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- Title
Long-Chain Fatty Acid Oxidation Is Not Essential to Drive Gluconeogenesis in Short Term Fasted Male CB57BL/6J Mice In Vivo.
- Authors
Van Dijk, Theo H.; Derks, Terry G.; Grefhorst, Aldo; Smit, G. Peter A.; Havinga, Rick; Kuipers, Folkert; Reijngoud, Dirk-Jan
- Abstract
Inappropriately high hepatic glucose production is a major contributor to hyperglycemia in type II diabetes,. Since long-chain fatty acid oxidation (1cFAO) is considered to be essential for driving gluconeogenesis, inhibition of 1cFAO has been explored as a therapeutic option to diminish glucose production. We assessed hepatic glucose metabolism in vivo after acute inhibition of 1cFAO by 2-tetradecylglycidic acid (TDGA) and subsequent short-term fasting in male C57BL/6J mice and control mice. We infused [U-13C]-glucose, [2-13C]glycerol, [1-2H]galactose and paracetamol for 6 hours, followed by mass isotopomer distribution analysis on blood glucose and urinary paracetamol-glucuronide. Under hypoketotic hypoglycaemic conditions induced by TDGA-treatment, endogenous glucose production was unaffected (127±10 vs. 118 ± 7 µmol⋅kg-1.⋅min-1, control vs. TDGA, NS), but metabolic clearance rate of glucose was enhanced (16 ± 1 vs. 26 ±1 ml⋅kg-l.⋅min-1, control vs. TDGA, p<0.05). Compared to control mice, the rate of de novo synthesis of glucose-6-phosphate (G6P) was only slightly decreased in TDGA-treated mice (108 ± 19 vs. 85 ± 6 µmol.⋅kg-1⋅min- 1, control vs. TDGA, p<0.05). Recycling of glucose was decreased upon TDGA-treatment (26 ±14 vs. 12 ±4 µmol.⋅kg -1⋅min-1, control vs. TDGA, p<0.05) due to decreased glucose phosphorylation (39 ± 8 vs. 16 ± 2 µmol⋅kg-1⋅min-1, control s. TDGA, p<0.05). Furthermore, glycogen synthesis decreased significantly (56 ± 5 vs. 33 ±1 µmol⋅kg-1⋅min-1, control vs. TDGA, p<0.05), resulting in an increased partitioning of newly synthesised G6P to blood glucose. Hepatic mRNA levels of genes encoding for enzymes involved in de novo G6P-synthesis were unaltered, while G6P-hydrolase mRNA expressions were increased in TDGA-treated mice. Glucokinase and pyruvate kinase mRNA levels were significantly decreased and Pdk-4 expression was increased 30-fold, suggesting decreased glycolytic activity. In conclusion, acute pharmacological inhibition of 1cFAO using TDGA in short-term fasted mice suppressed de novo G6P-synthesis only marginally, while endogenous glucose production remained unaffected. Hence, it appears that a fully active 1cFAO is not essential for maintenance of hepatic GNG in vivo, but affects predominantly metabolic handling of G6P.
- Publication
Diabetes, 2007, Vol 56, pA391
- ISSN
0012-1797
- Publication type
Academic Journal