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)

Type 2 diabetes results from the abnormal resistance of peripheral tissues to insulin and from the progressive insulin secretory failure of the pancreatic beta-cells. Treatment of type 2 diabetes has greatly improved due to the availability of new classes of oral antidiabetic drugs (OADs) and new insulin analogs. Three types of oral medications exert their antidiabetic action without directly stimulating insulin release: alpha-glucosidase inhibitors (e.g., acarbose) interfere with the digestion of dietary glucose precursors and the absorption of glucose; biguanides (e.g., metformin) inhibit hepatic gluconeogenesis, thereby lowering fasting blood glucose concentrations and increasing peripheral insulin sensitivity; and thiazolidinediones (e.g., rosiglitazone) improve the sensitivity of tissues to insulin-stimulated glucose disposal. In contrast, two classes of OADs stimulate insulin release from pancreatic beta-cells. Sulfonylureas (e.g., glyburide) have been used successfully for many years to treat type 2 diabetes, but their prolonged action may result in hypoglycemia. The third-generation sulfonylurea glimepiride is associated with a reduced risk of hypoglycemia and less weight gain than other sulfonylureas. Finally, the meglitinides (e.g., repaglinide) and D-phenylalanine derivatives (e.g., nateglinide) are powerful prandial insulin secretagogues. If the pancreatic beta-cells deteriorate to such an extent that insulin secretion is significantly impaired, treatment with additional exogenous insulin may be required.
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PMID:The pathophysiologic basis of efficacy and clinical experience with the new oral antidiabetic agents. 1187 80

Nateglinide is a novel insulinotropic agent for the treatment of type 2 diabetes. It is a D-phenylalanine derivative, chemically distinct from repaglinide and sulphonylureas (glyburide or glimepiride). Although each agent is known to stimulate insulin release via the signaling cascade initiated by closure of ATP-dependent K+ (K(ATP)) channels in pancreatic beta-cells, the pharmacological effect of nateglinide is reportedly fast-acting, short-lasting, sensitive to ambient glucose and more resistant to metabolic inhibition. The aim of the present study was to elucidate the molecular mechanism(s) underlying the distinct properties of the insulinotropic action of nateglinide. By using the patch-clamp methods, we comparatively characterized the potency and kinetics of the effect of these agents on K(ATP) channels in rat beta-cells at normal vs. elevated glucose and under physiological condition vs. experimentally induced metabolic inhibition. Our results demonstrated that the mode of the action of nateglinide on K(ATP) current was unique in (a) glucose dependency; (b) increased potency and efficacy under ATP depletion and uncoupling of mitochondrial oxidative phosphorylation than physiological condition; (c) substantially more rapid onset and offset kinetics. The data provide mechanistic rationale for the unique in vivo and ex vivo activity profile of nateglinide and may contribute to reduced hypoglycemic potential associated with excessive insulin secretion.
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PMID:Interaction of nateglinide with K(ATP) channel in beta-cells underlies its unique insulinotropic action. 1202 Jun 94

Inhibitors of PTP-1B could be therapeutically beneficial in the treatment of type 2 diabetes. Owing to the large number of phosphatases in the cell, inhibitors against PTP-1B must not only be potent but selective as well. N-Benzoyl-L-glutamyl-[4-phosphono(difluoromethyl)]-L-phenylalanine-[4-phosphono(difluoro-methyl)]-L-phenylalanineamide (BzN-EJJ-amide) is a low nanomolar inhibitor of PTP-1B that shows selectivity over several protein tyrosine phosphatases. To gain an insight into the basis of its potency and selectivity, we evaluated several analogues of the inhibitor and introduced amino acid substitutions into PTP-1B by site-directed mutagenesis. We also determined the crystal structure of PTP-1B in complex with BzN-EJJ-amide at 2.5 A resolution. Our results indicate that the high inhibitory potency is due to interactions of several of its chemical groups with specific protein residues. An interaction between BzN-EJJ-amide and Asp48 is of particular significance, as substitution of Asp48 to alanine resulted in a 100-fold loss in potency. The crystal structure also revealed an unexpected binding orientation for a bisphosphonate inhibitor on PTP-1B, where the second difluorophosphonomethyl phenylalanine (F(2)PMP) moiety is bound close to Arg47 rather than in the previously identified second aryl phosphate site demarked by Arg24 and Arg254. Our results suggest that potent and selective PTP-1B inhibitors may be designed by targeting the region containing Arg47 and Asp48.
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PMID:The structure of PTP-1B in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates. 1211 18

Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO(2max). We investigated the effect of 11 days of intensive insulin treatment (T(2)D+) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T(2)D-) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T(2)D-. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.
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PMID:Synthesis rate of muscle proteins, muscle functions, and amino acid kinetics in type 2 diabetes. 1214 50

The therapeutic goals in patients with type 2 diabetes mellitus and the mechanisms of insulin resistance and secretion are discussed. Sulfonylureas improve glycemic control, restore the acute insulin response, and help improve beta-cell function in the short term. Meglitinides and phenylalanine derivatives and alpha-glucosidase inhibitors may be useful for elderly patients and others with normal fasting blood glucose levels and postprandial hyperglycemia, but they are less effective in achieving goal HbA1c levels in patients with marked fasting hyperglycemia. Metformin and thiazolidinediones act on hepatic, muscle, and adipose tissue through different mechanisms to improve glycemic control, beta-cell function, and the lipid profile. Thiazolidinediones have a greater impact on free fatty acids than metformin. They may have an additive effect with sulfonylureas, metformin, or insulin in improving glycemic control and the lipid profile. Many patients require combination therapy with one or more insulin sensitizers and an insulin secretagogue to achieve therapeutic goals. Insulin therapy should be initiated in patients in whom an HbA1c level less than 7.0% cannot be maintained with other therapies. This is vital in preventing diabetes complications. Insulin sensitizers should be continued during insulin therapy to reduce insulin resistance and treat the insulin resistance syndrome. Therapeutic goals for patients with type 2 diabetes mellitus include improvement in glycemic control and prevention of diabetes complications. Elevated levels of fasting blood glucose should be addressed before postprandial levels to reduce HbA1c levels and glucotoxicity to the beta cell. Dyslipidemia, hypertension, and hypercoagulability should be treated to minimize the increased cardiovascular risk seen in people with diabetes, which is responsible for the majority of deaths.
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PMID:Treating dual defects in diabetes: insulin resistance and insulin secretion. 1248 81

The presence and biological significance of circulating glycated insulin has been evaluated by high-pressure liquid chromatography (HPLC), electrospray ionization mass spectrometry (ESI-MS), radioimmunoassay (RIA), receptor binding, and hyperinsulinemic-euglycemic clamp techniques. ESI-MS analysis of an HPLC-purified plasma pool from four male type 2 diabetic subjects (HbA(1c) 8.1 +/- 0.2%, plasma glucose 8.7 +/- 1.3 mmol/l [means +/- SE]) revealed two major insulin-like peaks with retention times of 14-16 min. After spectral averaging, the peak with retention time of 14.32 min exhibited a prominent triply charged (M+3H)(3+) species at 1,991.1 m/z, representing monoglycated insulin with an intact M(r) of 5,970.3 Da. The second peak (retention time 15.70 min) corresponded to native insulin (M(r) 5,807.6 Da), with the difference between the two peptides (162.7 Da) representing a single glucitol adduct (theoretical 164 Da). Measurement of glycated insulin in plasma of type 2 diabetic subjects by specific RIA gave circulating levels of 10.1 +/- 2.3 pmol/l, corresponding to approximately 9% total insulin. Biological activity of pure synthetic monoglycated insulin (insulin B-chain Phe(1)-glucitol adduct) was evaluated in seven overnight-fasted healthy nonobese male volunteers using two-step euglycemic-hyperinsulinemic clamps (2 h at 16.6 micro g x kg(-1) x min(-1), followed by 2 h at 83.0 micro g x kg(-1) x min(-1); corresponding to 0.4 and 2.0 mU x kg(-1) x min(-1)). At the lower dose, the exogenous glucose infusion rates required to maintain euglycemia during steady state were significantly lower with glycated insulin (P < 0.01) and approximately 70% more glycated insulin was required to induce a similar rate of insulin-mediated glucose uptake. Maximal responses at the higher rates of infusion were similar for glycated and control insulin. Inhibitory effects on endogenous glucose production, insulin secretion, and lipolysis, as indicated by measurements of C-peptide, nonesterified free fatty acids, and glycerol, were also similar. Receptor binding to CHO-T cells transfected with human insulin receptor and in vivo metabolic clearance revealed no differences between glycated and native insulin, suggesting that impaired biological activity is due to a postreceptor effect. The present demonstration of glycated insulin in human plasma and related impairment of physiological insulin-mediated glucose uptake suggests a role for glycated insulin in glucose toxicity and impaired insulin action in type 2 diabetes.
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PMID:Demonstration of glycated insulin in human diabetic plasma and decreased biological activity assessed by euglycemic-hyperinsulinemic clamp technique in humans. 1254 Jun 26

