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 sulfonylurea receptor (SUR1) of the pancreatic beta-cell ATP-sensitive potassium channel plays a key role in glucose-induced insulin secretion. The A-allele of a single nucleotide polymorphism (SNP) in exon 31 of the SUR1 gene (AGG-->AGA; Arg1273Arg) has previously been shown to be associated with hyperinsulinemia in nondiabetic Mexican-American subjects. Here, we have investigated the association of this SNP with type 2 diabetes mellitus (T2DM) in French Caucasian subjects. We have observed an increased frequency of the A allele (37.1% vs 27.6%, P=0.0048; odds ratio 1.54), of the AA genotype (15.7% vs 9.8%; P=0.025), and of the combined AA/AG genotypes (58.5% vs 45.5%, P=0.0098; odds ratio 1.69) in patients compared with controls. This association is stronger in the subgroup of patients with age of diagnosis of diabetes equal to or less than 45 years: A allele 43.2% (P=0.0003 compared with controls; odds ratio 1.99), AA genotype 21.4% (P=0.0032), and combined AA/AG genotypes 65.1% (P=0.0022; odds ratio 2.23). Unexpectedly, the G allele is strongly associated with arterial hypertension in obese diabetic subjects (GG vs AA odds ratio 19.97). In conclusion, we have observed an association of an SNP in exon 31 of the SUR1 gene with T2DM. These data reinforce the hypothesis that insulin secretion defects in T2DM might be at least partially related to allelic variations in the SUR1 gene.
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PMID:Association of a variant in exon 31 of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus in French Caucasians. 1103 Apr 11

The aim of this study was to measure cardiovascular and renal function, including the renal transport capacity for glucose, in male and female C57BL/6J mice with diet-induced Type II diabetes mellitus. Typical of Type II diabetes, mice fed a high-fat, high-simple carbohydrate diet for 3 months were obese (45-65 g), hyperglycemic (138-259 mg%), and hyperinsulinemic (1.8-15.06 ng/ml); significant gender differences were observed in all cases. Based on systolic pressure measurements in conscious mice and arterial blood pressure measurements in anesthetized mice, no diet-induced hypertension was observed in either male or female mice. Urine flow rate, sodium, potassium, osmolar, and protein excretion rates were significantly increased (P < 0.05) in male mice fed the high-fat, high-simple carbohydrate diet compared with female mice fed the same diet. However, no differences in the excretion variables existed between male and female mice fed the control diet. The glomerular filtration rate (ml min-1 g kw-1), determined by FITC-inulin, in male and female mice fed the control diet (0.87 +/- 0.01 and 0.90 +/- 0.1, respectively) and high-fat, high-simple carbohydrate diet (0.96 +/- 0.1 and 0.93 +/- 0.2, respectively) was not different between the groups. These hyperglycemic mice were also not glucosuric. Infusions of progressive amounts of glucose in male mice fed either diet for 3 or 6 months demonstrated that the renal threshold for glucose was 400 mg% for all these mice, well above the fasting plasma glucose concentrations observed in this study. Thus, C57BL/6J mice were valuable tools for studying diet-induced obesity, hyperglycemia, and hyperinsulinemia; however, no hypertension or kidney dysfunction was apparent within the time frame of the current study.
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PMID:Renal function and glucose transport in male and female mice with diet-induced type II diabetes mellitus. 1108 17

A reduced functional capacity of the sodium (Na), potassium (K) pump might reduce energy expenditure, inducing obesity and type 2 diabetes. Consequently, the Na and K content and [(3)H]ouabain binding capacity of skeletal muscle were measured in 10 monozygotic twin pairs discordant for type 2 diabetes and in 10 obese controls. Muscle [(3)H]ouabain binding capacity was reduced by approximately 20% in type 2 diabetes. Removing the genetic component by looking at differences within twin pairs, the difference in waist/hip ratio was associated with the difference in [(3)H]ouabain binding (r = -0.85; P < 0.002). Except for the type 2 diabetic twins in the basal state, both basal and insulin-stimulated energy expenditure were associated with the muscle K/Na ratio in the twins. In controls, the 2-h plasma glucose concentration during an oral glucose tolerance test was associated with the change in both muscle and plasma K induced by a euglycemic, hyperinsulinemic clamp. In conclusion, environmental factors related to the waist/hip ratio reduce the muscle [(3)H]ouabain binding capacity in type 2 diabetes. Without proving causality, the muscle K/Na ratio is associated with energy expenditure in individuals genetically predisposed to the development of type 2 diabetes.
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PMID:Muscle sodium, potassium, and [(3)H]ouabain binding in identical twins, discordant for type 2 diabetes. 1115 58

Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic beta-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macrovascular disease. Therefore one of the main aims of treatment is to minimise blood glucose oscillations and attain near-normal glycosylated haemoglobin levels. Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the beta-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals. The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e.g. nephropathy with creatinine clearance < or = 50 ml/min). Meglitinide analogues act synergistically with metformin and thiazolidinediones (pioglitazone and rosiglitazone) and can be also combined with long-acting insulin (NPH insulin at bedtime). Therefore, these drugs enrich the palette of antidiabetic drugs and make the treatment more flexible and better tolerated, which both add to better metabolic control and support the empowerment and compliance of the patient. However, this will only be the case if the patient and the diabetes care team are trained for this new therapeutic schedule and the healthcare system is able to pay for these rather expensive drugs.
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PMID:Meglitinide analogues in the treatment of type 2 diabetes mellitus. 1119 Apr 20

Sulphonylurea derivatives (SUD) are a mainstay of treatment of type 2 diabetes but questions have been raised about the potential adverse effects of these drugs as far as cardiovascular functions are concerned. An early prospective study which examined the effects of glycaemic control with various agents on coronary heart disease was stopped in the 70-ies due to excess cardiovascular mortality in the group receiving SUD of first generation: tolbutamide. The discovery of ATP-sensitive potassium channels in the heart, their role in ischaemic heart disease and mechanisms of endogenous cardiac cell protection--preconditioning have brought back concerns of SUD safety. Recently, a new SUD--glimepiride--claimed as the first representant of III generation of these agents--has been introduced into clinical practice. Glimepiride appears to be devoid of vascular ATP-sensitive potassium channels binding properties. Postulated and confirmed in animal experimental studies cardioprotective features of glimepiride were evaluated in a randomised, placebo-controlled study with glimepiride and glibenclamide comparing effects of these drugs on ischaemic preconditioning during angioplasty of high grade coronary artery stenoses in patients with stable angina. Myocardial ischaemia was quantified by intracoronary electrocardiography and time to occurrence of angina during vessel occlusion was measured. The results of the study confirmed glimepiride effects of maintaining myocardial preconditioning. The article summarises current knowledge of SUD influence on cardiovascular system and discusses some differences in pharmacodynamics of glimepiride which appear to provide this agent with clinical advantages over conventional SUD at least in cardiovascular aspects.
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PMID:[Sulphonylurea derivatives and the cardiovascular system]. 1129 25

This article reviews the pharmacological and clinical aspects of glimepiride, the latest second-generation sulfonylurea for treatment of Type 2 diabetes mellitus (DM). Glimepiride therapy ameliorates the relative insulin secretory deficit found in most patients with Type 2 DM. It is a direct insulin secretagogue; indirectly, it also increases insulin secretion in response to fuels such as glucose. Its action to augment insulin secretion requires binding to a high affinity sulfonylurea receptor, which results in closure of ATP-sensitive potassium channels in the beta-cells of the pancreas. The question has been raised whether insulin secretagogues by acting on vascular or myocardial potassium channels may prevent ischaemic preconditioning, a physiological adaptation that could affect the outcome of coronary heart disease, but there is evidence against this concern being applicable to glimepiride. Glimepiride's antihyperglycaemic efficacy is equal to other secretagogues. It has pharmacokinetic properties that make it less prone to cause hypoglycaemia in renal dysfunction than some other insulin secretagogues, particularly glyburide (also known as glibenclamide in Europe). Its convenient once daily dosing may enhance compliance for diabetic patients who often also require medications for other co-morbid conditions, such as hypertension, hyperlipidaemia and cardiac disease. Glimepiride is approved for monotherapy, for combination with metformin and with insulin. Clinically, its reduced risk of hypoglycaemia makes it preferable to some other insulin secretagogues when attempting to achieve recommended glycaemic control (haemoglobin A(1c) (HgbA(1c)) 7%). Using suppertime neutral protamine Hagedorn (NPH) and regular insulin with morning glimepiride in overweight diabetic patients achieves glycaemic goals more quickly than insulin alone and with lower insulin doses.
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PMID:Clinical review of glimepiride. 1133 17

Microalbuminuria (MA) is defined as persistent elevation of albumin in the urine, of 30-300 mg/day (20-200 microg/min). These values are less than the values detected by routine urine dipstick testing, which does not become positive until protein excretion exceeds 300-500 mg/day. Use of the albumin-to-creatinine ratio is recommended as the preferred screening strategy for all diabetic patients. MA is measured in spot morning urine obtained from the patient in the office and sent for measurement of both albumin and creatinine. A value above 0.03 mg/mg suggests that albumin excretion is above 30 mg/day and therefore MA is present. MA should be checked annually in everyone, and every 6 months within the first year of treatment to assess the impact in patients started on antihypertensive therapy. MA is an established risk factor for renal disease progression in type 1 diabetes and its presence is the earliest clinical sign of diabetic nephropathy. In addition, a number of studies suggest that MA is an important risk factor for cardiovascular disease and defines a group at high risk for early cardiovascular mortality in both type 2 diabetes and essential hypertension. MA also signifies abnormal vascular permeability and the presence of atherosclerosis. Among nondiabetic patients with essential hypertension, MA is associated with higher blood pressures, increased serum total cholesterol, and reduced serum high-density lipoprotein cholesterol. Thus, taken together these data support the concept that the presence of MA is the kidney's notice to the physician/patient that there is a problem with the vasculature. MA can be reduced, and progression to overt proteinuria prevented, by aggressive blood pressure reduction. The National Kidney Foundation recommends that blood pressure levels be maintained at or below 130/80 mm Hg in anyone with diabetes or renal disease. This should be accomplished with antihypertensive agents that prevent the rise in MA and hence prevent development of proteinuria. Such agents are angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and, to a lesser extent, Beta blockers, non-dihydropyridine calcium antagonists, and diuretics. In summary, the presence of MA is a marker of endothelial dysfunction and a harbinger of markedly enhanced cardiovascular risk. All patients with diabetes and/or hypertension should be screened for the presence of microalbuminuria with use of spot morning urine. To maximize prevention of MA development, the following goals should be instituted: 1) blood pressure should be maintained at less than 130/80 mm Hg and a low-salt, moderate-potassium diet instituted; 2) in diabetics, HbA1c should be kept at less than 7%; 3) in obese patients, a weight loss program should be implemented, with a goal BMI of less than 30; and 4) the physician and patient, working together, should maintain low-density lipoprotein cholesterol at less than 120 mg/dL, and less than 100 mg/dL if diabetes is present. (c)2001 by Le Jacq Communications, Inc.
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PMID:Microalbuminuria: what is it? Why is it important? What should be done about it? 1141 91

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, interactions, and dosage of nateglinide are reviewed. Nateglinide is an oral hypoglycemic agent approved for use alone or in combination with metformin as an adjunct to diet and exercise for the treatment of type 2 diabetes mellitus. Nateglinide, an amino acid derivative of D-phenylalanine, stimulates the secretion of insulin by binding to the ATP potassium channels in pancreatic beta cells. The result is an increase in beta-cell calcium influx, which leads to rapid, short-lived insulin release. The drug is rapidly and completely absorbed in the small intestine. The estimated bioavailability is 72%. Nateglinide is highly bound to plasma proteins, is metabolized extensively by the liver, and has an elimination half-life of 1.4 hours. Several clinical trials of nateglinide, alone and in combination with other oral hypoglycemic agents, have found the drug to be safe, effective, and well tolerated. The most common adverse effects are nausea, diarrhea, dizziness, and lightheadedness. There is a potential for interactions between nateglinide and medications affected by the cytochrome P-450 isoenzyme system. Dosage regimens ranging from 60 to 240 mg have been evaluated. The maximum effective dosage is 120 mg taken 10 minutes before meals three times a day. Nateglinide is an alternative to second-generation sulfonylureas for the treatment of type 2 diabetes mellitus. Additional comparative trials are needed to fully elucidate nateglinide's role.
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PMID:Nateglinide. 1144 77

