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)

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States, and accounts for 35% of all the patients with ESRD entering a dialysis program; 63% of patients with diabetic nephropathy have type II diabetes mellitus. Hypertension is a major risk factor for renal disease and is common in people with diabetes mellitus. Strategies for preventing the progression of renal failure in patients with diabetes mellitus include glycemic control, and control of blood pressure. Blocking the renin-angiotensin system (RAS) slows the progression of established diabetic nephropathy in type I diabetes mellitus, and inhibiting angiotensin II formation retards or impedes the progression from microalbuminuria to established diabetic nephropathy (macroproteinuria) in people with type I diabetes mellitus. The situation could be the same for people with type II diabetes mellitus. The ability of RAS blockade using irbesartan, an AT1 angiotensin II receptor antagonist, to slow the progression in renal failure has been compared with that of the calcium channel blocker amlodipine and placebo in a pilot study. The results suggest that blockade of the RAS, in this case with irbesartan, is at least equivalent to calcium channel blockers with respect to antihypertensive efficacy, but provides better renoprotective benefits.
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PMID:Renoprotection and renin-angiotensin system blockade in diabetes mellitus. 943 77

It is clear that pancreatic beta-cell dysfunction, including basal hyperinsulinemia and reduced insulin release in response to glucose, is a key determinant of disease progression in type 2 diabetes, but the underlying molecular defects are not known. In diabetes, the expression and function of ryanodine receptor (RyR) Ca2+ release channels are reduced. The present studies were undertaken to define the subcellular location and role of RyR in the control of stimulated and basal insulin release from human pancreatic beta cells. Using confocal microscopy, we observed RyR immunoreactivity in a vesicular pattern. RyRs did not colocalize with insulin secretory granules but partially colocalized with endosomes. Direct activation with nanomolar concentrations of ryanodine evoked increases in cytosolic Ca2+ that were coupled to transient insulin release. Insulin release stimulated by 1 nM ryanodine was sensitive to BAPTA-AM preincubation but independent of thapsigargin-sensitive endoplasmic reticulum (ER) Ca2+ pools. Blocking RyRs with micromolar concentrations of ryanodine led to BAPTA-resistant insulin release that was not associated with an increase in cytosolic Ca2+, which implicated alterations in luminal Ca2+. However, neither Ca2+ signals nor insulin release stimulated by glucose was blocked by 10-50 microM ryanodine, which suggests that the CD38/cyclic ADP-ribose/RyR pathway is not a primary mechanism of glucose action in nontransformed beta cells. We provide the first evidence that RyRs directly control insulin secretion in primary beta cells. Unexpectedly, stimulation of insulin secretion by ryanodine occurs independently of glucose and by two mechanisms, including a novel cytosolic Ca2+-independent mechanism likely involving changes in Ca2+ within the lumens of non-ER organelles, such as endosomes.
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PMID:Ryanodine receptors in human pancreatic beta cells: localization and effects on insulin secretion. 1503 25

Atherothrombotic complications are frequent in patients with type 2 diabetes. Red blood cells (RBC) from diabetic patients exhibited an increased adhesion which correlated to the extent of vascular complications. In the present study we have investigated the adhesive interactions of RBCs with endothelium, using flow-based assessments. RBCs and endothelial cells were unstimulated or stimulated using respectively adrenaline and TNFalpha. Adhesion assays were carried-out by drawing the RBC suspension through a glass microcapillary tube precoated by human umbilical vein endothelial cells. These microslides were then incorporated into a controlled flow system equipped with a computerized video-microscopic image analysis. RBCs from diabetic patients bind to endothelial cells and could withstand wall shear stresses above 0.1 Pa. After stimulation by TNFalpha the adhesion was 1.5-fold higher. Blocking experiments demonstrated that the adhesion was mediated by the receptor for AGE (RAGE). Adrenaline-treated RBCs showed a transient increase in adhesion at low shear stresses. Inflammatory mediators or catecholamine amplifying diabetic RBC adhesion may aggravate endothelial cell damages.
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PMID:Modulation of RAGE expression influences the adhesion of red blood cells from diabetic patients. 1689 60

