subcutaneous fat. Liraglutide had greater effects on reducing abdominal obesity in patients with less pronounced long-term hyperglycaemia but did not affect adiponectin levels.

Summary Background Omission of breakfast results in higher glucose and lower insulin and incretin hormone levels after both lunch and dinner. Whether omission of lunch has a similar impact on the following meal is not known. Aim This study therefore explored whether omission of lunch ingestion affects glucose, islet and incretin hormones after dinner ingestion in healthy subjects. Materials & Methods Twelve male volunteers (mean age 22 years, BMI 22.5 kg/m2) underwent two test days in random order with standard breakfast and dinner on both days with provision or omission of standard lunch in between. Results The results showed that throughout the 300 minutes study period, glucose, insulin, glucagon and GIP levels after dinner ingestion did not differ between the two tests. In contrast, C‐peptide, and GLP‐1 levels were 26%‐35% higher at later time points after dinner ingestion when lunch had been omitted (P, This study explored whether omission of lunch ingestion affects glucose, islet and incretin hormones after dinner ingestion in healthy subjects. Twelve male volunteers underwent two test days in random order with standard breakfast and dinner on both days with provision or omission of standard lunch in between. The results showed that omission of lunch increases GLP‐1 and insulin secretion and possibly also insulin clearance resulting in unchanged glucose and insulin levels after dinner ingestion.

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-naive 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. (Less)

To explore the effects of a single dose of the DPP-4 inhibitor sitagliptin on glucose-standardized insulin secretion and β-cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug-naive, well-controlled type 2 diabetes (T2D) subjects (mean HbA1c 43mmol/mol, 6.2%) received sitagliptin (100mg) or placebo before a meal (525kcal). β-cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β-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 β-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 β-cell function and incretin hormones after meal ingestion in both healthy and well-controlled T2D subjects. (Less)

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 β-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.

To study the integrative impact of macronutrients on postprandial glycaemia, β-cell function, glucagon and incretin hormones in humans.Macronutrients were ingested alone (glucose 330 kcal, protein 110 kcal or fat 110 kcal) or together (550 kcal) by healthy subjects (n = 18) and by subjects with drug-naïve type 2 diabetes (T2D; n = 18). β-cell function and insulin clearance were estimated by modelling glucose, insulin and C-peptide data. Secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured, and paracetamol was administered to estimate gastric emptying.In both groups, the mixed-meal challenge diminished glucose excursion compared with glucose challenge alone, and insulin levels, but not C-peptide levels, rose more than after the mixed meal than after glucose alone. β-cell function was augmented, insulin clearance was reduced and glucagon levels were higher after the mixed meal compared with glucose alone. GLP-1 and GIP levels increased after all challenges and GIP secretion was markedly higher after the mixed meal than after glucose alone. The appearance of paracetamol was delayed after the mixed-meal challenge compared with glucose alone.Adding protein and fat macronutrients to glucose in a mixed meal diminished glucose excursion. This occurred in association with increased β-cell function, reduced insulin clearance, delayed gastric emptying and augmented glucagon and GIP secretion. This suggests that the macronutrient composition regulates glycaemia through both islet and extra-islet mechanisms in both healthy subjects and in subjects with T2D.

Glucagon-like peptide-1 (GLP-1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aimed to investigate the effects of the once-daily prandial GLP-1 receptor agonist lixisenatide on postprandial plasma glucose (PPG), glucagon and insulin levels. Methods: Six randomized, placebo-controlled studies of lixisenatide 20μg once daily were included in this analysis: lixisenatide as monotherapy (GetGoal-Mono), as add-on to oral antidiabetic drugs (OADs; GetGoal-M, GetGoal-S) or in combination with basal insulin (GetGoal-L, GetGoal-Duo-1 and GetGoal-L-Asia). Change in 2-h PPG and glucose excursion were evaluated across six studies. Change in 2-h glucagon and postprandial insulin were evaluated across two studies. A meta-analysis was performed on least square (LS) mean estimates obtained from analysis of covariance (ANCOVA)-based linear regression. Results: Lixisenatide significantly reduced 2-h PPG from baseline (LS mean difference vs. placebo: -4.9mmol/l, p

