Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsyproven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study. (HEPATOLOGY 2004;39:188 -196.)

Several previous reports of small cohorts have found significantly higher serum 1,25-dihydroxy vitamin D (1,25-vit D) in obese compared with nonobese whites. Based on these reports and on recent in vitro studies of adipocytes which suggest that administration of 1,25-vit D can stimulate lipogenesis and inhibit lipolysis, some investigators have proposed that high 1,25-vit D may play a role in promoting or maintaining adipocyte triglyceride stores in obese adults. To test the hypothesis that obesity is commonly associated with increased 1,25-vit D, we examined the relationships between calciotropic hormones and body adiposity in a large cohort of healthy adults. Serum intact PTH, 25-hydroxy vitamin D, and 1,25-vit D were measured in the postabsorptive state in 302 healthy adults who were Caucasian (n = 190; 71% female), African-American (n = 84; 89% female), and of other race/ethnicity (n = 28; 61% female). Results from the 154 obese subjects [body mass index (BMI) 37.3 +/- 5.8 kg/m(2); range, 30.1-58.2 kg/m(2)] were compared with those from 148 nonobese (BMI 25.6 +/- 2.9 kg/m(2); range, 18.0-29.9 kg/m(2)) age-, race-, and sex-matched participants. Body composition was measured by dual energy x-ray absorptiometry. Serum intact PTH was positively correlated with both BMI (r = 0.42; P < 0.0001) and body fat mass (r = 0.37; P < 0.0001). Serum 25-hydroxy vitamin D was negatively correlated with BMI (r = -0.4; P < 0.0001) and body fat mass (r = -0.41; P < 0.0001). Serum 1,25-vit D was also negatively correlated with BMI (r = -0.26; P < 0.0001) and body fat mass (r = -0.25; P = 0.0001). Serum 1,25-vit D was significantly lower in obese than nonobese subjects (105.7 +/- 41.1 vs. 124.8 +/- 36.7 pmol/liter; P < 0.0001) in both Caucasian and African-American adults. We conclude that, because 1,25-vit D concentrations fall with increasing adiposity, it appears unlikely that elevation in 1,25-vit D is an important hormonal mechanism causing or maintaining obesity in adults.

OBJECTIVE -We sought to examine racial and ethnic differences in A1C in individuals with impaired glucose tolerance (IGT).RESEARCH DESIGN AND METHODS -We studied 3,819 individuals aged Ն25 years with IGT who were found to be eligible to participant in the Diabetes Prevention Program. A1C was compared among five racial and ethnic groups before and after adjustment for factors that differed among groups or might affect glycemia including age, sex, education, marital status, blood pressure, adiposity (BMI and waist circumference), hematocrit, fasting and post-glucose load glucose levels, glucose area under the curve (AUC), ␤-cell function, and insulin resistance.RESULTS -Mean Ϯ SD A1C was 5.91 Ϯ 0.50%. Among whites, A1C was 5.80 Ϯ 0.44%, among Hispanics 5.89 Ϯ 0.46%, among Asian 5.96 Ϯ 0.45%, among American Indians 5.96 Ϯ 0.46%, and among blacks 6.19 Ϯ 0.59%. Age, sex, systolic blood pressure, diastolic blood pressure, BMI, fasting glucose, glucose AUC, corrected insulin response, and insulin resistance were each independent predictors of A1C. Adjusting for these and other factors, mean A1C levels were 5.78% for whites, 5.93% for Hispanics, 6.00% for Asians, 6.12% for American Indians, and 6.18% for blacks (P Ͻ 0.001).CONCLUSIONS -A1C levels are higher among U.S. racial and ethnic minority groups with IGT after adjustment for factors likely to affect glycemia. Among patients with IGT, A1C may not be valid for assessing and comparing glycemic control across racial and ethnic groups or as an indicator of health care disparities. Diabetes Care 30:2453-2457, 2007 Carbohydrates are covalently attached to the NH 2 -terminal valine of the ␤-chain of hemoglobin by a slow nonenzymatic process. The most common modification, glucose attachment, can be measured as A1C. Since the early 1980s, A1C has been used as a clinical measure of average glycemia over the preceding weeks and months (1,2). With publication of the results of the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study, A1C has also come to be used as a measure of risk for the development of diabetes complications.In a recent systematic review, Kirk et al. (3) summarized 21 studies that compared A1C levels across racial and ethnic groups. Seven of the nine studies that tested differences between blacks and non-Hispanic whites and four of the five that tested differences between Hispanics and non-Hispanic whites demonstrated higher A1C levels among blacks or Hispanics. The authors concluded that blacks and Hispanics with diabetes have poorer glycemic control than nonHispanic whites (3). Five additional studies compared A1C levels among racial and ethnic groups within organized systems of health care and carefully adjusted for processes of care (4 -8). Although adjustment for covariates attenuated racial differences in A1C, the differences between racial groups remained statistically significant. Two reports have also assessed the association between A1C and race and ethnicity in nondiabetic populations. Eberhardt et al. (9) analyzed data ...

