The stimulation of insulin vs. inhibition of glucagon secretion in relation to the antidiabetic action of glucagon-like peptide-1 (GLP-1) is not established. Here, the influence of a 4-wk increase in circulating GLP-1 by inhibition of dipeptidyl peptidase-4 (DPP-4) on 24-h glucose and insulin and glucagon responses to breakfast was studied in subjects with dietary controlled diabetes [age: 65 +/- 8 yr (SD), body mass index: 27.3 +/- 3.3 kg/m(2), fasting plasma glucose: 9.0 +/- 1.3 mmol/liter]. Compared with placebo (n = 19), a specific DPP-4 inhibitor [(1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine) (LAF237); 100 mg daily, n = 18] reduced fasting glucose by 0.70 mmol/liter (P = 0.037), 4-h prandial glucose excursion by 1.45 mmol/liter (P < 0.001), and mean 24-h glucose by 0.93 mmol/liter (P < 0.001). Baseline and postprandial active GLP-1 were increased by LAF237. The glucagon response to breakfast was reduced by LAF237 (glucagon levels at 60 min were 88 +/- 8 pg/ml before treatment vs. 77 +/- 5 pg/ml after; P = 0.001). In contrast, the overall insulin levels were not altered. The 4-wk reduction in glucagon correlated with the reduction in 2-h glucose (r = 0.61; P = 0.008). No such association was observed for insulin. Thus, improved metabolic control by DPP-4 inhibition in type 2 diabetes is seen in association with reduced glucagon levels and, despite the lower glycemia, unaltered insulin levels.

BackgroundDifferent healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome.MethodsWe conducted a randomized dietary study lasting for 18–24 weeks in individuals with features of metabolic syndrome (mean age 55 years, BMI 31.6 kg m−2, 67% women). Altogether 309 individuals were screened, 200 started the intervention after 4-week run-in period, and 96 (proportion of dropouts 7.9%) and 70 individuals (dropouts 27%) completed the study, in the Healthy diet and Control diet groups, respectively. Healthy diet included whole-grain products, berries, fruits and vegetables, rapeseed oil, three fish meals per week and low-fat dairy products. An average Nordic diet served as a Control diet. Compliance was monitored by repeated 4-day food diaries and fatty acid composition of serum phospholipids.ResultsBody weight remained stable, and no significant changes were observed in insulin sensitivity or blood pressure. Significant changes between the groups were found in non-HDL cholesterol (−0.18, mmol L−1 95% CI −0.35; −0.01, P = 0.04), LDL to HDL cholesterol (−0.15, −0.28; −0.00, P = 0.046) and apolipoprotein B to apolipoprotein A1 ratios (−0.04, −0.07; −0.00, P = 0.025) favouring the Healthy diet. IL-1 Ra increased during the Control diet (difference −84, −133; −37 ng L−1, P = 0.00053). Intakes of saturated fats (E%, beta estimate 4.28, 0.02; 8.53, P = 0.049) and magnesium (mg, −0.23, −0.41; −0.05, P = 0.012) were associated with IL-1 Ra.ConclusionsHealthy Nordic diet improved lipid profile and had a beneficial effect on low-grade inflammation.

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0 -34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P ‫؍‬ 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P ‫؍‬ 0.03) and with INS VNTR (P ‫؍‬ 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P ‫؍‬ 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P ‫؍‬ 0.04), and all four autoantibody markers (P ‫؍‬ 0.004). The CTLA-4 3 end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development. Diabetes 51: 1346 -1355, 2002

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...

