Insulin resistance is a major risk factor for the development of NIDDM: A low acute insulin response to glucose is an additional but weaker risk factor.

Epidemiological studies have firmly established that obesity is a major risk factor for the development of Type II (non-insulin-dependent) diabetes mellitus [1±4]. Obesity does not, however, invariably result in diabetes and many people who are very obese are able to maintain normal glucose tolerance. The reason why some people with obesity develop Type II diabetes and others do not is largely not known.There is good evidence that differences in body fat distribution play a part [3±9]. A large number of cross-sectional studies have shown that obese people with an abdominal pattern of fat accumulation are Diabetologia (2000) Abstract Aims/hypothesis. Cross-sectional studies indicate that enlarged subcutaneous abdominal adipocyte size is associated with hyperinsulinaemia, insulin resistance and glucose intolerance. To further explore the pathophysiological significance of these associations, we examined prospectively whether enlarged subcutaneous abdominal adipocyte size predicts Type II (non-insulin-dependent) diabetes mellitus. Methods. Body composition (hydrodensitometry), mean subcutaneous abdominal adipocyte size (fat biopsy), insulin sensitivity (hyperinsulinaemic clamp) and the acute insulin secretory response (25-g i. v. GTT) were assessed in 280 Pima Indians with either normal (NGT), impaired (IGT) or diabetic glucose tolerance (75-g OGTT). Subjects with NGT were then followed prospectively. Results. After adjusting for age, sex and per cent body fat, mean subcutaneous abdominal adipocyte size was 19 % and 11 % higher in subjects with diabetes and IGT, compared with those with NGT (p < 0.001). Insulin sensitivity was inversely correlated with mean subcutaneous abdominal adipocyte size (r = ±0.53, p < 0.0001), even after adjusting for per cent body fat (r = ±0.31, p < 0.001). In 108 NGT subjects followed over 9.3 4.1 years (33 of whom developed diabetes), enlarged mean subcutaneous abdominal adipocyte size but not high per cent body fat, was an independent predictor of diabetes, in addition to a low insulin sensitivity and acute insulin secretory response [relative hazard 10 th vs 90 th centile (95 % CI): 5.8 (1.7±19.6), p < 0.005]. In 28 NGT subjects with a 9 % weight gain over 2.7 1.3 years, changes in insulin sensitivity were inversely and independently related to changes in mean subcutaneous abdominal adipocyte size and per cent body fat. Conclusion/interpretation. Although enlarged mean subcutaneous abdominal adipocyte size is associated with insulin resistance cross-sectionally, prospectively, both abnormalities are independent and additive predictors of Type II diabetes. [Diabetologia (2000

Vildagliptin is an incretin degradation inhibitor that improves beta-cell function in diabetic patients by increasing the insulin secretory tone.

This trial (NCT00099866) is registered with ClinicalTrials.gov. AbstractAims To evaluate the ability of vildagliptin and metformin to sustain reductions in HbA 1c over a 1-year treatment period in drug-naïve patients with Type 2 diabetes (Type 2 DM).Methods Double-blind, randomized, multicentre, active-controlled, parallel-group study of 52-week treatment with vildagliptin (100 mg daily, n = 526) or metformin (titrated to 2000 mg daily, n = 254) in drug-naïve patients (baseline HbA 1c = 7.5-11.0%). HbA 1c was measured periodically over 1 year.Results Vildagliptin and metformin each rapidly decreased HbA 1c from an equal baseline of 8.7%. Most of the HbA 1c reduction was attained by week 12, and the efficacy was sustained throughout 1-year treatment with both agents. At the study end, significant HbA 1c reductions from baseline were seen with both vildagliptin (-1.0 ± 0.1%, P < 0.001) and metformin (-1.4 ± 0.1%, P < 0.001); however, statistical non-inferiority of 50 mg vildagliptin twice daily to 1000 mg metformin twice daily was not established. Body weight did not change during the 1-year treatment with vildagliptin (0.3 ± 0.2 kg, P = 0.17) and decreased in metformin-treated patients (-1.9 ± 0.3 kg, P < 0.001). The proportion of patients experiencing an adverse event was 70.1 vs. 75.4% in patients receiving vildagliptin and metformin, respectively. The proportion of patients experiencing a gastrointestinal adverse event was twofold higher in the metformin group, driven by a 3-4-fold greater incidence of diarrhoea, nausea and abdominal pain. The incidence of hypoglycaemia was similarly low in both groups ( < 1%).Conclusions A clinically meaningful decrease in HbA 1c that was sustained throughout a 1-year treatment in drug-naïve patients with Type 2 DM was seen with both metformin and vildagliptin monotherapy. Diabet. Med. 24, 955-961 (2007)