Aims Preliminary data from randomized trials with metabolic outcomes have shown that treatment with dipeptidyl peptidase-4 inhibitors (DPP4i) could be associated with a reduced incidence of major cardiovascular events (MACE). The present meta-analysis is aimed at verifying this protective effect, collecting all available data from randomized trials. Methods A comprehensive search for published and unpublished trials with a duration =24 weeks comparing DPP4i with placebo or other drugs was performed, retrieving all MACE reported as serious adverse events together with death from any cause. MantelHaenzel odds ratio (MHOR) was calculated with random effect models for MACE, myocardial infarction, stroke and mortality. When available, effects on glycated haemoglobin, lipid profile and blood pressure were also assessed and used for the estimation of the modification of risk for myocardial infarction using the UKPDS risk engine. Results A total of 70 trials, enrolling 41?959 patients with a mean follow-up of 44.1 weeks, was collected and included in the analysis. The MHOR (95% Confidence Interval) was 0.71[0.59;0.86], 0.64[0.44;0.94], 0.77[0.48;1.24] and 0.60[0.41;0.88] for MACE, myocardial infarction, stroke and mortality, respectively. Conclusions Treatment with DPP4i reduces the risk of cardiovascular events (particularly myocardial infarction) and all-cause mortality in patients with type 2 diabetes. The reduction in the incidence of myocardial infarction is greater than what predicted on the basis of conventional risk factors, suggesting a role for other mechanisms. (Less)

Aims: During recent years, two strategies of incretin-based therapy [glucagon-like peptide-1 (GLP-1) receptor agonism and dipeptidyl peptidase-4 (DPP-4) inhibition] have entered the market for pharmacological management of type 2 diabetes. A main indication for this therapy is as add-on to on-going metformin therapy in subjects with type 2 diabetes who have insufficient glycaemic control with metformin alone. The aim of this study was to compare improvements in glycaemic control and changes in body weight, as well as adverse events, in comparable studies with incretin-based therapy as add-on to metformin. Methods: Studies having a duration of 16-30 weeks were identified from PubMed. Results: A total of 27 study groups in 21 studies fulfilled the criteria of examining incretin-based therapy as add-on to metformin at clinically recommended doses in patients with type 2 diabetes for 16-30 weeks; 7 of these used a short-acting GLP-1 receptor agonist (exenatide BID), 7 used longer acting GLP-1 receptor agonists (liraglutide or exenatide LAR), whereas 14 studies examined DPP-4 inhibitors. In all studies, incretin-based therapy reduced HbA1c concentrations. The reduction in HbA1c was significantly greater in study groups with long-acting GLP-1 receptor agonists than with the other two groups (both p < 0.001), whereas there were no differences between exenatide BID and DPP-4 inhibitors. Across all study groups, there was a negative linear correlation between baseline HbA1c and change in HbA1c (r = -0.70; p < 0.001). Fasting glucose also fell significantly more in study groups given liraglutide or exenatide LAR than in those given exenatide BID or DPP-4 inhibitors (both p < 0.001). Furthermore, body weight was reduced by a similar extent in the two groups with GLP-1 receptor agonists and was not significantly altered in the groups with DPP-4 inhibitors. Lipids, blood pressure and heart rate were not reported consistently, which did not allow general conclusions. Adverse events were rare, apart from increased incidence of nausea and vomiting with GLP-1 receptor agonists. Conclusion: Incretin-based therapy efficiently improves glycaemia when added to metformin in patients with type 2 diabetes, and within 16-30 weeks there is a more pronounced reduction in HbA1c with long-acting GLP-1 receptor agonists (liraglutide and exenatide LAR) than with exenatide BID and DPP-4 inhibitors, although the magnitude of the effect is dependent on the baseline values. Both strategies appear to be associated with a very low risk of adverse events, including hypoglycaemia. Finally, the injectable GLP-1 receptor agonists also reduce body weight (whereas the DPP-4 inhibitors are weight neutral) but are also associated with a greater incidence of gastrointestinal side effects and a tendency to increase heart rate. (Less)

During recent years, dipeptidyl peptidase-4 (DPP-4) inhibition has been included in the clinical management of type 2 diabetes, both as monotherapy and as add-on to several other therapies. DPP-4 inhibition prevents the inactivation of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This results in stimulation of insulin secretion and inhibition of glucagon secretion, and there is also a potential beta-cell preservation effect, as judged from rodent studies; that is, it might target the key islet dysfunction in the disease. In type 2 diabetes. This reduces 24-h glucose levels and reduces HbA1c by approximate to 0.81.1% from baseline levels of 7.78.5%. DPP-4 inhibition is safe, with a very low risk for adverse events including hypoglycemia, and it prevents weight gain. The present review summarizes the studies on the influence of DPP-4 inhibition on islet function. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00184.x, 2012) (Less)

Incretin-based therapy for type 2 diabetes is based on the antidiabetic effects of glucagon-like peptide-1 (GLP-1) and instituted by GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors targeting the key islet defects of the disease. The treatment is clinically efficient and safe, and associated with a low risk of adverse events. It can be used both in early and late stages of the disease and both as monotherapy and add-on to other therapies. Current research on the future of incretin-based therapy focuses on optimizing its place in diabetes treatment and examines its potential in type 1 diabetes, in subjects with obesity without type 2 diabetes and in cardiovascular and neurodegenerative disorders. Other studies aim at prolonging the duration of action of the GLP-1 receptor agonists to allow weekly administration, and to develop orally GLP-1 receptor agonists. Furthermore, other investigators focus on stimulation of GLP-1 secretion by activating GLP-1-producing L-cells or using gene therapy. Finally, also other gastro-entero-pancreatic bioactive peptides are potential targets for drug development as are synthetic peptides engineered as co-agonists stimulating more than one receptor. We can therefore expect a dynamic development within this field in the coming years.

Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycaemia in patients with type 2 diabetes mellitus, with low risk for hypoglycaemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner. At hypoglycaemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycaemia with low risk for hypoglycaemia. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.

Objective: A disturbed glucose metabolism has been observed in patients with aggressive behaviour. Interleukin (IL)-1I² is a pro-inflammatory cytokine that can induce hypoglycaemia, but has also been suggested to be involved in the generation of hostility and aggression. Our group has previously shown an altered glucose metabolism in patients with self-inflicted aggressive behaviour. We investigated the hypothesis that the levels of IL-1 would be increased in these patients, because this might explain the aberrant glucose metabolism and add further knowledge to the aetiology of self-inflicted aggressive behaviour. Method: We investigated plasma cytokine changes in 13 patients with borderline personality disorder and 13 healthy controls during a 5-h glucose challenge. Plasma samples were analysed for cytokines IL-1I², TNF-I± and IL-6 using high-sensitivity multiplex ELISA. Psychiatric symptoms were rated using the Aggression Questionnaire Revised Swedish Version. Results: Basal plasma levels of the three cytokines did not differ between patients and controls. All three cytokines reacted significantly upon the glucose challenge. The increase in IL-1I² levels in response to glucose was significantly greater in patients than in controls. Furthermore, IL-1I² reactivity was associated with symptoms of hostility. Conclusion: An increased reactivity of IL-1I² might be part of a pathogenetic mechanism in patients with deliberate self-harm. (Less)

Effects of a dietary combination of omega-3 polyunsaturated fatty acids (n-3-PUFA) and conjugated linoleic acids (CLAs) on fasting and postprandial plasma lipids was investigated in healthy volunteers with different ages and body mass index (BMI). Lean (BMI 20-26 kg/m2) and obese (BMI 29-35 kg/m2), young (20-37 years) and older (50-65 years) men consumed 3 g/day each of CLA and n-3-PUFA or 6 g/day control oil for 12 weeks in a double-blinded, placebo-controlled, randomized crossover study. In older lean subjects, CLA/n-3-PUFA supplementation reduced fasting nonesterified fatty acids (NEFAs) concentrations compared with the control oil (P < 0.05). However, in older obese subjects, CLA/n-3-PUFA increased fasting low-density lipoprotein cholesterol (P < 0.05) and postprandial total cholesterol levels (P < 0.05). In young lean subjects, CLA/n-3-PUFA reduced postprandial NEFA levels (P < 0.05) whereas in young obese subjects, postprandial total cholesterol and triacylglycerols were lowered (both P < 0.05). Therefore, a dietary combination of CLA together with n-3-PUFA may have favorable effects on plasma lipids in young and older lean men but detrimental effects in older obese men. PRACTICAL APPLICATIONS This study suggests that where individuals consume a combination of both omega-3 polyunsaturated fatty acids and conjugated linoleic acid supplements in order to obtain potential additive beneficial effects of each lipid on adiposity and health, this particular fatty acid combination may have harmful effects on plasma lipid biomarkers of cardiovascular disease in older obese men. (Less)

Islet hormone secretion is regulated by a variety of factors, and many of these signal through G protein-coupled receptors (GPCRs). A novel islet GPCR is GPR54, which couples to the Gq isoform of G proteins, which in turn signal through the phospholipase C pathway. Ligands for GPR54 are kisspeptins, which are peptides encoded in the KISS1 gene and also expressed in islet beta-cells. The KISS1 gene encodes a hydrophobic 145-amino acid protein that is cleaved into a 54-amino acid protein, kisspeptin-54 or KP54. Shorter kisspeptins also exist, such as kisspeptin-10 (KP10) and kisspeptin-13 (KP13). The involvement of GPR54 and kisspeptins in the regulation of islet function is not known. To address this problem, we incubated isolated mouse islets in the presence of KP13 and KP54 for 60 min and measured insulin secretion. We found that both KP13 and KP54 at 10 nM, 100 nM and 1microM inhibited insulin secretion in the presence of 2.8 mM glucose. However, by increasing the glucose concentration, this inhibitory action of the kisspeptins vanished. Thus, at 11.1 mM glucose, KP13 and KP54 inhibited insulin secretion only at high doses, and at 16.7 mM they no longer inhibited insulin secretion in any of the doses. We conclude that kisspeptins inhibit insulin secretion at glucose concentrations below 11.1 mM. This suggests that kisspeptins are regulating insulin secretion at physiological concentrations of glucose. The mechanisms by which kisspeptins regulate islet function and insulin secretion are unknown and will be further investigated.

