SREBP1 is required for the induction by glucose of pancreatic beta-cell genes involved in glucose sensing.
Previous studies have reported both positive and negative effects of culture of islets at high glucose concentrations on regulated insulin secretion. Here, we have reexamined this question in mouse islets and determined the role of changes in lipid synthesis in the effects of glucose. Glucose-stimulated insulin secretion (GSIS) and gene expression were examined in islets from C57BL/6 mice or littermates deleted for sterol-regulatory element binding protein-1 (SREBP1) after 4 days of culture at high glucose concentrations. Culture of control islets at 30 versus 8 mmol/l glucose led to enhanced secretion at both basal (3 mmol/l) and stimulatory (17 mmol/l) glucose concentrations and to enhanced triacylglycerol accumulation. These changes were associated with increases in the expression of genes involved in glucose sensing (glucose transporter 2, glucokinase, sulfonylurea receptor 1, inwardly rectifying K(+) channel 6.2), differentiation (pancreatic duodenal homeobox 1), and lipogenesis (Srebp1, fatty acid synthase, acetyl-coenzyme A carboxylase 1, stearoyl-coenzyme A desaturase 1). When cultured at either 8 or 30 mmol/l glucose, SREBP1-deficient (SREBP1(-/-)) islets displayed reduced GSIS and triacylglycerol content compared with normal islets. Correspondingly, glucose induction of the above genes in control islets was no longer observed in SREBP1(-/-) mouse islets. We conclude that enhanced lipid synthesis mediated by SREBP1c-dependent genes is required for the adaptive changes in islet gene expression and insulin secretion at high glucose concentrations.
Diraison
Frederique
F
Department of Cell Biology, Division of Medicine, Faculty of Medicine, Imperial College, London SW72A2, UK.
Ravier
Magalie A
MA
Richards
Sarah K
SK
Smith
Richard M
RM
Shimano
Hitoshi
H
Rutter
Guy A
GA
D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051780:Sterol Regulatory Element Binding Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014226:Triazenes / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism
D007328:Insulin; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014226:Triazenes; D014280:Triglycerides; C034613:triacsin C; D005947:Glucose