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Impaired β-cell glucokinase as an underlying mechanism in diet-induced diabetes
- Source :
- Disease Models & Mechanisms, Vol 11, Iss 6 (2018), Disease Models & Mechanisms
- Publication Year :
- 2018
- Publisher :
- The Company of Biologists, 2018.
-
Abstract
- High-fat diet (HFD)-fed mouse models have been widely used to study early type 2 diabetes. Decreased β-cell glucokinase (GCK) expression has been observed in HFD-induced diabetes. However, owing to its crucial roles in glucose metabolism in the liver and in islet β-cells, the contribution of decreased GCK expression to the development of HFD-induced diabetes is unclear. Here, we employed a β-cell-targeted gene transfer vector and determined the impact of β-cell-specific increase in GCK expression on β-cell function and glucose handling in vitro and in vivo. Overexpression of GCK enhanced glycolytic flux, ATP-sensitive potassium channel activation and membrane depolarization, and increased proliferation in Min6 cells. β-cell-targeted GCK transduction did not change glucose handling in chow-fed C57BL/6 mice. Although adult mice fed a HFD showed reduced islet GCK expression, impaired glucose tolerance and decreased glucose-stimulated insulin secretion (GSIS), β-cell-targeted GCK transduction improved glucose tolerance and restored GSIS. Islet perifusion experiments verified restored GSIS in isolated HFD islets by GCK transduction. Thus, our data identify impaired β-cell GCK expression as an underlying mechanism for dysregulated β-cell function and glycemic control in HFD-induced diabetes. Our data also imply an etiological role of GCK in diet-induced diabetes. This article has an associated First Person interview with the first author of the paper.<br />Summary: β-cell glucokinase expression is decreased in diet-induced diabetes. β-cell-targeted overexpression of glucokinase improved the diabetic phenotype, suggesting an etiological role of glucokinase downregulation in diet-induced diabetes.
- Subjects :
- Male
0301 basic medicine
Cell
Intracellular Space
lcsh:Medicine
Medicine (miscellaneous)
Impaired glucose tolerance
Immunology and Microbiology (miscellaneous)
Transduction, Genetic
Insulin-Secreting Cells
Glucokinase
Insulin
Glycolysis
Islet biology
geography.geographical_feature_category
Insulin secretion
Dependovirus
Islet
Potassium channel
Up-Regulation
medicine.anatomical_structure
Signal Transduction
Research Article
lcsh:RB1-214
medicine.medical_specialty
Neuroscience (miscellaneous)
Carbohydrate metabolism
Biology
Diet, High-Fat
General Biochemistry, Genetics and Molecular Biology
Diabetes Mellitus, Experimental
03 medical and health sciences
Gene therapy
Internal medicine
Diabetes mellitus
lcsh:Pathology
medicine
Animals
Cell Proliferation
geography
Diet-induced diabetes
lcsh:R
Glucose Tolerance Test
medicine.disease
Mice, Inbred C57BL
Glucose
030104 developmental biology
Endocrinology
Calcium
Subjects
Details
- ISSN :
- 17548411 and 17548403
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Disease Models & Mechanisms
- Accession number :
- edsair.doi.dedup.....6e036b59cb1e2faa5467437192c06e39