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)

ATP-sensitive potassium channels (K(ATP) channels) are heteromeric complexes of pore-forming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. K(ATP) channels were identified in a variety of tissues including muscle cells, pancreatic beta-cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening. Functionally, K(ATP) channels provide a means of linking the electrical activity of a cell to its metabolic state. Shortening of the cardiac action potential, smooth muscle relaxation, inhibition of both insulin secretion, and neurotransmitter release are mediated via K(ATP) channels. Given their many physiological functions, K(ATP) channels represent promising drug targets. Sulfonylureas like glibenclamide block K(ATP) channels; they are used in the therapy of type 2 diabetes. Openers of K(ATP) channels (KCOs), for example, relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines, and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols.
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PMID:KATP channel openers: structure-activity relationships and therapeutic potential. 1470 69

Impaired glucose stimulated insulin secretion is a prominent, early defect in type 2 diabetes. Insulin secretion is coupled to glucose metabolism by effects of the intracellular ATP/ADP ratio on the multimeric beta-cell potassium channel. The sulfonylurea receptor (SUR1 or ABCC8), the regulatory subunit of that channel, binds sulfonylurea agents and thus closes the channel and stimulates exocytosis of insulin-containing granules. alpha-Endosulfine (ENSA), has been proposed as the endogenous ligand for SUR1. We mapped ENSA in silico to chromosome 1q21 near a confirmed type 2 diabetes susceptibility locus, and derived the genomic structure of four exons and three introns. We identified four single nucleotide polymorphisms (SNP) and one insertion deletion polymorphism among 16 Caucasian and 16 African-American diabetic individuals. Only one SNP was common to both ethnic groups, and no SNP altered the coding sequence. No variant was associated with type 2 diabetes in Caucasian or African-American studies, but a single SNP in intron 3 (SNP 17) was associated with a reduced disposition index (insulin sensitivity x acute insulin response to glucose) in interaction with family membership in 126 members of 26 Caucasian families. Individuals homozygous for the rare allele showed a 70% reduction in insulin secretion (disposition index) relative to all other genotypes. Our data do not suggest that ENSA could explain the linkage of T2DM to this region, but ENSA SNP 17 may have an important role in reducing the ability of the beta-cell to compensate for reduced insulin sensitivity, which in turn would increase the susceptibility to T2DM.
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PMID:Alpha-endosulfine, a positional and functional candidate gene for type 2 diabetes: molecular screening, association studies, and role in reduced insulin secretion. 1472 86

Psammomys obesus (sand rat) is an appropriate model to highlight the development of hyperinsulinemia, insulin resistance, obesity, and diabetes. This animal species, with genetically predetermined diabetes, acquires non-insulin dependent diabetes mellitus when exposed to energy-rich diets. In the present study, we explored the possibility that glycation of LDL may occur in diabetes-prone P. obesus and affect platelet and macrophage functions. The glycation of LDL, isolated from diabetic animals, was significantly (P < 0.05) higher (40%) than that of control animals. The incubation of platelets with glycated LDL enhanced the reactivity of platelets by 32-44% depending on the aggregating agents (thrombin, collagen, ADP). Furthermore, LDL derived from diabetic rats were chemotactic for normal monocytes and stimulated the incorporation of [14C]oleate into cellular cholesteryl esters. The enhancement of platelet aggregation and cholesterol esterification in monocytes may contribute toward the accelerated development of atherosclerotic cardiovascular disease in diabetic P. obesus animals. This study also illustrates the relevance of studying atherosclerosis in the P. obesus animal model, as it shows an increased tendency to develop diet-induced diabetes, which is associated with cardiovascular disorders.
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PMID:Impact of in vivo glycation of LDL on platelet aggregation and monocyte chemotaxis in diabetic psammomys obesus. 1505 39

A low-taurine diet during fetal or early postnatal life causes abnormal pancreatic beta-cell development. Tissue and plasma taurine concentrations can also be low in diabetic patients. We examined the effect of taurine on impaired glucose responses in diabetic rat beta-cells adenovirally overexpressing uncoupling protein (UCP)2, which is upregulated in obesity-related type 2 diabetes. We found that taurine pretreatment restored the ATP-to-ADP (ATP/ADP) ratio and glucose-stimulated insulin secretion in UCP2-infected islets. ATP-sensitive K(+) channel sensitivity to dihydroxyacetone, another insulin secretagogue, was similar in both UCP2-infected and control beta-cells. In freshly isolated mitochondria from UCP2-overexpressing insulin-secreting (INS)-1 beta-cells, methyl pyruvate-mediated mitochondrial Ca(2+) increase was significantly ameliorated by taurine. A mitochondrial Ca(2+) uniporter blocker, ruthenium red, inhibited the action of taurine. This study suggests that taurine enhances the glucose sensitivity of UCP2-overexpressing beta-cells, probably by increasing mitochondrial Ca(2+) influx through the Ca(2+) uniporter, thereby enhancing mitochondrial metabolic function and increasing the ATP/ADP ratio.
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PMID:Taurine increases glucose sensitivity of UCP2-overexpressing beta-cells by ameliorating mitochondrial metabolism. 1526 58