Interleukin-1 receptor antagonist (IL-1Ra) expression is reduced in islets of patients with type 2 diabetes. 70 patients with type 2 diabetes were randomized to treatment with anakinra (IL-1Ra) or placebo for 13 weeks. Following treatment glycated hemoglobin was 0.46 percent lower, C-peptide secretion was enhanced, and systemic IL-6 and C-reactive protein levels were reduced in the anakinra group compared to the placebo group. Insulin resistance remained unchanged. Blocking IL-1 activity improved glycemia and b-cell secretory function and reduced markers of systemic inflammation.
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PMID:[Interleukin-1 receptor antagonist-treatment of patients with type 2 diabetes]. 1742 83

Pancreatic beta-cell death is a critical event in type 1 diabetes, type 2 diabetes, and clinical islet transplantation. We have previously shown that prolonged block of ryanodine receptor (RyR)-gated release from intracellular Ca(2+) stores activates calpain-10-dependent apoptosis in beta-cells. In the present study, we further characterized intracellular Ca(2+) channel expression and function in human islets and the MIN6 beta-cell line. All three RyR isoforms were identified in human islets and MIN6 cells, and these endoplasmic reticulum channels were observed in close proximity to mitochondria. Blocking RyR channels, but not sarco/endoplasmic reticulum ATPase (SERCA) pumps, reduced the ATP/ADP ratio. Blocking Ca(2+) flux through RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of hypoxia-inducible factor (HIF-1beta). Moreover, inhibition of RyR or inositol trisphosphate receptor channels, but not SERCA pumps, increased the expression of presenilin-1. Both HIF-1beta and presenilin-1 expression were also induced by low glucose. Overexpression of presenilin-1 increased HIF-1beta, suggesting that HIF is downstream of presenilin. Our results provide the first evidence of a presenilin-HIF signaling network in beta-cells. We demonstrate that this pathway is controlled by Ca(2+) flux through intracellular channels, likely via changes in mitochondrial metabolism and ATP. These findings provide a mechanistic understanding of the signaling pathways activated when intracellular Ca(2+) homeostasis and metabolic activity are suppressed in diabetes and islet transplantation.
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PMID:Glucose and endoplasmic reticulum calcium channels regulate HIF-1beta via presenilin in pancreatic beta-cells. 1817 59

Diabetes and insulin resistance are associated with an increased risk of hypertension and cardiovascular disease. Recent evidence demonstrates that AT2 receptors (AT2R) play an important role in the hemodynamic control of hypertension by vasodilation. The quantitative significance of AT2R in the establishment of diabetic vascular dysfunction, however, is not well defined and needs further investigation. Goto-Kakizaki (GK) rats, a polygenic model of spontaneous normotensive type 2 diabetes, were used to examine any abnormalities in cardiovascular function associated with AT2R at the early stage of the disease without endothelium influence. Using a myograph to measure the isometric force, we observed that ANG II-induced contraction was impaired in denuded GK aorta compared with control Wistar-Kyoto (WKY) aorta and exhibited a retarded AT1R antagonist response and enhanced Rho kinase signaling. When AT1R were blocked, ANG II induced a significant vasodilation of precontracted GK aorta via AT2R. The protein and mRNA of AT2R were increased in diabetic GK denuded aorta. Blocking AT2R restored the ANG II-induced contraction in the GK vasculature to control levels, demonstrating a counteractive role for AT2R in AT1R-induced contraction. Inhibition of inducible nitric oxide synthase (iNOS) by NG-monomethyl-L-arginine mimicked AT2R inhibition in denuded GK aorta, suggesting that AT2R-induced vasodilation was dependent on iNOS/NO generation. The protein and mRNA of iNOS were also increased in GK aorta. In conclusion, these results clearly demonstrate that enhanced AT2R and iNOS-induced, NO-mediated vasodilation impair ANG II-induced contraction in an endothelium-independent manner at the early stage of type 2 diabetes.
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PMID:Upregulation of AT2 receptor and iNOS impairs angiotensin II-induced contraction without endothelium influence in young normotensive diabetic rats. 1846 92

