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 granulocytes from elderly patients were investigated, in previous studies, with FMLP and it was found that the postreceptor signal, the inositol phosphate production and inositol phosphate dependent calcium signal were markedly reduced. It was observed that the 125I LDL binding was slightly reduced while the intracellular degradation of the LDL and endogenous cholesterol synthesis inhibitory effect was significantly decreased on monocytes of patients with non insulin dependent diabetes mellitus. It was suggested that of in patients suffering from NIDDM with hypercholesterolemia the LDL receptor numbers of monocytes are close to normal, while the post receptor signal transmission is damaged. In this study the monocytes from 12 patients with hypercholesterolemia were investigated before and after LDL treatment and were compared to the 11 age-matched healthy volunteer control patients. The cells were stimulated with LDL and chemotactic peptide FMLP. The postreceptor signal mechanism in monocytes was investigated. According to the results the inositol phosphate level of the patient group decreased independently from the stimulus. The LDL induced IP3 and Ca2+ level elevation was PT resistant both in the control and in the patients group.
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PMID:[Biologic effect of LDL binding and intracellular degradation in monocytes from patients with hypercholesterolemia]. 934 May 72

The spontaneously diabetic non-obese GK (Goto-Kakizaki) rat exhibits high basal plasma glucose and insulin levels and poor glucose-induced insulin secretion, which makes it a suitable model for non-insulin dependent diabetes mellitus, NIDDM. The aim of this study was to investigate the handling of cytosolic free Ca2+ concentration ([Ca2+]i), the key regulator of insulin secretion, in GK rat single pancreatic islets. For this purpose the influence of high glucose (16.7 mM) and arginine (20 mM) on [Ca2+]i was studied in GK and Wistar rat islets, which served as controls. The data obtained suggest that glucose which through its metabolism generates ATP needed for closure of the KATP channels and membrane depolarization, induces a delayed [Ca2+]i response in the GK rat pancreatic islet. This delay in [Ca2+]i response is likely to result from a defective metabolism of glucose in the diabetic islet.
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PMID:Delayed Ca2+ response to glucose in diabetic GK rat. 934 82

Both type I and type II diabetes mellitus are associated with derangements in the regulation of intracellular calcium. Hyperglycemia causes an acute rise in cytosolic calcium ([Ca2+]i) due to increased calcium influx and in certain cells to mobilization of intracellular calcium stores as well. The increase in calcium entry is secondary to the activation of calcium channels inhibitable by verapamil, nifedipine, or amlodipine. The stimulation of these calcium channels is mediated by the activation of G protein(s), leading to stimulation of various cellular pathways. Chronic hyperglycemia is also associated with decreased calcium exit from cells. The combination of increased calcium influx and decreased calcium efflux leads to sustained elevation in basal levels of [Ca2+]i. The latter abnormality may adversely affect cell function. Treatment of diabetic animals with calcium channel blockers normalizes cell [Ca2+]i and prevents and/or reverses the derangements in cellular function.
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PMID:Role of elevated cytosolic calcium in the pathogenesis of complications in diabetes mellitus. 938 28

We have used the whole-cell recording technique to determine whether ATP-sensitive potassium (K[ATP]) currents, voltage-dependent Ca2+ currents, and exocytosis are different in single beta-cells from pancreatic islets of Goto-Kakizaki (GK) rats, a novel model of NIDDM, and normal rats. In addition, we have also measured the insulin secretory responses, ATP content, and the rate of glucose metabolism in intact islets. Although the glucose sensitivity of the K(ATP) current was similar between GK rats and controls, in the absence of glucose, K(ATP) current density was larger in GK rats, which resulted in a more hyperpolarized membrane potential. Whole-cell Ca2+ currents were similar. By monitoring the cell capacitance with a fixed intracellular solution, no difference was detected in the exocytotic responses of beta-cells from normal and GK rats. In islets from GK rats, the rates of glucose utilization ([3H]H2O production from 5-[3H]glucose) and oxidation ([14C]CO2 production from U-[14C]glucose) were not significantly different from controls. Insulin secretion, however, was impaired (by 50%), and this was paralleled by a smaller increase in ATP content in response to stimulation by 10 mmol/l glucose in islets from GK rats when compared with controls. Under conditions in which K(ATP) channels were held open and the effects of glucose were independent of membrane potential, insulin release was still significantly lower in GK rat islets than in controls. These findings suggest that the impaired insulin secretion in islets from GK rats does not simply result from a failure to close K(ATP) channels, nor does it result from an impairment in calcium secretion coupling.
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PMID:Electrophysiological and metabolic characterization of single beta-cells and islets from diabetic GK rats. 942 77