The influence of two sulfonylureas on blood glucose and plasma immunoreactive insulin (IRI) and C-peptide responses to a standardized meal was investigated in a patient with type 2 diabetes and a liver disease with enhanced peripheral levels of liver enzymes. The very high fasting values of plasma IRI and C-peptide were further elevated by the meal. This response to the meal was markedly enhanced by both sulfonylureas, glipizide and glibenclamide. The blood glucose increment after the meal was diminished by sulfonyl-ureas. Sulfonylureas thus seem to have beneficial effects in this diabetic patient, who had a liver disease and markedly elevated basal levels of plasma IRI and C-peptide concentrations.

A high fibre and a low fibre breakfast meal were given to eight non insulin dependent diabetics ( NIDD ), and eight controls. Blood glucose response was monitored continuously for three hours and characterized using a straight line model. After the high fibre meal the rates of increase and decrease in blood glucose concentration were slower both in diabetics and controls than after the low fibre meal. The delay time, however, i.e. the time from meal intake to the start of glucose increase, hypothetically corresponding to gastric emptying time, was the same after both test meals. The postprandial glucose increment calculated as the area under the 0-120 min curve was lower after the high fibre meal in the NIDD , but not in the controls. The two-hour C-peptide and gastric inhibitory polypeptide values were lower for the diabetics after the high fibre breakfast. The results indicate a prolonged carbohydrate digestion and/or absorption after high fibre breakfast.

In order to investigate the potential usefulness of knowing the blood concentrations of HbAI in primary care, HbAI was measured in diabetic subjects attending a primary care centre. The values were compared with concentration of HbAI in a reference group on non-diabetics. The reference group had a mean value in HbAI of 7.6+/-0.1% with a tendency to increased values with advancing age. The diabetic subjects had a mean value in HbAI of 10.8+/-0.2%. Diabetics under good control had lower values (10.2+/-0.2%), than patients under poor control (12.0+/-0.2%) (p less than 0.001). There was a correlation (r=0.50, p less than 0.001) between HbAI and fasting blood glucose levels. It is concluded that determination of HbAI can be an aid in the control of diabetics in primary care. However, the method requires good technical management, and the results are most reliable when the same person analyses all samples. The objective in diabetic therapy in this respect should no doubt be to depress the concentrations of HbAI towards normal values.

In a recent study it was demonstrated that the C-terminal octapeptide of cholecystokinin (CCK-26-33; often abbreviated CCK-8) and CCK-39 (= CCK--6-33) potently and with the same efficacy stimulated basal insulin secretion when injected intravenously to mice. In the present study, the effects of four other CCK fragments, CCK-30-33 (= CCK-4), CCK-1-33 (= CCK-33), CCK-1-21 (= CCK-21) and CCK-10-20, on basal and glucose-induced insulin secretion were studied. It was found that CCK-33 stimulated insulin secretion. At a dose level of 4.25 nmol/kg, plasma insulin concentrations were elevated by 58 +/- 7 microU/ml (P less than 0.001). On the contrary, neither CCK-4, nor CCK-21, nor CCK-10-20 displayed any effect on basal insulin secretion, not even at high dose levels. When injecting CCK-8, CCK-33 or CCK-39 at dose levels substimulatory on basal insulin secretion (0.53 nmol/kg), together with glucose, CCK-39 potentiated glucose-induced insulin secretion whereas CCK-8 and CCK-33 were without effects. In contrast, at the higher dose level of 5.3 nmol/kg, CCK-8, CCK-33, and CCK-39 all potentiated glucose-induced insulin secretion. The three other fragments, CCK-4, CCK-21, and CCK-10-20, were all without effects on glucose-induced insulin secretion. In conclusion, the potent stimulatory action on basal insulin secretion in the mouse exerted by various CCK fragments is confined to the C-terminal octapeptide (= CCK-8 or CCK-26-33).(ABSTRACT TRUNCATED AT 250 WORDS)

