Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes in its early stages is associated with enhanced glomerular blood flow and systemic vasodilation. Possible consequences of enhanced glomerular blood flow are glomerular hypertrophy, increased shear stress, and subsequent glomerulosclerosis. The prosclerotic cytokine, transforming growth factor-beta (TGF-beta), has been well established to play a key role in mesangial matrix accumulation in diabetes; however, its role in regulating vascular tone has not been studied in depth. Earlier studies have demonstrated that vascular smooth muscle cells and mesangial cells pretreated with TGF-beta have impaired calcium mobilization to inositol 1,4,5-trisphosphate (IP3) generating agonists, such as platelet-derived growth factor (PDGF) and Angiotensin I1 (Ang II). We postulated that this action of TGF-beta may be caused by regulation of the key intracellular calcium channel, the inositol 1,4,5-trisphosphate receptor (IP3R). Mesangial and smooth muscle cells primarily contain the types I IP3R and III IP3R isoforms. Short-term exposure of mesangial cells to TGF-beta (15-60 min) leads to phosphorylation of the type I IP3R at specific serine residues. Long-term exposure of mesangial cells to TGF-beta (24 hours) leads to down-regulation of protein levels of both types I and III IP3Rs as assessed by Western blot and confocal analysis. Permeabilization of cells and exposure to IP3 leads to impaired calcium mobilization if cells are pretreated with TGF-beta. As an in vivo correlation, we found that streptozotocin-induced diabetic rats and mice have reduced renal type I IP3R expression. By immunostaining, we found reduction of type I IP3R in glomerular cells and arteriolar smooth muscle cells of the diabetic rat kidney. Treatment of diabetic mice with a neutralizing anti-TGF-beta antibody completely prevents diabetic glomerular hypertrophy. We conclude that the vascular dysfunction of diabetes leading to glomerular hypertrophy is mediated, in part, by TGF-beta-induced regulation of IP3Rs.
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PMID:Regulation of inositol 1,4,5-trisphosphate receptors by transforming growth factor-beta: implications for vascular dysfunction in diabetes. 1099 98

CD36 has been associated with diverse normal and pathologic processes. These include scavenger receptor functions (uptake of apoptotic cells and modified lipid), lipid metabolism and fatty acid transport, adhesion, angiogenesis, modulation of inflammation, transforming growth factor-beta activation, atherosclerosis, diabetes and cardiomyopathy. Although CD36 was identified more than 25 years ago, it is only with the advent of recent genetic technology that in-vivo evidence has emerged for its physiologic and pathologic relevance. As these in-vivo studies are expanded, we will gain further insight into the mechanism(s) by which CD36 transmits a cellular signal, and this will allow the design of specific therapeutics that impact on a particular function of CD36.
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PMID:CD36 and atherosclerosis. 1104 91

Activins are members of the transforming growth factor-beta superfamily. They have a wide range of biological effects on cell growth and differentiation. For transmembrane signaling, activins bind directly to activin receptor type 2A (ACVR2A) or 2B (ACVR2B). Transgenic and knock-out mice for the ACVR2B gene display various endocrine pancreas-related abnormalities, including islet hypoplasia and glucose intolerance, demonstrating the crucial role of ACVR2B in the regulation of pancreas development. We have thus examined the contribution of this factor to the development of mature-onset diabetes of the young (MODY) and type 2 diabetes. No evidence of linkage at the ACVR2B locus has been detected in MODY families with unknown etiology for diabetes or found in affected sib pairs from families with type 2 diabetes. Mutation screening of the coding sequence in MODY probands and in a family with severe type 2 diabetes, including a case of pancreatic agenesis, showed single nucleotide polymorphisms that did not cosegregate with MODY and were not associated with type 2 diabetes. Our results indicate that ACVR2B does not represent a common cause of either MODY or type 2 diabetes in the French Caucasian population.
Diabetes 2001 May
PMID:No evidence for linkage or for diabetes-associated mutations in the activin type 2B receptor gene (ACVR2B) in French patients with mature-onset diabetes of the young or type 2 diabetes. 1133 31