OBJECTIVE -To validate fasting indices of insulin sensitivity and secretion in a diverse pediatric population against gold standard estimates from euglycemic and hyperglycemic clamps. RESEARCH DESIGN AND METHODS-A total of 31 children (mean BMI 25.1 Ϯ 4.9 kg/m 2 , mean age 8.7 Ϯ 1.4 years, 15 girls and 16 boys, 12 black and 19 white) underwent euglycemic and hyperglycemic clamps 2-6 weeks apart to derive insulin sensitivity indices (SI Eug clamp and SI Hyper clamp ). Fasting samples were used to derive the homeostasis model assessment of insulin resistance index (HOMA-IR), HOMA of percent ␤-cell function (HOMA-B%), quantitative insulin sensitivity check index (QUICKI), insulinogenic index, antilipolytic insulin sensitivity index (ISI-FFA), and C-peptide-to-insulin ratio.RESULTS -The QUICKI correlated best with SI Eug clamp (r ϭ 0.69, P Ͻ 0.05) and had greater correlations to SI Eug clamp than did either SI Hyper clamp (r ϭ 0.45, P Ͻ 0.05) or the HOMA-IR (r ϭ Ϫ0.51, P Ͻ 0.05). Both fasting insulin and the insulinogenic index correlated well with first-and steady-phase insulin secretion (r's from 0.79 to 0.86, P Ͻ 0.05). HOMA-B% was not as highly correlated (r ϭ 0.69 -0.72, P Ͻ 0.05). Fasting C-peptide-to-insulin ratio was not significantly correlated with clamp-derived metabolic clearance rate of insulin. ISI-FFA was not correlated with the degree of free fatty acid suppression obtained from the clamps.CONCLUSIONS -The QUICKI, fasting insulin, and the insulinogenic index all closely correlate with corresponding clamp-derived indices of insulin sensitivity and secretion in this diverse pediatric cohort. These results, if replicated in similarly diverse populations, suggest that estimates based on fasting samples can be used to rank order insulin secretion and sensitivity in pediatric cohorts. Diabetes Care 25:2081-2087, 2002O besity and type 2 diabetes are diseases that have assumed considerable public health importance in the 21st century in both developed and developing countries (1-3). The increased prevalence of both these conditions in children adds an added dimension of seriousness to these modern day epidemics (4). Since insulin resistance appears central to the development of the metabolic syndrome X (1,5), accurate quantification of insulin's in vivo action, secretion, and disposal is necessary. While a combination of hyperglycemic and euglycemic-hyperinsulinemic clamp studies supplies the gold standard for quantifying these parameters (6), clamp studies are expensive and difficult tests to perform and require highly trained personnel. The difficulties with obtaining sequential clamp studies are even more pronounced for young children who may have more difficulty with clamp procedure requirements.For the purpose of epidemiologic studies, several indices based on fasting blood that estimate insulin sensitivity, secretion, and disposal have been developed for adults. The homeostasis model assessment of insulin resistance index (HOMA-IR), the HOMA of percent ␤-cell function (HOMA-B%), the insulinogenic index...