Oral Hypoglycemic Agents

A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)

Background-Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. Methods-In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. Results-At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P = 0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). Conclusions-As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.

Diabetes mellitus is a chronic disease that leads to complications including heart disease, stroke, kidney failure, blindness and nerve damage. Type 2 diabetes, characterized by target-tissue resistance to insulin, is epidemic in industrialized societies and is strongly associated with obesity; however, the mechanism by which increased adiposity causes insulin resistance is unclear. Here we show that adipocytes secrete a unique signalling molecule, which we have named resistin (for resistance to insulin). Circulating resistin levels are decreased by the anti-diabetic drug rosiglitazone, and increased in diet-induced and genetic forms of obesity. Administration of anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, treatment of normal mice with recombinant resistin impairs glucose tolerance and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment. Resistin is thus a hormone that potentially links obesity to diabetes.

Background-In the 2·8 years of the Diabetes Prevention Program (DPP) randomised clinical trial, diabetes incidence in high-risk adults was reduced by 58% with intensive lifestyle intervention and by 31% with metformin, compared with placebo. We investigated the persistence of these effects in the long term.

To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.

In part II of this review, we describe the epidemiology and clinical consequences of vascular disease in patients with diabetes, and discuss the efficacy of risk factor modification and antiplatelet treatment. Specifically, evidence-based cardiovascular therapies are discussed through novel clinical insights on management of hyperglycaemia, hypertension, dyslipidaemia as well as platelet dysfunction. Recent trends in the incidence and outcomes of vascular disease in diabetes suggest that timely and effective implementation of therapies is making a favourable impact.

Omega-3 fatty acids (u-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an u-3 FA receptor/sensor. Stimulation of GPR120 with u-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without u-3 FA supplementation. The u-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional u-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.

Diabetes mellitus is a major health concern, affecting more than 5% of the population. Here we describe a potential novel therapeutic agent for this disease, FGF-21, which was discovered to be a potent regulator of glucose uptake in mouse 3T3-L1 and primary human adipocytes. FGF-21-transgenic mice were viable and resistant to diet-induced obesity. Therapeutic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in both ob/ob and db/db mice. These effects persisted for at least 24 hours following the cessation of FGF-21 administration. Importantly, FGF-21 did not induce mitogenicity, hypoglycemia, or weight gain at any dose tested in diabetic or healthy animals or when overexpressed in transgenic mice. Thus, we conclude that FGF-21, which we have identified as a novel metabolic factor, exhibits the therapeutic characteristics necessary for an effective treatment of diabetes.

This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from LifeScan, Inc., a Johnson & Johnson company. Abbreviations: CVD, cardiovascular disease; GDM, gestational diabetes mellitus; IGT, impaired glucose tolerance; MNT, medical nutrition therapy; SMBG, self-monitoring of blood glucose. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Epidemiologic evidence suggests that cancer incidence is associated with diabetes as well as certain diabetes risk factors and diabetes treatments. This consensus statement of experts assembled jointly by the American Diabetes Association and the American Cancer Society reviews the state of science concerning 1) the association between diabetes and cancer incidence or prognosis, 2) risk factors common to both diabetes and cancer, 3) possible biologic links between diabetes and cancer risk, and 4) whether diabetes treatments influence risk of cancer or cancer prognosis. In addition, key unanswered questions for future research are posed.

Background Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the effi cacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist.

Background Rosiglitazone is an insulin sensitiser used in combination with metformin, a sulfonylurea, or both, for lowering blood glucose in people with type 2 diabetes. We assessed cardiovascular outcomes after addition of rosiglitazone to either metformin or sulfonylurea compared with the combination of the two over 5-7 years of follow-up. We also assessed comparative safety.

Background Roux-en-Y gastric bypass and biliopancreatic diversion can markedly ameliorate diabetes in morbidly obese patients, often resulting in disease remission. Prospective, randomized trials comparing these procedures with medical therapy for the treatment of diabetes are needed. Methods

HIAZOLIDINEDIONES ARE AGOnists of the peroxisome proliferation-activated receptor ␥ (PPAR-␥), which regulate transcription of a variety of genes encoding proteins involved in glucose homeostasis and lipid metabolism. 1,2 By virtue of their efficacy in achieving glycemic control, the thiazolidinediones pioglitazone and rosiglitazone are both widely used to treat patients with type 2 diabetes mellitus. Although these agents can cause peripheral edema and congestive heart failure, 3,4 their beneficial effects on glucose metabolism and insulin sensitivity have stimulated interest that thiazolidinediones might reduce ischemic cardiovascular complications of diabetes mellitus. However, a recent meta-analysis of 42 trials comparing rosiglitazone with placebo or active comparators in more than 27 000 patients with diabetes suggested that treatment with rosiglitazone was associated with an increased risk of myocardial infarction and cardiovascular death. 5 Furthermore, a previous analysis had demonstrated that muraglitazar, an investigational dual agonist of both ␣and ␥-isoforms of PPAR, was also associated with an excess incidence of death and major cardiovascular events in patients with diabetes. 6 See also pp 1189 and 1216.

paper. All authors contributed to data interpretation, discussions and editing of the paper. MetaHIT consortium members contributed to the design and execution of the study. Accession codes Raw nucleotide data can be found for all samples used in the study in the Sequence Read Archive (SRA045646, SRA050230-CHN samples) and the European Nucleotide Archive (ERP002469-SWE samples, ERA000116, ERP003612, ERP002061, ERP004605-MHD samples).

The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the ␣ (NR1C1) and ␥ (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the ␦ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPAR␦ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPAR␦ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

Like obese humans, Zucker diabetic fatty (ZDF) rats exhibit early ␤ cell compensation for insulin resistance (4-fold ␤ cell hyperplasia) followed by decompensation (>50% loss of ␤ cells). In prediabetic and diabetic ZDF islets, apoptosis measured by DNA laddering is increased 3and >7-fold, respectively, compared with lean ZDF controls. Ceramide, a fatty acid-containing messenger in cytokineinduced apoptosis, was significantly increased (P < 0.01) in prediabetic and diabetic islets. Free fatty acids (FFAs) in plasma are high (>1 mM) in prediabetic and diabetic ZDF rats; therefore, we cultured prediabetic islets in 1 mM FFA. DNA laddering rose to 19.6% vs. 4.6% in lean control islets, preceded by an 82% increase in ceramide. C 2 -Ceramide without FFA induced DNA laddering, but fumonisin B 1 , a ceramide synthetase inhibitor, completely blocked FFA-induced DNA laddering in cultured ZDF islets.

Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes. ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA(1c) concentrations (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;7.5%), and cardiovascular disease (or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A(1c) [HbA(1c)] of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;6.0%) or standard (7.0-7.9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;291.7 micromol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620. 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1.00, 95% CI 0.88-1.14; p=1.00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0.96, 0.89-1.02; p=0.19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0.95, 95% CI 0.85-1.07, p=0.42]; and second 1956 of 5119 vs 2046 of 5115, respectively [0.95, 0.89-1.01, p=0.12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy…

We determined whether interindividual variation in hepatic insulin sensitivity could be attributed to variation in liver fat content (LFAT) independent of obesity. We recruited 30 healthy nondiabetic men whose LFAT (determined by proton spectroscopy); intraabdominal, sc, and total (determined by magnetic resonance imaging) fat; and insulin sensitivity of endogenous glucose rate of production (R a ) and suppression of serum FFA [euglycemic insulin clamp combined with [3-3 H]glucose (0 -300 min); insulin infusion rate, 0.3 mU/ kg⅐min, 120 -300 min] were measured. The men were divided into groups of low (mean ؎ SD, 1.7 ؎ 0.2%) and high (10.5 ؎ 2.0%) LFAT based on their median fat content. The low and high LFAT groups were comparable with respect to age (44 ؎ 2 vs. 42 ؎ 2 yr), body mass index (25 ؎ 1 vs. 26 ؎ 1 kg/m 2 ), waist to hip ratio (0.953 ؎ 0.013 vs. 0.953 ؎ 0.013), maximal oxygen uptake (35.6 ؎ 1.5 vs. 33.5 ؎ 1.5 ml/kg⅐min), and intraabdominal, sc, and total fat. The high compared with the low LFAT group had several features of insulin resistance, including fasting hyperinsulinemia 7.3 ؎ 0.6 vs. 5.3 ؎ 0.6 mU/liter; P < 0.02, high vs. low LFAT) hypertriglyceridemia (1.4 ؎ 0.2 vs. 0.9 ؎ 0.1 mmol/liter; P < 0.02), a low high density lipoprotein (HDL) cholesterol concentration (1.4 ؎ 0.1 vs. 1.6 ؎ 0.1 mmol/ liter; P < 0.05), and a higher ambulatory 24-h systolic blood pressure (130 ؎ 3 vs. 122 ؎ 3 mm Hg; P < 0.05). Basal glucose R a and serum FFA were comparable between the groups, whereas insulin suppression of glucose R a [51 ؎ 8 vs. 20 ؎ 12 mg/m 2 ⅐min during 240 -300 min (P < 0.05) or ؊55 ؎ 7 vs. ؊85 ؎ 12% below basal (P < 0.05, high vs. low LFAT)] and of serum FFA (299 ؎ 33 vs. 212 ؎ 13 mol/liter; 240 -300 min; P < 0.02) were impaired in the high compared with the low LFAT group. Insulin stimulation of glucose Rd were comparable in the men with high LFAT (141 ؎ 12 mg/m 2 ⅐min) and those with low LFAT (156 ؎ 14 mg/m 2 ⅐min; P ‫؍‬ NS). Fat accumulation in the liver is, independent of body mass index and intraabdominal and overall obesity, characterized by several features of insulin resistance in normal weight and moderately overweight subjects. (J Clin Endocrinol Metab 87: 3023-3028, 2002)

24 25 IL-1β is an important inflammatory mediator of type 2 diabetes (T2D). Here we 26 show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms 27 amyloid deposits in the pancreas during T2D, trigger the Nlrp3 inflammasome and 28 generate mature interleukin (IL)-1β. A T2D therapy, glyburide, suppresses IAPP-29 mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first 30 requires priming, a process that involves glucose metabolism and can be facilitated 31 by minimally oxidized low density lipoprotein. Finally, mice transgenic for human 32 IAPP have increased IL-1β in pancreatic islets, which colocalizes with amyloid and 33 macrophages. Our findings reveal novel mechanisms in the pathogenesis of T2D and 34 treatment of pathology caused by IAPP. 35 36 37 3 38 39 Introduction 40

A nonlinear model predictive controller has been developed to maintain normoglycemia in subjects with type 1 diabetes during fasting conditions such as during overnight fast. The controller employs a compartment model, which represents the glucoregulatory system and includes submodels representing absorption of subcutaneously administered short-acting insulin Lispro and gut absorption. The controller uses Bayesian parameter estimation to determine time-varying model parameters. Moving target trajectory facilitates slow, controlled normalization of elevated glucose levels and faster normalization of low glucose values. The predictive capabilities of the model have been evaluated using data from 15 clinical experiments in subjects with type 1 diabetes. The experiments employed intravenous glucose sampling (every 15 min) and subcutaneous infusion of insulin Lispro by insulin pump (modified also every 15 min). The model gave glucose predictions with a mean square error proportionally related to the prediction horizon with the value of 0.2 mmol L −1 per 15 min. The assessment of clinical utility of model-based glucose predictions using Clarke error grid analysis gave 95% of values in zone A and the remaining 5% of values in zone B for glucose predictions up to 60 min (n = 1674). In conclusion, adaptive nonlinear model predictive control is 0967-3334/04/040905+16$30.00 © 2004 IOP Publishing Ltd Printed in the UK 905 906 R Hovorka et al promising for the control of glucose concentration during fasting conditions in subjects with type 1 diabetes.

Dissolution tests are used for many purposes in the pharmaceutical industry: in the development of new products, for quality control and, to assist with the determination of bioequivalence. Recent regulatory developments such as the Biopharmaceutics Classification Scheme have highlighted the importance of dissolution in the regulation of post-approval changes and introduced the possibility of substituting dissolution tests for clinical studies in some cases. Therefore, there is a need to develop dissolution tests that better predict the in vivo performance of drug products. This could be achieved if the conditions in the gastrointestinal tract were successfully reconstructed in vitro. The aims of this article are, first, to clarify under which circumstances dissolution testing can be prognostic for in vivo performance, and second, to present physiological data relevant to the design of dissolution tests, particularly with respect to the composition, volume, flow rates and mixing patterns of the fluids in the gastrointestinal tract. Finally, brief comments are made in regard to the composition of in vitro dissolution media as well as the hydrodynamics and duration of the test.

Background The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. Methods We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. Results In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in ...

This report presents an algorithm to assist primary care physicians, endocrinologists, and others in the management of adult, nonpregnant patients with type 2 diabetes mellitus. In order to minimize the risk of diabetesrelated complications, the goal of therapy is to achieve a hemoglobin A1c (A1C) of 6.5% or less, with recognition of the need for individualization to minimize the risks of hypoglycemia. We provide therapeutic pathways stratified on the basis of current levels of A1C, whether the patient is receiving treatment or is drug naïve. We consider monotherapy, dual therapy, and triple therapy, including 8 major classes of medications (biguanides, dipeptidyl-peptidase-4 inhibitors, incretin mimetics, thiazolidinediones, a-glucosidase inhibitors, sulfonylureas, meglitinides, and bile acid sequestrants) and insulin therapy (basal, premixed, and multiple daily injections), with or without orally administered medications. We prioritize choices of medications according to safety, risk of hypoglycemia, efficacy, simplicity, anticipated degree of patient adherence, and cost of medications. We recommend only combinations of medications approved by the US Food and Drug Administration that provide complementary mechanisms of action. It is essential to monitor therapy with A1C and self-monitoring of blood glucose and to adjust or advance therapy frequently (every 2 to 3 months) if the appropriate goal for each patient has not been achieved. We provide a flowchart and table summarizing the major considerations. This algorithm represents a consensus of 14 highly experienced clinicians, clinical researchers, practitioners, and academicians and is based on the American Association of Clinical Endocrinologists/American College of Endocrinology Diabetes Guidelines and the recent medical literature. (Endocr Pract. 2009;15:540-559) Abbreviations: AACE = American Association of Clinical Endocrinologists; A1C = hemoglobin A1c; ACCORD = Action to Control Cardiovascular Risk in Diabetes; ACE = American College of Endocrinology; ADA = American Diabetes Association; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; AGIs = a-glucosidase inhibitors; DCCT/EDIC = Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; DPP-4 = dipeptidyl-peptidase-4; EASD = European Association for the Study of Diabetes; FDA = US Food and Drug Administration; GLP-1 = glucagonlike peptide-1; LDL = low-density lipoprotein; PROACTIVE = Prospective Pioglitazone Clinical Trial in Macrovascular Events; RCTs = randomized controlled trials; RECORD = Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes; SMBG = self-monitoring of blood glucose; TZDs = thiazolidinediones; UKPDS = United Kingdom Prospective Diabetes Study; VADT = Veterans Affairs Diabetes Trial

Aims Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice. Methods and results DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n ¼ 474), 2 (n ¼ 473), and 3 (n ¼ 306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood

There is currently much interest in biological active compounds derived from natural resources, especially compounds that can efficiently act on molecular targets, which are involved in various diseases. Astaxanthin (3,3′-dihydroxy-β, β′-carotene-4,4′-dione) is a xanthophyll carotenoid, contained in Haematococcus pluvialis, Chlorella zofingiensis, Chlorococcum, and Phaffia rhodozyma. It accumulates up to 3.8% on the dry weight basis in H. pluvialis. Our recent published data on astaxanthin extraction, analysis, stability studies, and its biological activities results were added to this review paper. Based on our results and current literature, astaxanthin showed potential biological activity in in vitro and in vivo models. These studies emphasize the influence of astaxanthin and its beneficial effects on the metabolism in animals and humans. Bioavailability of astaxanthin in animals was enhanced after feeding Haematococcus biomass as a source of astaxanthin. Astaxanthin, used as a nutritional supplement, antioxidant and anticancer agent, prevents diabetes, cardiovascular diseases, and neurodegenerative disorders, and also stimulates immunization. Astaxanthin products are used for commercial applications in the dosage forms as tablets, capsules, syrups, oils, soft gels, creams, biomass and granulated powders. Astaxanthin patent applications are available in food, feed and nutraceutical applications.

Background Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. Methods We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of t...

Background Exenatide is an incretin mimetic that shares glucoregulatory properties with glucagon-like peptide 1 (GLP-1), and improves glycaemic control, with progressive bodyweight reductions, when administered twice a day in patients with type 2 diabetes. We compared the effi cacy of a once-weekly formulation of exenatide to that of a twice daily dose.

All-trans-retinoic acid (ATRA), an RA receptor-specific NHR ligand, is now used for selective cancers. The NHR, peroxisome proliferator-activated receptor ␥ (PPAR␥) is expressed in breast cancer cells. Activation of PPAR␥ through a synthetic ligand, troglitazone (TGZ), and other PPAR␥activators cause inhibition of proliferation and lipid accumulation in cultured breast cancer cells. TGZ (10 ؊5 M, 4 days) reversibly inhibits clonal growth of MCF7 breast cancer cells and the combination of TGZ (10 ؊5 M) and ATRA (10 ؊6 M, 4 days) synergistically and irreversibly inhibits growth and induces apoptosis of MCF7 cells, associated with a dramatic decrease of their bcl-2 protein levels. Similar effects are noted with in vitro cultured breast cancer tissues from patients, but not with normal breast epithelial cells. The observed apoptosis mediated by TGZ and ATRA may be related to the striking down-regulation of bcl-2, because forced over-expression of bcl-2 in MCF7 cells cultured with TGZ and ATRA blocks their cell death. TGZ significantly inhibits MCF7 tumor growth in triple immunodeficient mice. Combined administration of TGZ and ATRA causes prominent apoptosis and fibrosis of these tumors without toxic effects on the mice. Taken together, this combination may provide a novel, nontoxic and selective therapy for human breast cancers.

The three peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homology with all members of the superfamily, particularly in the DNA-binding domain and ligand-and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPAR␣ is expressed at high levels in organs with significant catabolism of fatty acids. PPAR␤/␦ has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPAR␥ is expressed as two isoforms, of which PPAR␥2i s found at high levels in the adipose tissues, whereas PPAR␥1 has a broader expression pattern. Transcrip-tional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a peroxisome proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compounds was identified as PPAR ligands. Among the synthetic ligands, the lipidlowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPAR␣ and PPAR␥ agonists, respectively, which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities. proliferator response element; LBD, ligand-binding domain; HDL-C, high-density lipoprotein cholesterol.

We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K ATP channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes.