Increased gluconeogenesis in hepatocytes from GTG-obese mice is insensitive to inhibition by insulin
Greenaway, T.M.; Cooney, G.J.; Blair, S.C.; Caterson, I.D.
International Journal of Obesity and Related Metabolic Disorders Journal of the International Association for the Study of Obesity 16(12): 985-990
1992
ISSN/ISBN: 0307-0565 PMID: 1335978 Document Number: 393641
The effect of a supraphysiological concentration of insulin on gluconeogenesis from L-(U-14C) lactate was studied in hepatocytes isolated from control mice and mice made obese by a single injection of gold-thioglucose (GTG). At the time of experimentation (10-12 weeks post GTG injection) the obese mice weighed significantly more than controls (41.7 +- 0.5 vs. 29.6 +- 0.8 g respectively; P lt 0.001), and exhibited fasting hyperinsulinaemia (35.9 +- 4.6 vs. 21.3 +- 4.2 mu-U/ml; P lt 0.05) and hyperglycaemia (16.4 +- 1.2 vs. 9.2 +- 1.1 mmol/l; P lt 0.001). The amount of lactate converted to glucose by hepatocytes isolated from GTG-obese mice was significantly greater than from lean controls (322 +- 44 vs. 209 +- 20 nmol/30 min/10-6 cells; P lt 0.05). The addition of 10-6M insulin to the incubations significantly reduced lactate conversion to glucose by hepatocytes isolated from control mice (209 +- 20 vs. 123 +- 22 nmol/30 min/10-6 cells; P lt 0.02), but there was no effect of insulin on glucose production from lactate by hepatocytes isolated from GTG-obese mice (322 +- 44 vs. 294 +- 47 nmol/30 min/10-6 cells). Glycogen production and triacylglycerol glycerol production from L-(U-14C) lactate were also significantly increased in hepatocytes from GTG-obese mice compared with controls. There was no effect of 10-6M insulin on glycogen or triacylglycerol glycerol production from lactate by hepatocytes from GTG-obese mice but the addition of 10-6M insulin to the incubations of control hepatocytes significantly reduced the amount of lactate converted to glycogen and triacylglycerol glycerol. We conclude that gluconeogenic flux from lactate is increased in hepatocytes from GTG-obese mice and that this increase in gluconeogenesis is insensitive to inhibition by a supraphysiological concentration of insulin. This increased and uncontrolled glucose production by the liver may significantly contribute ot the hyperglycaemia observed in this animal model of obesity and NIDDM.