Proportion of participants with type 2 diabetes achieving a metabolic composite endpoint with once-weekly semaglutide treatment versus comparators: Post hoc pooled analysis from SUSTAIN 1-5, 7-10 and SUSTAIN China.

AIM: To compare the proportion of participants with type 2 diabetes (T2D) treated with once-weekly (OW) subcutaneous (SC) semaglutide versus comparators who achieved a composite metabolic endpoint. MATERIALS AND METHODS: SUSTAIN 1-5, 7-10 and SUSTAIN China trial data were pooled. Participants with T2D (aged ≥18 years) and glycated haemoglobin ≥7.0% (≥53 mmol/mol) who had been randomized to OW SC semaglutide (0.5 or 1.0 mg) or comparator in addition to background medication. Using patient-level data pooled by treatment, proportions of participants achieving the metabolic composite endpoint, defined as glycated haemoglobin <7% (<53 mmol/mol), blood pressure <140/90 mmHg and non-high-density lipoprotein cholesterol <130 mg/dl (<3.37 mmol/L), were evaluated following baseline adjustments. Endpoints were analysed per trial using a binomial logistic regression model with treatment, region/country and stratification factor as fixed effects and baseline value as covariate. Pooled analysis used logistic regression with treatment and trial as fixed effects and baseline value as covariate. RESULTS: This post hoc analysis included data from 7633 participants across 10 trials. The proportion of participants who achieved the metabolic composite endpoint was significantly higher with OW SC semaglutide 0.5 and 1.0 mg versus comparators (23.7% and 32.0% vs. 11.5%, respectively; p < .0001). Likewise, when the OW SC semaglutide doses were pooled, significantly higher proportions of patients receiving semaglutide achieved the composite metabolic endpoint versus comparators (29.1% vs. 11.4%, respectively; p < .0001). CONCLUSIONS: Treatment with OW SC semaglutide versus comparators was associated with increased proportions of participants with T2D meeting the composite metabolic endpoint.

Ageing-related changes in nap neuroscillatory activity are mediated and moderated by grey matter volume.

Ageing-related changes in grey matter result in changes in the intensity and topography of sleep neural activity. However, it is unclear whether these findings can be explained by ageing-related differences in sleep pressure or circadian influence. The current study used high-density electroencephalography to assess how grey matter volume differences between young and older adults mediate and moderate neuroscillatory activity differences during a midday nap following a motor sequencing task. Delta, theta, and sigma amplitude were reduced in older relative to young adults, especially over frontocentral scalp, leading to increases in relative delta frontality and relative sigma lateral centroposteriority. Delta reductions in older adults were mediated by grey matter loss in frontal medial cortex, primary motor cortex, thalamus, caudate, putamen, and pallidum, and were moderated by putamen grey matter volume. Theta reductions were mediated by grey matter loss in primary motor cortex, thalamus, and caudate, and were moderated by putamen and pallidum grey matter volume. Sigma changes were moderated by putamen and pallidum grey matter volume. Moderation results suggested that across frequencies, young adults with more grey matter had increased activity, whereas older adults with more grey matter had unchanged or decreased activity. These results provide a critical extension of previous findings from overnight sleep in a midday nap, indicating that they are not driven by sleep pressure or circadian confounds. Moreover, these results suggest brain regions associated with motor sequence learning contribute to sleep neural activity following a motor sequencing task.

Encoding and consolidation of motor sequence learning in young and older adults.

Sleep benefits motor memory consolidation in young adults, but this benefit is reduced in older adults. Here we sought to understand whether differences in the neural bases of encoding between young and older adults contribute to aging-related differences in sleep-dependent consolidation of an explicit variant of the serial reaction time task (SRTT). Seventeen young and 18 older adults completed two sessions (nap, wake) one week apart. In the MRI, participants learned the SRTT. Following an afternoon interval either awake or with a nap (recorded with high-density polysomnography), performance on the SRTT was reassessed in the MRI. Imaging and behavioral results from SRTT performance showed clear sleep-dependent consolidation of motor sequence learning in older adults after a daytime nap, compared to an equal interval awake. Young adults, however, showed brain activity and behavior during encoding consistent with high SRTT performance prior to the sleep interval, and did not show further sleep-dependent performance improvements. Young adults did show reduced cortical activity following sleep, suggesting potential systems-level consolidation related to automatization. Sleep physiology data showed that sigma activity topography was affected by hippocampal and cortical activation prior to the nap in both age groups, and suggested a role of theta activity in sleep-dependent automatization in young adults. These results suggest that previously observed aging-related sleep-dependent consolidation deficits may be driven by aging-related deficiencies in fast learning processes. Here we demonstrate that when sufficient encoding strength is reached with additional training, older adults demonstrate intact sleep-dependent consolidation of motor sequence learning.

