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This report examines what is known about the relationship between obesity and type 2 diabetes and how future research in these areas might be directed to benefit prevention, interventions, and overall patient care. An international working group of 32 experts in the pathophysiology, genetics, clinical trials, and clinical care of obesity and/or type 2 diabetes participated in a conference held on 6-7 January 2011 and cosponsored by The Endocrine Society, the American Diabetes Association, and the European Association for the Study of Diabetes. A writing group comprising eight participants subsequently prepared this summary and recommendations. Participants reviewed and discussed published literature and their own unpublished data. The writing group unanimously supported the summary and recommendations as representing the working group's majority or unanimous opinions. The major questions linking obesity to type 2 diabetes that need to be addressed by combined basic, clinical, and population-based scientific approaches include the following: 1) Why do not all patients with obesity develop type 2 diabetes? 2) Through what mechanisms do obesity and insulin resistance contribute to β-cell decompensation, and if/when obesity prevention ensues, how much reduction in type 2 diabetes incidence will follow? 3) How does the duration of type 2 diabetes relate to the benefits of weight reduction by lifestyle, weight-loss drugs, and/or bariatric surgery on β-cell function and glycemia? 4) What is necessary for regulatory approval of medications and possibly surgical approaches for preventing type 2 diabetes in patients with obesity? Improved understanding of how obesity relates to type 2 diabetes may help advance effective and cost-effective interventions for both conditions, including more tailored therapy. To expedite this process, we recommend further investigation into the pathogenesis of these coexistent conditions and innovative approaches to their pharmacological and surgical management.

OBJECTIVE:--Numerous studies in the U.S. and elsewhere have reported an increased risk of gestational diabetes mellitus (GDM) among women who are overweight or obese compared with lean or normal-weight women. Despite the number and overall consistency of studies reporting a higher risk of GDM with increasing weight or BMI, the magnitude of the association remains uncertain. This meta-analysis was conducted to better estimate this risk and to explore differences across studies. RESEARCH DESIGN AND METHODS--We identified studies from three sources: 1) a PubMed search of relevant articles published between January 1980 and January 2006, 2) reference lists of publications selected from the PubMed search, and 3) reference lists of review articles on obesity and maternal outcomes published between January 2000 and January 2006. We used a Bayesian model to perform the meta-analysis and meta-regression. We included cohort-designed studies that reported obesity measures reflecting pregnancy body mass, that had a normal-weight comparison group, and that presented data allowing a quantitative measurement of risk. RESULTS:--Twenty studies were included in the meta-analysis. The unadjusted ORs of developing GDM were 2.14 (95% CI 1.82-2.53), 3.56 (3.05-4.21), and 8.56 (5.07-16.04) among overweight, obese, and severely obese compared with normal-weight pregnant women, respectively. The meta-regression analysis found no evidence that these estimates were affected by selected study characteristics (publication date, study location, parity, type of data collection [retrospective vs. prospective], and prevalence of GDM among normal-weight women). CONCLUSIONS:--Our findings indicate that high maternal weight is associated with a substantially higher risk of GDM.

