The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus |
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Authors: | S Andrikopoulos Professor J Proietto |
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Institution: | (1) Department of Medicine, Royal Melbourne Hospital, University of Melbourne, 3050 Parkville, Victoria, Australia |
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Abstract: | Summary The mechanism of increased hepatic glucose production in obese non-insulin-dependent diabetic (NIDDM) patients is unknown. The New Zealand Obese (NZO) mouse, a polygenic model of obesity and NIDDM shows increased hepatic glucose production. To determine the mechanism of this phenomenon, we measured gluconeogenesis from U-14C-glycerol and U-14C-alanine and relevant gluconeogenic enzymes. Gluconeogenesis from glycerol (0.07±0.01 vs 0.21±0.02 mol · min–1 · body mass index (BMI)–1, p<0.005) and alanine (0.57±0.07 vs 0.99±0.07 mol · min–1 · BMI–1, p<0.005) was elevated in control mice NZO vs as was glycerol turnover (0.25±0.02 vs 0.63±0.09 mol · min–1 · BMI–1, p<0.05). Fructose 1,6-bisphosphatase activity (44.2±1.9 vs 55.7±4.1 nmol · min–1 · mg protein–1, p<0.05) and protein levels (6.9±1.1 vs 16.7±2.3 arbitrary units, p<0.01) were increased in NZO mouse livers, as was the activity of pyruvate carboxylase (0.12±0.01 vs 0.17±0.02 nmol · min–1 · mg protein–1, p<0.05). To ascertain whether elevated lipid supply is responsible for these biochemical changes in NZO mice, we fed lean control mice a 60% fat diet for 2 weeks. Fat-fed mice were hyperinsulinaemic (76.37±4.06 vs 98.00±7.07 pmol/l, p=0.05) and had elevated plasma non-esterified fatty acid levels (0.44±0.05 vs 0.59±0.03 mmol/l, p=0.05). Fructose 1,6-bisphosphatase activity (43.86±2.54 vs 52.93±3.09 nmol · min–1 · mg protein–1, p=0.05) and protein levels (33.03±0.96 vs 40.04±1.26 arbitrary units, p=0.005) and pyruvate carboxylase activity (0.10±0.003 vs 0.14±0.01 nmol · min–1 · mg protein–1, p<0.05) were elevated in fat-fed mice. We conclude that in NZO mice increased hepatic glucose production is due to elevated lipolysis resulting from obesity.Abbreviations HGP
Hepatic glucose production
- NZO
New Zealand Obese
- FBPase
fructose 1,6-bisphosphatase
- PC
pyruvate carboxylase
- PEPCK
phosphoenolpyruvate carboxykinase
- BMI
body mass index
- NIDDM
non-insulin-dependent diabetes mellitus
- NZC
lean control mice
- NEFA
non-esterified fatty acids |
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Keywords: | Gluconeogenesis glycerol alanine fructose 1 6-bisphosphatase pyruvate carboxylase |
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