The incretin effect is reduced in NIDDM, although a corresponding attenuation of incretin hormone secretion does not occur. We characterized the direct interaction of GLP-I, an important incretin hormone, and leptin on insulin secretion and signal transduction in B-cells. Leptin inhibited GLP-I stimulated insulin release from the isolated perfused rat pancreas. Both phases of the biphasic insulin secretory response were inhibited. GLP-I receptor binding and GLP-I induced cAMP generation remained unchanged. Leptin reduced the GLP-I mediated increase of cytosolic Ca2+ concentration. It had similar effects on calcium elevations induced by forskolin. The effect was more pronounced during the plateau phase than during the initial peak. These effects could help to explain leptin's inhibitory effects on insulin secretion. The inhibition of GLP-I's insulinotropic effects by leptin may be an interesting aspect in the pathophysiology of NIDDM. The existence of an "adipo-insular axis" is suggested, in which leptin represents a negative feed-back signal from the adipose tissue to the endocrine pancreas.
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PMID:Interaction of GLP-I and leptin at rat pancreatic B-cells: effects on insulin secretion and signal transduction. 947 58

While insulin is known to promote vascular smooth muscle (VSM) relaxation, it also enhances endothelin-1 (ET-1) secretion and action in conditions such as NIDDM and hypertension. We examined the effect of insulin pretreatment on intracellular free calcium ([Ca2+]i) responses to ET-1 in cultured aortic smooth muscle cells (ASMCs) isolated from Sprague-Dawley (SD) rats and measured ET(A) receptor characteristics and ET-1-evoked tension responses in aorta obtained from insulin-resistant, hyperinsulinemic Zucker-obese (ZO) and control Zucker-lean (ZL) rats. Pretreatment of rat ASMCs with insulin (10 nmol/l for 24 h) failed to affect basal [Ca2+]i levels but led to a significant increase in peak [Ca2+]i response (1.7-fold; P < 0.01) to ET-1. The responses to IRL-1620 (an ET(B) selective agonist), ANG II, and vasopressin remained unaffected. ET-1-evoked peak [Ca2+]i responses were significantly attenuated by the inclusion of the ET(A) antagonist, BQ123, in both groups. The ET(B) antagonist, BQ788, abolished [Ca2+]i responses to IRL-1620 but failed to affect the exaggerated [Ca2+]i responses to ET-1. Saturation binding studies revealed a twofold increase (P < 0.01) in maximal number of binding sites labeled by 125I-labeled ET-1 in insulin-pretreated cells and no significant differences in sites labeled by 125I-labeled IRL-1620 between control and treatment groups. Northern blot analysis revealed an increase in ET(A) mRNA levels after insulin pretreatment for 20 h, an effect that was blocked by genistein, actinomycin D, and cycloheximide. Maximal tension development to ET-1 was significantly greater (P < 0.01), and microsomal binding studies using [3H]BQ-123 revealed a twofold higher number of ET(A) specific binding sites (P < 0.01) in aorta from ZO rats compared with that of ZL rats. These data suggest that insulin exaggerates ET-1-evoked peak [Ca2+]i responses via increased vascular ET(A) receptor expression, which may contribute to enhanced vasoconstriction observed in hyperinsulinemic states.
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PMID:Insulin increases endothelin-1-evoked intracellular free calcium responses by increased ET(A) receptor expression in rat aortic smooth muscle cells. 960 72

The prevalence of abnormally elevated albumin excretion rate (> 30 mg/24 h) is approximately 40% in insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients. Diabetes has become the leading cause of end-stage renal failure in the US, Japan and Europe. Approximately 90% of the direct and indirect cost of caring for diabetic patients are spent on the complications of diabetes. Identification of patients at high risk of developing diabetic nephropathy is possible by screening for microalbuminuria (30-300 mg/24 h). Elevated urinary albumin excretion rate indicates a substantially increased mortality risk in diabetic patients. Randomised controlled trials in normotensive IDDM and NIDDM patients with persistent microalbuminuria indicate that ACE inhibitors diminish urinary albumin excretion rate, postpone it and may even prevent progression to clinical overt nephropathy. These findings indicate that screening and intervention programs are likely to have life saving effects and lead to considerable economic savings. Systemic blood pressure elevation to a hypertensive level is an early and frequent phenomenon in diabetic nephropathy. Furthermore, nocturnal blood pressure elevation (non-dippers) occurs more frequently in patients with nephropathy. Systemic blood pressure elevation and to a lesser degree albuminuria accelerate the progression of diabetic nephropathy. Effective blood pressure reduction with non-ACE-inhibitors and/or ACE-inhibitors frequently in combination with diuretics: (a) reduces albuminuria; (b) delays the progression of nephropathy; (c) postpones renal insufficiency; and (d) improves survival in IDDM and NIDDM patients with diabetic nephropathy. A specific renal protective effect of ACE-inhibitors in diabetic nephropathy has been demonstrated in IDDM patients with moderately reduced kidney function (s-creatinine > 133 mumol/l) while the data conflict with NIDDM patients. Antihypertensive treatment for diabetic nephropathy simultaneously extends life and saves money. Finally, reduced risk of fatal and non-fatal cardiovascular events have been demonstrated when diabetic patients with isolated systolic hypertension are treated with blood pressure lowering agents. Absolute risk reduction with active treatment compared to placebo was twice as great for the diabetic versus non-diabetic patients (101/1000 versus 51/1000 randomised participants at the 5-year follow-up), reflecting the higher risk of diabetic patients. In conclusion, early detection and aggressive treatment of arterial hypertension with ACE-inhibitors, long acting calcium antagonist and low dose diuretics as first line drugs are highly warranted in diabetic patients with or without diabetic renal disease.
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PMID:Is antihypertensive treatment the same for NIDDM and IDDM patients? 964 59

