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

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.
 ...
PMID:Granuphilin is activated by SREBP-1c and involved in impaired insulin secretion in diabetic mice. 1689 May 42

Molecular mechanisms involving oxidative stress have been increasingly implicated in the pathogenesis of type 2 diabetes. These implications have arisen from reports that glucolipotoxicity of the pancreatic islet and non-islet tissues can lead to deterioration of islet function and insulin sensitivity, as well as structural abnormalities in tissues adversely affected by diabetes. Co-incident with these changes are profound alterations in insulin gene expression, which involve greatly diminished levels of two transcription factors, MafA and Pdx-1.
 ...
PMID:Oxidative stress and impaired insulin secretion in type 2 diabetes. 1704 27

DNA sequences that regulate expression of the insulin gene are located within a region spanning approximately 400 bp that flank the transcription start site. This region, the insulin promoter, contains a number of cis-acting elements that bind transcription factors, some of which are expressed only in the beta-cell and a few other endocrine or neural cell types, while others have a widespread tissue distribution. The sequencing of the genome of a number of species has allowed us to examine the manner in which the insulin promoter has evolved over a 450 million-year period. The major findings are that the A-box sites that bind PDX-1 are among the most highly conserved regulatory sequences, and that the conservation of the C1, E1, and CRE sequences emphasize the importance of MafA, E47/beta2, and cAMP-associated regulation. The review also reveals that of all the insulin gene promoters studied, the rodent insulin promoters are considerably dissimilar to the human, leading to the conclusion that extreme care should be taken when extrapolating rodent-based data on the insulin gene to humans.
Diabetes 2006 Dec
PMID:Comparative analysis of insulin gene promoters: implications for diabetes research. 1713 Apr 62

The Onecut homeodomain transcription factor hepatic nuclear factor 6 (Hnf6) is necessary for proper development of islet beta-cells. Hnf6 is initially expressed throughout the pancreatic epithelium but is downregulated in endocrine cells at late gestation and is not expressed in postnatal islets. Transgenic mice in which Hnf6 expression is maintained in postnatal islets (pdx1(PB)Hnf6) show overt diabetes and impaired glucose-stimulated insulin secretion (GSIS) at weaning. We now define the mechanism whereby maintenance of Hnf6 expression postnatally leads to beta-cell dysfunction. We provide evidence that continued expression of Hnf6 impairs GSIS by altering insulin granule biosynthesis, resulting in a reduced response to secretagogues. Sustained expression of Hnf6 also results in downregulation of the beta-cell-specific transcription factor MafA and a decrease in total pancreatic insulin. These results suggest that downregulation of Hnf6 expression in beta-cells during development is essential to achieve a mature, glucose-responsive beta-cell.
Diabetes 2006 Dec
PMID:Maintenance of hepatic nuclear factor 6 in postnatal islets impairs terminal differentiation and function of beta-cells. 1713 Apr 69

Prolonged elevations of glucose concentration have deleterious effects on beta-cell function. One of the hallmarks of such glucotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that inhibits nuclear receptor signaling in diverse metabolic pathways. In this study, we found that sustained culture of INS-1 cells at high glucose concentrations leads to an increase in SHP mRNA expression, followed by a decrease in insulin gene expression. Inhibition of endogenous SHP gene expression by small interfering RNA partially restored high-glucose-induced suppression of the insulin gene. Adenovirus-mediated overexpression of SHP in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. SHP downregulates insulin gene expression via two mechanisms: by downregulating PDX-1 and MafA gene expression and by inhibiting p300-mediated pancreatic duodenal homeobox factor 1-and BETA2-dependent transcriptional activity from the insulin promoter. Finally, the pancreatic islets of diabetic OLETF rats express SHP mRNA at higher levels than the islets from LETO rats. These results collectively suggest that SHP plays an important role in the development of beta-cell dysfunction induced by glucotoxicity.
Diabetes 2007 Feb
PMID:Glucotoxicity in the INS-1 rat insulinoma cell line is mediated by the orphan nuclear receptor small heterodimer partner. 1725 88

Pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development, beta-cell differentiation, and maintaining mature beta-cell function. During pancreas development, PDX-1 expression is maintained in precursor cells, and later it becomes restricted to beta-cells. In mature beta-cells, PDX-1 regulates gene expression of various beta-cell-related factors including insulin. Also, PDX-1 has potency to induce insulin-producing cells from non-beta-cells in various tissues, and PDX-1-VP16 fusion protein more efficiently induces insulin-producing cells, especially in the presence of NeuroD or Ngn3. MafA is a recently isolated beta-cell-specific transcription factor which functions as a potent activator of insulin gene transcription. During pancreas development, MafA expression is first detected at the beginning of the principal phase of insulin-producing cell production. Furthermore, MafA markedly enhances insulin gene promoter activity and ameliorates glucose tolerance in diabetic mice, especially in the presence of PDX-1 and NeuroD. Taken together, PDX-1 and MafA play a crucial role in inducing surrogate beta-cells and could be a therapeutic target for diabetes.
Diabetes Res Clin Pract 2007 Sep
PMID:Role of PDX-1 and MafA as a potential therapeutic target for diabetes. 1744 32

