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)

ChREBP (Carbohydrate response element binding protein) is considered to mediate the stimulatory effect of glucose on the expression of lipogenic genes. Its activity is stimulated by glucose. Less is known on the control of its expression. This expression could be controlled by nutritional (glucose, fatty acids) and hormonal (insulin) factors. We examined the in vivo nutritional control of ChREBP expression in liver and adipose tissue of Wistar rats. Compared respectively to the fed state and to a high carbohydrate diet, ChREBP mRNA concentrations were not modified by fasting or a high fat diet in rat liver and adipose tissue. FAS and ACC1 mRNA concentrations were on the contrary decreased as expected by fasting and high fat diets and these variations of FAS and ACC1 mRNA were positively related to those of SREBP-1c mRNA and protein, but not of ChREBP mRNA. Therefore i) ChREBP expression appears poorly responsive to modifications of nutritional condition, ii) modifications of the expression of ChREBP do not seem implicated in the physiological control of lipogenesis. To investigate the possible role of ChREBP in pathological situations we measured its mRNA concentrations in the liver and adipose tissue of obese Zucker rats. ChREBP expression was increased in the liver but not the adipose tissue of obese rats compared to their lean littermates. These results support a role of ChREBP in the development of hepatic steatosis and hypertriglyceridemia but not of obesity in this experimental model.
Diabetes Metab 2005 Dec
PMID:In vivo expression of carbohydrate responsive element binding protein in lean and obese rats. 1635 4

Hypertriglyceridemia is an independent risk factor for the development of cardiovascular disease and is often associated with diabetes, inflammation and the metabolic syndrome. Recently, apolipoprotein A5 (APOA5) was identified as a novel member of the APOA1/C3/A4 gene cluster. Data from mice over-expressing or lacking APOA5 provide direct evidence that this apolipoprotein plays a role in triglyceride metabolism. Moreover, plasma triglyceride levels were found to be strongly associated with APOA5 polymorphisms. The human APOA5 gene is regulated by transcription factors known to affect triglyceride metabolism such as PPARa, RORa, LXR and SREBP-1c and this supports its function. Insulin and interleukins regulate APOA5 gene expression and provide novel clues for the role of this apolipoprotein. To date, the triglyceride lowering action of apoA-V is attributed to the activation of lipoprotein lipase and an acceleration of very low density lipoprotein catabolism. Recent findings indicate that APOA5 could also influence cholesterol homeostasis and probably play a role in hypertriglyceridemia associated with diabetes and inflammation. This review aims to give a comprehensive summary of the current literature and supports the view that APOA5 plays a relevant role in lipid metabolism.
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PMID:Is apolipoprotein A5 a novel regulator of triglyceride-rich lipoproteins? 1644 83

Stearoyl-CoA desaturase (SCD)1 catalyzes the rate-limiting reaction of monounsaturated fatty acid (MUFA) synthesis and plays an important role in the development of obesity. SCD1 is suppressed by leptin but induced by insulin. We have used animal models to dissect the effects of these hormones on SCD1. In the first model, leptin-deficient ob/ob mice were treated with either leptin alone or with both leptin and insulin to prevent the leptin-mediated fall in insulin. In the second model, mice with a liver-specific knockout of the insulin receptor (LIRKO) and their littermate controls (LOXs) were treated with leptin. As expected, leptin decreased SCD1 transcript, protein, and activity by >60% in ob/ob and LOX mice. However, the effects of leptin were not diminished by the continued presence of hyperinsulinemia in ob/ob mice treated with both leptin and insulin or the absence of insulin signaling in LIRKO mice. Furthermore, genetic knockout of sterol regulatory element-binding protein (SREBP)-1c, the lipogenic transcription factor that mediates the effects of insulin on SCD1, also had no effect on the ability of leptin to decrease either SCD1 transcript or activity. Thus, the effect of leptin on SCD1 in liver is independent of insulin and SREBP-1c, and leptin, rather than insulin, is the major regulator of hepatic MUFA synthesis in obesity-linked diabetes.
Diabetes 2006 Jul
PMID:Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c. 1680 73

Granuphilin is a crucial component of the docking machinery of insulin-containing vesicles to the plasma membrane. Here, we show that the granuphilin promoter is a target of SREBP-1c, a transcription factor that controls fatty acid synthesis, and MafA, a beta cell differentiation factor. Potassium-stimulated insulin secretion (KSIS) was suppressed in islets with adenoviral-mediated overexpression of granuphilin and enhanced in islets with knockdown of granuphilin (in which granuphilin had been knocked down). SREBP-1c and granuphilin were activated in islets from beta cell-specific SREBP-1c transgenic mice, as well as in several diabetic mouse models and normal islets treated with palmitate, accompanied by a corresponding reduction in insulin secretion. Knockdown- or knockout-mediated ablation of granuphilin or SREBP-1c restored KSIS in these islets. Collectively, our data provide evidence that activation of the SREBP-1c/granuphilin pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity.
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PMID:Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice. 1689 May 42