SummaryInsulin-dependent diabetes mellitus (IDDM) is associated with autoreactivity against GAD but the diagnostic sensitivity (positivity in disease) and specificity (negativity in health) of isoform-specific GAD antibodies have yet to be defined in assay systems suitable for screening large number of samples. One set of IDDM patient (n = 10) and control (n = 50) standard sera were used to develop quantitative antibody assays with in vitro synthesized recombinant 35S-methionine-labelled GAD65 and GAD67, respectively, and protein A-Sepharose to separate free from antibody-bound ligand. Binding levels were not normally distributed (p < 0.0001) and therefore, the diagnostic accuracy of GAD antibodies was analysed by the ROC plots in population-based, consecutively-diagnosed, recent onset, 0-14year-old patients (n = 105), and matched, healthy control subjects (n = 157). The ROC plots showed that the diagnostic sensitivity of GAD65 antibodies was 77 % and the specificity 92 % compared with 8 % and 98 %, respectively for GAD67 antibodies. In the IDDM sera, GAD65 and GAD67 antibodies were concordant in 7% (6 of 81) and GAD65 antibodies and ICA in 89 % (72 of 81) without a correlation between the autoantibody levels. Autoantibodies to recombinant human islet GAD65 are specific and sensitive markers for childhood IDDM in this immunoassay with in vitro synthesized 35S-methioninelabelled recombinant GAD. [Diabetologia (1994) Abbreviations: IDDM, insulin-dependent diabetes mellitus; GAD, glutamic acid decarboxylase; ROC, receiver-operating characteristic; ICA, islet cell antibodies; JDF, Juvenile Diabetes Foundation 10p11.3-p12 [7]. GAD65 shows 65 % amino acid identity with GAD67, the isoform coded for by the GAD1 gene on chromosome 2q31 [7][8][9]. The molecular cloning of full-length human islet GAD65 [7] and rat islet GAD67 [10] cDNA has made it possible to demonstrate autoreactivity in diabetes to the recombinant proteins in both eukaryotic [11,12] and bacterial [13] expression systems. GAD65 (but not GAD67) is expressed in human islets [11,14], however, variable reactivity of patient sera has been reported [12,13,[15][16][17][18][19]. GAD65 specificity of IDDM sera was first demonstrated in our immunoprecipitation assay with recombinant GAD expressed in transfected cells [12] and recently confirmed in other assays with recombinant antigens [18,20]. The use of different assay systems and species-specific GAD65 and GAD67 may explain the lower frequency of GAD67 antibodies in these compared to previous reports [13,16]. We now report the

OBJECTIVE -Insulin detemir is a soluble long-acting basal insulin analog designed to overcome the limitations of conventional basal insulin formulations. Accordingly, insulin detemir has been compared with NPH insulin with respect to glycemic control (HbA 1c , prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration.RESEARCH DESIGN AND METHODS -People with type 1 diabetes (n ϭ 408) were randomized in an open-label, parallel-group trial of 16-week treatment duration using either insulin detemir or NPH insulin. Insulin detemir was administered twice daily using two different regimens, either before breakfast and at bedtime (IDet mornϩbed ) or at a 12-h interval (IDet 12h ). NPH insulin was administered before breakfast and at bedtime. Mealtime insulin was given as the rapid-acting insulin analog insulin aspart.RESULTS -With both insulin detemir groups, clinic fasting plasma glucose was lower than with NPH insulin (IDet 12h vs. NPH, Ϫ1.5 mmol/l [95% CI Ϫ2.51 to Ϫ0.48], P ϭ 0.004; IDet mornϩbed vs. NPH, Ϫ2.3 mmol/l (Ϫ3.32 to Ϫ1.29), P Ͻ 0.001), as was self-measured prebreakfast plasma glucose (P ϭ 0.006 and P ϭ 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P ϭ 0.046; 32%, P ϭ 0.002; respectively) compared with NPH insulin in the last 12 weeks of treatment, this being mainly attributable to a 53% reduction in nocturnal hypoglycemia in the IDet mornϩbed group (P Ͻ 0.001). Although HbA 1c for each insulin detemir group was not different from the NPH group, HbA 1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference Ϫ0.18% [Ϫ0.34 to Ϫ0.02], P ϭ 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P Ͻ 0.001). The NPH group gained weight during the study, but there was no change in weight in either of the insulin detemir groups (IDet 12h vs. NPH, Ϫ0.8 kg [Ϫ1.44 to Ϫ0.24], P ϭ 0.006; IDet mornϩbed vs. NPH, Ϫ0.6 kg [Ϫ1.23 to Ϫ0.03], P ϭ 0.040).CONCLUSIONS -Overall glycemic control with insulin detemir was improved compared with NPH insulin. The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person's needs. Diabetes Care 27:1081-1087, 2004L andmark studies show that intensive diabetes management delays progression of the late complications of type 1 diabetes (1,2). Although the introduction of rapid-acting insulin analogs has given improvement in postprandial blood glucose control, these analogs are not ideal for use with NPH insulin, which has inadequate duration of action to cover nighttime requirements and an undesirable peak effect ϳ5 h after administration (3). These problems, together with the high day-to-day variability in absorption (4,5), present a major barrier to achieving appropriate targets of blood glucose control.These limitations have stimulated the development of a soluble basal insulin analog that does not require resuspension before injection ...

