Biochemical mechanism of lipid-induced impairment of glucose-stimulated insulin secretion and reversal with a malate analogue.
Hyperlipidemia appears to play an integral role in loss of glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. This impairment can be simulated in vitro by chronic culture of 832/13 insulinoma cells with high concentrations of free fatty acids, or by study of lipid-laden islets from Zucker diabetic fatty rats. Here we show that impaired GSIS is not a simple result of saturation of lipid storage pathways, as adenovirus-mediated overexpression of a cytosolically localized variant of malonyl-CoA decarboxylase in either cellular model results in dramatic lowering of cellular triglyceride stores but no improvement in GSIS. Instead, the glucose-induced increment in "pyruvate cycling" activity (pyruvate exchange with tricarboxylic acid cycle intermediates measured by (13)C NMR), previously shown to play an important role in GSIS, is completely ablated in concert with profound suppression of GSIS in lipid-cultured 832/13 cells, whereas glucose oxidation is unaffected. Moreover, GSIS is partially restored in both lipid-cultured 832/13 cells and islets from Zucker diabetic fatty rats by addition of a membrane permeant ester of a pyruvate cycling intermediate (dimethyl malate). We conclude that chronic exposure of islet beta-cells to fatty acids grossly alters a mitochondrial pathway of pyruvate metabolism that is important for normal GSIS.
Boucher
Anne
A
Sarah W. Stedman Nutrition and Metabolism Center and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Lu
Danhong
D
Burgess
Shawn C
SC
Telemaque-Potts
Sabine
S
Jensen
Mette V
MV
Mulder
Hindrik
H
Wang
May-Yun
MY
Unger
Roger H
RH
Sherry
A Dean
AD
Newgard
Christopher B
CB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008293:Malates / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D019301:Oleic Acid / Q000378:metabolism* / Q000633:toxicity; D010101:Oxygen Consumption; D010168:Palmitates / Q000378:metabolism* / Q000633:toxicity; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D014161:Transduction, Genetic; D014280:Triglycerides / Q000172:deficiency / Q000378:metabolism
D007328:Insulin; D008293:Malates; D010168:Palmitates; D014280:Triglycerides; D019301:Oleic Acid; D019289:Pyruvic Acid; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D005947:Glucose