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)

A prospective, randomized, three-armed, double-blind, placebo-controlled clinical trial has been completed in 210 sites worldwide to determine whether the angiotensin II receptor blocker irbesartan or the calcium channel blocker amlodipine has a renoprotective effect in patients with overt type 2 diabetic nephropathy. A total of 1,715 subjects randomized during a 3-year period were followed a minimum of 2 years. The goal for all treatment groups was to achieve equivalent blood pressure control, with the blinded study drug (irbesartan, amlodipine, or placebo) as primary therapy with additional antihypertensive drugs, excluding angiotensin-converting enzyme inhibitors, calcium antagonists, and angiotensin II receptor antagonists, to achieve seated systolic blood pressure less than 135 mm Hg and diastolic blood pressure less than 85 mm Hg. The primary outcome was the combined endpoint of time to doubling of entry serum creatinine, end-stage renal disease, or death. Secondary outcomes included fatal and nonfatal cardiovascular events. A Clinical Management Committee monitored the conduct of the study. An Outcome Confirmation Committee classified all study outcome events in blinded fashion. An external Data Safety Monitoring Committee monitored unblinded data for interim safety and efficacy analyses of the study. Eligibility criteria included informed consent, age 30 to 70 years, adult-onset diabetes, hypertension, urine protein excretion greater than 900 mg/24 hours, and serum creatinine values of 90 to 265 micromol/L in women and 110 to 265 micromol/L in men. Baseline characteristics were age, 59 +/- 8 years; body mass index, 31 +/- 7 kg/m(2); 67% male; 73% white, 14% black, and 13% other; duration of diabetes, 15 +/- 9 years; retinopathy, 66%; neuropathy, 48%; congestive heart failure, 7.5%; screening seated systolic blood pressure, 156 +/- 18 mm Hg, and diastolic blood pressure, 85 +/- 11 mm Hg; urine protein excretion, 4.0 +/- 3.5 g/24 hours; serum creatinine, 150 +/- 53 micromol/L; serum potassium, 4.6 +/- 0.5 mEq/L; total cholesterol, 229 +/- 58 mg/dL; and hemoglobin A(1c), 8.1 +/- 1.7%. This large-scale international trial should help define the clinical course and standards of care for hypertensive adults with type 2 diabetes mellitus and nephropathy. Results available on May 19, 2001, will help in defining the current controversy of the risks and benefits of blockade of the renin-angiotensin system versus calcium channel blockade versus standard antihypertensive therapy in this large patient population.
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PMID:A clinical trial in type 2 diabetic nephropathy. 1157 53

ATP sensitive potassium (K(ATP)) channels reside in the plasma membrane of many excitable cells such as pancreatic beta-cells, heart, skeletal muscle and brain, where they link cellular metabolic energy to membrane electrical activity. They are composed of two subunits, K+ ion selective pore (Kir) and sulfonylurea receptor (SUR). In addition to the central role of pancreatic beta-cell K(ATP) channels in glucose-mediated insulin secretion, several lines of evidence support the hypothesis that K(ATP) channels modulate glucose transport in the insulin target tissues. Inhibition of K(ATP) channels by glibenclamide or gliclazide or an increase in intracellular ATP during hyperglycemia (glucose effect) or exercise facilitates glucose utilization, while activation of the channels by potassium channel openers, hypothermia (cardiac surgery), or ischemic damage (myocardial and brain infarction) reduces glucose uptake induced by insulin or hyperglycemia. Because insulin action has been known to depend on the energy level of the target cells, K(ATP) channel may function as an effector in this respect. It is now evident that long chain acyl-CoA esters, metabolically active forms of fatty acids, are the most potent and physiologically important activator of K(ATP) channels. Thus, I suppose that the sustained activation of K(ATP) channels by long chain fatty acyl-CoA seems to be a missing link between lipotoxicity and insulin resistance in obesity and type 2 diabetes mellitus.
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PMID:Adenosine triphosphate-sensitive potassium (K(ATP)) channel activity is coupled with insulin resistance in obesity and type 2 diabetes mellitus. 1186 13

