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

The epidemic characteristics of type 2 diabetes mellitus (DM) pose a formidable challenge in terms of healthcare, given the tremendous impact it has on the healthcare resources needed not only to treat it, but also to prevent and treat the associated cardiovascular complications. This makes up the number 1 cause of DM-associated morbidity-mortality in addition to its social and personal impact. We currently have a growing number of available treatment tools that make it possible to achieve the target glycemic control in most of our patients, albeit unfortunately, only temporarily in a good many of them, because of the progressive nature of the disease. Furthermore, current therapy often entails undesirable effects, such as weight gain or the emergence of hypoglycemias that limit their optimization. Recently, a new class of drugs has been incorporated into the treatment of DM - incretin mimetics. These new drugs act in very much the same way as the intestinal hormones that are naturally secreted following the intake of nutrients, called incretins (e.g., glucagon like peptide-1 [GLP-1]), with the added advantage that these molecules are resistant to enzymatic degradation by the DPP-IV enzyme. This provides them with a half-life that makes ambulatory treatment possible, unlike natural incretins whose half-life is too short to make them viable as treatment. The incretin mimetics bind to GLP-1 receptors, increasing glucose-dependent secretion of insulin and decreasing glucose-dependent posprandial secretion of glucagon, slowing gastric emptying, and reducing food intake. All these mechanisms have a significant impact on glucose homeostasis and a beneficial effect on body weight. Moreover, studies in experimental models suggest that these new molecules might have a promising effect on pancreatic beta cell function and mass. Exenatide is the first incretin mimetic available to date. Efficacy and safety data of this drug show it as a therapeutic option for the treatment of type 2 DM.
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PMID:[Incretins as new therapeutic targets of type 2 diabetes]. 1766 2

C-reactive protein (CRP) is one of the acute-phase proteins in inflammation and CRP serum concentrations are therefore of interest. Data for high-sensitivity CRP (hs-CRP) with a low detection limit of approximately 0.04 mg/L have become available over the past decade and research has shown a link between high concentrations of hs-CRP and obesity as well as smoking. Expanded adipose tissue is in fact known to secrete proinflammatory cytokines which enhance hepatic synthesis of CRP. Moderate alcohol consumption and high physical activity have been associated with low levels of hs-CRP, but the evidence in these cases is not conclusive. It has been suggested that hs-CRP is an independent marker of the risk of cardiovascular disease, but the predictive capacity remains controversial. However, many prospective studies have observed increased risk of type 2 diabetes mellitus associated with high concentrations of hs-CRP, independent of obesity and other cardiovascular risk factors. On the other hand, no measurable increase in the risk associated with high levels of hs-CRP was observed with multivariate adjustment in several studies. A number of authors have reported that high concentrations of hs-CRP are associated with increased risks of colorectal and other cancers, but the findings again are inconsistent. Diet and hs-CRP are also of increasing research interest. High intakes of carotenoids and vitamin C, but not of vitamin E, seem to decrease the level of circulating hs-CRP. In addition, high consumption of vegetables and fruit are associated with lower levels of circulating hs-CRP, perhaps by exerting anti-inflammatory effects. Both mechanistic and epidemiologic studies regarding dietary factors and low-grade inflammation are necessary to add to our knowledge of dietary influence on chronic disease development.
Asian Pac J Cancer Prev
PMID:Impact of C-reactive protein on disease risk and its relation to dietary factors. 1769 26

In France, prevalence of drug-treated diabetes reached 3.60% in 2005, with 92% of type 2 diabetic patients. In 2007, there are probably nearly 3000 000 diagnosed or undiagnosed diabetic patients. Ageing of the population and increase in obesity are the main causes of this "diabetes epidemic". Type 2 diabetes is a multifactorial disease, defined as resulting from defects in insulin secretion (including abnormalities in pulsatility and kinetics, quantitative and qualitative abnormalities of insulin, beta-cell loss progressing with time) associated with insulin resistance (affecting liver, and skeletal muscle) and increased glucagon secretion. The lack of compensation of insulin resistance by augmented insulin secretion results in rise in blood glucose. To achieve satisfactory glycaemic control in order to prevent diabetes related complications, drug therapy is generally required in addition to life style changes. Currently available oral therapies offer a large panel of complementary drugs, but they have several contraindications and side effects. In spite of major advances in the management of type 2 diabetes, and the strictness of new guidelines, some goals remain unachieved and the new family of insulin-secretors (DPP-IV inhibitors, GLP-1 analogues) should enrich therapeutic approaches.
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PMID:Type 2 diabetes mellitus: epidemiology, pathophysiology, unmet needs and therapeutical perspectives. 1770 79