Objective: To identify factors contributing to the variation in weight loss after Roux-en-Y gastric bypass (RYGB). Design: Cross-sectional study of patients with good (excess body mass index lost (EBL) >60%) and poor weight loss response (EBL <50%) >12 months after RYGB and a lean control group matched for age and gender. Materials and methods: Sixteen patients with good weight loss response, 17 patients with poor weight loss response, and eight control subjects were included in the study. Participants underwent dual energy X-ray absorptiometry scan, indirect calorimetry and a 9 h multiple-meal test with measurements of glucose, insulin, total bile acids (TBA), glucagon-like peptide (GLP)-1, peptide YY 3–36 (PYY), cholecystokinin (CCK), ghrelin, neurotensin and pancreatic polypeptide (PP) as well as assessment of early dumping and appetite. Results: Suppression of hunger was more pronounced in the good than the poor responders in response to the multiple-meal test ( P =0.006). In addition, the good responders had a larger release of GLP-1 ( P =0.009) and a greater suppression of ghrelin ( P =0.037) during the test, whereas the postprandial secretion of CCK was highest in the poor responders ( P =0.005). PYY, neurotensin, PP and TBA release did not differ between the RYGB-operated groups. Compared with control subjects, patients had exaggerated release of GLP-1 ( P <0.001), PYY ( P =0.008), CCK ( P =0.010) and neurotensin ( P <0.001). Early dumping was comparable in the good and poor responders, but more pronounced than in controlled subjects. Differences in resting energy expenditure between the three groups were entirely explained by differences in body composition. Conclusion: Favorable meal-induced changes in hunger and gut hormone release in patients with good compared with poor weight loss response support the role of gut hormones in the weight loss after RYGB.

A tonic to the blood A previously unidentified modulator of vertebrate haematopoietic stem cell (HSC) number has been discovered using a chemical genetic screen in zebrafish. Prostaglandin E2 (PGE2) increases HSCs in the embryo and enhances marrow recovery following irradiation of adult fish. These effects of PGE2 on stem and progenitor cell number are conserved across vertebrate species. This suggests that modulation of this pathway could be used to treat patients undergoing bone marrow transplant and for some forms of anaemia. This study identifies Prostaglandin E2 (PGE2) as an important modulator of vertebrate haematopoietic stem cell (HSC) number. Chemicals that enhance PGE2 synthesis increase the number of HSCs whereas the opposite effect is achieved by blocking PGE2 synthesis. Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta–gonad–mesonephros region subsequently colonize fetal and adult haematopoietic organs 1 , 2 . To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta–gonad–mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.

Human placental aromatase structure Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. This enzyme catalyses the three-step conversion of androstenedione, testosterone, and 16α-hydroxytestosterone to oestrone, 17β-oestradiol, and 17β,16α-oestriol (respectively). Inhibitors of aromatase are potential therapeutics for oestrogen-dependent breast cancer. In this paper, Ghosh et al . solve the X-ray crystal structure of the first natural mammalian, full-length P450, human placental aromatase. The locations of catalytically important residues shed new light on the reaction mechanism of this enzyme, and it may be possible to utilize this information to develop new aromatase inhibitors. Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens. This paper solves the X-ray crystal structure of the first natural mammalian, full-length P450, human placental aromatase. Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyse the biosynthesis of all oestrogens from androgens 1 , 2 , 3 . Aromatase inhibitors therefore constitute a frontline therapy for oestrogen-dependent breast cancer 3 , 4 . In a three-step process, each step requiring 1 mol of O 2 , 1 mol of NADPH, and coupling with its redox partner cytochrome P450 reductase, aromatase converts androstenedione, testosterone and 16α-hydroxytestosterone to oestrone, 17β-oestradiol and 17β,16α-oestriol, respectively 1 , 2 , 3 . The first two steps are C19-methyl hydroxylation steps, and the third involves the aromatization of the steroid A-ring, unique to aromatase. Whereas most P450s are not highly substrate selective, it is the hallmark androgenic specificity that sets aromatase apart. The structure of this enzyme of the endoplasmic reticulum membrane has remained unknown for decades, hindering elucidation of the biochemical mechanism. Here we present the crystal structure of human placental aromatase, the only natural mammalian, full-length P450 and P450 in hormone biosynthetic pathways to be crystallized so far. Unlike the active sites of many microsomal P450s that metabolize drugs and xenobiotics, aromatase has an androgen-specific cleft that binds the androstenedione molecule snugly. Hydrophobic and polar residues exquisitely complement the steroid backbone. The locations of catalytically important residues shed light on the reaction mechanism. The relative juxtaposition of the hydrophobic amino-terminal region and the opening to the catalytic cleft shows why membrane anchoring is necessary for the lipophilic substrates to gain access to the active site. The molecular basis for the enzyme’s androgenic specificity and unique catalytic mechanism can be used for developing next-generation aromatase inhibitors.