Glibenclamide inhibits the opening of vascular ATP-sensitive potassium (K(ATP)) channels, which represents a protective mechanism during ischaemia. This effect may imply harmful cardiovascular effects of glibenclamide when used under conditions of ischaemia in patients with Type II diabetes. Acarbose is not associated with effects on the cardiovascular system, because the drug is not absorbed from the bowel. Therefore we hypothesized that treatment of Type II diabetes patients with glibenclamide will impair the vasodilator function of K(ATP) opening, unlike treatment with acarbose. A double-blind randomized cross-over study in 12 patients with Type II diabetes was performed to compare the effects of glibenclamide with those of acarbose on the vasodilator responses to K(ATP) channel opening in the forearm vascular bed. The study consisted of two periods: 8 weeks of treatment with orally administered glibenclamide (10 mg x day(-1)) followed by 8 weeks of treatment with acarbose (300 mg x day(-1)), or vice versa. At the end of each treatment period, forearm blood flow (venous occlusion plethysmography) in response to intra-arterially administered diazoxide, acetylcholine and dipyridamole and to forearm ischaemia was measured. The diazoxide-mediated increase in the forearm blood flow ratio (infused/control arm) was significantly less pronounced after glibenclamide than after acarbose (290 +/- 58% and 561 +/- 101% respectively; P<0.0005). Forearm blood flow responses to acetylcholine, dipyridamole and forearm ischaemia were similar during glibenclamide and acarbose treatment. Thus, in patients with Type II diabetes mellitus, treatment with glibenclamide is associated with an attenuated response to K(ATP) opening as compared with treatment with acarbose. This implies that glibenclamide may affect defensive mechanisms under conditions of K(ATP) channel activation.
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PMID:Vascular K(ATP) channel blockade by glibenclamide, but not by acarbose, in patients with Type II diabetes. 1186 71

The pancreatic B-cell ATP-sensitive potassium channel (K(ATP)) is composed of two distinct subunits, an inwardly rectifying ion channel forming the pore (Kir6.2), and a regulatory subunit, namely the sulfonylurea receptor-1 (SUR1), which binds this widely used class of insulin-secreting drugs. Mutations in the genes encoding Kir6.2 and SUR1 may result in familial persistent hyperinsulinemic hypoglycaemia of infancy, demonstrating their role in the regulation of insulin secretion. Studies in various populations with different ethnic background provided evidence that various alleles of single nucleotide polymorphisms (SNPs) in the SUR1 gene, and to a less extent in the Kir6.2 gene, confer a significantly increased risk for the development of type 2 diabetes mellitus (T2DM). Allelic variations of these SNPs were shown to modulate insulin secretion and insulin sensitivity in vivo, thus providing a pathophysiological background to explain their contribution to the genetic susceptibility to T2DM. The aim of this review is to summarise and discuss the significant results of recent literature on the implication of K(ATP), and particularly of SUR1, in the genetic and pathopysiological mechanisms of T2DM.
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PMID:Sulfonylurea receptor -1 (SUR1): genetic and metabolic evidences for a role in the susceptibility to type 2 diabetes mellitus. 1193 23

Diabetes mellitus affects approximately 135 million people in the world. Diabetes and hypertension are both relatively common diseases in westernised countries. Both entities increase with age. Essential hypertension accounts for the majority of hypertension in people with type 2 diabetes, who constitute more than 90% of those with a dual diagnosis of diabetes and hypertension. The benefit conferred per mm Hg blood pressure reduction appears to be greater in persons with type 2 diabetes than in those with hypertension and non-coexistent diabetes mellitus. Similar to a subset of patients with essential hypertension, type 2 diabetic patients manifest dietary NaCl-induced exacerbation of hypertension. Recent guidelines have emphasised that the target blood pressure levels for patients with diabetes should be lower than in other hypertensive groups. An increased total body sodium and enhanced vascular reactivity are found in people with diabetes and most type 2 diabetic patients are salt sensitive. Type 2 diabetes with hypertension is associated with reduced renal plasma flow when dietary salt intake is high. Experimental, observational and interventional evidence support the benefits of sodium restriction in hypertensives. However, the full effects of sodium restriction are usually not obvious for at least 5 weeks. Other favourable effects of moderate reduction in sodium intake are a regress left ventricular hypertrophy, decrease in diuretic-induced potassium wastage, reduction in proteinuria, protection against stroke and from osteoporosis and renal stones, and enhancement of the antihypertensive effect of the antihypertensive agents.
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PMID:Salt intake, hypertension and diabetes mellitus. 1198 94