The system that regulates insulin secretion from beta-cells in the islet of Langerhans has a capsaicin-sensitive inhibitory component. As calcitonin gene-related peptide (CGRP)-expressing primary sensory fibers innervate the islets, and a major proportion of the CGRP-containing primary sensory neurons is sensitive to capsaicin, the islet-innervating sensory fibers may represent the capsaicin-sensitive inhibitory component. Here, we examined the expression of the capsaicin receptor, vanilloid type 1 transient receptor potential receptor (TRPV1) in CGRP-expressing fibers in the pancreatic islets, and the effect of selective elimination of capsaicin-sensitive primary afferents on the decline of glucose homeostasis and insulin secretion in Zucker diabetic fatty (ZDF) rats, which are used to study various aspects of human type 2 diabetes mellitus. We found that CGRP-expressing fibers in the pancreatic islets also express TRPV1. Furthermore, we also found that systemic capsaicin application before the development of hyperglycemia prevents the increase of fasting, non-fasting, and mean 24-h plasma glucose levels, and the deterioration of glucose tolerance assessed on the fifth week following the injection. These effects were accompanied by enhanced insulin secretion and a virtually complete loss of CGRP- and TRPV1-coexpressing islet-innervating fibers. These data indicate that CGRP-containing fibers in the islets are capsaicin sensitive, and that elimination of these fibers contributes to the prevention of the deterioration of glucose homeostasis through increased insulin secretion in ZDF rats. Based on these data we propose that the activity of islet-innervating capsaicin-sensitive fibers may have a role in the development of reduced insulin secretion in human type 2 diabetes mellitus.

PACAP is an islet peptide that serves as an endogenous amplifier of glucose induced insulin secretion. Furthermore, we has recently found that PACAP also potentiates insulin stimulated glucose uptake in adipocytes. Therefore, an antidiabetic action of PACAP is possible. In the present study, we examined the effect of PACAP treatment of the hyperglycemia in GK rats, an animal model of type 2 diabetes, and in high fat fed C47BL/6J mice, an animal model for glucose intolerance. GK rats housed with normal diet exhibited a normal level of blood glucose until three weeks old but significant hyperglycemia at eight weeks. When GK rats were treated with daily PACAP38 (i.p. injection, 6 pmol/kg) from age three weeks, development of hyperglycemia was prevented. In high fat fed mice, i.p. administration of PACAP27 for five (25 nmol/kg twice daily) reduced plasma glucose levels to 6.9 +/- 0.2 mmol/l compared to 8.1 +/- 0.2 mmol/l in saline injected animals (p < 0.001) without altering baseline insulin levels. We conclude that PACAP reduces circulating glucose in animal models of type 2 diabetes and glucose intolerance. The mechanism of this action needs to be established.

objective Leptin and growth hormone-binding protein (GHBP) both show gender differences that might be explained by sex hormones. To study the potential relevance of oestradiol and testosterone, we have examined 80-year-old subjects in whom oestradiol is higher in men than in women. The interrelationships between leptin, insulin, GHBP and fat mass in this age group were also investigated. design and subjects Ninety-four subjects (55 females and 39 males), all 80 years old, were investigated in a community-based study. None of the investigated subjects was being treated for diabetes mellitus and none of the women had oestrogen replacement. methods Levels of testosterone, oestradiol, SHBG, IGF-I, GHBP, glucose, insulin and leptin were analysed. Body composition was measured with bioimpedance analysis (BIA). results As in younger age groups, serum leptin, the ratio leptin/kilogram fat mass and serum GHBP were higher in the women (all, P 0·1). Leptin correlated to kilogram fat mass in both women (r = 0·55, P 0·2). Insulin and leptin were significantly associated with GHBP, both in women (r = 0·48, P < 0·001 and r = 0·43, P = 0·001, respectively) and in men (r = 0·40, P = 0·01 and r = 0·34, P = 0·03, respectively). conclusions Although the 80-year-old men had higher oestradiol levels than the women, the women had higher levels of leptin and GHBP. There were no correlations between sex hormones and leptin and GHBP, which indicates that the gender differences are not caused by sex hormones in old age. In contrast to studies in younger subjects, GHBP did not correlate to fat mass in the investigated 80-year-old men and women. In the older subjects investigated, as in younger subjects, GHBP was significantly correlated with leptin and insulin. (Less)

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide in the autonomic nerves innervating the pancreatic islets and previous studies have shown that it stimulates insulin and glucagon secretion. It is known that autonomic nerve activation contributes to the glucagon response to hypoglycaemia. In the present study, we evaluated whether PACAP is involved in this glucagon response by examining the glucagon response to insulin-induced hypoglycaemia in mice genetically deleted of the specific PACAP receptor, the PAC1 receptor. We found that insulin (1 U kg-1 ip) reduced circulating glucose to a hypoglycaemic level of approximately 2.5 mmol L-1 in PAC1R-/- mice and their wild-type counterparts with no difference between the groups. However, the glucagon response to this hypoglycaemia was markedly impaired in the PAC1R-/- mice. Thus, after 120 min, plasma glucagon was 437 +/- 79 ng L-1 in wild-type mice vs. only 140 +/- 36 ng L-1 in PAC1R-/- mice (P=0.004). In contrast, the glucagon response to intravenously administered arginine (0.25 g kg-1) was the same in the two groups of mice. We conclude that PACAP through activation of PAC1 receptors contribute to the glucagon response to insulin-induced hypoglycaemia. Therefore, the glucagon response to hypoglycaemia is dependent not only on the classical neurotransmitters but also on the neuropeptide PACAP.