Most autoimmune diabetes occurs in those without a diabetic relative, but few cases are identifiable prospectively. To model general population prediction, 491 consecutive newly diabetic children from all of Sweden were tested for autoantibodies to glutamate decarboxylase (GAD65ab), insulin (IAA), and islet cells (ICA), and for HLA-DQ genotypes by PCR; 415 matched control children were tested in parallel. GAD65ab sensitivity/specificity was 70/96%, versus 84/96% for ICA, 56/97% for IAA, 93/93% (any positive), 39/99.7% (all positive), and 41/99.7% (GAD65ab plus IAA). The latter's 25% predictive value was not improved by requiring concomitant high-risk HLA genotypes. GAD65ab were associated with DQA1 *0501/Bi *0201 (DQ2; P = 0.007) but not DQA1*0301/Bl*0302 (DQ8), and IAA with DQA1*0301/Bl*0302 (DQ8; P = 0.03) but not DQA1*0501/B1*0201 (DQ2). GAD65ab were more prevalent in females than males (79 vs. 63%; P < 0.0001) but did not vary with onset age nor season. Combining the three antibody assays yielded sufficient sensitivity for screening. GADab were relatively sensitive/specific for diabetes, but even with HLA marker combinations yielded predictive values insufficient for early immunointervention in the low-prevalence general population. (J. Clin. Invest. 1995. 95:1505-1511

ObjeCtiveTo investigate the long term effects of continuous subcutaneous insulin infusion (insulin pump therapy) on cardiovascular diseases and mortality in people with type 1 diabetes. DesignObservational study. PartiCiPants 18 168 people with type 1 diabetes, 2441 using insulin pump therapy and 15 727 using multiple daily insulin injections. Main OutCOMe MeasuresCox regression analysis was used to estimate hazard ratios for the outcomes, with stratification of propensity scores including clinical characteristics, risk factors for cardiovascular disease, treatments, and previous diseases. results Follow-up was for a mean of 6.8 years until December 2012, with 114 135 person years. With multiple daily injections as reference, the adjusted hazard ratios for insulin pump treatment were significantly lower: 0.55 (95% confidence interval 0.36 to 0.83) for fatal coronary heart disease, 0.58 (0.40 to 0.85) for fatal cardiovascular disease (coronary heart disease or stroke), and 0.73 (0.58 to 0.92) for all cause mortality. Hazard ratios were lower, but not significantly so, for fatal or non-fatal coronary heart disease and fatal or non-fatal cardiovascular disease. Unadjusted absolute differences were 3.0 events of fatal coronary heart disease per 1000 person years; corresponding figures were 3.3 for fatal cardiovascular disease and 5.7 for all cause mortality. When lower body mass index and previous cardiovascular diseases were excluded, results of subgroup analyses were similar to the results from complete data. A sensitivity analysis of unmeasured confounders in all individuals showed that an unmeasured confounders with hazard ratio of 1.3 would have to be present in >80% of the individuals treated with multiple daily injections versus not presence in those treated with pump therapy to invalidate the significantly lower hazard ratios for fatal cardiovascular disease. Data on patient education and frequency of blood glucose monitoring were missing, which might have influenced the observed association. COnClusiOnAmong people with type 1 diabetes use of insulin pump therapy is associated with lower cardiovascular mortality than treatment with multiple daily insulin injections.