SummaryBackground: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor 7 (PPAR 7) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes.

Meal and oral glucose tests for assessment of ␤-cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab 283: E1159-E1166, 2002. First published August 6, 2002 10.1152/ajpendo.00093.2002We investigated ␤-cell function and its relationship to insulin sensitivity in 17 normal volunteers. For insulin secretion (derived by C-peptide deconvolution), a mathematical model was applied to 24-h triple-meal tests (MT) as well as oral glucose tolerance tests (OGTT); insulin sensitivity was assessed by the euglycemic insulin clamp technique. The ␤-cell model featured a glucose concentration-insulin secretion dose response (characterized by secretion at 5 mM glucose and slope), a secretion component proportional to the glucose concentration derivative, and a time-dependent potentiation factor (modulating the dose response and accounting for effects of sustained hyperglycemia and incretins). The ␤-cell dose-response functions estimated from the whole 24-h MT, the first 2 h of the MT, and the OGTT differed systematically, because a different potentiation factor was involved. In fact, potentiation was higher than average during meals (1.6 Ϯ 0.1-fold during the first meal) and had a different time course in the MT and OGTT. However, if potentiation was accounted for, the 24-and 2-h MT and the OGTT yielded similar dose responses, and most ␤-cell function parameters were intercorrelated (r ϭ 0.50-0.86, P Յ 0.05). The potentiation factor was found to be related to plasma glucose-dependent insulin-releasing polypeptide concentrations (r ϭ 0.49, P Ͻ 0.0001). Among ␤-cell function parameters, only insulin secretion at 5 mM glucose from MT correlated inversely with insulin sensitivity (24-h MT: r ϭ Ϫ0.74, P Ͻ 0.001; 2-h MT: r ϭ Ϫ0.52, P Ͻ 0.05), whereas the dose-response slope and the OGTT parameters did not. In nine other subjects, reproducibility of model parameters was evaluated from repeated MTs. Coefficients of variation were generally ϳ20%, but the derivative component was less reproducible. We conclude that our model for the multiple MT yields useful information on ␤-cell function, particularly with regard to the role of potentiation. With cautious interpretation, a 2-h MT or a standard OGTT can be used as surrogates of 24-h tests in assessing spontaneous ␤-cell function. insulin secretion; glucose-induced insulin release; potentiation of glucose-induced insulin release; insulin sensitivity

Targeted capture combined with massively parallel exome sequencing is a promising approach to identify genetic variants implicated in human traits. We report exome sequencing of 200 individuals from Denmark with targeted capture of 18,654 coding genes and sequence coverage of each individual exome at an average depth of 12-fold. On average, about 95% of the target regions were covered by at least one read. We identified 121,870 SNPs in the sample population, including 53,081 coding SNPs (cSNPs). Using a statistical method for SNP calling and an estimation of allelic frequencies based on our population data, we derived the allele frequency spectrum of cSNPs with a minor allele frequency greater than 0.02. We identified a 1.8-fold excess of deleterious, non-syonomyous cSNPs over synonymous cSNPs in the low-frequency range (minor allele frequencies between 2% and 5%). This excess was more pronounced for X-linked SNPs, suggesting that deleterious substitutions are primarily recessive.

Glucagon-like peptide 1 (GLP-1) is a potent glucoselowering agent of potential interest for the treatment of type 2 diabetes. To evaluate actions of NN2211, a long-acting GLP-1 derivative, we examined 11 patients with type 2 diabetes, age 59 ؎ 7 years (mean ؎ SD), BMI 28.9 ؎ 3.0 kg/m 2 , HbA 1c 6.5 ؎ 0.6%, in a double-blind, placebo-controlled, crossover design. A single injection (10 g/kg) of NN2211 was administered at 2300 h, and profiles of circulating insulin, C-peptide, glucose, and glucagon were monitored during the next 16.5 h. A standardized mixed meal was served at 1130 h. Efficacy analyses were performed for the fasting (7-8 h) and mealtime (1130 -1530 h) periods. Insulin secretory rates (ISR) were estimated by C-peptide deconvolution analysis. Glucose pulse entrainment (6 mg ⅐ kg ؊1 ⅐ min P atients with type 2 diabetes experience relative insulin deficiency as well as delayed and blunted meal-related insulin response (1). Glucagon excess contributes to the elevated fasting and postprandial glycemia (2). Because of a marked and glucosedependent insulinotropic action and a restraining effect on glucagon release, glucagon like peptide-1 (GLP-1) is an obvious candidate for the treatment of type 2 diabetes (3). In addition, GLP-1 delays gastric emptying and reduces appetite in patients with type 2 diabetes also in nonemetic doses (4). Continuous intravenous infusion and repeated subcutaneous injections of GLP-1 (7-36 amide) effectively reduce fasting plasma glucose as well as meal-related glycemia (3,5). Even in patients with type 2 diabetes and secondary failure of sulfonylurea treatment, GLP-1 has been demonstrated to reduce glycemia effectively (6).Increased ␤-cell function has been reported after overnight GLP-1 infusion, as measured by homeostasis model assessment (HOMA) and by first-and second-phase insulin secretion (7). The secretagogue effect is achieved by a concomitant increase of basal (nonpulsatile) and highfrequency pulsatile insulin release in patients with type 2 diabetes (8). In a study of ultradian insulin pulsatility, GLP-1 was reported to restore glucose entrainment in individuals with impaired glucose tolerance (9), indicating preferential effects on the coordination of insulin release.GLP-1 is rapidly cleaved by dipeptidyl-peptidase IV after both intravenous and subcutaneous injections, and the development of long-acting derivatives is needed for clinical use. NN2211 is an acylated GLP-1 derivative with prolonged action due to a combination of albumin binding, metabolic stability, and slow release from the injection site. NN2211 has shown a favorable pharmacokinetic