Free fatty acids (FFA) cause apoptosis of pancreatic beta-cells and might contribute to beta-cell loss in type 2 diabetes via the induction of endoplasmic reticulum (ER) stress. We studied here the molecular mechanisms implicated in FFA-induced ER stress initiation and apoptosis in INS-1E cells, FACS-purified primary beta-cells and human islets exposed to oleate and/or palmitate. Treatment with saturated and/or unsaturated FFA led to differential ER stress signaling. Palmitate induced more apoptosis and markedly activated the IRE1, PERK and ATF6 pathways, owing to a sustained depletion of ER Ca(2+) stores, whereas the unsaturated FFA oleate led to milder PERK and IRE1 activation and comparable ATF6 signaling. Non-metabolizable methyl-FFA analogs induced neither ER stress nor beta-cell apoptosis. The FFA-induced ER stress response was not modified by high glucose concentrations, suggesting that ER stress in primary beta-cells is primarily lipotoxic, and not glucolipotoxic. Palmitate, but not oleate, activated JNK. JNK inhibitors reduced palmitate-mediated AP-1 activation and apoptosis. Blocking the transcription factor CHOP delayed palmitate-induced beta-cell apoptosis. In conclusion, saturated FFA induce ER stress via ER Ca(2+) depletion. The IRE1 and resulting JNK activation contribute to beta-cell apoptosis. PERK activation by palmitate also contributes to beta-cell apoptosis via CHOP.
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PMID:Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. 1855 92

Melatonin is a circulating hormone that is primarily released from the pineal gland. It is best known as a regulator of seasonal and circadian rhythms; its levels are high during the night and low during the day. Interestingly, insulin levels also exhibit a nocturnal drop, which has previously been suggested to be controlled, at least in part, by melatonin. This regulation can be explained by the proposed inhibitory action of melatonin on insulin release. Indeed, both melatonin receptor 1A (MTNR1A) and MTNR1B are expressed in pancreatic islets. The role of melatonin in the regulation of glucose homeostasis has been highlighted by three independent publications based on genome-wide association studies of traits connected with type 2 diabetes, such as elevated fasting glucose, and, subsequently, of the disease itself. The studies demonstrate a link between variations in the MTNR1B gene, hyperglycaemia, impaired early phase insulin secretion and beta cell function. The risk genotype predicts the future development of type 2 diabetes. Carriers of the risk genotype exhibit increased expression of MTNR1B in islets. This suggests that these individuals may be more sensitive to the actions of melatonin, leading to impaired insulin secretion. Blocking the inhibition of insulin secretion by melatonin may be a novel therapeutic avenue for type 2 diabetes.
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PMID:Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene. 1937 88

Islets of patients with type 2 diabetes mellitus (T2DM) display features of an inflammatory process including elevated levels of the cytokine IL-1beta, various chemokines, and macrophages. IL-1beta is a master regulator of inflammation, and IL-1 receptor type I (IL-1RI) blockage improves glycemia and insulin secretion in humans with T2DM and in high-fat-fed mice pointing to a pivotal role of IL-1RI activity in intra-islet inflammation. Given the association of dyslipidemia and T2DM, we tested whether free fatty acids (FFA) promote the expression of proinflammatory factors in human and mouse islets and investigated a role for the IL-1RI in this response. A comparison of 22 mouse tissues revealed the highest IL-1RI expression levels in islets and MIN6 beta-cells. FFA induced IL-1beta, IL-6, and IL-8 in human islets and IL-1beta and KC in mouse islets. Elevated glucose concentrations enhanced FFA-induced proinflammatory factors in human islets. Blocking the IL-1RI with the IL-1R antagonist (IL-1Ra) strongly inhibited FFA-mediated expression of proinflammatory factors in human and mouse islets. Antibody inhibition of IL-1beta revealed that FFA stimulated IL-1RI activity via the induction of the receptor ligand. FFA-induced IL-1beta and KC expression in mouse islets was completely dependent on the IL-1R/Toll-like receptor (TLR) docking protein Myd88 and partly dependent on TLR2 and -4. Activation of TLR2 in purified human beta-cells and islets stimulated the expression of proinflammatory factors, and IL-1RI activity increased the TLR2 response in human islets. We conclude that FFA and TLR stimulation induce proinflammatory factors in islets and that IL-1RI engagement results in signal amplification.
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PMID:Free fatty acids induce a proinflammatory response in islets via the abundantly expressed interleukin-1 receptor I. 1981 43

There is now convincing evidence of an increased risk of patients with obesity or type 2 diabetes developing cancer. To understand the possible causation, type 2 diabetic muscle lysine to arginine (MKR) mice were studied. Introduction of mammary tumour cell lines resulted in aggressive growth of the mammary tumours in the hyperinsulinaemic MKR female mice. Blocking the insulin receptor activation or reducing the hyperinsulinaemia reduced the mammary tumour burden. Thus, hyperinsulinaemia may be one of the factors in the increased breast cancer risk seen with obesity and type 2 diabetes.
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PMID:Can endogenous hyperinsulinaemia explain the increased risk of cancer development and mortality in type 2 diabetes: evidence from mouse models. 2094 6


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