Tight coupling between glucose and mitochondrial metabolism in clonal beta-cells is required for robust insulin secretion.
Författare
Summary, in English
The biochemical mechanisms underlying glucose-stimulated insulin secretion from pancreatic beta-cells are not completely understood. To identify metabolic disturbances in beta-cells that impair glucose-stimulated insulin secretion, we compared two INS-1-derived clonal beta-cell lines, which are glucose-responsive (832/13) or glucose-unresponsive (832/2). We found that despite a marked impairment of glucose-stimulated insulin secretion, 832/2 cells exhibited a higher rate of glycolysis. Still, no glucose-induced increases in respiratory rate, ATP production or respiratory chain complex I, III and IV activities were seen in the 832/2 cells. Instead, 832/2 cells, which expressed lactate dehydrogenase, released lactate regardless of ambient glucose concentrations. In contrast, the glucose-responsive 832/13 line lacked lactate dehydrogenase and did not produce lactate. Accordingly, in 832/2 cells mRNA expression of genes for glycolytic enzymes were up-regulated, whereas mitochondria-related genes were down-regulated. In human islets, mRNA expression of genes such as lactate dehydrogenase A and hexokinase I correlated positively with long-term glucose homeostasis reflected by HbA1c levels, while that of Slc2a2 (GLUT2) correlated negatively with Hb1Ac. We conclude that tight metabolic regulation enhancing mitochondrial metabolism and restricting glycolysis in 832/13 cells is required for clonal beta-cells to secrete insulin robustly in response to glucose. Moreover, a similar expression pattern of genes controlling glycolytic and mitochondrial metabolism in clonal beta-cells and human islets was observed, suggesting that a similar prioritization of mitochondrial metabolism is required in healthy human beta-cells. The 832 beta-cell lines may be helpful tools to resolve metabolic perturbations occurring in Type 2 Diabetes.
Avdelning/ar
Publiceringsår
2009
Språk
Engelska
Sidor
32395-32404
Publikation/Tidskrift/Serie
Journal of Biological Chemistry
Volym
284
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
American Society for Biochemistry and Molecular Biology
Ämne
- Endocrinology and Diabetes
- Neurosciences
Status
Published
Forskningsgrupp
- Brain Repair and Imaging in Neural Systems (BRAINS)
- Genomics, Diabetes and Endocrinology
- Diabetes - Molecular Metabolism
ISBN/ISSN/Övrigt
- ISSN: 1083-351X