OBJECTIVE -Glucagon-like peptide-1 (GLP-1) has been proposed as a new treatment modality for type 2 diabetes. To circumvent the drawback of the short half-life of GLP-1, inhibitors of the GLP-1-degrading enzyme dipeptidyl peptidase IV (DPP IV) have been examined. Such inhibitors improve glucose tolerance in insulin-resistant rats and mice. In this study, we examined the 4-week effect of 1- [[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP DPP728), a selective, orally active inhibitor of DPP IV, in subjects with diet-controlled type 2 diabetes in a placebo-controlled double-blind multicenter study. -A total of 93 patients (61 men and 32 women), aged 64 Ϯ 9 years (means Ϯ SD) and with BMI 27.3 Ϯ 2.7 kg/m 2 , entered the study. Fasting blood glucose was 8.5 Ϯ 1.5 mmol/l, and HbA 1c was 7.4 Ϯ 0.7%. Before and after treatment with NVP DPP728 at 100 mg ϫ 3 (n ϭ 31) or 150 mg ϫ 5 (n ϭ 32) or placebo (n ϭ 30), subjects underwent a 24-h study with standardized meals (total 2,000 kcal). RESEARCH DESIGN AND METHODSRESULTS -Compared with placebo, NVP DPP728 at 100 mg t.i.d. reduced fasting glucose by 1.0 mmol/l (mean), prandial glucose excursions by 1.2 mmol/l, and mean 24-h glucose levels by 1.0 mmol/l (all P Ͻ 0.001). Similar reductions were seen in the 150-mg b.i.d. treatment group. Mean 24-h insulin was reduced by 26 pmol/l in both groups (P ϭ 0.017 and P ϭ 0.023).Although not an efficacy parameter foreseen in the study protocol, HbA 1c was reduced to 6.9 Ϯ 0.7% in the combined active treatment groups (P Ͻ 0.001). Laboratory safety and tolerability was good in all groups.CONCLUSIONS -We conclude that inhibition of DPP IV is a feasible approach to the treatment of type 2 diabetes in the early stage of the disease. Diabetes Care 25:869 -875, 2002T he gut hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are both incretin hormones that are released postprandially and markedly augment glucose-stimulated insulin secretion through sensitizing the ␤-cell action of glucose (1-3). GLP-1 also exhibits other effects of importance for glucose homeostasis, viz., inhibiting glucagon secretion, delaying gastric emptying, and stimulating insulin biosynthesis (2,3). These effects, along with a potential increase in peripheral insulin action (4), will together be antidiabetogenic. GLP-1 has also been shown to reduce postprandial and fasting glycemia in subjects with type 1 and type 2 diabetes (3,4 -9) and may, therefore, be a potentially useful new therapeutic agent in the treatment of diabetes. However, GLP-1 is rapidly degraded in plasma by the enzyme dipeptidyl peptidase IV (DPP IV), resulting in the short circulating half-life of intact GLP-1 being Ͻ1 min (3,10,11). Therefore, GLP-1 is unattractive as chronic therapy because multiple daily injections are required to maintain glycemic control.The short half-life of GLP-1 has prompted development of alternate strategies to harness the potent antidiabetic activity of GLP-1. One approach is to inhibit DPP IV activity, thereb...

Aims/hypothesis: The aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight. Methods: HLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skåne (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW). Results: Genotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08-1.33], p=0.0006). The HLA-DQB1*0603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB1*0603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]= 0.72 [0.56-0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors. Conclusions/interpretation: HLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes.

It has previously been demonstrated that plasma leptin correlates to body fat content. Increased body fat content is accompanied by low insulin sensitivity, which is compensated with increased insulin secretion. We therefore studied whether plasma levels of leptin also correlate to insulin secretion and sensitivity in humans. Therefore, we examined insulin sensitivity by the euglycemic-hyperinsulinemic clamp technique and measured the insulin response to intravenous arginine (5 g) at fasting and 14 mmol/l glucose in postmenopausal women. Percent body fat content was determined with impedance measurements. Log plasma leptin significantly correlated to percent body fat (r = 0.84, P < 0.001). In women with normal glucose tolerance (n = 36), partial correlation studies controlling for body fat content revealed significant correlations between log plasma leptin and fasting insulin levels (r = 0.39, P = 0.029), the insulin response to arginine at both glucose levels (r = 0.38 and r = 0.37, P < 0.036 for both), and the glucose potentiation of arginine-stimulated insulin secretion (r = 0.40, P = 0.025). In contrast, in women with impaired glucose tolerance (n = 17), these correlations were not significant. Plasma leptin did not correlate with insulin sensitivity independently of body fat content. To study whether the correlation between leptin and insulin would be explained by insulin stimulating leptin secretion, we examined plasma leptin during hyperinsulinemic conditions (689 +/- 41 pmol/l), under both euglycemia (5.0 mmol/l, n = 10) and hypoglycemia (2.5 mmol/l, n = 7). However, under both these conditions, plasma leptin was unaltered. In conclusion, plasma leptin 1) reflects body fat content and 2) correlates to insulin secretion independently of percent body fat in postmenopausal women with normal glucose tolerance.

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We investigate the consequences of generalizing certain well established properties of the open string metric to the conjectured open membrane and open Dpbrane metrics. By imposing deformation independence on these metrics their functional dependence on the background fields can be determined including the notorious conformal factor. In analogy with the non-commutativity parameter Θ µν in the string case, we also obtain 'generalized' theta parameters which are rank (q + 1) antisymmetric tensors (polyvectors) for open Dq-branes and rank 3 for the open membrane case. The expressions we obtain for the open membrane quantities are expected to be valid for general background field configurations, while the open D-brane quantities are only valid for one parameter deformations. By reducing the open membrane data to five dimensions, we show that they, modulo a subtlety with implications for the relation between OM-theory and NCYM, correctly generate the open string and open D2-data.