Activation of the renal transforming growth factor-beta (TGF-beta) system likely mediates the excess production of extracellular matrix in the diabetic kidney. To establish the role of the TGF-beta system in type 2 diabetic nephropathy, we examined the intrarenal localization and expression of the TGF-beta1 isoform, the TGF-beta type II receptor, and the Smad signaling pathway in the 16-week-old db/db mouse, a genetic model of type 2 diabetes that exhibits mesangial matrix expansion, glomerular basement membrane thickening, and renal insufficiency that closely resemble the human disease. Compared with its nondiabetic db/m littermate, the db/db mouse showed significantly increased TGF-beta1 mRNA expression by in situ hybridization in both glomerular and tubular compartments. Likewise, TGF-beta1 protein, by immunohistochemical staining, was increased in both renal compartments, but the fractional expression of TGF-beta1 protein was less than that of the mRNA in the glomerulus. In situ hybridization and immunohistochemical staining for the TGF-beta type II receptor revealed concordant and significant increases of both mRNA and protein in the glomerular and tubular compartments of diabetic animals. Finally, immunohistochemistry showed preferential accumulation of Smad3 in the nuclei of glomerular and tubular cells in diabetes. The complementary technique of Southwestern histochemistry using a labeled Smad-binding element demonstrated increased binding of nuclear proteins to Smad-binding element, indicating active signaling downstream of the TGF-beta stimulus. We therefore propose that the TGF-beta system is up-regulated at the ligand, receptor, and signaling levels throughout the renal cortex in this animal model of type 2 diabetes. Our findings suggest that the profibrotic effects of TGF-beta may underlie the progression to glomerulosclerosis and tubulointerstitial fibrosis that characterize diabetic nephropathy.
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PMID:Increased glomerular and tubular expression of transforming growth factor-beta1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse. 1133 63

Diabetes is commonly associated with both microvascular and macrovascular complications. These vascular complications are accelerated in the context of systemic hypertension. During the past few years the underlying molecular mechanisms responsible for diabetic vascular complications have begun to be clarified. It appears that both metabolic and hemodynamic factors interact to stimulate the expression of cytokines and growth factors in the various vascular trees. Overexpression of the prosclerotic cytokine transforming growth factor-beta has been observed in glomeruli and tubules from the diabetic kidney. In the retina the angiogenic cytokine vascular endothelial growth factor and its receptor, vascular endothelial growth factor R-2 are increased in experimental diabetes. These changes in growth factors are viewed to be responsible for the extracellular matrix accumulation in the diabetic kidney and new vessel formation in the diabetic retina. Changes in cytokines have also been observed at other vascular sites including the mesenteric vascular tree. Vasoactive hormones, such as angiotensin II and endothelin, are potent stimulators of cytokines with recent studies showing that inhibitors of these vasoactive hormone pathways may confer organ protection in diabetes by inhibition of growth factor expression. Glucose-dependent factors, such as the formation of advanced glycation end products that interact with specific receptors and lead to overexpression of a range of cytokines, may play an important role in diabetic vascular complications including atherosclerosis. It is likely that the effects of inhibitors of this pathway such as aminoguanidine on cytokine production may play a pivotal role in mediating the renal, retinal, and vasoprotective effects observed with this agent in experimental diabetes. It is anticipated that the advent of specific inhibitors of cytokine formation or action will provide new approaches for the prevention and treatment of diabetic vascular complications.
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PMID:Mechanisms of diabetic vasculopathy: an overview. 1136 71

IL-10 is an immunoregulatory cytokine that can modulate immune processes, inhibiting the expression of inflammatory T(h)1 type responses as well as affecting antigen-presenting cell function. In addition, IL-10 has been shown to be active at mucosal surfaces. In the present study, we examined the role of IL-10 on orally and nasally induced tolerance. Treatment of (PL/J x SJL)F(1) mice with low-dose oral myelin basic protein (MBP) (0.5 mg) and simultaneous oral IL-10 given 3 times reduced the severity and incidence of experimental autoimmune encephalomyelitis (EAE), whereas administration of oral IL-10 alone or MBP alone given in these doses had no effect. Lymphocytes from mice treated orally with MBP and IL-10 proliferated less, and produced decreased amounts of IFN-gamma and IL-2 and increased amounts of IL-10 and transforming growth factor-beta upon in vitro stimulation with MBP. Nasal administration of antigen and IL-10 reduced proliferative responses and IFN-gamma production, increased IL-10 production, and enhanced protection from EAE. In addition, oral IL-10 combined with oral myelin oligodendrocyte glycoprotein (MOG) 35-55 reduced relapses in MOG-induced EAE in the NOD mouse, as well as enhanced the protective effect of oral insulin in the NOD model of diabetes. These results demonstrate that IL-10 is biologically active at mucosal surfaces and can act synergistically to enhance the tolerogenic effects of mucosally administered antigen.
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PMID:Mucosal administration of IL-10 enhances oral tolerance in autoimmune encephalomyelitis and diabetes. 1136 11

Progressive renal injury in diabetes mellitus leads to major morbidity and mortality. The manifestations of diabetic nephropathy may be a consequence of the actions of certain cytokines and growth factors. Prominent among these is transforming growth factor-beta (TGF-beta) because it promotes renal cell hypertrophy and stimulates extracellular matrix accumulation, the two hallmarks of diabetic renal disease. In cell culture, high ambient glucose increases TGF-beta mRNA and protein in proximal tubular, glomerular epithelial, and mesangial cells. Neutralizing anti-TGF-beta antibodies prevent the hypertrophic and matrix stimulatory effects of high glucose in these cells. In experimental and human diabetes mellitus, several reports describe overexpression of TGF-beta in the glomeruli and tubulointerstitium. We demonstrate that short-term treatment of diabetic mice with neutralizing monoclonal antibodies against TGF-beta significantly reduces kidney weight and glomerular hypertrophy and attenuates the increase in extracellular matrix mRNAs. Long-term treatment of diabetic mice further improves the renal pathology and also ameliorates the functional abnormalities of diabetic nephropathy. Finally, we provide evidence that the renal TGF-beta system is significantly up-regulated in human diabetes. The kidney of a diabetic patient actually elaborates TGF-beta1 protein into the circulation whereas the kidney of a non-diabetic subject extracts TGF-beta1 from the circulation. The data we review here strongly support the hypothesis that elevated production or activity of the TGF-beta system mediates diabetic renal hypertrophy and extracellular matrix expansion.
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PMID:The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy. 1149 62

Ex vivo and in vitro observations implicate superoxide as a mediator of cell injury in diabetes, but in vivo evidence is lacking. In the current studies, parameters of glomerular injury were examined in hemizygous nondiabetic transgenic mice (SOD) and streptozotocin-diabetic (D) transgenic mice (D-SOD), which overexpress human cytoplasmic Cu2+/Zn2+ superoxide dismutase (SOD-1), and in corresponding wild-type littermates (WT, D-WT) after 4 months of diabetes. In both SOD and D-SOD mice, renal cortical SOD-1 activity was twofold higher than values in the WT mice; blood glucose and glycosylated hemoglobin (GHb) levels did not differ in the two diabetic groups. Urinary albumin excretion, fractional albumin clearance, urinary transforming growth factor-beta (TGF-beta) excretion, glomerular volume, glomerular content of immunoreactive TGF-beta, and collagen alpha1 (IV) and renal cortical malondialdehyde (MDA) levels were significantly higher in D-WT mice compared with corresponding values in D-SOD mice. Glomerular volume, glomerular content of TGF-beta and collagen IV, renal cortical MDA, and urinary excretion of TGF-beta in D-SOD mice did not differ significantly from corresponding values in either the nondiabetic SOD or WT mice. In separate groups of mice studied after 8 months of diabetes, mesangial matrix area, calculated as a fraction of total glomerular tuft area, and plasma creatinine were significantly higher in D-WT but not in D-SOD mice, compared with corresponding values in the nondiabetic mice. In vitro infection of mesangial cells (MC) with a recombinant adenovirus encoding human SOD-1 increased SOD-1 activity threefold over control cells and prevented the reduction of aconitase activity, an index of cellular superoxide, and the increase in collagen synthesis that otherwise occurred in control MC in response to culture with 300 or 500 mg/dl glucose. Thus, increases in cellular SOD-1 activity attenuate diabetic renal injury in vivo and also prevent stimulation of MC matrix protein synthesis induced in vitro by high glucose.
Diabetes 2001 Sep
PMID:Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice. 1152 79