Mixed meal ingestion diminishes glucose excursion in comparison with glucose ingestion via several adaptive mechanisms in people with and without type 2 diabetes.

AIMS: To study the integrative impact of macronutrients on postprandial glycaemia, ß-cell function, glucagon and incretin hormones in humans. METHODS: 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). ß-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. RESULTS: 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. ß-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. CONCLUSIONS: Adding protein and fat macronutrients to glucose in a mixed meal diminished glucose excursion. This occurred in association with increased ß-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.

Musical Meter Modulates the Allocation of Attention across Time.

Dynamic attending theory predicts that attention is allocated hierarchically across time during processing of hierarchical rhythmic structures such as musical meter. ERP research demonstrates that attention to a moment in time modulates early auditory processing as evidenced by the amplitude of the first negative peak (N1) approximately 100 msec after sound onset. ERPs elicited by tones presented at times of high and low metric strength in short melodies were compared to test the hypothesis that hierarchically structured rhythms direct attention in a manner that modulates early perceptual processing. A more negative N1 was observed for metrically strong beats compared with metrically weak beats; this result provides electrophysiological evidence that hierarchical rhythms direct attention to metrically strong times during engaged listening. The N1 effect was observed only on fast tempo trials, suggesting that listeners more consistently invoke selective processing based on hierarchical rhythms when sounds are presented rapidly. The N1 effect was not modulated by musical expertise, indicating that the allocation of attention to metrically strong times is not dependent on extensive training. Additionally, changes in P2 amplitude and a late negativity were associated with metric strength under some conditions, indicating that multiple cognitive processes are associated with metric perception.

Dipeptidyl peptidase 4 (DPP-4) is expressed in mouse and human islets and its activity is decreased in human islets from individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4), which cleaves and inactivates glucagon-like peptide 1 (GLP-1), is a glucose-lowering strategy in type 2 diabetes. Since DPP-4 is a ubiquitously distributed enzyme, we examined whether it is expressed in islets and whether an islet effect to inhibit DPP-4 may result in stimulated insulin secretion. METHODS: We investigated DPP-4 expression and activity in the islets of mouse models of obesity as well as human islets from non-diabetic and type 2 diabetic donors. We further investigated whether inhibition with DPP-4 inhibitors could promote insulin secretion via islet GLP-1 in isolated islets. RESULTS: DPP-4 was readily detected in mouse and human islets with species-specific cellular localisation. In mice, DPP-4 was expressed predominantly in beta cells, whereas in humans it was expressed nearly exclusively in alpha cells. DPP-4 activity was significantly increased in islets from diet-induced obese mice compared with mice fed a control diet. In humans, DPP-4 activity was significantly lower in islets from type 2 diabetic donors than in non-diabetic donors. In human islets, there was a significant positive correlation between DPP-4 activity and insulin secretory response to 16.7 mmol/l glucose. Treatment of mouse islets with the DPP-4 inhibitors, NVPDPP728 and vildagliptin, resulted in a significant potentiation of insulin secretion in a GLP-1-dependent manner, as this was inhibited by the GLP-1 receptor antagonist, Exendin (9-39), and was retained in glucose-dependent insulinotropic polypeptide (GIP) receptor-deficient mice but lost in mice lacking GLP-1 receptors or both incretin receptors. Human islets treated with the DPP-4 inhibitor, vildagliptin, showed increased secretion of insulin and intact GLP-1. CONCLUSIONS/INTERPRETATION: We conclude that DPP-4 is present and active in mouse and human islets, is regulated by the disease state, and that inhibition of islet DPP-4 activity can have direct effects on islet function. Inhibiting islet DPP-4 activity may therefore contribute to the insulin-secretory and glucose-lowering action of DPP-4 inhibition.

