Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Insulin receptor substrate (IRS)-2(-/-) mice develop diabetes because of insulin resistance in the liver and failure to undergo beta-cell hyperplasia. Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2(-/-) mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The expression of SREBP-1 downstream genes, such as the spot 14, ATP citrate-lyase, and fatty acid synthase genes, was also increased. Increased liver triglyceride content in IRS-2(-/-) mice assures the physiological importance of SREBP-1 gene induction. IRS-2(-/-) mice showed leptin resistance; low dose leptin administration, enough to reduce food intake and body weight in wild-type mice, failed to do so in IRS-2(-/-) mice. Interestingly, high dose leptin administration reduced SREBP-1 expression in IRS-2(-/-) mouse liver. Thus, IRS-2 gene disruption results in leptin resistance, causing an SREBP-1 gene induction, obesity, fatty liver, and diabetes.
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PMID:Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) mouse liver. 1154 55

Diabetic renal disease is associated with lipid deposits in the kidney. The purpose of our study was to determine whether there is altered regulation of the sterol regulatory element-binding proteins (SREBPs) in the diabetic kidney and whether SREBPs mediate the abnormal renal lipid metabolism and diabetic renal disease. In streptozotocin-induced diabetes in the rat, there were marked increases in SREBP-1 and fatty acid synthase (FAS) expression, resulting in increased triglyceride (TG) accumulation. Treatment of diabetic rats with insulin prevented the increased renal expression of SREBP-1 and the accumulation of TG. The role of hyperglycemia in the up-regulation of SREBP-1 was confirmed in renal cells cultured in a high glucose media. High glucose induced increased expression of SREBP-1a and -1c mRNA, SREBP-1 protein, and FAS, resulting in increased TG content. To determine a direct role for SREBP in mediating the increase in renal lipids and glomerulosclerosis, we studied SREBP-1a transgenic mice with increased renal expression of SREBP-1. The increase in SREBP-1 was associated with increased expression of FAS and acetyl CoA carboxylase, resulting in increased TG content, increased expression of transforming growth factor beta1 and vascular endothelial growth factor, mesangial expansion, glomerulosclerosis, and proteinuria. Our study therefore indicates that renal SREBP-1 expression is increased in diabetes and that SREBP-1 plays an important role in the increased lipid synthesis, TG accumulation, mesangial expansion, glomerulosclerosis, and proteinuria by increasing the expression of transforming growth factor beta and vascular endothelial growth factor.
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PMID:Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus. 1187 60

Sterol regulatory element binding protein (SREBP)-1 is a transcription factor with important roles in the control of fatty acid metabolism and adipogenesis. Little information is available regarding the expression of this molecule in human health or disease. Exposure of isolated human adipocytes to insulin enhanced SREBP1 gene expression and promoted its proteolytic cleavage to the active form. Furthermore, 3 h of in vivo hyperinsulinemia also significantly increased SREBP1 gene expression in human skeletal muscle. Transcript levels of SREBP1c, the most abundant isoform in adipose tissue, were significantly decreased in the subcutaneous adipose tissue of obese normoglycemic and type 2 diabetic subjects compared with that of nonobese normoglycemic control subjects. In skeletal muscle, SREBP1 expression was significantly reduced in type 2 diabetic subjects but not in obese subjects. Within the diabetic group, the extent of SREBP1 suppression was inversely related to metabolic control and was normalized by 3 h of in vivo hyperinsulinemia. Exposure of isolated human adipocytes to tumor necrosis factor-alpha (TNF-alpha) produced a marked and specific decrease in the mRNA encoding the SREBP1c isoform and completely blocked the insulin-induced cleavage of SREBP1 protein. Thus, both the expression and proteolytic maturation of human SREBP1 are positively modulated by insulin. The specific reduction in the SREBP1c isoform seen in the adipose tissue of obese and type 2 diabetic subjects can be recapitulated ex vivo by TNF-alpha, suggesting a possible mechanism for this association.
Diabetes 2002 Apr
PMID:Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha. 1191 23