Prolonged periods of "beta-cell rest" exert beneficial effects on insulin secretion from pancreatic islets subjected to a high-glucose environment. Here, we tested for effects of short-term intermittent rest achieved by diazoxide. Rat islets were cultured for 48 h with 27 mmol/l glucose alone, with diazoxide present for 2 h every 12 h or with continuous 48-h presence of diazoxide. Both protocols with diazoxide enhanced the postculture insulin response to 27 mmol/l glucose, to 200 mumol/l tolbutamide, and to 20 mmol/l KCl. Intermittent diazoxide did not affect islet insulin content and enhanced only K(ATP)-dependent secretion, whereas continuous diazoxide increased islet insulin contents and enhanced both K(ATP)-dependent and -independent secretory effects of glucose. Intermittent and continuous diazoxide alike increased postculture ATP-to-ADP ratios, failed to affect [(14)C]glucose oxidation, but decreased oxidation of [(14)C]oleate. Neither of the two protocols affected gene expression of the ion channel-associated proteins Kir6.2, sulfonylurea receptor 1, voltage-dependent calcium channel-alpha1, or Kv2.1. Continuous, but not intermittent, diazoxide decreased significantly mRNA for uncoupling protein-2. A 2-h exposure to 20 mmol/l KCl or 10 mumol/l cycloheximide abrogated the postculture effects of intermittent, but not of continuous, diazoxide. Intermittent diazoxide decreased islet levels of the SNARE protein SNAP-25, and KCl antagonized this effect. Thus short-term intermittent diazoxide treatment has beneficial functional effects that encompass some but not all characteristics of continuous diazoxide treatment. The results support the soundness of intermittent beta-cell rest as a treatment strategy in type 2 diabetes.
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PMID:Short-term intermittent exposure to diazoxide improves functional performance of beta-cells in a high-glucose environment. 1529 32

This study was done to evaluate the effect of treatment with manidipine as compared with atenolol on thrombin-mediated platelet aggregation in elderly patients with isolated systolic hypertension and type II diabetes mellitus. After a 2-week washout placebo period, 60 elderly patients (aged 65-80 years) with isolated systolic hypertension (SBP > 140 mm Hg and DBP < 90 mm Hg) were randomly assigned to manidipine 10 mg or atenolol 50 mg 6-week treatment according to a double-blind, crossover design. Thirty patients had a concomitant well-controlled type 2 diabetes mellitus (HbA1c < or = 6.5%). At the end of the washout and of each treatment period, blood pressure (BP) (by mercury sphygmomanometer) and platelet aggregation (by Born-type aggregometer) were evaluated. Blood samples were collected using sodium citrate as anticoagulant, and platelet aggregation was induced by 2 different concentrations of ADP and collagen. Manidipine and atenolol produced a significant BP reduction in both diabetic and nondiabetic patients, with no difference between treatments. Despite the similar BP effect, in diabetic patients manidipine produced a significant reduction in platelet aggregation induced by both doses of either ADP or collagen. In nondiabetic hypertensives, manidipine inhibited platelet aggregation only at the highest doses of both inducers. The difference in the platelet inhibitory effect of manidipine between diabetic and nondiabetic subjects was statistically significant (P < 0.05) at both inducer concentrations. No changes in platelet aggregation were observed in the atenolol group. These data indicate that, unlike atenolol, manidipine inhibits platelet aggregation in elderly hypertensive patients, expecially in those with associated type II diabetes mellitus. The clinical impact of this positive effect in terms of prevention of cardiovascular complications in these high-risk patients remains to be clarified.
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PMID:Effect of manidipine as compared to atenolol on platelet aggregation in elderly patients with isolated systolic hypertension and type II diabetes mellitus. 1577 18

Mitochondrial dysfunction causes dozens of debilitating diseases, and is implicated in the etiology of type 2 diabetes, Parkinson's, and Alzheimer's diseases, among others. However, development of mitochondrially targeted therapeutic agents has been impeded by the lack of high-throughput screening techniques that are capable of distinguishing in intact cells the mitochondrial membrane potential (deltapsi(m)) from the plasma membrane potential, (deltapsi(p)). We report here a fluorescence resonance energy transfer (FRET) assay that specifically monitors deltapsi(m) that is not confounded by background signal arising from potentiometric dye responding to deltapsi(p). The technique relies on energy transfer between nonyl acridine orange (NAO), which stains diphosphatidyl glycerol (cardiolipin) that is indigenous to the inner mitochondrial membrane, and tetramethylrhodamine methyl ester (TMR), a potentiometric dye that is sequestered by mitochondria as a Nernstian function of deltapsi(m) and concentration. FRET occurs only when both dyes co-localize to the mitochondria, and results in quenching of NAO emission by TMR in proportion to deltapsi(m). Validation studies using compounds with well-characterized mitochondrial effects, including oligomycin, CCCP+, bongkrekic acid, cyclosporin A, nigericin, ADP, and ruthenium red, demonstrate that the FRET-based deltapsi(m) assay responds in accord with the known pharmacology. Validation studies assessing the suitability of the technique for high-throughput compound screening indicate that the assay provides a sensitive and robust assessment not only of mitochondrial integrity in situ, but also, when used in conjunction with agents such as cyclosporin A, an indicator of permeability transition.
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PMID:High-throughput assessment of mitochondrial membrane potential in situ using fluorescence resonance energy transfer. 1612 Feb 99

As the rate-limiting controller of glucose metabolism, glucokinase represents the primary beta-cell "glucose sensor." Inactivation of both glucokinase (GK) alleles results in permanent neonatal diabetes; inactivation of a single allele causes maturity-onset diabetes of the young type 2 (MODY-2). Similarly, mice lacking both alleles (GK(-/-)) exhibit severe neonatal diabetes and die within a week, whereas heterozygous GK(+/-) mice exhibit markedly impaired glucose tolerance and diabetes, resembling MODY-2. Glucose metabolism increases the cytosolic [ATP]-to-[ADP] ratio, which closes ATP-sensitive K(+) channels (K(ATP) channels), leading to membrane depolarization, Ca(2+) entry, and insulin exocytosis. Glucokinase insufficiency causes defective K(ATP) channel regulation, which may underlie the impaired secretion. To test this prediction, we crossed mice lacking neuroendocrine glucokinase (nGK(+/-)) with mice lacking K(ATP) channels (Kir6.2(-/-)). Kir6.2 knockout rescues perinatal lethality of nGK(-/-), although nGK(-/-)Kir6.2(-/-) animals are postnatally diabetic and still die prematurely. nGK(+/-) animals are diabetic on the Kir6.2(+/+) background but only mildly glucose intolerant on the Kir6.2(-/-) background. In the presence of glutamine, isolated nGK(+/-)Kir6.2(-/-) islets show improved insulin secretion compared with nGK(+/-)Kir6.2(+/+). The significant abrogation of nGK(-/-) and nGK(+/-) phenotypes in the absence of K(ATP) demonstrate that a major factor in glucokinase deficiency is indeed altered K(ATP) signaling. The results have implications for understanding and therapy of glucokinase-related diabetes.
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PMID:ATP-sensitive K+ channel signaling in glucokinase-deficient diabetes. 1618 94

Triflusal is an antiplatelet drug related to aspirin, with different pharmacological properties and a lower haemorrhagic risk. We aimed at comparing their effects on platelet and endothelial activation in type 2 diabetes mellitus (T2DM). In a randomized, double-blind, parallel group study, we compared the effects of three daily regimens (300, 600, and 900 mg) of triflusal, and aspirin (100mg/day) on urinary 11-dehydro-thromboxane (TX)B(2), index of in vivo platelet activation, ex vivo platelet function using the analyzer PFA-100, plasma von Willebrand factor (vWF), P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and serum nitrite and nitrate (NO(2)(-)+NO(3)(-)) in 60 T2DM patients. Triflusal induced a dose-dependent reduction in 11-dehydro-TXB(2) and a prolongation of closure time in the presence of collagen plus epinephrine (Coll/Epi-CT). The effects of the highest triflusal dose were not different from those of aspirin. The closure time in the presence of collagen plus ADP (Coll/ADP-CT), ICAM-1, VCAM-1, and NO(2)(-)+NO(3)(-) were not modified either by triflusal or aspirin. Plasma P-selectin and vWF were reduced by triflusal but not by aspirin. In T2DM triflusal causes a profound inhibition of platelet TXA(2) biosynthesis in vivo, acting on different targets involved in the platelet-endothelial cell interactions.
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PMID:Inhibition of thromboxane biosynthesis by triflusal in type 2 diabetes mellitus. 1628 96

The aim of this study was to investigate the impact of improved metabolic control on platelet reactivity in patients with type 2 diabetes undergoing percutaneous coronary intervention (PCI). Twenty-two patients were randomised to intensive insulin or conventional treatment for diabetes. Platelet P-selectin expression was analysed before and three months after PCI. Metabolic control, as measured by level of glycosylated haemoglobin (HbA1c) and platelet P-selectin expression, was similar in the two treatment groups after three months. However, six of the 12 patients in the intensive group had increased levels of HbA1c after three months and three patients of the 10 in the conventionally treated group showed improved metabolic control. A re-analysis was performed, based on metabolic control. It showed that patients with improved control at three months (HbA1c 6.1% +/- 0.7 at baseline; 5.7% +/- 0.5 at three months; p<0.01; n=9) had lower ADP-induced P-selectin expression (p<0.05) than patients with worsened glycaemic control (HbA1c 5.9% +/- 1.0 at baseline; 6.5% +/- 1.4 at three months; p<0.01; n=13). Levels of HbA1c and fasting glucose were correlated to P-selectin expression (R=0.34 and R=0.31; p<0.05). We conclude from this study that improved glycaemic control reduces platelet reactivity in type 2 diabetes patients following PCI.
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PMID:Effects of improved metabolic control on platelet reactivity in patients with type 2 diabetes mellitus following coronary angioplasty. 1678 82


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