Protein kinase Czeta (PKCzeta) is a member of the PKC family, serving downstream of insulin receptor and phosphatidylinositol (PI) 3-kinase. Many evidences suggest that PKCzeta plays a very important role in activating glucose transport response. Not only insulin but also glucose and exercise can activate PKCzeta through diverse pathways. PKCzeta activation and activity are impaired with insulin resistance in muscle and adipose tissues of type II diabetes individuals, but heightened in liver tissue, wherein it also increases lipid synthesis mediated by SREBP-1c (sterol-regulatory element-binding protein). Many studies have focused on linkage between PKCzeta and GLUT4 translocation and activation. Exploring the molecular mechanisms and pathways by which PKCzeta mediates glucose transport will highlight the insulin-signaling pathway.
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PMID:Protein kinase Czeta and glucose uptake. 1690 23

Genes involved in carbohydrate and lipid metabolism are nutritionally regulated at the transcriptional level in a coordinated fashion. SREBP-1c is a bHLH transcription factor that controls lipogenesis and is induced during overnutrition to facilitate the conversion of glucose to fatty acids and triglycerides for the storage of the excess energy. Uncontrolled activation of nuclear SREBP-1c in the liver can cause hepatosteatosis, hypertriglyceridemia, and hepatic insulin resistance due to direct suppression of insulin signaling pathways, precipitating development of metabolic syndrome. Conversely, TFE3 is a novel bHLH transcription factor that strongly activates various insulin signaling molecules, protecting against the development of insulin resistance and the metabolic syndrome. Regulation of IRS-2 is the primary site where TFE3 in synergy with Foxo1, and SREBP-1c converge. Taken together, TFE3/Foxo1 and SREBP-1c reciprocally regulate IRS-2 expression and insulin sensitivity in the liver. This scenario provides a mechanistic explanation for the physiological link between glucose and lipid metabolism such as physiological switching of glycogen synthesis to lipogenesis. In addition, these two transcription factors may ultimately contribute to pathophysiological effects of overnutrition leading to the development of the metabolic syndrome and diabetes. In this review, I will discuss roles of SREBP-1c and TFE3 in homeostasis of energy metabolism and in metabolic disturbances, focusing on hepatic insulin sensitivity.
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PMID:SREBP-1c and TFE3, energy transcription factors that regulate hepatic insulin signaling. 1727 46

Our previous work demonstrated that the sterol response element binding proteins (SREBP)-1 and SREBP-2, which are the key regulators of storage lipid and cholesterol metabolism respectively, are highly expressed in Schwann cells of adult peripheral nerves. In order to evaluate the role of Schwann cell SREBPs in myelination and functioning of peripheral nerves we have determined their expression during development, after fasting and refeeding, and in a rodent model of diabetes. Our results show that SREBP-1c and SREBP-2, unlike SREBP-1a, are the major forms of SREBPs present in peripheral nerves. The expression profile of SREBP-2 follows the expression of genes involved in cholesterol biosynthesis, while SREBP-1c is co-expressed with genes involved in storage lipid metabolism. In addition, the expression of SREBP-1c in the endoneurial compartment of peripheral nerves depends on nutritional status and is disturbed in type 1 diabetes. In line with this, insulin elevates the expression of SREBP-1c in primary cultured Schwann cells by activating the SREBP-1c promoter. Taken together, these findings reveal that SREBP-1c expression in Schwann cells responds to metabolic stimuli including insulin and that this response is affected in type 1 diabetes mellitus. This suggests that disturbed SREBP-1c regulated lipid metabolism may contribute to the pathophysiology of diabetic peripheral neuropathy.
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PMID:SREBP-1c expression in Schwann cells is affected by diabetes and nutritional status. 1763 11