Gliclazide modified release (MR) is a new formulation of the drug gliclazide and is given once daily. The hydrophilic matrix of hypromellose-based polymer in the new formulation effects a progressive release of the drug which parallels the 24-hour glycaemic profile in untreated patients with type 2 diabetes mellitus. The formulation shows high bioavailability and its absorption profile is unaffected by coadministration with food. Mean plasma glucose levels are significantly reduced over a 24-hour period in patients with type 2 diabetes mellitus treated with gliclazide MR once daily, in both fasting and postprandial states. No cardiovascular ATP-sensitive potassium channel interaction has been observed at therapeutic concentrations of gliclazide MR. Gliclazide MR has also demonstrated antioxidant properties that are independent of glycaemic control. In a randomised, double-blind, multicentre study, gliclazide MR 30 to 120 mg once daily showed similar efficacy to gliclazide immediate release (IR) 80 to 320 mg/day (in divided doses for doses >80 mg) in patients with type 2 diabetes mellitus over a 10-month period, reducing glycosylated haemoglobin (HbA(1c)) and fasting plasma glucose (FPG) to a similar extent. The drug appeared most efficacious in patients who had previously been treated by diet alone, where significant reductions in HbA(1c) from baseline of 0.9% and 0.95% were seen at 10 and 24 months. Similarly, a sustained effect of gliclazide MR was observed in a subgroup of elderly patients defined a priori; HbA(1c) was decreased to a similar degree to that observed in the general study population. Gliclazide MR showed similar tolerability to gliclazide IR after 10 months' treatment in the randomised trial. The most commonly observed adverse events were arthralgia, arthritis, back pain and bronchitis (each <5%). Bodyweight remained stable. In this study no episodes of nocturnal hypoglycaemia or hypoglycaemia requiring third party assistance were observed during treatment with gliclazide MR. Episodes of symptomatic hypoglycaemia were infrequent, occurring in approximately 5% of patients.
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PMID:Gliclazide modified release. 1207 88

Both ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) are renoprotective beyond their effects on blood pressure (BP), but their widespread use is limited by their tendency to provoke hyperkalemia. The comparative effects of ACEI and ARB on potassium handling have not been investigated. The objective of this study was to determine whether there are differences in dynamic renal potassium handling between ACEI and ARB in response to an oral potassium challenge. This was a randomized crossover study of candesartan versus lisinopril titrated to control BP followed by an inpatient study of renal potassium handling in 24 hypertensive patients with type II diabetes mellitus (DMII) and preserved renal function. Following an oral potassium challenge (0.75 mmol/kg), differences in hourly serum K (mmol/L), rate of urinary potassium excretion (UkV, micromol/min), and fractional excretion of potassium (FEK) were assessed by repeated-measures ANOVA. Hourly UkV(p = .45) and FEK (p = .19) were similar for candesartan and lisinopril, although FEK at 2 hours for candesartan tended to exceed that for lisinopril (.34 [.04] vs. .26 [.03]) and approached significance (p = .096). UkVfor candesartan at hour 2 was 177 (26) and 121 (21) for lisinopril and also approached significance (p = .10). Serial serum potassium did not differ (p = .70). No statistical differences were discovered in renal potassium handling between candesartan and lisinopril in patients with DMII and preserved renal function. Whether there are differences between the drug classes in renal impairment remains to be determined.
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PMID:Comparative effects on dynamic renal potassium excretion of ACE inhibition versus angiotensin receptor blockade in hypertensive patients with type II diabetes mellitus. 1209 42

In the 1970s and 1980s it became evident that progression of renal disease and blood pressure are correlated. Subsequently, it was shown that antihypertensive treatment, especially with agents that block the renin-angiotensin system (RAS), could slow the progression of diabetic renal disease. Several studies, particularly with RAS blockers, have confirmed beneficial effects on urinary albumin excretion in patients with diabetes and microalbuminuria or proteinuria. There are good reasons to explore dual blockade of the RAS with an AT(1)-receptor blocker and an ACE inhibitor. Receptor blockers may block the effects of angiotensin II more effectively than ACE inhibitors; moreover, ACE inhibitors increase bradykinins which may have positive effects on blood pressure and renal function. Such combination treatment has been found to be well tolerated and more effective in reducing blood pressure than either monotherapy. Positive effects on microalbuminuria or proteinuria have also been noted. Studies have shown that treatment with AT(1)-receptor blockers postpones end-stage renal disease and reduces the rate of decline in glomerular filtration rate (GFR) in patients with type 2 diabetes and nephropathy. Moreover, albuminuria was reduced to a greater extent with AT(1)-receptor blockers than with conventional antihypertensive therapy producing the same blood pressure reductions. In summary, AT(1)-receptor blockers are effective in all stages of diabetic renal disease, and have an excellent tolerability profile. Usually the side-effect profile is comparable with placebo. In certain situations, there may be a slight, readily reversible, increase in serum potassium. There may also be a slight reduction in GFR, reflecting a decrease in glomerular filtration pressure.
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PMID:The reno-protective role of AT(1)-receptor blockers. 1214 Jul 29