The aim of this study is to evaluate the short-term effectiveness of our individual-based counseling program and tools among individuals in ordinary Japanese communities with impaired fasting glucose (IFG) and mild type 2 diabetes. A total of 233 eligible participants (age 30-69 years) in 14 local study centers were randomly assigned to an intervention group (INT, N=119) and a control group (CONT, N=114). During the 4-month intervention, the INT received 4 individual counseling sessions and one reminder on life style modification. The CONT received only an explanation of blood test results and general information on diabetes. Baseline characteristics did not differ significantly between groups. Percentages of participants with desirable changes in glycemic level and weight were significantly higher in INT than CONT: fasting plasma glucose reduction of more than 10 mg/dL (39% in INT vs. 26% in CONT, p=0.045), hemoglobinA1c reduction greater than 0.3% (14% vs. 4%, p=0.01), and weight reduction of more than 4 kg (13% vs. 4%, p=0.025). Decreases in total energy intake and percentage of heavy alcohol drinkers (more than 46 g/day) were significantly greater in INT than CONT. The increase in percentages of participants who engaged in leisure time physical activity more than 12 times per month was significantly greater in INT than CONT. Our program resulted in life style modification and glycemic level improvement in the short-term among individuals with IFG and mild type 2 diabetes. Results indicated that the program was sufficiently effective and feasible for implementation in ordinary communities.
Asia Pac J Clin Nutr 2007
PMID:Short-term effectiveness of an individual counseling program for impaired fasting glucose and mild type 2 diabetes in Japan: a multi-center randomized control trial. 1770 31

Neutral endopeptidase (NEP) is the major enzyme involved in the metabolic inactivation of a number of bioactive peptides including the enkephalins, substance P, endothelin, bradykinin and atrial natriuretic factor, as well as the incretin hormone glucagon-like peptide 1 (GLP-1), which is a potent stimulator of insulin secretion. The activity of GLP-1 is also rapidly abolished by the serine protease dipeptidyl peptidase IV (DPP-IV), which led to an elevated interest in inhibitors of this enzyme for the treatment of type II diabetes. A dual NEP/DPP-IV inhibitor concept is proposed, offering an alternative strategy for the treatment of type 2 diabetes. Here, the synthesis and crystal structures of the soluble extracellular domain of human NEP (residues 52-749) complexed with the NEP, competitive and potent dual NEP/DPP-IV inhibitor MCB3937 are described.
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PMID:Structural studies of a bifunctional inhibitor of neprilysin and DPP-IV. 1770 66

Incretins are gut peptides that potentiate nutrient-stimulated insulin secretion following meal ingestion. Activities of the dominant incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, include glucose-dependent stimulation of insulin secretion and, in preclinical models, improvement in islet beta-cell mass. GLP-1 additionally reduces glucagon secretion, inhibits gastric emptying and promotes satiety. Patients with type 2 diabetes mellitus (T2DM) exhibit reduced total and intact GLP-1 levels, and exogenous administration of the hormone via continuous infusion results in glucose profiles similar to those in non-diabetic subjects. Incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). Thus, strategies to enhance incretin activity have included development of GLP-1 receptor agonists resistant to the action of DPP-4 (e.g. exenatide and liraglutide) and DPP-4 inhibitors that act to increase concentrations of endogenous intact incretins (e.g. sitagliptin and vildagliptin). Clinical trials of these incretin-based therapies have shown them to be effective in improving glycaemic control in patients with T2DM.
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PMID:Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. 1787 44

Vildagliptin is a potent selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycaemic control by increasing islet alpha-cell and beta-cell responsiveness to glucose. In patients with type 2 diabetes mellitus (T2DM), vildagliptin improves beta-cell function, measured as insulin secretory rate relative to glucose level, and reduces glucagon secretion and endogenous glucose production in the postprandial period, resulting in reduced glucose levels. In clinical trials in T2DM, vildagliptin 100 mg/day monotherapy is effective in reducing haemoglobin A1c (HbA1c) across the spectrum of hyperglycaemia and has maintained efficacy over long-term treatment with neutral effects on body weight and lipids. Vildagliptin is associated with a low risk of hypoglycaemia, and has an adverse event profile comparable to placebo, including a reduced rate of gastrointestinal adverse effects compared with metformin and a reduced rate of oedema compared with rosiglitazone. As add-on combination therapy, vildagliptin produces significant further reductions in HbA1c in patients receiving metformin, pioglitazone, glimepiride and insulin, and has been found to reduce frequency of hypoglycaemia as an add-on to insulin. Preliminary findings indicate that the improved islet cell function underlying the efficacy of vildagliptin in T2DM is also observed in patients with impaired glucose tolerance, with vildagliptin treatment resulting in reduced glycaemic excursions. The overall profile of vildagliptin and the preliminary evidence of beneficial effects in the prediabetic state suggest that DPP-4 inhibition could be an effective strategy to prevent or delay progression from the prediabetic state to overt T2DM.
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PMID:The DPP-4 inhibitor vildagliptin: robust glycaemic control in type 2 diabetes and beyond. 1787 45