Protein elicits a stronger early (30 min) glucose-dependent insulinotropic polypeptide (GIP) response than fat ingestion in lean individuals, with no difference in glucagon-like peptide-1 (GLP-1). We assessed the incretin hormone response to protein versus fat ingestion in obesity. Equicaloric (8 kcal/kg) fat (olive oil) or protein (whey protein) was ingested by non-diabetic obese male volunteers [body mass index (BMI) >30 kg/m(2) ; n = 12] and plasma GIP and GLP-1 were determined. We found no difference in the early GIP or GLP-1 responses to fat versus protein. However, the total 300-min GIP response was greater after fat than after protein ingestion (20.3 ± 3.9 vs. 10.0 ± 2.8 nmol/l × min; p = 0.026), whereas the 300-min GLP-1 responses were the same. Thus, in obesity, protein and fat ingestion elicit similar early (30 min) incretin hormone responses, whereas 300-min GIP secretion is more pronounced after fat than protein ingestion.

To study whether free fatty acids (FFAs) contribute to glucose intolerance in high-fat fed mice, the derivative of nicotinic acid, acipimox, which inhibits lipolysis, was administered intraperitoneally (50 mg kg(-1)) to C57BL/6J mice which had been on a high-fat diet for 3 months. Four hours after administration of acipimox, plasma FFA levels were reduced to 0.46 +/- 0.06 mmol L(-1) compared with 0.88 +/- 0.10 mmol L(-1) in controls (P < 0.001). At this point, the glucose elimination rate after an intravenous glucose load (1 g kg(-1)) was markedly improved. Thus, the elimination constant (KG) for the glucose disposal between 1 and 50 min after the glucose challenge was increased from 0.54 +/- 0.01% min-1 in controls to 0.66 +/- 0.01% min-1 by acipimox (P < 0.001). In contrast, the acute insulin response to glucose (1-5 min) was not significantly different between the groups, although the area under the insulin for the entire 50-min period after glucose administration was significantly reduced by acipimox from 32.1 +/- 2.9 to 23.9 +/- 1.2 nmol L(-1) x 50 min (P = 0.036). This, however, was mainly because of lower insulin levels at 20 and 50 min because of the lowered glucose levels. In contrast, administration of acipimox to mice fed a normal diet did not affect plasma levels of FFA or the glucose elimination or insulin levels after the glucose load. It is concluded that reducing FFA levels by acipimox in glucose intolerant high-fat fed mice improves glucose tolerance mainly by improving insulin sensitivity making the ambient islet function adequate, suggesting that increased FFA levels are of pathophysiological importance in this model of glucose intolerance.

Leptin is an adipocyte hormone involved in the regulation of energy homeostasis. Its circulating levels show a diurnal rhythm with a nocturnal peak. We examined the influences of gender, feeding state, and plasma insulin and glucose on the diurnal rhythm in normal mice. Plasma was sampled at 4-h interval for 24 h in female (n = 80) and male (n = 80) mice, which were freely fed or fasted. In both genders, plasma leptin displayed a diurnal rhythm with a nadir at 8 or 10 AM and a nocturnal peak at 10 PM to 2 AM. The nocturnal increase in leptin was higher in females (+160 ± 18%) than in males (61 ± 16%; P < 0.001), completely abolished by fasting, and correlated significantly to the diurnal variation in plasma insulin both in females (r = 0.44, P = 0.003) and males (r = 0.46, P < 0.001). Baseline plasma leptin in non-fasted animals were not different between the genders, whereas during fasting, the reduction in leptin was more pronounced in males than in females, resulting in a higher plasma leptin after fasting in females Plasma insulin was higher in males under non-fasted conditions (P = 0.003), but not significantly different between genders in fasted animals In conclusion, plasma leptin displays a nocturnal increase in mice, which is more pronounced in female mice than in male mice, is completely abolished by fasting and correlates to the diurnal variation in circulating insulin It is suggested that the nocturnal rise in leptin shows gender dependency and is caused by the increase in plasma insulin caused by food intake.