Nateglinide a new short-acting D-phenylalanine derivative represents a new chemical class of drugs for treating type 2 diabetes that is pharmacologically and therapeutically distinct from currently existing agents. Studies in normal patients and those with type 2 diabetes have shown that nateglinide reduces mealtime blood glucose excursions by physiologic regulation of insulin secretion. Nateglinide binds to and inhibits the K+(ATP) channel of the beta-cell, causing membrane depolarisation, with a subsequent influx of extracellular calcium that results in insulin secretion. A total of 105 patients in 5 centres with type II diabetes mellitus were taken according to the inclusion criteria and given drug treatment and were evaluated on their improvement in fasting and postprandial plasma glucose and glycosylated haemoglobin values for efficacy, besides physician's assessment of the overall safety and efficacy. Nateglinide in a dose of 60 mg before three main meals was given and increased to a maximum of 120 mg thrice daily over the first 3-4 weeks. Nateglinide had to be taken 10 minutes before meals. Duration of treatment was 12 weeks. The patients showed decrease in fasting plasma glucose from 2nd week onwards and reduction in glycosylated haemoglobin by 6th week onwards. Postprandial glucose reduction was also significant at the end of 12th week. The frequency of adverse effects was low and no serious adverse effects were encountered.
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PMID:Efficacy and safety of nateglinide in the treatment of type II diabetes mellitus. 1267 76

Metformin (dimethylbiguanide) is an antihyperglycemic agent used in type 2 diabetes. Beyond its action on glycemic control, metformin exhibits other intrinsic effects that could play a role in prevention against diabetes complications. Some studies thus reported an improvement in the antioxidant status in patients treated with metformin. This might be in part related to its property to limit formation of advanced glycation end products (AGEs) and to decrease the overproduction of free radicals in diabetic subjects. The aim of this study was to investigate the in vitro ability of metformin to modulate the action of reactive oxygen species (ROS) generated either by water gamma radiolysis or by stimulated human leukocytes. Our results showed that metformin at pharmacologically relevant concentrations was in vitro able to scavenge hydroxyl ((.)OH) but not superoxide (O(.-)(2)) free radicals and that hydrogen peroxide did not react with metformin. Nevertheless, when polymorphonuclear cells (PMN) are stimulated by phorbol myristate acetate (PMA), or above all by formyl methionine leucyl phenylalanine (fMLP), a systematic (although nonsignificant) decrease of the ROS-induced chimiluminescence (CL) was observed. These results suggest that metformin could directly scavenge ROS or indirectly act by modulating the intracellular production of superoxide anion, of which NADPH oxidase constitutes the major source. This could contribute to the additional benefits of metformin, especially those related to the improvement in the cardiovascular outcomes in diabetes.
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PMID:An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress. 1275 88

