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)

The emergence of the glucoregulatory hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide has expanded our understanding of glucose homeostasis. In particular, the glucoregulatory actions of the incretin hormone GLP-1 include enhancement of glucosedependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to overcome rapid degradation of GLP-1. One is the use of agents that mimic the enhancement of glucose-dependent insulin secretion, and potentially other antihyperglycemic actions of incretins, and the other is the use of dipeptidyl peptidase-IV inhibitors, which reduce the inactivation of GLP-1, increasing the concentration of endogenous GLP-1. The development of incretin mimetics and dipeptidyl peptidase-IV inhibitors opens the door to a new generation of antihyperglycemic agents to treat several otherwise unaddressed pathophysiologic defects of type 2 diabetes mellitus. We review the physiology of glucose homeostasis, emphasizing the role of GLP-1, the pathophysiology of type 2 diabetes mellitus, the clinical shortcomings of current therapies, and the potential of new therapies -- including the newly approved incretin mimetic exenatide -- that elicit actions similar to those of GLP-1.
 ...
PMID:Incretin mimetics and dipeptidyl peptidase-IV inhibitors: potential new therapies for type 2 diabetes mellitus. 1650 16

Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote beta cell proliferation and inhibit apoptosis, leading to expansion of beta cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. Furthermore, GLP-1, unlike GIP, potently stimulates insulin secretion and reduces blood glucose in human subjects with type 2 diabetes. This article summarizes current concepts of incretin action and highlights the potential therapeutic utility of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes.
 ...
PMID:The biology of incretin hormones. 1651 3

Exenatide is a 39 amino acid incretin mimetic for the treatment of type 2 diabetes, with glucoregulatory activity similar to glucagon-like peptide-1 (GLP-1). Exenatide is a poor substrate for the major route of GLP-1 degradation by dipeptidyl peptidase-IV, and displays enhanced pharmacokinetics and in vivo potency in rats relative to GLP-1. The kidney appears to be the major route of exenatide elimination in the rat. We further investigated the putative sites of exenatide degradation and excretion, and identified primary degradants. Plasma exenatide concentrations were elevated and sustained in renal-ligated rats, when compared to sham-operated controls. By contrast, exenatide elimination and degradation was not affected in rat models of hepatic dysfunction. In vitro, four primary cleavage sites after amino acids (AA)-15, -21, -22 and -34 were identified when exenatide was degraded by mouse kidney membranes. The primary cleavage sites of exenatide degradation by rat kidney membranes were after AA-14, -15, -21, and -22. In rabbit, monkey, and human, the primary cleavage sites were after AA-21 and -22. Exenatide was almost completely degraded into peptide fragments <3 AA by the kidney membranes of the species tested. The rates of exenatide degradation by rabbit, monkey and human kidney membranes in vitro were at least 15-fold slower than mouse and rat membranes. Exenatide (1-14), (1-15), (1-22), and (23-39) were not active as either agonists or antagonists to exenatide in vitro. Exenatide (15-39) and (16-39) had moderate-to-weak antagonist activity compared with the known antagonist, exenatide (9-39). In conclusion, the kidney appears to be the primary route of elimination and degradation of exenatide.
 ...
PMID:Investigation of exenatide elimination and its in vivo and in vitro degradation. 1672 26

Inhibitors of dipeptidyl peptidase-4 (DPP-4), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major unanswered question concerns the potential ability of DPP-4 inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic beta-cell mass and function. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of sitagliptin (des-fluoro-sitagliptin), on glycemic control and pancreatic beta-cell mass and function in a mouse model with defects in insulin sensitivity and secretion, namely high-fat diet (HFD) streptozotocin (STZ)-induced diabetic mice. Significant and dose-dependent correction of postprandial and fasting hyperglycemia, HbA(1c), and plasma triglyceride and free fatty acid levels were observed in HFD/STZ mice following 2-3 months of chronic therapy. Treatment with des-fluoro-sitagliptin dose dependently increased the number of insulin-positive beta-cells in islets, leading to the normalization of beta-cell mass and beta-cell-to-alpha-cell ratio. In addition, treatment of mice with des-fluoro-sitagliptin, but not glipizide, significantly increased islet insulin content and improved glucose-stimulated insulin secretion in isolated islets. These findings suggest that DPP-4 inhibitors may offer long-lasting efficacy in the treatment of type 2 diabetes by modifying the courses of the disease.
 ...
PMID:Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. 1673 32