Nkx2.2 is a homeodomain transcription factor that is critical for pancreatic endocrine cell specification and differentiation in the developing mouse embryo. The purpose of this study was to determine whether Nkx2.2 is also required for the maintenance and function of the mature beta-cell in the postnatal islet. We have demonstrated previously that a repressor derivative of Nkx2.2 can functionally substitute for endogenous Nkx2.2 to fully restore alpha- and immature beta-cells in the embryonic islet; however, Nkx2.2 activator functions appear to be required to form a functional beta-cell. In this study, we have created transgenic mouse lines to express the Nkx2.2-repressor derivative in the mature beta-cell in the presence of endogenous Nkx2.2. The transgenic mice were assessed for beta-cell function, overall islet structure, and expression of beta-cell-specific markers. Using this transgenic approach, we have determined that the Nkx2.2-repressor derivative disrupts endogenous Nkx2.2 expression in adult mice and causes downregulation of the mature beta-cell factors, MafA and Glut2. Consistently, the Nkx2.2-repressor mice display reduced insulin gene expression and pancreatic insulin content and impaired insulin secretion. At weaning, the male Nkx2.2-repressor mice are overtly diabetic and all Nkx2.2-repressor transgenic mice exhibit glucose intolerance. Furthermore, the loss of beta-cell function in the Nkx2.2-repressor transgenic mice is associated with disrupted islet architecture. These studies indicate a previously undiscovered role for Nkx2.2 in the maintenance of mature beta-cell function and the formation of normal islet structure.
Diabetes 2007 Aug
PMID:Nkx2.2 regulates beta-cell function in the mature islet. 1745 46

Forkhead transcription factors of the FoxO family have important roles in cellular proliferation, apoptosis, differentiation and stress resistance. FoxO proteins also play important roles in metabolism of complex organisms. FoxO1 regulates glucose and lipid metabolism in liver, as well as preadipocyte, myoblast and vascular endothelial cell differentiation. In the hypothalamus, FoxO controls food intake. In this chapter, we review the role of FoxO in pancreatic beta cells. Pancreatic beta cells secrete insulin to maintain the plasma glucose levels in a strict physiological range. Defects of beta cell function cause diabetes. The expression pattern of FoxO1 during pancreatic organogenesis is similar to that of Pdx1, Nkx2.2 and Pax4, transcription factors known to be critical for beta cell development. FoxO1 is expressed in a subset of pancreatic duct cells, in which insulin and/or Pdx1 are occasionally expressed. FoxO1 inhibits beta cell proliferation through suppression of Pdx1 by competing with FoxA2 and protects against beta cell failure induced by oxidative stress through NeuroD and MafA induction. Thus, a series of FoxO1 studies in pancreas suggested that FoxO1 plays important roles in pancreatic beta cell differentiation, neogenesis, proliferation and stress resistance. Genetic or pharmacological manipulation of FoxO can be used to prevent beta cell failure or aid in the differentiation of uncommitted endocrine progenitors into beta cells for transplantation.
 ...
PMID:Role of FoxO Proteins in Pancreatic beta Cells. 1751 Apr 98

Pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development, beta-cell differentiation, and maintaining mature beta-cell function. At an early stage of embryonic development, PDX-1 is initially expressed in the gut region when the foregut endoderm becomes committed to common pancreatic precursor cells. During pancreas development, PDX-1 expression is maintained in precursor cells, and later it becomes restricted to beta-cells. In mature beta-cells, PDX-1 transactivates the insulin gene and other genes involved in glucose sensing and metabolism, such as GLUT2 and glucokinase. MafA is a recently isolated beta-cell-specific transcription factor which functions as a potent activator of insulin gene transcription. During pancreas development, MafA expression is first detected at the beginning of the principal phase of insulin-producing cell production. Furthermore, these transcription factors play a crucial role in inducing surrogate beta-cells from non-beta-cells and thus could be therapeutic targets for diabetes.
 ...
PMID:Crucial role of PDX-1 in pancreas development, beta-cell differentiation, and induction of surrogate beta-cells. 1762 12

Type 2 diabetes is characterized by a relentless decline in pancreatic islet beta cell function and worsening hyperglycemia despite optimal medical treatment. Our central hypothesis is that residual hyperglycemia, especially after meals, generates reactive oxygen species (ROS), which in turn causes chronic oxidative stress on the beta cell. This hypothesis is supported by several observations. Exposure of isolated islets to high glucose concentrations induces increases in intracellular peroxide levels. The beta cell has very low intrinsic levels of antioxidant proteins and activities and thus is very vulnerable to ROS. Treatment with antioxidants protects animal models of type 2 diabetes against complete development of phenotypic hyperglycemia. The molecular mechanisms responsible for the glucose toxic effect on beta cell function involves disappearance of two important regulators of insulin promoter activity, PDX-1 and MafA. Antioxidant treatment in vitro prevents disappearance of these two transcription factors and normalizes insulin gene expression. These observations suggest that the ancillary treatment with antioxidants may improve outcomes of standard therapy of type 2 diabetes in humans.
 ...
PMID:Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in type 2 diabetes. 1770 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>