Conjugated linoleic acid (CLA) is a heterogeneous group of positional and geometric isomers of linoleic acid. This study demonstrates the divergent effects of the cis-9 trans-11 (c9,t11-CLA) and trans-10 cis-12 (t10,c12-CLA) isomers of CLA on lipid metabolism and nutrient regulation of gene expression in ob/ob mice. The c9, t11-CLA diet decreased serum triacylglycerol (P = 0.01) and nonesterified fatty acid (NEFA) (P = 0.05) concentrations, and this was associated with reduced hepatic sterol regulatory element-binding protein-1c (SREBP-1c; P = 0.0045) mRNA expression, coupled with reduced levels of both the membrane-bound precursor and the nuclear forms of the SREBP-1 protein. C9,t11-CLA significantly reduced hepatic LXRalpha (P = 0.019) mRNA expression, a novel regulator of SREBP-1c. In contrast, c9,t11-CLA increased adipose tissue SREBP-1c mRNA expression (P = 0.0162) proportionally to the degree of reduction of tumor necrosis factor alpha (TNF-alpha) mRNA (P = 0.012). Recombinant TNF-alpha almost completely abolished adipose tissue SREBP-1c mRNA expression in vivo. The t10,c12-CLA diet promoted insulin resistance and increased serum glucose (P = 0.025) and insulin (P = 0.01) concentrations. T10, c12-CLA induced profound weight loss (P = 0.0001) and increased brown and white adipose tissue UCP-2 (P = 0.001) and skeletal muscle UCP-3 (P = 0.008) mRNA expression. This study highlights the contrasting molecular and metabolic effect of two isomers of the same fatty acids. The ameliorative effect of c9,t11-CLA on lipid metabolism may be ascribed to reduced synthesis and cleavage of hepatic SREBP-1, which in turn may be regulated by hepatic LXRalpha expression.
Diabetes 2002 Jul
PMID:Isomer-dependent metabolic effects of conjugated linoleic acid: insights from molecular markers sterol regulatory element-binding protein-1c and LXRalpha. 1208 31

Ciliary neurotrophic factor (CNTF) is primarily known for its roles as a lesion factor released by the ruptured glial cells that prevent neuronal degeneration. However, CNTF has also been shown to cause weight loss in a variety of rodent models of obesity/type II diabetes, whereas a modified form also causes weight loss in humans. CNTF administration can correct or improve hyperinsulinemia, hyperphagia, and hyperlipidemia associated with these models of obesity. In order to investigate the effects of CNTF on fat cells, we examined the expression of CNTF receptor complex proteins (LIFR, gp130, and CNTFRalpha) during adipocyte differentiation and the effects of CNTF on STAT, Akt, and MAPK activation. We also examined the ability of CNTF to regulate the expression of adipocyte transcription factors and other adipogenic proteins. Our studies clearly demonstrate that the expression of two of the three CNTF receptor complex components, CNTFRalpha and LIFR, decreases during adipocyte differentiation. In contrast, gp130 expression is relatively unaffected by differentiation. In addition, preadipocytes are more sensitive to CNTF treatment than adipocytes, as judged by both STAT 3 and Akt activation. Despite decreased levels of CNTFRalpha expression in fully differentiated 3T3-L1 adipocytes, CNTF treatment of these cells resulted in a time-dependent activation of STAT 3. Chronic treatment of adipocytes resulted in a substantial decrease in fatty-acid synthase and a notable decline in SREBP-1 levels but had no effect on the expression of peroxisome proliferator-activated receptor gamma, acrp30, adipocyte-expressed STAT proteins, or C/EBPalpha. However, CNTF resulted in a significant increase in IRS-1 expression. CNTFRalpha receptor expression was substantially induced in the fat pads of four rodent models of obesity/type II diabetes as compared with lean littermates. Moreover, we demonstrated that CNTF can activate STAT 3 in adipose tissue and skeletal muscle in vivo. In summary, CNTF affects adipocyte gene expression, and the specific receptor for this cytokine is induced in rodent models of obesity/type II diabetes.
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PMID:The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. 1242 52