Bone morphogenetic protein-7 (BMP7), a member of the transforming growth factor-beta (TGF-beta) superfamily of cytokines, is highly expressed in renal tubules and generally promotes maintenance of epithelial phenotype. It was examined whether, during the evolution of experimental diabetic nephropathy, the renal expression of BMP7 and BMP7 receptors declines, and the hypothesis that loss of BMP7 activity is profibrogenic in proximal tubular cells was tested. Moreover, in vitro studies in cultured proximal tubular cells were performed to examine putative mechanisms that cause these changes. At 15 wk of streptozotocin-induced diabetes, renal expression of BMP7 is declined by about half, and it decreased further by 30 wk to <10% of timed controls. Renal expression of the high-affinity BMP type II receptor and the type I receptor Alk2 (activin receptor-like kinase-2) decreased. Alk3 tended to decrease, but Alk6 remained unchanged. During the evolution of diabetic nephropathy, the secreted BMP antagonist gremlin increased substantially. In cultured tubular cells, TGF-beta reduced BMP7 and Alk3 expression and increased gremlin but did not interrupt BMP7-induced activation of smad5 or Erk1 and -2. In contrast, BMP7 did not alter TGF-beta expression. Neutralization of endogenous BMP7 in cultured proximal tubular cells raised the expression of fibronectin and tended to increase collagen alpha(1) III mRNA levels. In conclusion, in experimental diabetic nephropathy, renal tubular BMP7 and some of its receptors decreased and gremlin, a secreted BMP antagonist, increased. Some, but not all, of these changes are explained by increased TGF-beta. The loss of BMP7 activity per se is profibrogenic in tubular cells.
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PMID:Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy. 1167 15

Bone morphogenetic proteins are members of the transforming growth factor-beta superfamily of cytokines and consist of a group of at least 15 morphogens involved in intracellular messaging through complex bone morphogenetic protein receptor mediated Smad signaling. Bone morphogenetic protein-7 knockout mice die shortly after birth due to uremia, demonstrating that this morphogenetic protein is essential for renal development. Recent investigations have characterized renal bone morphogenetic protein-7 receptors, shown exogenous bone morphogenetic protein-7 to prevent fibrogenesis associated with ureteral obstruction, indicated a loss of renal bone morphogenetic protein-7 associated with diabetic nephropathy, and an improvement in glomerular pathology in rodent streptozocin-induced diabetes with bone morphogenetic protein-7 treatment. In addition, this morphogenetic protein has been shown to reduce glomerulonephritis and tubulointerstitial fibrosis in a murine model of lupus nephritis as well as decrease the peritrabecular fibrosis associated with murine high turnover renal osteodystrophy. Finally, we review the effects of bone morphogenetic protein-7 on vascular calcification in an animal model, a potential complication of this therapy given its osseous morphogenetic effect.
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PMID:Bone morphogenetic protein-7: an anti-fibrotic morphogenetic protein with therapeutic importance in renal disease. 1175 84


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