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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PMID:G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. 1790 Jul

Dipeptidyl peptidase (DPP-IV) rapidly metabolizes hormones such as glucagon-like peptide-1(7-36)amide. This study evaluated circulating DPP-IV activity in type 2 diabetic patients in relation to GLP-1 degradation and metabolic control. Blood samples were collected from type 2 diabetic patients in three main categories: good glycaemic control (HbA(1c) <7%, upper limit of non-diabetic range), moderate glycaemic control (HbA(1c) 7-9%) and poor glycaemic control (HbA(1c) >9%). Age- and sex-matched non-diabetic subjects were used as controls. Circulating DPP-IV activity of healthy control subjects was 22.5+/-0.7 nmol/ml/min (n=70). In the combined groups of type 2 diabetic subjects, circulating DPP-IV activity was significantly decreased at 18.1+/-0.7 nmol/ml/min (p<0.001, n=54). DPP-IV activity was negatively correlated with both glucose (p<0.01) and HbA(1c) (p<0.01) in this population. Furthermore, DPP-IV activity was reduced 1.2-fold (p<0.01, n=25), 1.3-fold (p<0.001, n=19) and 1.3-fold (p<0.05, n=10) in good, moderate and poorly controlled diabetic groups, 18.7+/-1.0, 17.4+/-1.4 and 18.0+/-1.5 nmol/ml/min, respectively. Degradation of GLP-1 by in vitro incubation with pooled plasma samples from healthy and type 2 diabetic subjects revealed decreased degradation to the inactive metabolite, GLP-1(9-36), in the diabetic group. These data indicate decreased DPP-IV activity and GLP-1 degradation in type 2 diabetes. DPP-IV enzyme activity appears to be depressed in response to poor glycaemic control.
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PMID:Decreased dipeptidyl peptidase-IV activity and glucagon-like peptide-1(7-36)amide degradation in type 2 diabetic subjects. 1790 81

The two incretin hormones GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-dependent Insulinotropic Peptide) are released by the gut in response to nutrient ingestion. Both of them potentiate glucose-induced insulin response, enhance insulin biosynthesis and, at least in rodents, preserve beta-cell mass through reduction of apoptosis and stimulation of beta-cell proliferation. In addition to its insulinotropic action, GLP-1 (but not GIP) suppresses glucagon secretion, delays gastric emptying and promotes satiety. Since in type 2 diabetes, the secretion of GLP-1 is dramatically reduced whereas its effects are retained, a number of pharmacological strategies aiming at restoring the incretin activity of this peptide have been explored. Because GLP-1 is rapidly degraded by the ubiquitous enzyme, dipeptidyl peptidase-IV (DPP-IV) and has a very short-lived action, DPP-IV resistant mimetics have been designed. Several randomized placebo-controlled studies with DPP-IV resistant GLP-1 analogues confirmed their efficacy to improve glycemic control in type 2 diabetic patients. The first one, exenatide, has been approved by the Food and Drug Administration (FDA) in 2005 for the treatment of type 2 diabetes. Longer-acting mimetics requiring only one injection per day or even per week are currently assessed in phase 3 trials. Another successful approach has been the development of orally active DPP-IV inhibitors which reversibly and selectively block the enzymatic activity. Many small-molecule DPP-IV inhibitors, called gliptins, have been shown to be effective as antihyperglycemic agents and, up to now, devoid of major adverse events. The first drug of this new therapeutic class having received FDA approval, sitagliptin, is now available for the treatment of type 2 diabetes in U.S. However, the efficacy/safety profile of these compounds and their positioning in the therapeutic algorithm of type 2 diabetes remains to be defined.
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PMID:[The incretin effect: a new therapeutic target in type 2 diabetes]. 1795 29


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