The recognition that the increase of plasma triglyceride rich lipoproteins (TRLs) is associated with multiple alterations of other lipoproteins species that are potentially atherogenic has expanded the picture of diabetic dyslipidaemia. The discovery of heterogeneity within major lipoprotein classes VLDL, LDL and HDL opened new avenues to reveal the specific pertubations of diabetic dyslipidaemia. The increase of large VLDL 1 particles in Type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense LDL and small dense HDL particles. Together these components comprise the atherogenic lipid triad. Notably the malignant nature of diabetic dyslipidaemia is not completely shown by the lipid measures used in clinical practice. The key question is what are the mechanisms behind the increase of VLDL 1 particles in diabetic dyslipidaemia? Despite the advances of recent years, our understanding of VLDL assembly and secretion is still surprisingly incomplete. To date it is still unclear how the liver is able to regulate the amount of triglycerides incorporated into VLDL particles to produce either VLDL 1 or VLDL 2 particles. The current evidence suggests that the machinery driving VLDL assembly in the liver includes (i) low insulin signalling via PI-3 kinase pathway that enhances lipid accumulation into "nascent " VLDL particles (ii) up-regulation of SREBP-1C that stimulates de novo lipogenesis and (iii) excess availability of "polar molecules" in hepatocytes that stabilizes apo B 100. Recent data suggest that all these steps could be fundamentally altered in Type 2 diabetes explaining the overproduction of VLDL apo B as well as the ability of insulin to suppress VLDL 1 apo B production in Type 2 diabetes. Recent discoveries have established the transcription factors including PPARs, SREBP-1 and LXRs as the key regulators of lipid assembly in the liver. These observations suggest these factors as a new target to tailor more efficient drugs to treat diabetic dyslipidaemia.
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PMID:Diabetic dyslipidaemia: from basic research to clinical practice. 1277 65

Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that regulate cholesterol and fatty acid homeostasis. In mammals, three SREBP isoforms designated SREBP-1a, SREBP-1c, and SREBP-2 have been identified. SREBP-1a and SREBP-1c are derived from the same gene by virtue of alternatively spliced first exons. SREBP-1a has a longer transcriptional activation domain and is a more potent transcriptional activator than SREBP-1c in cultured cells and liver. Here, we describe the physiologic consequences of overexpressing the nuclear form of SREBP-1a (nSREBP-1a) in adipocytes of mice using the adipocyte-specific aP2 promoter (aP2-nSREBP-1a). The transgenic aP2-nSREBP-1a mice developed markedly enlarged white and brown adipocytes that were fully differentiated. Adipocytes isolated from aP2-nSREBP-1a mice had significantly increased rates of fatty acid synthesis and enhanced fatty acid secretion. The increased production and release of fatty acids from adipocytes led, in turn, to a fatty liver. Overexpression of the alternative SREBP-1 isoform, nSREBP-1c, in adipose tissue inhibits adipocyte differentiation; as a result, the transgenic nSREBP-1c mice develop a syndrome resembling human lipodystrophy, which includes a loss of peripheral white adipose tissue, diabetes, and fatty livers (Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakov, Y., Goldstein, J. L., and Brown, M. S. (1998) Genes Dev. 12, 3182-3194). In striking contrast, nSREBP-1a overexpression in fat resulted in the hypertrophy of fully differentiated adipocytes, no diabetes, and mild hepatic steatosis. These results suggest that nSREBP-1a and nSREBP-1c have distinct roles in adipocyte fat metabolism in vivo.
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PMID:Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver. 1285 91

