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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance of the skeletal muscle plays a key role in the development of the metabolic endocrine syndrome and its further progression to non-insulin dependent diabetes (NIDDM). Available data suggest that insulin resistance is caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. The impaired response of the insulin receptor tyrosine kinase which is found in NIDDM appears to contribute to the pathogenesis of the signalling defect. The reduced kinase activation is not caused by mutations within the insulin receptor gene. We investigated two potential mechanisms that might be relevant for the abnormal function of the insulin receptor in NIDDM, i.e. changes in the expression of the receptor isoforms and the effect of hyperglycaemia on insulin receptor tyrosine kinase activity. The insulin receptor is expressed in two different isoforms (HIR-A and HIR-B). We found that HIR-B expression in the skeletal muscle is increased in NIDDM. However, the characterisation of the functional properties of HIR-A and HIR-B revealed no difference in their tyrosine kinase activity in vivo. The increased expression of HIR-B might represent a compensatory event. In contrast, hyperglycaemia might directly inhibit insulin-receptor function. We have found that in rat-1 fibroblasts which overexpressing human insulin receptor an inhibition of the tyrosine kinase activity of the receptor may be induced by high glucose levels. This appears to be mediated through activation of certain protein kinase C isoforms which form stable complexes with the insulin receptor and modulate the tyrosine kinase activity of the insulin receptor through serine phosphorylation of the receptor beta subunit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of insulin receptor signalling: significance of altered receptor isoform patterns and mechanism of hyperglycaemia-induced receptor modulation. 782 30

The activities of protein kinase C, total, Mg2 and Na+, K(+)-dependent ATPases in red cell membranes were compared in 46 patients with insulin independent, 30 ones with insulin dependent diabetes mellitus with various degrees of vascular disorders, and in 17 patients with atherosclerosis with the predominant involvement of the main vessels of the lower limbs. Diabetes mellitus and the progress of vascular disorders were associated with a more marked depression of protein kinase C, total and Na+, K(+)-dependent ATPase activities, this being particularly characteristic of the patients with insulin-independent diabetes and macrovascular disorders. Inhibited activities of protein kinase C and ATPases in red cell membranes in the course of diabetic vascular disorders progress evidence their contribution to the pathogenesis of diabetic angiopathy.
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PMID:[Activity of membrane-bound protein kinase C and ATPase in erythrocytes in diabetic angiopathy]. 805 53

Glomerular vasodilatation in the early stages of type I diabetes mellitus apparently results from arteriolar insensitivity to vasoconstrictors. Since cytosolic free calcium ([Ca2+]i) is a major signaling mechanism for smooth muscle contraction, we studied whether growth of smooth muscle-like rat glomerular mesangial cells in media with high glucose concentration affects [Ca2+]i responses to vasoconstrictors. In cells grown for five days in 22 mM glucose, we observed blunted responsiveness to three structurally unrelated vasoconstrictors that elevate [Ca2+]i via a phospholipase C-dependent mechanism, angiotensin II, prostaglandin F2 alpha, and arginine vasopressin. Inhibition of [Ca2+]i responses was not due to an osmotic effect of high glucose, since it was not mimicked by hypertonic mannitol. While the size of intracellular Ca2+ pools was unaffected by elevated glucose, Na+/Ca2+ exchange was markedly inhibited, thus ruling out both impaired filling of Ca2+ stores and enhanced counter-regulatory mechanisms. Impaired myoinositol transport or intracellular sorbitol accumulation were not responsible for the effects of high glucose, since supplementation of media with myo-inositol or with the aldose reductase inhibitor. Alcon 1576, failed to reverse insensitivity to vasoconstrictors. On the other hand, down-regulation or pharmacological inhibition of protein kinase C completely reversed the effects of high glucose, thus indicating involvement of this signal transduction pathway. These data suggest a possible intracellular mechanism for the impaired vascular sensitivity underlying early renal hemodynamic changes in diabetes mellitus.
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PMID:High glucose inhibits cytosolic calcium signaling in cultured rat mesangial cells. 845 57