It has long been known that excess intracellular fatty acids cause impaired insulin secretion, referred to as beta-cell lipotoxicity. Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls hepatic fatty acid synthesis. Activation of SREBP-1c by overnutrition also inhibits insulin receptor substrate-2 (IRS-2) and induces insulin resistance in the liver. As SREBP-1c is also expressed in beta cells, we hypothesized that activation of SREBP-1c could be a part of the mechanism by which saturated fatty acids induce beta-cell lipotoxicity. We found that nuclear SREBP-1c has a negative impact on both glucose- and potassium-stimulated insulin secretion as determined in islets from beta-cell-specific SREBP-1c transgenic mice as well as SREBP-1c knockout mice. This effect of SREBP-1c involves multiple functional pathways required for insulin secretion from beta cells: (i) decreased ATP caused by energy consumption through lipogenesis and uncoupling protein-2 (UCP-2) activation; (ii) repressed IRS-2 and pancreas duodenum homeobox 1 (PDX1) expression, leading to impaired beta-cell mass; and (iii) impaired post-ATP membrane voltage-dependent steps of the insulin secretion pathway caused by upregulated granuphilin and other ion channel proteins. Saturated fatty acids, such as palmitic acid (PA), impair insulin secretion through SREBP-1c activation, whereas polyunsaturated fatty acids including eicosapentaenoic acid (EPA) restore PA-suppressed insulin secretion through suppression of SREBP-1c. These data implicate a therapeutic potential of EPA against insulin secretion defects caused by lipotoxicity.
Diabetes Obes Metab 2007 Nov
PMID:Sterol regulatory element-binding protein-1c and pancreatic beta-cell dysfunction. 1791 87

The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an increased risk of cardiovascular disease and diabetes. The metabolic syndrome can be defined as a cluster of cardiovascular disease risk factors including visceral obesity, insulin resistance, dyslipidemia, increased blood pressure, and hypercoagulability. The farnesoid X receptor (FXR) belongs to the superfamily of ligand-activated nuclear receptor transcription factors. FXR is activated by bile acids, and FXR-deficient (FXR(-/-)) mice display elevated serum levels of triglycerides and high-density lipoprotein cholesterol, demonstrating a critical role of FXR in lipid metabolism. In an opposite manner, activation of FXR by bile acids (BAs) or nonsteroidal synthetic FXR agonists lowers plasma triglycerides by a mechanism that may involve the repression of hepatic SREBP-1c expression and/or the modulation of glucose-induced lipogenic genes. A cross-talk between BA and glucose metabolism was recently identified, implicating both FXR-dependent and FXR-independent pathways. The first indication for a potential role of FXR in diabetes came from the observation that hepatic FXR expression is reduced in animal models of diabetes. While FXR(-/-) mice display both impaired glucose tolerance and decreased insulin sensitivity, activation of FXR improves hyperglycemia and dyslipidemia in vivo in diabetic mice. Finally, a recent report also indicates that BA may regulate energy expenditure in a FXR-independent manner in mice, via activation of the G protein-coupled receptor TGR5. Taken together, these findings suggest that modulation of FXR activity and BA metabolism may open new attractive pharmacological approaches for the treatment of the metabolic syndrome and type 2 diabetes.
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PMID:Role of bile acids and bile acid receptors in metabolic regulation. 1912 57

Hepatic GK (glucokinase) plays a key role in maintaining glucose homoeostasis. Many stimuli regulate GK activity by controlling its gene transcription. We hypothesized that endogenous lipophilic molecules modulate hepatic Gck expression. Lipophilic molecules were extracted from rat livers, saponified and re-constituted as an LE (lipophilic extract). LE synergized with insulin to induce primary hepatocyte, but not beta-cell, Gck expression in an SREBP-1c (sterol-regulatory-element-binding protein-1c)-independent manner. The dramatic induction of Gck mRNA resulted in a significant increase in GK activity. Subsequently, the active molecules were identified as retinol and retinal by MS after the purification of the active LE fractions. Retinoids synergized with insulin to induce Gck expression by the activation of both RAR [RA (retinoic acid) receptor] and RXR (retinoid X receptor). Inhibition of RAR activation completely abolished the effect of retinal. The hepatic GK specific activity and Gck mRNA levels of Zucker lean rats fed with a VAD [VA (vitamin A)-deficient] diet were significantly lower than those of rats fed with VAS (VA-sufficient) diet. Additionally, the hepatic Gck mRNA expression of Sprague-Dawley rats fed with a VAD diet was lower than that of rats fed with VA-marginal, -adequate or -supplemented diets. The reduced expression of Gck mRNA was increased after an intraperitoneal dose of RA in VAD rats. Furthermore, an intravenous injection of RA rapidly raised hepatic Gck expression in rats fed with a VAS control diet. Understanding the underlying mechanism that mediates the synergy may be helpful for developing a treatment strategy for patients with diabetes.
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PMID:Retinoids synergize with insulin to induce hepatic Gck expression. 1917 78


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