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Glucagon-like peptide 1 agonists and the development and growth of pancreatic [beta]-cells. Am J Physiol Endocrinol Metab 286:E875-E881, 2004; .1152/ajpendo.00007.2004.--Glucagon-like peptide 1 (GLP-1) is an intestine-derived insulinotropic hormone that stimulates glucose-dependent insulin production and secretion from pancreatic [beta]-cells. Other recognized actions of GLP-1 are to suppress glucagon secretion and hepatic glucose output, delay gastric emptying, reduce food intake, and promote glucose disposal in peripheral tissues. All of these actions are potentially beneficial for the treatment of type 2 diabetes mellitus. Several GLP-1 agonists are in clinical trials for the treatment of diabetes. More recently, GLP-1 agonists have been shown to stimulate the growth and differentiation of pancreatic [beta]-cells, as well as to exert cytoprotective, antiapoptotic effects on [beta]-cells. Recent evidence indicates that GLP-1 agonists act on receptors on pancreas-derived stem/progenitor cells to prompt their differentiation into [beta]-cells. These new findings suggest an approach to create [beta]-cells in vitro by expanding stem/progenitor cells and then to convert them into [beta]-cells by treatment with GLP-1. Thus GLP-1 may be a means by which to create [beta]-cells ex vivo for transplantation into patients with insulinopenic type 1 diabetes and severe forms of type 2 diabetes. stem cells; diabetes

Two studies published in 2003 focus on a gene mutation that could cause 5% of all obesity cases, as well as possibly causing binge eating. The mutation is in the gene for the receptor for alpha melanocyte-stimulating hormone. This hormone usually causes people to stop eating when they are full. One study found that a group of obese people who binged on food all had the mutation, whereas only 14% of another group of obese people who did not binge had the mutation.

OBJECTIVE--To examine the safety and efficacy of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added on to pioglitazone in type 2 diabetes inadequately controlled on pioglitazone. RESEARCH DESIGN AND METHODS--Treatment-naive patients or those receiving metformin, sulfonylurea, or thiazolidinedione entered a 10-week pioglitazone dose-optimization period with only pioglitazone. They were then randomized, along with patients previously receiving pioglitazone ≥30 mg, to 48 weeks of double-blind dapagliflozin 5 (n = 141) or 10mg (n = 140) or placebo (n = 139) every day plus open-label pioglitazone. The primary objective compared HbA1c change from baseline with dapagliflozin plus pioglitazone versus placebo plus pioglitazone at week 24. Primary analysis was based on ANCOVA model using last observation carried forward; all remaining analyses used repeated-measures analysis. RESULTS--At week 24, the mean reduction from baseline in HbA1c was --0.42% for placebo versus --0.82 and --0.97% for dapagliflozin 5 and 10 mg groups, respectively (P = 0.0007 and P < 0.0001 versus placebo). Patients receiving pioglitazone alone had greater weight gain (3 kg) than those receiving dapagliflozin plus pioglitazone (0.7--1.4 kg) at week 48. Through 48 weeks: hypoglycemia was rare; more events suggestive of genital infection were reported with dapagliflozin (8.6--9.2%) than placebo (2.9%); events suggestive of urinary tract infection showed no clear drug effect (5.0--8.5% for dapagliflozin and 7.9% for placebo); dapagliflozin plus pioglitazone groups had less edema (2.1--4.3%) compared with placebo plus pioglitazone (6.5%); and congestive heart failure and fractures were rare. CONCLUSIONS--In patients with type 2 diabetes inadequately controlled on pioglitazone, the addition of dapagliflozin further reduced HbA1c levels and mitigated the pioglitazone-related weight gain without increasing hypoglycemia risk. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of glucuretic, antihyperglycemic drugs that target the process of renal glucose reabsorption and induce glucuresis independently of insulin secretion or action. In patients with type 2 diabetes mellitus, SGLT2 inhibitors have been found to consistently reduce measures of hyperglycemia, including hemoglobin A1c, fasting plasma glucose, and postprandial glucose, throughout the continuum of disease. By inducing the renal excretion of glucose and its associated calories, SGLT2 inhibitors reduce weight and have the potential to be disease modifying by addressing the caloric excess that is believed to be one of the root causes of type 2 diabetes mellitus. Additional benefits, including the possibility for combination with insulin-dependent antihyperglycemic drugs, a low potential for hypoglycemia, and the ability to reduce blood pressure, were anticipated from the novel mechanism of action and have been demonstrated in clinical studies. Mechanism-related risks include an increased incidence of urinary tract and genital infections and the possibility of over-diuresis in volume-sensitive patients. Taken together, the results of Phase III clinical studies generally point to a positive benefit-risk ratio across the continuum of diabetes patients. To date, data on dapagliflozin, a selective SGLT2 inhibitor in development, demonstrate that the kidney is an efficacious and safe target for therapy, and that SGLT2 inhibition may have benefits for patients with type 2 diabetes mellitus beyond glycemic control. [ABSTRACT FROM AUTHOR]

Simian virus 40 (SV40) DNA replication was studied in monolayers of infected monkey CV-1 cells, permeabilized with lysolecithin, by incubation with [α-32P]dTTP, the other dNTPs and rNTPs and an ATP- regenerating system. Analysis of the labeled SV40 DNA by sedimentation in alkaline sucrose gradients showed that about 30% of the material synthesized by the permeable cells in the course of 60 min consisted of covalently closed circular SV40 DNA (form 1), with the remainder sedimenting as relaxed circles (form II) and replicative intermediates between 18 S and 4 S. The synthesis of SV40 DNA in the permeabilized cell system required the presence of all four dNTPs and was completely inhibited by aphidicolin, consistent with the involvement of DNA polymerase α. A detailed analysis of the distribution of radioactivity in the DNA synthesized involved cleavage with BstNI restriction endonuclease, followed by polyacrylamide gel electrophoresis and radioautography. The extent of labeling of all restriction fragments was nearly proportional to their length, suggesting that the entire SV40 chromosome was being replicated. This was confirmed by the careful comparison of the rate of labeling of a DNA fragment which includes the replication origin, and a fragment which includes the replication terminus. Their labeling was proportional to their size, regardless of the time for which the labeling was carried out. This demonstrated that the replication of the entire SV40 chromosome occurred in a steady state and that the start and termination of replication continuously occurred throughout the labeling period. The availability of an in vitro system in which replication of SV40 DNA undergoes multiple replication cycles should be of considerable value in the analysis of the mechanism of replication of this viral genome. [ABSTRACT FROM AUTHOR]

Dapagliflozin (DAPA), a selective SGLT2 inhibitor, improves glycemic control in diverse patient populations as monotherapy or in combination with other glucose-lowering drugs. We assess DAPA as monotherapy in drug-naïve Asian patients inadequately controlled on diet and exercise (hemoglobin A1 c [HbA1 c] 7.0-10.5%) in a 24-week double-blind study (NCT01095653) that randomized patients to placebo (PBO; N = 132) or DAPA (5 or 10 mg; N = 128 and 133, respectively) groups. Baseline characteristics were balanced across groups. Most patients (89%) were Chinese. Median duration of type 2 diabetes mellitus was 0.2 years. At week 24 (last observation carried forward [LOCF]), DAPA 5 and 10 mg provided dose-dependent, statistically significant reductions in HbA1 c versus PBO (primary endpoint) and in fasting plasma glucose (FPG), postprandial glucose (PPG), body weight and proportion of patients with HbA1c <7% (secondary endpoints) [Table 1]. Adverse events (AEs) were balanced across groups. Few patients had serious AEs or AEs leading to discontinuation. Hypoglycemia was uncommon (1.5, 0.8 and 0.8% in the PBO, DAPA 5 mg and 10 mg groups, respectively); none led to discontinuation. Genital infections were more common with DAPA; 0.8%, 3.1% and 4.5% of PBO, DAPA 5 mg or 10 mg patients, respectively. Urinary tract infections occurred in 3.0%, 3.9% and 5.3% of patients, respectively. No AEs of renal failure or pyelonephritis and no deaths occurred. In summary, DAPA as monotherapy in drug-naïve Asian patients was well-tolerated, significantly improving glycemic control with the additional benefit of modest weight loss. [ABSTRACT FROM AUTHOR]

Advances in experimental medicine and technological innovation during the past century have brought tremendous progress in modern medicine and generated an ever-increasing amount of data from bench and bedside. The desire to extend scientific knowledge motivates effective data integration. Technological innovation makes this possible, which in turn accelerates the advancement in science. This mutually beneficial interaction is illustrated by the development of an expanded mechanism-based model for understanding a novel mechanism, sodium— glucose cotransporter-2 SGLT2 inhibition for potential treatment of type 2 diabetes mellitus. [ABSTRACT FROM PUBLISHER]