OBJECTIVE -To examine the effects of dipeptidyl peptidase-IV (DPP-4) inhibition on meal-related ␤-cell function and insulin sensitivity over 52 weeks in type 2 diabetes. RESEARCH DESIGN AND METHODS-In a 12-week core study, placebo (n ϭ 51) or vildagliptin (n ϭ 56; 50 mg OD) was added to metformin treatment (1.5-3.0 mg/day). A 40-week extension followed in 71 patients. Meal tests were performed at 0, 12, 24, and 52 weeks; glucose, insulin, and C-peptide were evaluated.RESULTS -In subjects completing 52 weeks with participation in all meal tests (n ϭ 57), HbA 1c (A1C) decreased in the vildagliptin/metformin group (VM group, n ϭ 31) but increased in the placebo/metformin group (PM group, n ϭ 26; between-group difference Ϫ1.0 Ϯ 0.2%; P Ͻ 0.001; baseline of all subjects combined 7.7 Ϯ 0.1%). Also, fasting glucose decreased in the VM group but increased in the PM group (difference Ϫ0.9 Ϯ 0.3 mmol/l, P ϭ 0.016; baseline 9.8 Ϯ 0.3 mmol/l). Insulin secretion (postmeal suprabasal area under the 0-to 30-min C-peptide curve divided by the 30-min increase in glucose) was increased in the VM group but was reduced in the PM group (difference ϩ0.011 Ϯ 0.03 pmol/l 30 min/mmol/l, P ϭ 0.018; baseline 0.036 Ϯ 0.02). Insulin sensitivity during meal ingestion (oral glucose insulin sensitivity) increased in the VM group but was not altered in the PM group (difference ϩ27 Ϯ 4 ml ⅐ min Ϫ1 ⅐ m Ϫ2 , P ϭ 0.036; baseline 246 Ϯ 6). Insulin secretion related to insulin sensitivity (adaptation index) increased in the VM group but decreased in the PM group (difference ϩ3.2 Ϯ 1.0, P ϭ 0.040; baseline 9.1 Ϯ 0.5). The change in adaptation index correlated to the change in A1C (r ϭ Ϫ0.39, P ϭ 0.004).CONCLUSIONS -This study presents evidence that DPP-4 inhibition by vildagliptin when added to metformin in type 2 diabetes over 52 weeks improves ␤-cell function along with improved postmeal insulin sensitivity. Diabetes Care 28:1936 -1940, 2005T he enzyme dipeptidyl peptidase-IV (DPP-4) inactivates glucagon-like peptide-1 (GLP-1) (1). Since GLP-1 has antidiabetic actions (2), prevention of its inactivation by DPP-4 inhibition is currently explored as a novel approach for treatment of type 2 diabetes (3). DPP-4 inhibition thereby shows antidiabetic action both in animal models of diabetes (4 -6) and in patients with type 2 diabetes (7-9).One of the DPP-4 inhibitors in clinical development is vildagliptin (previously called LAF237) (10). Vildagliptin has thus been shown to inhibit plasma DPP-4 activity, increase circulating levels of intact GLP-1, and improve glycemic control in diabetic patients (8,9). Although several mechanisms may contribute to the improved metabolic control by DPP-4 inhibition, in comparison to the actions of GLP-1 (2), previous studies have indicated the importance of increased insulin secretion. Thus, a standardized meal test performed before and after 28 days of treatment with the DPP-4 inhibitors NVPDPP728 and vildagliptin showed sustained insulin levels in the presence of reduced circulating glycemia in drug-naïve patients (7,8...

Aims/hypothesis We assessed the effects of vildagliptin, a novel dipeptidyl peptidase IV inhibitor, on postprandial lipid and lipoprotein metabolism in patients with type 2 diabetes. Subjects, materials and methods This was a single-centre, randomised, double-blind study in drug-naive patients with type 2 diabetes. Patients received vildagliptin (50 mg twice daily, n=15) or placebo (n=16) for 4 weeks. Triglyceride, cholesterol, lipoprotein, glucose, insulin, glucagon and glucagon-like peptide-1 (GLP-1) responses to a fat-rich mixed meal were determined for 8 h postprandially before and after 4 weeks of treatment. Results Relative to placebo, 4 weeks of treatment with vildagliptin decreased the AUC 0-8h for total trigyceride by 22±11% (p=0.037), the incremental AUC 0-8h for total triglyceride by 85±47% (p=0.065), the AUC 0-8h for chylomicron triglyceride by 65±19% (p=0.001) and the IAUC 0-8h for chylomicron triglyceride by 91±28% (p=0.002). This was associated with a decrease in chylomicron apolipoprotein B-48 (AUC 0-8h , −1.0±0.5 mg l −1 h, p=0.037) and chylomicron cholesterol (AUC 0-8h , −0.14± 0.07 mmol l −1 h, p=0.046). Consistent with previous studies, 4 weeks of treatment with vildagliptin also increased intact GLP-1, suppressed inappropriate glucagon secretion, decreased fasting and postprandial glucose, and decreased HbA 1c from a baseline of 6.7% (change, −0.4±0.1%, p<0.001), all relative to placebo. Conclusions/interpretation Treatment with vildagliptin for 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal. The mechanisms underlying the effects of this dipeptidyl peptidase IV inhibitor on postprandial lipid metabolism remain to be explored.

Aims/Hypothesis: Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A 1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration.Methods: Sixteen patients with type 2 diabetes (age, 48 Ϯ 3 yr; body mass index, 34.4 Ϯ 1.7 kg/m 2 ; hemoglobin A 1c , 9.0 Ϯ 0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-3 H-glucose iv and 1-14 C-glucose orally).Results: After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02 Ϯ 0.06 vs. 0.74 Ϯ 0.06 mg⅐kg Ϫ1 ⅐min Ϫ1 ; P ϭ 0.004), and insulin secretion rate increased by 21% (P ϭ 0.003) despite significant reduction in mean plasma glucose (213 Ϯ 4 vs. 230 Ϯ 4 mg/dl; P ϭ 0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P ϭ 0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P Ͻ 0.02). The decline in EGP was positively correlated (r ϭ 0.55; P Ͻ 0.03) with the decrease in fasting plasma glucose (change ϭ Ϫ14 mg/dl). Conclusions

Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.