We previously found that long-term exposure to fatty acids impairs glucose-induced insulin release. In the present study, we investigated whether impairment is related to decreased pyruvate dehydrogenase (PDH) and increased PDH kinase activity. Rat pancreatic islets were cultured for 48 h in RPMI-1640 medium with or without 0.125 mmol/l palmitate. Potentiation of insulin responses to succinic acid monomethylester (SAM) by 10 mmol/l acetate and pyruvate were subsequently compared in order to assess whether generation of acetyl-coenzyme A (CoA) from pyruvate was deficient in the intact β-cell. Potentiation by acetate was similar in control and palmitate-preexposed islets. In contrast, pyruvate potentiated SAM-induced response by 122% in control but by only 39% in palmitate-exposed islets (P < 0.001). In extracts of palmitate-exposed islets, the active (unphosphorylated) form of PDH was decreased by 50% and total PDH activity (assessed after phosphatase treatment) by 25%. The proportion of active form to total PDH activity was also reduced (42.7 ± 2.6% after palmitate vs. 66.6 ± 4.3% in control islets, P < 0.01). In the same preparations, PDH kinase activity was enhanced 1.7-fold by palmitate in terms of the rate constant of ATP-dependent inactivation of PDH (P < 0.05). To test for a role of free (not PDH-bound) kinase, a PDH-free mitochondrial fraction was prepared, and its kinase activity was tested against a pig heart PDH preparation. Free kinase activity was increased 1.9-fold in palmitate-treated islets (P < 0.01). In conclusion, long-term exposure to fatty acids limits the conversion of pyruvate to acetyl-CoA through inhibition of PDH activity, which is linked to increased activity of a non-PDH-bound kinase. These findings could have relevance for deficient insulin release in type II diabetes.
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Original Articles|
April 01 1995
Palmitate-Induced β-Cell Insensitivity to Glucose is Coupled to Decreased Pyruvate Dehydrogenase Activity and Enhanced Kinase Activity in Rat Pancreatic Islets
Yun-Ping Zhou;
Yun-Ping Zhou
Department of Molecular Medicine, Karolinska Hospital, Karolinska Institute
Stockholm, Sweden
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Valdemar E Grill
Valdemar E Grill
Department of Molecular Medicine, Karolinska Hospital, Karolinska Institute
Stockholm, Sweden
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Address correspondence and reprint requests to Dr. Valdemar Grill, Department of Molecular Medicine, The Endocrine and Diabetes Unit, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Diabetes 1995;44(4):394–399
Article history
Revision Received:
January 04 1994
Accepted:
January 04 1994
Received:
October 19 1994
PubMed:
7698506
Citation
Yun-Ping Zhou, Valdemar E Grill; Palmitate-Induced β-Cell Insensitivity to Glucose is Coupled to Decreased Pyruvate Dehydrogenase Activity and Enhanced Kinase Activity in Rat Pancreatic Islets. Diabetes 1 April 1995; 44 (4): 394–399. https://doi.org/10.2337/diab.44.4.394
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