OBJECTIVE Previous studies have shown that serum levels of testosterone correlate negatively with leptin and positively with insulin-like growth factor binding protein 1 (IGFBP-1). The present study examined whether these associations are linked. DESIGN AND PATIENTS The association between serum levels of IGFBP-1, free testosterone and insulin on one hand and leptin on the other hand were investigated in 38 healthy men with a median age of 48 years (range 23-62 years). RESULTS Univariate analyses revealed that serum levels of leptin correlated negatively with serum free testosterone (r = - 0.42, P = 0.008) and with serum IGFBP-1 (r = - 0. 45, P = 0.005) and positively with body mass index (BMI; r = 0.46, P = 0.003) and serum insulin (r = 0.45, P = 0.004). Serum free testosterone correlated with IGFBP-1 (r = 0.42, P = 0.008) but not with serum insulin (r = - 0.08, ns). The correlations between leptin and free testosterone and between leptin and IGFBP-1 remained significant after adjustement for the influences of BMI and insulin. Forward stepwise multiple regression when BMI, insulin, testosterone and IGFBP-1 were entered in a model as independent variables and leptin as the dependent variable showed that BMI and IGFBP-1 were independent predictors of circulating leptin. These two parameters yielded an r 2 of 0.38, thereby together explaining approximately 40% of serum leptin. CONCLUSION Serum levels of free testosterone and IGFBP-1 correlate negatively with serum leptin in healthy nonobese men but this influence is dependent on the influence of IGFBP-1. The study therefore suggests an important impact of IGFBP-1 on the regulation of circulating leptin in young and middle-aged men.

Johansson A, Ahren B, Nasman B, Carlstrom K, Olsson T (Umea University Hospital, Umea; Malmo University Hospital, Malmo; Karolinska Instituitet, Huddinge University Hospital, Huddinge, Sweden). Cortisol axis abnormalities early after stroke – relationships to cytokines and leptin. J Intern Med 2000; 247: 179–187. Objective. To assess the relationships between circulating levels of proinflammatory cytokines and adrenocortical hormones and leptin early after stroke. Design. Blood samples were collected four times daily the first two days after stroke, twice daily the next 4 days and four times at day 7. Cognitive function and functional outcome was measured at admittance and at day 7. Setting. Consecutive inclusion of patients admitted to the stroke unit at Umea University Hospital. Subjects. Eight men and 4 women with acute stroke and 10 healthy volunteers. Main outcome measures. Levels and diurnal variations of plasma proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), serum adrenocortical hormones (cortisol and DHEA) and leptin, and MMSE, SSS, and ADL scores. Results. A significant correlation was present between IL-6 and cortisol levels the first two days after stroke (P

Soderberg S, Olsson T, Eliasson M, Johnson O, Ahren B (Umea University Hospital, Lulea County Hospital and Lund University, Malmo, Sweden). Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women. J Intern Med 1999; 245: 533–543. Background. Leptin is a crucial mediator of satiety signals and energy balance, and its circulating levels are increased in obesity. It has recently been shown that plasma leptin levels in humans correlate with circulating insulin and to insulin secretion. This indicates that leptin may be an important link in metabolic consequences of the insulin resistance syndrome. Whether this includes abnormalities in fibrinolysis has not been studied. Methods and results. Healthy subjects (n = 165; 85 men and 80 women) from the Northern Sweden MONICA population were investigated. Anthropometric measurements, oral glucose tolerance tests and sampling for plasma leptin, lipids, fibrinogen and fibrinolytic variables were made. Leptin levels were 342% higher in women than in men and were in both sexes strongly correlated to body mass index (BMI). After adjustments for age and BMI, leptin levels correlated significantly to pre/post glucoseload insulin levels in both sexes. After further adjustment for baseline insulin levels, leptin levels were in males significantly associated with increased waist circumference (P

It has been proposed that leptin and insulin through central effects are involved in the regulation of energy balance and body weight. Whether circulating leptin or insulin levels predict subsequent changes in body weight is, however, not known. We examined plasma leptin and insulin at 2, 3, 6, 9 and 12 months of age in C57BI/6J mice given a normal diet (n = 12) or a high-fat diet (58% fat on a caloric base; n = 15). Plasma leptin levels increased by age and correlated with body weight in the entire material (r = 0.81, P < 0.001). Also plasma insulin increased by high-fat diet and correlated across all age periods with body weight (r = 0.56, P < 0.001). In mice, given normal diet, plasma leptin or insulin did not correlate to subsequent changes in body weight at any of the time points studied. However, in mice given the high-fat diet, plasma leptin at 6 (r = -0.57, P = 0.027) and 9 months of age (r = -0.56, P = 0.042) as well as plasma insulin at 6 (r = - 0.51, P = 0.049) and 9 months (r = -0.58, P = 0.037) correlated inversely to the change in body weight during the subsequent 3-month period. Hence, both leptin and insulin are negative predictors for future weight gain in high-fat fed mice. This suggests that when the regulation of body weight is challenged by a high-fat diet, leptin and insulin act to restrain or prevent future weight gain. This in turn may suggest that impairment of these (probably central) actions of leptin and insulin might underlie excessive increase in body weight under such conditions.

