A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse.
We studied the effects of fatty acid oxidation on insulin secretion of db/db mice and underlying molecular mechanisms of these effects. At 2-3 months of age, db/db mice were markedly obese, hyperglycemic, and hyperinsulinemic. Serum free fatty acid (FFA) levels were increased in 2-month-old (1.5 +/- 0.1 vs. 1.1 +/- 0.1 mmol/l, P < 0.05) and 3-month-old (1.9 +/- 0.1 vs. 1.2 +/- 0.1 mmol/l, P < 0.01) mice compared with the age and sex-matched db/+ mice serving as controls. Glucose-induced insulin release from db/db islets was markedly decreased compared with that from db/+ islets and was specifically ameliorated (by 54% in 2-month-old and 38% in 3-month-old mice) by exposure to a carnitine palmitoyltransferase I inhibitor, etomoxir (1 micromol/l). Etomoxir failed to affect the insulin response to alpha-ketoisocaproate. The effect of etomoxir on glucose-induced insulin release was lost after culturing db/db islets in RPMI medium containing 22 mmol/l glucose but no fatty acid. Culture of db/+ islets with 0.125 mmol/l palmitate led to a decrease in glucose-induced insulin secretion, which was partially reversible by etomoxir. Both islet glucose oxidation and the ratio of glucose oxidation to utilization were decreased in db/db islets. Etomoxir significantly enhanced glucose oxidation by 60% and also the ratio of oxidation to glucose utilization (from 27 +/- 2.5 to 37 +/-3.0%, P < 0.05). Pyruvate dehydrogenase (PDH) activity was decreased in islets of db/db mice (75 +/-4.2 vs. 91 +/- 2.9 nU/ng DNA, P < 0.01), whereas PDH kinase activity was increased (rate of PDH inactivation -0.25 +/- 0.02 vs. - 0.11 +/- 0.02/min, P < 0.0 1). These abnormalities were partly but not wholly reversed by a 2-h preexposure to etomoxir. In conclusion, elevated FFA levels in the db/db mouse diminish glucose-induced insulin secretion by a glucose-fatty acid cycle in which fatty acid oxidation inhibits glucose oxidation by decreasing PDH activity and increasing PDH kinase activities.
Zhou
Y P
YP
Department of Molecular Medicine, Karolinska Hospital and Institute, Stockholm, Sweden.
Berggren
P O
PO
Grill
V
V
D000375:Aging; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004247:DNA / Q000032:analysis; D003920:Diabetes Mellitus / Q000097:blood / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000097:blood / Q000503:physiopathology*; D006946:Hyperinsulinism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D007651:Keto Acids / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008928:Mitochondria / Q000201:enzymology*; D009765:Obesity / Q000097:blood / Q000503:physiopathology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D007651:Keto Acids; D011768:Pyruvate Dehydrogenase Complex; C013082:alpha-ketoisocaproic acid; D004247:DNA; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; C054207:etomoxir