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Dominant-negative suppression of HNF-1alpha function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic beta-cell line.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Wang, Huijuan Maechler, Pierre Wollheim, Claes B. |
| Copyright Year | 1998 |
| Abstract | Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) have been linked to subtype 3 of maturity-onset diabetes of the young (MODY3), which is characterized by a primary defect in insulin secretion. The role of HNF-1alpha in the regulation of pancreatic beta-cell function was investigated. Gene manipulation allowed graded overexpression of HNF-1alpha and controlled dominant-negative suppression of HNF-1alpha function in insulinoma INS-1 cells. We show that HNF-1alpha is essential for insulin gene transcription, as demonstrated by a pronounced decrease in insulin mRNA expression and in insulin promoter activity under dominant-negative conditions. The expression of genes involved in glucose transport and metabolism including glucose transporter-2 and L-type pyruvate kinase is also regulated by HNF-1alpha. Loss of HNF-1alpha function leads to severe defects in insulin secretory responses to glucose and leucine, resulting from impaired glucose utilization and mitochondrial oxidation. The nutrient-evoked ATP production and subsequent changes in plasma membrane potential and intracellular Ca2+ were diminished by suppression of HNF-1alpha function. These results suggest that HNF-1alpha function is essential for maintaining insulin storage and nutrient-evoked release. The defective mitochondrial oxidation of metabolic substrates causes impaired insulin secretion, indicating a molecular basis for the diabetic phenotype of MODY3 patients. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://archive-ouverte.unige.ch/files/downloads/0/0/0/3/5/0/8/8/unige_35088_attachment01.pdf |
| Alternate Webpage(s) | http://emboj.embopress.org/content/embojnl/17/22/6701.full.pdf |
| PubMed reference number | 9822613v1 |
| Volume Number | 17 |
| Issue Number | 22 |
| Journal | The EMBO journal |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Adenosine Triphosphate Beta-cell Function Measurement Cell physiology Cell secretion Diabetes Mellitus, Non-Insulin-Dependent FOXM1 gene HNF1A wt Allele Hepatocyte Nuclear Factor 1-alpha Leucine MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3 (disorder) Maturity onset diabetes mellitus in young Membrane Potentials Metabolic Process, Cellular Patients Plasma membrane Pyruvate Kinase Transcription, Genetic glucose transport insulin secretion insulinoma oxidation |
| Content Type | Text |
| Resource Type | Article |