The flavonoid naringenin improves hyperlipidemia and hyperglycemia in streptozotocin-treated rats. In HepG2 human hepatoma cells, naringenin inhibits apolipoprotein B (apoB) secretion primarily by inhibiting microsomal triglyceride transfer protein and enhances LDL receptor (LDLr)-mediated apoB-containing lipoprotein uptake. Phosphatidylinositol 3-kinase (PI3K) activation by insulin increases sterol regulatory element-binding protein (SREBP)-1 and LDLr expression and inhibits apoB secretion in hepatocytes. Thus, we determined whether naringenin activates this pathway. Insulin and naringenin induced PI3K-dependent increases in cytosolic and nuclear SREBP-1 and LDLr expression. Similar PI3K-mediated increases in SREBP-1 were observed in McA-RH7777 rat hepatoma cells, which express predominantly SREBP-1c. Reductions in HepG2 cell media apoB with naringenin were partially attenuated by wortmannin, whereas the effect of insulin was completely blocked. Both treatments reduced apoB100 secretion in wild-type and LDLr(-/-) mouse hepatocytes to the same extent. Insulin and naringenin increased HepG2 cell PI3K activity and decreased insulin receptor substrate (IRS)-2 levels. In sharp contrast to insulin, naringenin did not induce tyrosine phosphorylation of IRS-1. We conclude that naringenin increases LDLr expression in HepG2 cells via PI3K-mediated upregulation of SREBP-1, independent of IRS-1 phosphorylation. Although this pathway may not regulate apoB secretion in primary hepatocytes, PI3K activation by this novel mechanism may explain the insulin-like effects of naringenin in vivo.
Diabetes 2003 Oct
PMID:Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. 1451 40

We comprehensively analyzed gene expression during peripheral nerve development by performing microarray analyses of premyelinating, myelinating, and postmyelinating mouse sciatic nerves, and we generated a database of candidate genes to be tested in mapped peripheral neuropathies. Unexpectedly, we identified a large cluster of genes that are (1) maximally expressed only in the mature nerve, after myelination is complete, and (2) tied to the metabolism of storage (energy) lipids. Many of these late-onset genes are expressed by adipocytes, which we find constitute the bulk of the epineurial compartment of the adult nerve. However, several such genes, including SREBP-1, SREBP-2, and Lpin1, are also expressed in the endoneurium. We find that Lpin1 null mutations lead to lipoatrophy of the epineurium, and to the dysregulation of a battery of genes required for the regulation of storage lipid metabolism in both the endoneurium and peri/epineurium. Together with the observation that these mutations also result in peripheral neuropathy, our findings demonstrate a crucial role for local storage lipid metabolism in mature peripheral nerve function, and have important implications for the understanding and treatment of peripheral neuropathies that are commonly associated with metabolic diseases such as lipodystrophy and diabetes.
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PMID:Local regulation of fat metabolism in peripheral nerves. 1452 48

Akt is critical in insulin-induced metabolism of glucose and lipids. To investigate functions induced by hepatic Akt activation, a constitutively active Akt, NH(2)-terminally myristoylation signal-attached Akt (myr-Akt), was overexpressed in the liver by injecting its adenovirus into mice. Hepatic myr-Akt overexpression resulted in a markedly hypoglycemic, hypoinsulinemic, and hypertriglyceridemic phenotype with fatty liver and hepatomegaly. To elucidate the sterol regulatory element binding protein (SREBP)-1c contribution to these phenotypic features, myr-Akt adenovirus was injected into SREBP-1 knockout mice. myr-Akt overexpression induced hypoglycemia and hepatomegaly with triglyceride accumulation in SREBP-1 knockout mice to a degree similar to that in normal mice, whereas myr-Akt-induced hypertriglyceridemia in knockout mice was milder than that in normal mice. The myr-Akt-induced changes in glucokinase, phosphofructokinase, glucose-6-phosphatase, and PEPCK expressions were not affected by knocking out SREBP-1, whereas stearoyl-CoA desaturase 1 induction was completely inhibited in knockout mice. Constitutively active SREBP-1-overexpressing mice had fatty livers without hepatomegaly, hypoglycemia, or hypertriglyceridemia. Hepatic acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and glucose-6-phosphate dehydrogenase expressions were significantly increased by overexpressing SREBP-1, whereas glucokinase, phospho-fructokinase, glucose-6-phosphatase, and PEPCK expressions were not or only slightly affected. Thus, SREBP-1 is not absolutely necessary for the hepatic Akt-mediated hypoglycemic effect. In contrast, myr-Akt-induced hypertriglyceridemia and hepatic triglyceride accumulation are mediated by both Akt-induced SREBP-1 expression and a mechanism involving fatty acid synthesis independent of SREBP-1.
Diabetes 2003 Dec
PMID:Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement. 1463 50


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