Glucagon dynamics during hypoglycaemia and food-re-challenge following treatment with vildagliptin in insulin-treated patients with type 2 diabetes.

AIMS: To determine the effects of dipeptidyl peptidase-4 (DPP-4) inhibition on glucagon dynamics in patients with insulin-treated type 2 diabetes (T2D). METHODS: The study was a single-centre, double-blind, randomized, placebo controlled crossover study in patients with T2D, mean age 59 ± 6 (s.d.) years and mean haemoglobin A1c 7.7 ± 0.8%, treated with exogenous insulin with or without oral antihyperglycaemic agents. Patients received vildagliptin (50 mg BID) or placebo as add-on to insulin for 4 weeks in random order with a 4-week washout in-between. On day 28 of the respective treatment, patients were served a standard meal (500 kcal) followed by a hyperinsulinaemic hypoglycaemic clamp (target 2.5 mmol/l) and a subsequent food re-challenge (700 kcal). The completers population (n = 29) was analysed. RESULTS: Glucose levels were lower with vildagliptin than with placebo during the meal [areas under the curve (AUC) 1.23 ± 0.07 vs. 1.46 ± 0.05 mol/l min, P < 0.001] and similar between the groups during the clamp. During the meal, glucagon levels were lower with vildagliptin (AUC 1.98 ± 0.15 vs. 2.15 ± 0.17 nmol/l min, P = 0.016). In contrast, the glucagon counter-regulation to the insulin-induced hypoglycaemia was sustained by vildagliptin (6.05 ± 1.20 pmol/l during vildagliptin vs.6.94 ± 1.09 pmol/l during placebo, NS). During the food re-challenge after hypoglycaemia, glucagon levels were, again, significantly lower after vildagliptin (AUC 1.30 ± 0.11 vs. 1.52 ± 0.12 nmol/l min, P < 0.039). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels were significantly elevated by vildagliptin compared to placebo during meal, hypoglycaemia and food re-challenge. CONCLUSIONS: Vildagliptin action to block GLP-1 and GIP inactivation by DPP-4 improves glucagon dynamics during hypoglycaemia, hyperglycaemia and food re-challenge.

Pronounced reduction of postprandial glucagon by lixisenatide: a meta-analysis of randomized clinical trials.

AIM: 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 20 µg 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: -4.9 mmol/l, p < 0.001) and glucose excursion (LS mean difference vs. placebo: -4.5 mmol/l, p < 0.001). As measured in two studies, lixisenatide also reduced postprandial glucagon (LS mean difference vs. placebo: -19.0 ng/l, p < 0.001) and insulin (LS mean difference vs. placebo: -64.8 pmol/l, p < 0.001). There was a stronger correlation between 2-h postprandial glucagon and 2-h PPG with lixisenatide than with placebo. CONCLUSIONS: Lixisenatide significantly reduced 2-h PPG and glucose excursion together with a marked reduction in postprandial glucagon and insulin; thus, lixisenatide appears to have biological effects on blood glucose that are independent of increased insulin secretion. These effects may be, in part, attributed to reduced glucagon secretion.

Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model.

AIMS/HYPOTHESIS: Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old). METHODS: After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. RESULTS: Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice. CONCLUSIONS/INTERPRETATION: In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.

Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials.

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. Mantel-Haenzel odds ratio (MH-OR) 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 MH-OR (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.

Glucose-lowering effect of the DPP-4 inhibitor sitagliptin after glucose and non-glucose macronutrient ingestion in non-diabetic subjects.

AIM: Recent studies suggest that the incretin concept is not restricted to glucose ingestion but relevant also after non-glucose macronutrient administration. We therefore hypothesized that raising incretin hormones reduces circulating glucose after both glucose and non-glucose macronutrient ingestion in healthy subjects. METHODS: Twelve healthy subjects received the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg) or placebo before ingestion of glucose, fat (olive oil) or protein mix in equicaloric amounts (8 kcal/kg) plus paracetamol (1.5 g). The 120-min areas under curve (AUC) of intact glucagon-like peptide-1 (GLP-1), glucose, insulin, C-peptide, glucagon and paracetamol, and model-derived insulin secretion rate (ISR), insulin sensitivity, insulin clearance and glucose absorption were measured. RESULTS: The increased plasma intact GLP-1 levels after each macronutrient was augmented by sitagliptin. This was associated with a robust lowering of glucose: glucose excursion after oral glucose was diminished, and glucose fell below baseline after oral fat and protein. In spite of lower glucose, AUCC -peptide and ISR did not differ significantly between sitagliptin and placebo after any macronutrient. AUCglucagon , insulin sensitivity and insulin clearance were also not different between sitagliptin and placebo. Glucose absorption after oral glucose was reduced by sitagliptin, whereas AUCparacetamol was not statistically different between sitagliptin and placebo. CONCLUSIONS: Physiological elevation of intact GLP-1 levels after ingestion of glucose and non-glucose macronutrients is robustly glucose-lowering in healthy subjects. Hence, the incretin concept is not restricted to glucose ingestion in normal physiology. The glucose-lowering action of sitagliptin at these low glucose levels in healthy subjects may have complex mechanisms, involving both islet-dependent and islet-independent mechanisms.

Sitagliptin and pioglitazone provide complementary effects on postprandial glucose and pancreatic islet cell function.

AIMS: The effects of sitagliptin and pioglitazone, alone and in combination, on α- and ß-cell function were assessed in patients with type 2 diabetes. METHODS: Following a 6-week diet/exercise period, 211 patients with HbA1c of 6.5-9.0% and fasting plasma glucose of 7.2-14.4 mmol/l were randomized (1 :1 :1 : 1) to sitagliptin, pioglitazone, sitagliptin + pioglitazone or placebo. At baseline and after 12 weeks, patients were given a mixed meal followed by frequent blood sampling for measurements of glucose, insulin, C-peptide and glucagon. RESULTS: After 12 weeks, 5-h glucose total area under the curve (AUC) decreased in all active treatments versus placebo; reduction with sitagliptin + pioglitazone was greater versus either monotherapy. The 5-h insulin total AUC increased with sitagliptin versus all other treatments and increased with sitagliptin + pioglitazone versus pioglitazone. The 3-h glucagon AUC decreased with sitagliptin versus placebo and decreased with sitagliptin + pioglitazone versus pioglitazone or placebo. Φ(s), a measure of dynamic ß-cell responsiveness to above-basal glucose concentrations, increased with either monotherapy versus placebo and increased with sitagliptin + pioglitazone versus either monotherapy. The insulin sensitivity index (ISI), a composite index of insulin sensitivity, improved with pioglitazone and sitagliptin + pioglitazone versus placebo. The disposition index, a measure of the relationship between ß-cell function and insulin sensitivity, improved with all active treatments versus placebo. CONCLUSIONS: Sitagliptin and pioglitazone enhanced ß-cell function (increasing postmeal Φ(s)), and sitagliptin improved α-cell function (decreasing postmeal glucagon) after 12 weeks in patients with type 2 diabetes. Through these complementary mechanisms of action, the combination of sitagliptin and pioglitazone reduced postmeal glucose more than either treatment alone.

Islet nerves in focus--defining their neurobiological and clinical role.

Although it is well established that the pancreatic islets are innervated by autonomic nerves, the detailed islet innervation pattern is still unclear. In this issue of Diabetologia (DOI: 10.1007/s00125-012-2699-6 ) novel details of the islet neuroanatomy and its plasticity in experimental diabetes are described. By using a 3-dimensional (3-D) imaging technique, it has been shown that, in islets from normal mice, sympathetic nerves mainly form a neurovascular complex in addition to innervating peripherally located islet alpha cells. There are also pronounced changes in islet neuroanatomy in experimental diabetes. These findings suggest novel neural-islet regulatory mechanisms as well as neural involvement in the development of diabetes, and therefore advance both basic and clinical knowledge of islet neurobiology.

Using albumin to improve the therapeutic properties of diabetes treatments.