Like most cytokines, IL-1 transduces its signals for growth, differentiation and diverse cellular functions after binding to specific receptors on the cell surface. Up to now two IL-1 receptors have been reported, type I which induces signal transduction and type II which binds IL-1 but does not transduce signalling. By using the rat insulinoma RIN-5AH cell line that expresses both types of receptor mRNA, and computer-assisted binding analysis, we show that interleukin-1 beta (IL-1 beta) binds to a single class of high affinity receptors with a Kd of 155 pmol/l. The average number of receptors on adherent cell layer is calculated to be 7300 per cell. 125I-IL-1 beta binding can be competed out by unlabelled IL-1 beta. 125I-IL-1 alpha binding can be also obtained and is subject to competition by cold IL-1 alpha. Its saturation curve, however, varies within experiments due to differential receptor up-regulation. These results have also been confirmed by FACS analysis using specific antibodies to type I and II IL-1 receptors, where type I receptor antibody binds strongly to RIN-5AH cells, and type II receptor antibody shows weak staining, also due to inadequate receptor up-regulation. In order to determine whether functional signal transduction occurs via the receptors detected, it is shown that IL-1 beta is able to induce MHC class II antigen expression on the surface of the RIN cells, whereas IL-1 alpha is unable to do so, indicating different signal reception by the cells. IL-1 beta-induced class II upregulation shows moderate signs of p21ras or/and PKC dependency, whereas IL-1 alpha strongly activates both pathways that probably regulate different functions. Finally, both IL-1 alpha and beta induce nitric oxide (NO) production in a time-dependent fashion which appears to be unrelated to the signals and pathways described, but may be involved in the onset of autoimmune type 1 diabetes.
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PMID:IL-1 beta transduces different signals than IL-1 alpha leading to class II antigen expression on beta-insulinoma RIN-5AH cells through specific receptors. 902 92

Intracellular calcium ([Ca2+]i) and phorbol ester binding were studied in intact platelets of young patients with insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. Our objective was to evaluate disturbances in calcium regulation and signal transduction in platelets of diabetics. [Ca2+]i in platelets of the IDDM group (135 +/- 20 nmol/L) under basal conditions was significantly higher than that of the control group (81 +/- 8 nmol/L, P = .019), whereas at 60 seconds after stimulation with 0.1 National Institutes of Health (NIH) U/mL thrombin, [Ca2+]i in the NIDDM group (484 +/- 36 nmol/L) was significantly higher than that of the controls (347 +/- 22 nmol/L, P = .003) and IDDM group (360 +/- 45 nmol/L, P = .04), respectively. Phorbol 12,13-dibutyrate (PdBu) maximal binding capacity (Bmax) in the IDDM group was significantly lower than that in the control group either under basal conditions or after stimulation with thrombin (P = .0034 and P = .015, respectively). Bmax in the NIDDM group was significantly lower than that in the controls only after stimulation with thrombin (P = .047). The Kd for PdBu of the IDDM group was lower than that of the control group under basal conditions (P = .017). When analyzing the pooled data of all subjects, a significant correlation was observed between Bmax and Kd (under basal conditions, r = .544, P < .0001; after stimulation, r = .601, P < .0001). Our results support the idea that the increased affinity for PdBu may compensate for the decreased binding capacity. We interpret the data as indicating that the change in the binding of phorbol ester to protein kinase C (PKC) units may result in an altered PKC/calcium interaction in the pathogenesis of diabetes mellitus. Our study indicates that such metabolic derangements of [Ca2+]i have already been developing in young diabetic patients.
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PMID:Increased intracellular calcium and altered phorbol dibutyrate binding to intact platelets in young subjects with insulin-dependent and non-insulin-dependent diabetes mellitus. 925 80

Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced glomerular dysfunction such as glomerular hyperfiltration and albuminuria, but also overexpression of glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes. Administration of a PKC beta inhibitor reduced urinary albumin excretion rates and inhibited glomerular PKC activation in diabetic db/db mice. Administration of a PKC beta inhibitor also prevented the mesangial expansion observed in diabetic db/db mice, possibly through attenuation of glomerular expression of TGF-beta and ECM proteins such as fibronectin and type IV collagen. These findings provide the first in vivo evidence that the long-term inhibition of PKC activation in the renal glomeruli can ameliorate glomerular pathologies in diabetic state, and thus suggest that a PKC beta inhibitor might be an useful therapeutic strategy for the treatment of diabetic nephropathy.
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PMID:Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. 1069 58

IA-2, a member of the protein tyrosine phosphatase family, represents a major target autoantigen in type 1 diabetes. To study the regulation of IA-2 gene expression, we used INS-1 insulinoma cells to analyze beta-cell signal transduction pathways as well as the effect of metabolic and hormonal factors involved in the regulation of the insulin secretory pathway. Quantitative competitive reverse transcriptase-polymerase chain reaction revealed that an increase of cellular cAMP mediated by forskolin (10 micromol/l, 24 h) or 3-isobutyl-1-methylxanthine (100 micromol/l, 24 h) induced maximal stimulation of IA-2 mRNA levels (451 +/- 85 and 338 +/- 86% compared with basal conditions; P < 0.001). In contrast, activation of protein kinase C (PKC) by short-term treatment with phorbol 12-myristate 13-acetate (PMA) (1 micromol/l, 6 h) did not alter IA-2 expression, whereas depletion of PKC by prolonged culturing (24 h) exerted a significant inhibition (57 +/- 24%; P < 0.05). cAMP-dependent upregulation was confirmed by the findings that glucagon (10 micromol/l, 24-48 h) increased levels of IA-2 mRNA (190 +/- 35%; P < 0.05), whereas short-term incubation with high glucose concentration showed no effect. However, prolonged incubation in high glucose (21 mmol/l) induced a time- and dose-dependent increase of IA-2 mRNA expression, reaching maximal values after 144 h (285 +/- 68%; P < 0.05). These studies demonstrate that stimuli of insulin secretion that operate by activation of adenylate cyclase generating cAMP significantly increase IA-2 gene expression. In contrast, activation of PKC by high glucose concentration or PMA exerted no effect, suggesting that IA-2 gene expression is not simply coupled to insulin secretion, but may be involved in the fine regulation of beta-cell function. These findings may be important to clarify the function of IA-2 in beta-cells and elucidate mechanisms involved in the induction of autoimmunity to IA-2.
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PMID:Regulation of the diabetes-associated autoantigen IA-2 in INS-1 pancreatic beta-cells. 1090 70

Insulin dependent diabetes mellitus, marked by high blood glucose levels and no insulin secretion, is associated with decreased bone mass and increased fracture rates. Analysis of bone histology suggests that osteoblast phenotype and function are influenced by diabetes. To determine if elevated extracellular glucose levels could directly influence osteoblast phenotype we treated mouse osteoblasts, MC3T3-E1 cells, with 22 mM glucose and analyzed osteoblast gene expression. Collagen I mRNA levels significantly increased while osteocalcin mRNA levels decreased 24 h after the addition of glucose. Expression of other genes, actin, osteopontin, and histone H4, was unaffected. Effects on collagen I expression were seen as early as 1 h after treatment. c-Jun, an AP-1 transcription factor involved in the regulation of osteoblast gene expression and growth, was also modulated by glucose. Specifically, an increase in c-jun expression was found at 1 h and maintained for 24 h following glucose treatment. Treatment of osteoblasts with an equal concentration of mannitol completely mimicked glucose treatment effects on collagen I and c-jun expression, demonstrating that osmotic stress rather than glucose metabolism is responsible for the effects on osteoblast gene expression and phenotype. Additional studies using staurosporine and Ro-31-8220 demonstrate that protein kinase C is required for the glucose up regulation of collagen I and c-jun. Taken together, our results demonstrate that osteoblasts respond to increasing extracellular glucose concentration through an osmotic response pathway that is dependent upon protein kinase C activity and results in upregulation of c-jun and modulation of collagen I and osteocalcin expression.
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PMID:Extracellular glucose influences osteoblast differentiation and c-Jun expression. 1096 57