OBJECTIVES: To ascertain whether patients with Crohn's disease treated with azathioprine maintained bone mineral mass better than patients treated with steroids alone. DESIGN: Retrospective study. SETTING: University Hospital of Malmo, Sweden. SUBJECTS: A total of 59 patients with ileocolonic, ileocaecal or colonic Crohn's disease. METHODS: Bone mass was assessed by dual photon X-ray absorptiometry at the level of L2-L4. RESULTS: Patients treated with a high lifetime dose of steroids (> 5 g prednisolone) had significantly (P = 0.011) lower Z-score of L2-L4 (-0.87 +/- 1.11; 11 SD) than steroid-treated patients, who had received a low dose of prednisolone (< 5 g) (0.08 +/- 1.16 SD). Azathioprine did not negatively influence the steroid effect on bone mineral density. CONCLUSIONS: Azathioprine does not seem to affect bone mineral density by itself. However, by being steroid-saving, it seems to conserve bone mineral mass in patients with Crohn's disease. (Less)

Pancreastatin is known to be produced in islet B cells and to inhibit insulin secretion. In this study. we examined whether the peptide affects insulin secretion from the perfused rat pancreas during raising or lowering the glucose concentration within the physiological range. We found that synthetic porcine pancreastatin (15 nmol L -1 ) significantly inhibited the first phase (5 min) of insulin release induced by raising the glucose concentration from 4.2 to 8.3 mmol L -1 (P < 0.05) without affecting the second phase. Furthermore, the fall in insulin secretion induced by lowering the glucose concentration from 8.3 to 5.5 mmol L -1 was significantly exaggerated in presence of pancreastatin during the first 5 min (P < 0.05). In contrast. pancreastatin did not affect the inhibition of insulin secretion induced by either the α 2 -adrenoceptor agonist, clonidine (2 nmol L -1 ), or the P 1 -purinoceptor (A 1 -subtype) agonist. N 6 (+)-phenylisopropyladenosine (DPIA) (1.65 μmol L -1 ). In conclusion. our results show that pancreastatin is a modulator of the early changes in insulin secretion after increase or decrease of the glucose concentration within the physiological range. This suggests that pancreastatin is a modulator of glucose-stimulated insulin secretion.

Objectives. To determine the usefulness of a single, fasting blood glucose (FBG) value in measuring the prevalence of diabetes mellitus in a large, homogeneous population. Design. Fasting blood glucose and 2-h oral glucose tolerance test (OGTT) values were determined. Based on the results of the OGTT, the sensitivity and specificity of different cut-off levels of FBG for the diagnosis of diabetes were assessed. ROC (receiver operating characteristic) analysis was performed on the data. Setting. A health screening unit at the University Hospital in Malmo, Sweden. Subjects. A total of 1843 Caucasian women without known diabetes aged 55–57 years. Results. The prevalence of previously undiagnosed diabetes was 3.9% and the prevalence of impaired glucose tolerance (IGT) was 27.9% using the WHO cut-off values for 2-h blood glucose values after an OGTT. With an FBG cut-off value of 6.7 mmol IT−1, the sensitivity of a single FBG value was 36.6%. Reducing the cut-off value to 6.0 mmol L−1 increased the sensitivity to 53.4%. At a cut-off level of 4.8 mmol L−1, the sensitivity reached the high value of 85.9%, but the specificity was only 45% and the predictive value of a positive test as low as 5.9%. ROC analysis showed that the optimal cut-off value for FBG in this population was 5.3 mmol L−1, giving a sensitivity and specificity of 77% but a positive predictive value of only 11.9%. Conclusions. This study has shown that in a large and homogeneous Caucasian population of women aged 55–57 years with a high prevalence of IGT, a single FBG value is not useful as a screening tool for diabetes mellitus.

Galanin inhibits insulin secretion and has been proposed to function as a sympathetic neurotransmitter in the endocrine pancreas in some species, for example in the dog. In this study, pancreatic and adrenal gland galanin content were measured following experimental diabetes induced by alloxan in mice. Three days after administration of alloxan (70 mg kg-1, i.p.) in normal mice, pancreatic content of galanin-like immunoreactivity (GLIR) was reduced to 65 +/- 11% of that in untreated controls (P0.01), whereas adrenal gland GLIR was unchanged. Similarly, 8 days after alloxan administration, pancreatic GLIR was reduced (P0.002), whereas adrenal gland GLIR was unaffected. Pancreatic GLIR also inversely correlated with plasma glucose levels (r = -0.5055, P0.005). To distinguish between the direct effects of alloxan vs. indirect metabolic effects induced by the drug, alloxan-diabetic mice were treated with insulin twice daily, which normalized the plasma glucose levels (7.6 +/- 0.3 mmol l-1). Pancreatic GLIR was then not significantly different from controls. Thus pancreatic but not adrenal gland GLIR content is reduced in alloxan-induced diabetes in mice. The data support a role for galanin as a pancreatic sympathetic neurotransmitter which may participate in the metabolic alterations seen in alloxan diabetes in mice.