Achieving tight glycaemic control remains an unmet need for many patients with type 2 diabetes, despite improved treatments. To meet glycaemic targets, attempts have been made to improve existing drugs and to develop new classes of drugs. Recent advances include insulin analogues that more closely mimic physiologic insulin levels, and incretin-based therapies, which capitalize on the glucoregulatory properties of native glucagon-like peptide-1 (GLP-1). Although promising, these agents are associated with limitations, including hypoglycaemia with insulin, gastrointestinal adverse events with GLP-1 receptor agonists and frequent dosing with both classes. Albumin is an abundant natural drug carrier that has been used to improve the half-life, tolerability and efficacy of a number of bioactive agents. Here, we review the physiologic roles of albumin and how albumin technologies are being used to prolong duration of action of therapies for diabetes, including insulin and incretin-based therapies.

Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes-a review and meta analysis.

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.

Plasma lipid fatty acid composition, desaturase activities and insulin sensitivity in Amerindian women.

BACKGROUND AND AIMS: Two Amerindian populations--Shuar women living in the Amazonian rain forest under traditional conditions and urbanized women in a suburb of Lima were studied. The fatty acid composition in plasma lipids and the relationships between fatty acid composition and metabolic variables were studied, as well as in a reference group of Swedish women. METHODS AND RESULTS: Fasting plasma was used for analyses of glucose, insulin, leptin and fatty acid composition. Women in Lima had more body fat, higher fasting insulin and leptin and lower insulin sensitivity than the Shuar women, who had insulin sensitivity similar to Swedish women. Shuar women had very high proportions (mean; SD) of palmitoleic (13.2; 3.9%) and oleic (33.9; 3.7%) acids in the plasma cholesteryl esters with very low levels of linoleic acid (29.1; 6.1 3%), as expected on a low fat, high carbohydrate diet. The estimated activity of delta 9 (SCD-1) desaturase was about twice as high in the Shuar compared with Lima women, suggesting neo lipogenesis, while the delta 5 desaturase activity did not differ. The Lima women, as well as the Swedish, showed strong positive correlations between SCD-1 activity on the one hand and fasting insulin and HOMA index on the other. These associations were absent in the Shuar women. CONCLUSIONS: The high SCD-1 activity in the Shuar women may reflect increased lipogenesis in adipose tissue. It also illustrates how a low fat diet rich in non-refined carbohydrates can be linked to a good metabolic situation.

The future of incretin-based therapy: novel avenues--novel targets.

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.

Clinical evidence and mechanistic basis for vildagliptin's action when added to metformin.

Several new oral antidiabetic agents, known as 'gliptins' or 'enzyme dipeptidyl peptidase-IV (DPP-4) inhibitors', have been developed for the treatment of type 2 diabetes and a key clinical use of the gliptins is in combination with metformin. There are important differences in the kinetics of the interaction of different gliptins with the catalytic site of DPP-4, which may lead to varying pharmacokinetics, pharmacodynamics and dosing regimens. Therefore, individual gliptins need to be characterized and here we discuss the extensively studied DPP-4 inhibitor vildagliptin, which has binding characteristics that ensure inhibition of the enzyme beyond the presence of detectable drug levels in plasma. As vildagliptin has been used most often at doses of 50 mg once or twice daily, in combination with metformin, this review focuses on these dose regimens. All clinical trials employing vildagliptin (50 mg once or twice daily) as an add-on therapy to metformin (identified by MEDLINE search using keywords vildagliptin and metformin or known by authors to be in press) are reviewed, as is current knowledge of the mechanism of action of vildagliptin. Vildagliptin added to a stable dose of metformin elicits a dose-related decrease in both HbA1c and fasting plasma glucose. The additional efficacy seen with 50 mg twice daily [ΔHbA1c ∼- 1.1% (-12.1 mmol/mol)] relative to 50 mg once daily [ΔHbA1c ∼- 0.7% (-7.7 mmol/mol)] is attributable to an overnight effect of the evening dose of vildagliptin, with prolonged DPP-4 inhibition and elevated fasting levels of the intact and insulinotropic form of glucagon-like peptide-1 (GLP-1). Vildagliptin's therapeutic actions are primarily mediated by GLP-1 and metformin enhances vildagliptin's effect to raise plasma levels of intact GLP-1. Vildagliptin is weight-neutral and has a very low hypoglycaemic potential, explained by its remarkable ability to enhance both α-cell and ß-cell sensitivity to glucose. Therefore, vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect.

Dissociated incretin hormone response to protein versus fat ingestion in obese subjects.

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.

Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans.

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.