In this trial, low-dose radioiodine was as effective as high-dose radioiodine in patients with differentiated thyroid tumors, and recombinant human thyrotropin (thyrotropin alfa) was as effective as thyroid hormone withdrawal. Thyroid cancer is the most frequently occurring endocrine cancer, with more than 2100 new cases each year in the United Kingdom and more than 48,000 in the United States. 1 , 2 Most cases are differentiated thyroid cancer, which is associated with a high 10-year survival rate (90 to 95%). 3 Many patients with differentiated thyroid cancer undergo radioiodine ablation to remove residual normal thyroid tissue after surgery. Some nonrandomized studies have suggested that radioiodine ablation reduces rates of death and recurrence. 4 – 7 However, there is uncertainty over the dose (administered activity) of radioiodine required for effective ablation. A systematic review of randomized . . .

In univariate regression analysis, NAFLD (hazard ratio [HR] 2.01 [95% CI 1.4-2.9]), metabolic syndrome (1.74 [1.3-3]), age (1.11 [1.05-1.2]), male sex (1.52 [1.3-1.8]), smoking (1.48 [1.22.2]), AlC (1.44 [1.4-2.9]), LDL cholesterol (1.37 [1.1-1.8]), alanine aminotransferase (1.47 [1.2-1.9]), and other liver enzymes were significantly (P < 0.01) associated with incident CVD, whereas diabetes duration and medications were not. In multivariate regression analysis, the significant association between NAFLD and incident CVD was little affected (1.96 [1.4-2.7], P < 0.001) by adjustment for sex, age, smoking, diabetes duration, AlC, LDL cholesterol, and medications (hypoglycemic, antihypertensive, lipid-lowering, or antiplatelet drugs); further adjustment for the metabolic syndrome did not appreciably change the association (1.87 [1.2-2.6], P < 0.001).

OBJECTIVE:--To assess the efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control on diet and exercise. RESEARCH DESIGN AND METHODS--In a 24-week, randomized, double-blind, placebo-controlled, parallel-group study, 1,091 patients with type 2 diabetes and A1C 7.5-11% were randomized to one of six daily treatments: sitagliptin 100 mg/metformin 1,000 mg (S100/M1000 group), sitagliptin 100 mg/metformin 2,000 mg (S100/M2000 group), metformin 1,000 mg (M1000 group), metformin 2,000 mg (M2000 group) (all as divided doses administered twice daily [b.i.d.]), sitagliptin 100 mg q.d. (S100 group), or placebo. Patients who had an A1C >11% or a fasting glucose value >280 mg/dl after the run-in period were not eligible to be randomized; these patients could participate in an open-label substudy and were treated with S100/M2000 for 24 weeks. RESULTS:--The mean baseline A1C was 8.8% in the randomized patients. The placebo-subtracted A1C change from baseline was -2.07% (S100/M2000), -1.57% (S100/M1000), -1.30% (M2000), -0.99% (M1000), and -0.83% (S100) (P < 0.001 for comparisons versus placebo and for coadministration versus respective monotherapies). The proportion of patients achieving an A1C <7% and <6.5% was 66 and 44%, respectively, in the S100/M2000 group (P < 0.001 vs. S100 or M2000). For the open-label cohort (n = 117; baseline A1C 11.2%) treated with S100/M2000, the within-group mean A1C change from baseline was -2.9%. The incidence of hypoglycemia was low (0.5-2.2%) across active treatment groups and not significantly different from that in the placebo group (0.6%). The incidence of gastrointestinal adverse experiences was similar for coadministration therapies compared with their respective metformin monotherapy. CONCLUSIONS:--The initial combination of sitagliptin and metformin provided substantial and additive glycemic improvement and was generally well tolerated in patients with type 2 diabetes.