Long-term exposure of beta-INS cells to high glucose concentrations increases anaplerosis, lipogenesis, and lipogenic gene expression.
Chronic exposure of pancreatic beta-cells to high glucose has pleiotropic action on beta-cell function. In particular, it induces key glycolytic genes, promotes glycogen deposition, and causes beta-cell proliferation and altered insulin secretion characterized by sensitization to low glucose. Postglycolytic events, in particular, anaplerosis and lipid signaling, are thought to be implicated in beta-cell activation by glucose. To understand the biochemical nature of the beta-cell adaptive process to hyperglycemia, we studied the regulation by glucose of lipogenic genes in the beta-cell line INS-1. A 3-day exposure of cells to elevated glucose (5-25 mmol/l) increased the enzymatic activities of fatty acid synthase 3-fold, acetyl-CoA carboxylase 30-fold, and malic enzyme 1.3-fold. Pyruvate carboxylase and citrate lyase expression remained constant. Similar observations were made at the protein and mRNA levels except for malic enzyme mRNA, which did not vary. Metabolic gene expression changes were associated with chronically elevated levels of citrate, malate, malonyl-CoA, and conversion of glucose carbon into lipids, even in cells that were subsequently exposed to low glucose. Similarly, fatty acid oxidation was suppressed and phospholipid and triglyceride synthesis was enhanced independently of the external glucose concentration in cells preexposed to high glucose. The results suggest that a coordinated induction of glycolytic and lipogenic genes in conjunction with glycogen and triglyceride deposition, as well as increased anaplerosis and altered lipid partitioning, contribute to the adaptive process to hyperglycemia and glucose sensitization of the beta-cell.
Roche
E
E
Department of Nutrition, University of Montreal, and CHUM, Centre de Recherche L.-C. Simard, Quebec, Canada.
Farfari
S
S
Witters
L A
LA
Assimacopoulos-Jeannet
F
F
Thumelin
S
S
Brun
T
T
Corkey
B E
BE
Saha
A K
AK
Prentki
M
M
D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002952:Citric Acid Cycle / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D006019:Glycolysis / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis* / Q000235:genetics*; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008316:Malonyl Coenzyme A / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism
D008055:Lipids; D012333:RNA, Messenger; D014280:Triglycerides; D008316:Malonyl Coenzyme A; D008291:Malate Dehydrogenase; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose