Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Strong evidence exists demonstrating the benefits of tight glycemic control in type 1 and type 2 diabetes mellitus patients, but glycemic goals are not adequately achieved for many patients. Advancement in the knowledge surrounding the physiology of endogenous glucoregulatory peptide hormones, such as glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, has led to new therapeutic targets for the treatment of type 2 diabetes mellitus. Dipeptidyl peptidase-4 (DPP-4) inhibitors provide practitioners with a novel mechanism of action to use for combination therapies for the treatment of type 2 diabetes mellitus. This article, part 3 of a 3-part series, reviews the new class of medications known as DPP-4 inhibitors as well as discusses a future buccal insulin formulation, Oral-Lyn, on the horizon for the treatment of diabetes mellitus.
 ...
PMID:Looking to the future: focus on DPP-4 inhibitors for the treatment of type 2 diabetes and emerging therapies. 1837 72

Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone with the potential to change diabetes. The physiological effects of GLP-1 are multiple, and many seem to ameliorate the different conditions defining the diverse physiopathology seen in type 2 diabetes. In animal studies, GLP-1 stimulates beta-cell proliferation and neogenesis and inhibits beta-cell apoptosis. In humans, GLP-1 stimulates insulin secretion and inhibits glucagon and gastrointestinal secretions and motility. It enhances satiety and reduces food intake and has beneficial effects on cardiovascular function and endothelial dysfunction. Enhancing incretin action for therapeutic use includes GLP-1 receptor agonists resistant to degradation (incretin mimetics) and dipeptidyl peptidase (DPP)-4 inhibitors. In clinical trials with type 2 diabetic patients on various oral antidiabetic regimes, both treatment modalities efficaciously improve glycaemic control and beta-cell function. Whereas the incretin mimetics induce weight loss, the DPP-4 inhibitors are considered weight neutral. In type 1 diabetes, treatment with GLP-1 shows promising effects. However, several areas need clinical confirmation: the durability of the weight loss, the ability to preserve functional beta-cell mass and the applicability in other than type 2 diabetes. As such, long-term studies and studies with cardiovascular end-points are needed to confirm the true benefits of these new classes of antidiabetic drugs in the treatment of diabetes mellitus.
 ...
PMID:GLP-1: physiological effects and potential therapeutic applications. 1843 75

Dipeptidyl peptidase (DPP)-IV inhibitors are expected to become a useful new class of antidiabetic agent. The aim of the present study is to characterize the in vitro and in vivo profile of ASP8497, (2S,4S)-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate, which is a novel DPP-IV inhibitor. ASP8497 inhibited DPP-IV in plasma from mice, rats, dogs and humans with IC(50) values of 3.86, 2.36, 5.53 and 5.30 nM, respectively. In contrast, ASP8497 did not potently inhibit DPP8 or DPP9 activity (IC(50)>200 nM). Kinetic analysis indicated that ASP8497 inhibits DPP-IV activity in a competitive manner. In streptozotocin-nicotinamide-induced diabetic mice, ASP8497 (3 mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 0.5 and 8.5 h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels. In contrast, ASP8497 (3 and 30 mg/kg) did not cause hypoglycemia in fasted normal mice. Furthermore, administration of exogenous GLP-1 induced significant inhibition of gastric emptying and small intestinal transit rates, but ASP8497 (30 mg/kg) had no significant effects in normal mice. These present preclinical studies indicate that ASP8497 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes.
 ...
PMID:ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity. 1846 82

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes by increasing plasma active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide levels. However, the effects of chronic DPP-4 inhibition on in vivo beta-cell function are poorly characterized. We thus evaluated the chronic effects of the DPP-4 inhibitor alogliptin benzoate (formerly SYR-322) on metabolic control and beta-cell function in obese diabetic ob/ob mice. Alogliptin (0.002%, 0.01%, or 0.03%) was administered in the diet to ob/ob mice for 2 days to determine effects on plasma DPP-4 activity and active GLP-1 levels and for 4 weeks to determine chronic effects on metabolic control and beta-cell function. After 2 days, alogliptin dose-dependently inhibited DPP-4 activity by 28-82% and increased active GLP-1 by 3.2-6.4-fold. After 4 weeks, alogliptin dose-dependently decreased glycosylated hemoglobin by 0.4-0.9%, plasma glucose by 7-28% and plasma triglycerides by 24-51%, increased plasma insulin by 1.5-2.0-fold, and decreased plasma glucagon by 23-26%, with neutral effects on body weight and food consumption. In addition, after drug washout, alogliptin (0.03% dose) increased early-phase insulin secretion by 2.4-fold and improved oral meal tolerance (25% decrease in glucose area under the concentration-time curve), despite the lack of measurable plasma DPP-4 inhibition. Importantly, alogliptin also increased pancreatic insulin content up to 2.5-fold, and induced intense insulin staining of islets, suggestive of improved beta-cell function. In conclusion, chronic treatment with alogliptin improved glycemic control, decreased triglycerides, and improved beta-cell function in ob/ob mice, and may exhibit similar effects in patients with type 2 diabetes.
 ...
PMID:Chronic administration of alogliptin, a novel, potent, and highly selective dipeptidyl peptidase-4 inhibitor, improves glycemic control and beta-cell function in obese diabetic ob/ob mice. 1849

Incretin hormones, secreted upon food intake, play an important role in the regulation of blood glucose levels. In type 2 diabetes mellitus, the incretin response is decreased. Substitution of incretin is a novel pharmacological target which restores postprandial glucose homeostasis. Exenatide is a mimetic of the incretin glucagon-like peptide-I (GLP-I). Sitagliptin is an inhibitor of the enzyme dipeptidyl peptidase 4 (DPP-4), which breaks down GLP-I. Both drugs increase the GLP-I concentration, thereby improving insulin secretion from pancreatic p cells, restoring glycaemic control, preventing beta cell destruction, delaying gastric emptying, and reducing food intake.
 ...
PMID:[New drugs; exenatide and sitagliptin]. 1871 16

The goal of antidiabetes therapy is to reduce glycosylated hemoglobin (HbA(1c)) levels to prevent or minimize the microvascular complications associated with this disease, such as retinopathy, nephropathy, and neuropathy. Glycemic control, defined by the American Diabetes Association (ADA) as HbA(1c) <7.0%, is often difficult to achieve despite current treatments, including oral antidiabetes agents, such as biguanides (metformin), sulfonylureas, thiazolidinediones, dipeptidyl peptidase-IV (DPP-IV) inhibitors, meglitinides, and alpha-glucosidase inhibitors, as well as injectable agents, such as glucagon-like peptide-1 (GLP-1) analogues and insulin. In addition, antidiabetes treatments often become less effective over time as insulin resistance increases and pancreatic beta-cell function deteriorates. The latest ADA guidelines also recommend a range of interventions to control the multiple coexisting conditions associated with this chronic, progressive disease, including dyslipidemia and hypertension. This review highlights the new antidiabetes drug classes, which include incretin mimetics, cannabinoid receptor type 1 antagonists, and bile acid sequestrants, and compares these agents to established treatments with regard to efficacy and tolerability. The more recently developed antidiabetes drugs have been shown in clinical trials to produce glucose-lowering effects similar to those of established antidiabetes agents. Many of the new antidiabetes agents can be safely combined with established therapies to further improve glycemic control. In addition, the new agents may provide additional significant cardiometabolic benefits, including improving the lipid profile, lowering blood pressure, and reducing body weight. These new treatments may have the potential to greatly improve the management of type 2 diabetes.
 ...
PMID:More choices than ever before: emerging therapies for type 2 diabetes. 1853 25

Inhibition of dipeptidyl peptidase-4 (DPP-4) as a novel therapy for type 2 diabetes is based on prevention of the inactivation process of bioactive peptides, the most important in the context of treatment of diabetes of which is glucagon-like peptide-1 (GLP-1). Most clinical experience with DPP-4 inhibition is based on vildagliptin (GalvusR, Novartis) and sitagliptin (JanuviaR, Merck). These compounds improve glycemic control both in monotherapy and in combination with other oral hyperglycemic agents. Both have also been shown to efficiently improve glycemic control when added to ongoing metformin therapy in patients with inadequate glycemic control. Under that condition, they reduce HbA1C levels by 0.65%-1.1% (baseline HbA1C 7.2-8.7%) in studies up to 52 weeks of duration in combination versus continuous therapy with metformin alone. Sitagliptin has also been examined in initial combination therapy with metformin have; HbA1 was reduced by this combination by 2.1% (baseline HbA1C 8.8%) after 24 weeks of treatment. Both fasting and prandial glucose are reduced by DPP-4 inhibition in combination with metformin in association with improvement of insulin secretion and insulin resistance and increase in concentrations of active GLP-1. The combination of DPP-4 inhibition and metformin has been shown to be highly tolerable with very low risk of hypoglycemia. Hence, DPP-4 inhibition in combination with metformin is an efficient, safe and tolerable combination therapy for type 2 diabetes.
 ...
PMID:Novel combination treatment of type 2 diabetes DPP-4 inhibition + metformin. 1856 13

The management of type 2 diabetes mellitus (T2DM) typically focuses on correcting dysglycaemia to reduce risk for microvascular and macrovascular complications, possibly by reducing glucose-mediated oxidative stress. However, other cardiometabolic risk factors, including abdominal obesity and dyslipidaemia are often overlooked in the quest for perfect glucose control. The currently used antidiabetic agents, including insulin, metformin, sulphonylureas and thiazolidinediones, have limited efficacy on these risk factors. A number of new therapeutic agents are undergoing clinical development, including glucagon-like peptide 1 mimetics (exenatide and liraglutide) and dipeptidyl peptidase 4 inhibitors (sitagliptin and vildagliptin), which target the incretin system, and the cannabinoid-1 receptor antagonists (rimonabant), which target the endocannabinoid system, may hold some promise for meeting these unmet needs. In this review, the clinical properties of these agents and potential treatment pathways to best use these agents are discussed for improving the management of T2DM and cardiovascular risk.
 ...
PMID:Beyond insulin replacement: addressing the additional needs of the diabetes patient. 1857 60

ASP4,000, (2S)-1-{[(1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecar bonitrile hydrochloride, is a novel dipeptidyl peptidase (DPP) 4 inhibitor. In the present study, we characterized the compound as an oral antidiabetic agent both in vitro and in vivo. ASP4,000 inhibited human recombinant DPP4 with an IC(50) value of 2.25 nM, and the enzyme-kinetic curve indicated that the inhibition type was competitive. In addition, ASP4,000 also potently inhibited DPP4 activity in human, rat, dog, and monkey plasma at concentrations of the order of 10(-9) M, and showed high selectivity against other related enzymes, including DPP8 and DPP9. The antihyperglycemic activity of ASP4,000 in vivo was examined using Zucker fa/fa rats, a type 2 diabetes animal model. A single oral administration of ASP4,000 at doses of 0.03-1 mg/kg suppressed plasma DPP4 activity, and then reduced the glucose level with increasing the active GLP-1 and insulin levels in oral glucose tolerance test. These results indicate that ASP4,000 is a potent, competitive, selective DPP4 inhibitor with antihyperglycemic activity, and could be a promising candidate agent for the treatment of patients with type 2 diabetes.
 ...
PMID:ASP4,000, a novel, selective, dipeptidyl peptidase 4 inhibitor with antihyperglycemic activity. 1858 61

New therapeutic agents are needed to combat the ever-increasing prevalence of diabetes. The two incretins glucagon-like peptide-1 (7-36) (GLP-1(7-36)) amide and glucose-dependent insulinotropic peptide (GIP) are released from the small intestine in response to the ingestion of nutrients and regulate glucose homeostasis in a glucose-dependent fashion; however, the action of both incretins is terminated by the rapid N-terminal cleavage of two amino acid residues of GLP-1 and GIP by dipeptidyl peptidase-IV (DPP-IV). The preservation of active GLP-1 and GIP by inhibiting DPP-IV activity is an attractive strategy for the treatment of diabetes in patients who exhibit a reduced incretin response. This strategy has resulted in the launch of two DPP-IV inhibitor drugs; sitagliptin in North America, several European territories, and various other countries, and vildagliptin in the EU as well as various countries. This article provides an overview of the recent advances in and the lessons learned from the design of potent and selective small-molecule inhibitors of DPP-IV for the treatment of type 2 diabetes.
 ...
PMID:From the bench to the bedside: dipeptidyl peptidase IV inhibitors, a new class of oral antihyperglycemic agents. 1860 May 68


<< Previous 1 2 3 4 5 6 7 8 9 10