Here we propose that glucose metabolism can be understood on the basis of three concept-derived axioms: (I) A hierarchy exists among the glucose-utilizing organs with the brain served first, followed by muscle and fat. (II) Tissue-specific glucose transporters allocate glucose among organs in order to maintain brain glucose concentrations. (III) Exogenous carbohydrate supply compensates for glucose alterations that can temporarily occur in muscle and fat. Derived from the control theory, the simplest solution of allocating supply to 2 organs, e.g. brain and muscle, is a "fishbone"-structured model. We reviewed the literature, searching for neuroendocrine and metabolic mechanisms that can fulfill control functions in such a model: The tissue-specific glucose transporters are differentially regulated. GLUT 1, carrying glucose across the blood-brain-barrier, is independent of insulin. Instead, this trans-endothelial glucose transporter is rather dependent on potent regulators of blood vessel function like vascular endothelial growth factor - a pituitary counterregulatory hormone. GLUT 4, carrying glucose across the membranes of muscle and fat cells, depends on insulin. Thereby, insulin allocates glucose to muscle and fat. The hypothalamus-pituitary-adrenal (HPA) axis, the sympathetic nervous system (SNS), and vascular endothelial growth factor allocate glucose to the brain. Multiple "sensors" (some of which have only recently been identified as ATP sensitive potassium channels) measure glucose or glucose equivalents at various sites of the body: the ventromedial hypothalamus, the lateral hypothalamus, portal vein, pancreatic beta cell, renal tubule, muscle and adipose tissue. Feedback pathways both from the brain and from muscle and fat are involved in regulating glucose allocation and exogenous glucose supply. The main feedback signal from the brain is found to be glucose, that from muscle and fat appears to be leptin. In fact, the literature search revealed two or more biological mechanisms for the function of each component in the model, finding glucose regulation highly redundant. This review focuses on "brain glucose" control. The concept of glucose allocation presented here challenges the common opinion of "blood glucose" being the main parameter controlled. According to the latter opinion, hyperglycemia in the metabolic syndrome is due to a putative defect located within the closed loop including the beta cell, muscle and fat cells. That traditional view leaves some peculiarities of e.g. the metabolic syndrome unexplained. The concept of glucose allocation, however, would predict that weight gain - with abundance of glucose in muscle and fat - increases feedback to the brain (via hyperleptinemia) which in turn results in HPA-axis and SNS overdrive, impaired insulin secretion, and insulin resistance. HPA-axis overdrive would account for metabolic abnormalities such as central adiposity, hyperglycemia, dyslipidemia, and hypertension, that are well known clinical aspects the metabolic syndrome. This novel viewpoint of "brain glucose" control may shed new light on the pathogenesis of the metabolic syndrome and type 2 diabetes.
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PMID:The neuroendocrine control of glucose allocation. 1214 83

Genetic factors play an important role in the pathogenesis of type 2 diabetes. The relevance to type 2 diabetes of the common polymorphism Glu23Lys in the potassium inward rectifier 6.2 (KIR6.2) gene is still controversial. The aim of this study was to assess whether this polymorphism influences beta-cell function, alpha-cell function, or insulin action. We therefore studied 298 nondiabetic subjects using an oral glucose tolerance test (OGTT) and 75 nondiabetic subjects using a hyperglycemic clamp (10 mmol/l) with additional glucagon-like peptide (GLP)-1 and arginine stimulation. The prevalence of the Lys allele was approximately 37%, and the Lys allele was associated with higher incremental plasma glucose during the OGTT (P = 0.03, ANOVA). Neither first- nor second-phase glucose-stimulated C-peptide secretion was affected by the presence of the polymorphism; nor were maximal glucose-, GLP-1-, or arginine-induced C-peptide secretion rates; nor was insulin sensitivity (all P > 0.7). However, the relative decrease in plasma glucagon concentrations during the 10 min after the glucose challenge was reduced in carriers of the Lys allele (10 +/- 3% decrease from baseline in Lys/Lys, 18 +/- 2% in Glu/Lys, and 20 +/- 2% in Glu/Glu; P = 0.01, ANOVA). In conclusion, our findings suggest that the common Glu23Lys polymorphism in KIR6.2 is not necessarily associated with beta-cell dysfunction or insulin resistance but with diminished suppression of glucagon secretion in response to hyperglycemia. Our findings thus confirm its functional relevance for glucose metabolism in humans.
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PMID:The prevalent Glu23Lys polymorphism in the potassium inward rectifier 6.2 (KIR6.2) gene is associated with impaired glucagon suppression in response to hyperglycemia. 1219 81


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