Type 2 diabetes is thought to develop as a result of progressive beta-cell dysfunction in the setting of insulin resistance, leading to increased risks of microvascular and macrovascular complications. Type 2 diabetes is currently treated with diet and exercise, followed by oral drug therapy, and finally exogenous insulin. While this approach is known to improve glycemic control, none of the currently available therapies significantly improve beta-cell function. In addition, this approach does not address defects in hormonal secretion thought to play key roles in the pathophysiology of type 2 diabetes. Type 2 diabetes is characterized by excess glucagon secretion and insufficient secretion of the hormone amylin from the pancreatic beta-cell. In addition, individuals with type 2 diabetes demonstrate insufficient secretion of the incretin hormone glucagon-like peptide-1 (GLP-1). Novel therapies that leverage the so-called "incretin effect" of GLP-1 (including the incretin mimetics and dipeptidyl peptidase-IV (DPP-IV) inhibitors) are being actively developed for the management of type 2 diabetes. Incretin mimetics are either derivatives of GLP-1, modified to resist proteolysis, or are novel peptides that share glucoregulatory functions with GLP-1 and are naturally resistant to proteolysis. DPP-IV inhibitors enhance the concentration of endogenous GLP-1 by limiting proteolysis of native GLP-1. With the approval of exenatide- the first "incretin mimetic"-treatment of type 2 diabetes will no doubt be changed. An understanding of the effects of these compounds will be needed to enhance the clinical approach to diabetes treatment.
 ...
PMID:Incretin mimetics and dipeptidyl peptidase-IV inhibitors: a review of emerging therapies for type 2 diabetes. 1680 Jul 60

Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post-oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion.
 ...
PMID:Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. 1685 72

The actions of the structurally related proglucagon-derived peptides (PGDPs)-glucagon, glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores beta-cell sensitivity to glucose, increases beta-cell proliferation, and reduces apoptosis, leading to expansion of the beta-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.
 ...
PMID:Biologic actions and therapeutic potential of the proglucagon-derived peptides. 1692 63

Type 2 diabetes is now one of the most challenging health-care problems, and novel treatment strategies are required. The pancreatic islet dysfunction of type 2 diabetes involves problems with both insulin and glucagon since appropriate levels of both hormones are required for maintenance of glucose homeostasis. Enhancement of pancreatic function by incretins such as glucagon-like peptide (GLP)-1 is a new therapeutic approach. These incretins are inactivated by the enzyme dipeptidyl peptidase (DPP)-4. Vildagliptin is a potent, orally active, highly selective DPP-4 inhibitor that enhances the antidiabetic actions of the incretins. Pharmacokinetic studies showed that it is absorbed rapidly but has a sufficiently long period of action to require only once-daily dosing. Three phase II studies of vildagliptin use for 12 weeks in patients with type 2 diabetes have been reported. When vildagliptin was used either as monotherapy or combined with metformin, the treatment versus placebo resulted in significant reductions in hemoglobin (Hb)A(1c). The HbA(1c) was maintained during extended treatment over one year in the study of combination use with metformin. The studies indicated that the greater glycemic control appears to reflect an improvement in islet function. The improvement in glycemic control with vildagliptin was not associated with any body weight gain. Vildagliptin did not cause any clinically relevant changes in safety and was well tolerated. Therefore, further studies are being carried out on vildagliptin to assess long-term efficacy and safety in patients with type 2 diabetes.
 ...
PMID:Vildagliptin: a novel DPP-4 inhibitor with pancreatic islet enhancement activity for treatment of patients with type 2 diabetes. 1696 29

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
 ...
PMID:Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes. 1703 48

The dipeptidyl peptidase 4 (DPP-4) inhibitors enhance the body's own ability to control blood glucose by increasing the active levels of incretin hormones in the body. Their mechanism of action is distinct from any existing class of oral glucose-lowering agents. They control elevated blood glucose by triggering pancreatic insulin secretion, suppressing pancreatic glucagon secretion, and signalling the liver to reduce glucose production. The leading DPP-4 inhibitors have shown clinically significant HbA1c reductions up to 1 year of treatment and offer many potential advantages over existing diabetes therapies including a low risk of hypoglycaemia, no effect on body weight, and the potential, based on animal and in vitro studies, for the regeneration and differentiation of pancreatic beta-cells. They are efficacious as monotherapy and also in combination with commonly prescribed antidiabetic agents and are suitable for once-daily oral dosing. Consequently, many DPP-4 inhibitors such as vildagliptin (Galvus; LAF-237), sitagliptin (Januvia; MK-0431), and saxagliptin (BMS-477118) have advanced into late-stage human clinical trials. Search strategy and selection criteria This review was built on a systematic MEDLINE search for publications on the subject with the key words: DPP-4 inhibitor; vildagliptin (LAF-237); sitagliptin (MK-0431); saxagliptin (BMS-477118); and type 2 diabetes; up to August 2006. Meeting abstracts were also searched, as much of the data currently only exists in abstract form. Take home message for clinician The DPP-4 inhibitors appear to have great potential for the treatment of type 2 diabetes, but time will tell if this will be realized. While they do not lower glucose to a greater extent than existing therapies, they offer many potential advantages, including the ability to achieve sustainable reductions in HbA1c with a well-tolerated agent that has a low risk of hypoglycaemia and no weight gain, and which can be administered as a once-daily oral dose.
 ...
PMID:DPP-4 inhibitors and their potential role in the management of type 2 diabetes. 1707 41


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