Amadori-glycated albumin in diabetic nephropathy: Pathophysiologic connections. Nonenzymatic glycation of proteins represents a major mechanism by which hyperglycemia leads to diabetic renal disease. Recent research has shown that Amadori-modified albumin, the principal glycated protein in plasma, elicits pathobiologic effects in cultured renal cells that are identical to those of high ambient glucose. When added to the incubation media of glomerular mesangial and endothelial cells, glycated albumin stimulates protein kinase C (PKC) activity, increases transforming growth factor-beta (TGF-beta) bioactivity, and induces gene overexpression and enhanced production of extracellular matrix proteins. These cellular events, whereby PKC-mediated TGF-beta activation leads to increased matrix expression, are inextricably linked, and they form the central tenets of a pathophysiologic connection between glycated proteins and diabetic nephropathy. In vivo studies further corroborate the role of glycated proteins in the pathogenesis of diabetic nephropathy. Reduction or neutralization of glycated albumin in the db/db mouse model of type 2 diabetes significantly ameliorates the proteinuria, renal insufficiency, mesangial expansion, and overexpression of matrix proteins. In human type 1 diabetes, the plasma-glycated albumin concentration is independently associated with the presence of nephropathy. Abrogating the biologic effects of increased glycated albumin has novel therapeutic potential in the management of renal complications in diabetes.
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PMID:Amadori-glycated albumin in diabetic nephropathy: pathophysiologic connections. 1099 89

Preceding the onset of type 1 diabetes mellitus, pancreatic islets are infiltrated by macrophages secreting interleukin-1beta (IL-1beta) which induces beta-cell apoptosis and exerts inhibitory actions on islet beta-cell insulin secretion. IL-1beta seems to act chiefly through induction of nitric oxide (NO) synthesis. Hence, IL-1beta and NO have been implicated as key effector molecules in type 1 diabetes mellitus. In this paper, the influence of endogenously produced and exogenously delivered NO on the regulation of cell proliferation, cell viability and discrete parts of the stimulus-secretion coupling in insulin-secreting RINm5F cells was investigated. Because vitamin E may delay diabetes onset in animal models, we also investigated whether tocopherols may protect beta-cells from the suppressive actions of IL-1 and NO in vitro. To this end, the impact of NO on insulin secretory responses to activation of phospholipase C (by carbamylcholine), protein kinase C (by phorbol ester), adenylyl cyclase (by forskolin), and Ca(2+) influx through voltage-activated Ca(2+) channels (by K(+)-induced depolarization) was monitored in culture after treatment with IL-1beta or by co-incubation with the NO donor spermine-NONOate. It was found that cell proliferation, viability, insulin production and the stimulation of insulin release evoked by carbamylcholine and phorbol ester were impeded by IL-1beta or spermine-NONOate, whereas the hormone output by the other secretagogues was not altered by NO. Pretreatment with gamma-tocopherol (but not alpha-tocopherol) afforded a partial protection against the inhibitory effects of NO, whereas specifically inhibiting inducible NO synthase with N-nitro-L-arginine completely reversed the IL-1beta effects. In contrast, inhibiting guanylyl cyclase with ODQ (1H-[1,2, 4]oxadiazolo[4,3-alpha]-quinoxaline-1-one) or blocking low voltage-activated Ca(2+) channels with NiCl(2) failed to influence the actions of NO. In conclusion, our data show that NO inhibits growth and insulin secretion in RINm5F cells, and that gamma-tocopherol may partially prevent this. The results suggest that phospholipase C or protein kinase C may be targeted by NO. In contrast, cGMP or low voltage-activated Ca(2+) channels appear not to mediate the toxicity of NO in these cells. These adverse effects of NO on the beta-cell, and the protection by gamma-tocopherol, may be of importance for the development of the impaired insulin secretion characterizing type 1 diabetes mellitus, and offer possibilities for intervention in this process.
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PMID:gamma-tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide. 1103 27


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