Phospholipase A2, Group IVA (PLA2G4A) belongs to the class of cytosolic calcium-dependent phospholipases (cPLA2s) that preferentially cleave arachidonic acid (AA) from membrane glycerophospholipids. AA and AA metabolites play key roles in glucose disposal and insulin secretion. PLA2G4A is located on Chromosome 1q, where a number of groups have reported linkage to type 2 diabetes mellitus. We have screened the PLA2G4A gene and identified a C-->G variant, which predicts a phenylalanine to leucine substitution. In logistic regression analyses adjusted for age, sex, ethnicity, and birth year, we found a trend toward association between this SNP and diabetes [OR=1.53 (0.97-2.40); p=0.06]. Individuals with the variant genotype had lower mean basal endogenous glucose output (1.8+/-0.03 vs. 1.9+/-0.01 mg/kgEMBS/min; p=0.04) and lower mean basal glucose oxidation (1.2+/-0.11 vs. 1.4+/-0.03 mg/kgEMBS/min; p=0.005) compared to individuals with the wild-type genotype. During a low dose insulin infusion, non-diabetic individuals with the variant genotype had a lower mean glucose oxidation (1.9+/-0.11 vs. 2.0+/-0.03 mg/kgEMBS/min; p=0.04) and total glucose turnover rate (2.5+/-0.22 vs. 2.6+/-0.06 mg/kgEMBS/min; p=0.01) compared to subjects with the wild-type genotype. In addition, under basal conditions, individuals with the variant genotype had a higher mean lipid oxidation rate compared to individuals with the wild-type genotype (0.77+/-0.25 vs. 0.67+/-0.23 mg/kgEMBS/min; p=0.02). These results provide evidence supporting a role for the eicosanoid biosynthesis pathway in type 2 diabetes mellitus pathophysiology.
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PMID:Association of a F479L variant in the cytosolic phospholipase A2 gene (PLA2G4A) with decreased glucose turnover and oxidation rates in Pima Indians. 1276 47

Neutral endopeptidase (NEP), a membrane-bound metallopeptidase enzyme that degrades neuropeptides, bradykinin, atrial natriuretic factor, enkephalins, and endothelin may regulate response to injury. We have previously demonstrated increased NEP localization and enzyme activity in diabetic wounds and skin compared with normal controls. We hypothesized that hyperlipidemia and hyperglycemia associated with type 2 diabetes mellitus may induce excessive NEP activity and thereby diminish normal response to injury. Human microvascular endothelial cells were treated with five different fatty acids (40 microM) with varying degrees of saturation, including oleic acid, linoleic acid, palmitic acid, stearic acid, and linolenic acid and/or glucose (40 mM) for 48 h. The effect of the antioxidative agents vitamin E and C on NEP enzyme activation was determined by treating the cultured cells with alpha-tocopherol succinate and/or L-ascorbic acid. Cell membrane preparations were assayed for NEP activity by incubation with glutaryl-Ala-Ala-Phe-4-methoxy-beta naphthylamide to generate a fluorescent degradation product methoxy 2 naphthylamine. High glucose or fatty acid concentration upregulated NEP activity. The highest NEP activity was observed with combined elevated glucose, linoleic acid, and oleic acid (P < 0.05). Antioxidant vitamin E and C treatment significantly reduced NEP enzyme activity after fatty acid exposure (P < 0.05). Thus, hyperglycemia and hyperlipidemia associated with type 2 diabetes mellitus may increase endothelial cell NEP activity and thereby decrease early pro-inflammatory responses. The modulator effect of vitamin E and C on NEP membrane enzyme activity after exposure to fatty acid stimulation suggests that lipid oxidation may activate NEP.
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PMID:Fatty acids and glucose increase neutral endopeptidase activity in human microvascular endothelial cells. 1278 4


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