A variety of compounds containing an imidazoline ring have the ability to stimulate insulin secretion. Many of these also improve glycaemia in experimental models of type 2 diabetes and in man, suggesting that this class may be useful in the development of new orally active anti-diabetic drugs. However, the mechanisms by which imidazolines promote insulin secretion have not been clarified. The response does not appear to be due to the binding of ligands to either of the two major types of "imidazoline receptor" defined by pharmacological criteria (I1 and I2 sites) but may result from interaction with a novel imidazoline binding site. One such site has been identified in association with the ATP-sensitive potassium (K(ATP)) channel in the beta-cell and has been designated "I3". Electrophysiological and biochemical evidence suggest that the I3 site may be intrinsic to the ion-conducting pore component, Kir6.2, of the K(ATP) channel, but the effects of imidazoline ligands on insulin secretion can be dissociated from the regulation of Kir6.2. Indeed, there is increasing evidence that some imidazolines can control exocytosis directly, both in beta-cells and in pancreatic alpha-cells. Thus, it is proposed that a further imidazoline binding site is primarily responsible for control of hormone secretion. Evidence is reviewed which suggests that this site occupies a central position within an amplification pathway that also mediates the effects of cAMP in the beta-cell. Characterisation of this site should provide the stimulus for the design of new insulin secretagogues that are devoid of K(ATP) channel-blocking properties.
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PMID:Imidazoline binding sites in the endocrine pancreas: can they fulfil their potential as targets for the development of new insulin secretagogues? 1147 76

To investigate the role of intracellular potassium (K(i))and other ions in hypertension and diabetes, we utilized (39)K-, (23)Na-, (31)P-, and (19)F-nuclear magnetic resonance (NMR) spectroscopy to measure K(i), intracellular sodium (Na(i)), intracellular free magnesium (Mg(i)), and cytosolic free calcium (Ca(i)), respectively, in red blood cells of fasting normotensive nondiabetic control subjects (n=10), untreated (n=13) and treated (n=14) essential hypertensive subjects, and diabetic subjects (n=5). In 12 subjects (6 hypertensive and 6 normotensive controls), ions were also measured before and after the acute infusion of 1 L of normal saline. Compared with those in controls (K(i)=148+/-2.0 mmol/L), K(i) levels were significantly lower in hypertensive (132.2+/-2.9 mmol/L, sig=0.05) and in type 2 diabetic subjects (121.2+/-6.8 mmol/L, sig=0.05). K(i) was higher in treated hypertensives than in untreated hypertensives (139+/-3.1 mmol/L, sig=0.05) but was still lower than in normals. Although no significant relation was observed between basal K(i) and Na(i) values, saline infusion elevated Na(i) (P<0.01) and reciprocally suppressed K(i) levels (142+/-2.4 to 131+/-2.2 mmol/L, P<0.01). K(i) was strongly and inversely related to Ca(i) (r=-0.846, P<0.001), and was directly related to Mg(i) (r=0.664, P<0.001). We conclude that (1) K(i) depletion is a common feature of essential hypertension and type 2 diabetes, (2) treatment of hypertension at least partially restores K(i) levels toward normal, and (3) fasting steady-state K(i) levels are closely linked to Ca(i) and Mg(i) homeostasis. Altogether, these results emphasize the similar and coordinate nature of ionic defects in diabetes and hypertension and suggest that their interpretation requires an understanding of their interaction.
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PMID:Relation of cellular potassium to other mineral ions in hypertension and diabetes. 1156 62


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