Cyclic ADP-ribose (cADPR) has been shown to be a mediator for intracellular Ca2+ mobilization for insulin secretion by glucose in pancreatic beta cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cADPR from NAD+ and cADPR hydrolase to hydrolyze cADPR to ADP-ribose. We show here that 13.8% of Japanese non-insulin-dependent diabetes (NIDDM) patients examined have autoantibodies against CD38 and that the sera containing anti-CD38 autoantibodies inhibit the ADP-ribosyl cyclase activity of CD38 (P </= 0.05). Insulin secretion from pancreatic islets by glucose is significantly inhibited by the addition of the NIDDM sera with anti-CD38 antibodies (P </= 0.04-0.0001), and the inhibition of insulin secretion is abolished by the addition of recombinant CD38 (P </= 0.02). The increase of cADPR levels in pancreatic islets by glucose was also inhibited by the addition of the sera (P </= 0.05). These results strongly suggest that the presence of anti-CD38 autoantibodies in NIDDM patients can be one of the major causes of impaired glucose-induced insulin secretion in NIDDM.
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PMID:Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients. 966 81

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene cause maturity onset diabetes of the young type 3, a form of type 2 diabetes mellitus. In mice lacking the HNF-1alpha gene, insulin secretion and intracellular calcium ([Ca2+]i) responses were impaired following stimulation with nutrient secretagogues such as glucose and glyceraldehyde but normal with non-nutrient stimuli such as potassium chloride. Patch clamp recordings revealed ATP-sensitive K+ currents (KATP) in beta-cells that were insensitive to suppression by glucose but normally sensitive to ATP. Exposure to mitochondrial substrates suppressed KATP, elevated [Ca2+]i, and corrected the insulin secretion defect. NAD(P)H responses to glucose were substantially reduced, and inhibitors of glycolytic NADH generation reproduced the mutant phenotype in normal islets. Flux of glucose through glycolysis in islets from mutant mice was reduced, as a result of which ATP generation in response to glucose was impaired. We conclude that hepatocyte nuclear factor-1alpha diabetes results from defective beta-cell glycolytic signaling, which is potentially correctable using substrates that bypass the defect.
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PMID:Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice. 973 37

Recent trials in hypertensive patients with type 2 diabetes reveal important differences in the risk for major cardiovascular events when individual agents are compared. In the Fosinopril Amlodipine Cardiovascular Events Trial (FACET), 380 patients with hypertension and type 2 diabetes were randomized to fosinopril or amlodipine and followed for up to 3.5 years to assess effects on serum lipids. Although both agents effectively controlled blood pressure, amlodipine caused a significantly greater decrease in systolic pressure. At the end of the trial, serum cholesterol, high-density lipoprotein cholesterol, triglycerides, HbA1c, serum glucose, plasma insulin, serum creatinine, and microalbuminuria were similar in both groups. The patients randomized to fosinopril were significantly less likely to experience the prospectively defined combined outcome of acute myocardial infarction (MI), hospitalized angina, or stroke compared to those randomized to amlodipine (RR 0.49; 95% CI 0.26-0.95). In the Appropriate Blood pressure Control in Diabetes (ABCD) trial, 470 patients with hypertension and type 2 diabetes who were randomized to long-acting nisoldipine had an adjusted sevenfold increased risk for acute MI compared to those randomized to enalapril (RR 7.0; 95% CI 2.3-21.4). In the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) trial, the patients with hypertension and above the median of HbA1c (> or =6.7%) randomized to isradipine had a threefold increased risk for major cardiovascular events compared to those randomized to hydrochlorothiazide (RR 2.81; 95% CI 1.09-7.26). These findings are supported by several observational studies. Therefore, evidence is emerging that angiotensin-converting enzyme inhibitors and low-dose diuretics may be more effective than calcium antagonists for prevention of cardiovascular events in hypertensive patients with diabetes or impaired glucose control.
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PMID:New evidence on the prevention of cardiovascular events in hypertensive patients with type 2 diabetes. 973 37


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