Increased gluconeogenesis in hepatocytes from GTG-obese mice is insensitive to inhibition by insulin.
The effect of a supraphysiological concentration of insulin on gluconeogenesis from L-[U14C] 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 weighted significantly more than controls (41.7 +/- 0.5 vs. 29.6 +/- 0.8 g respectively; P < 0.001), and exhibited fasting hyperinsulinaemia (35.9 +/- 4.6 vs. 21.3 +/- 4.2 microU/ml; P < 0.05) and hyperglycaemia (16.4 +/- 1.2 vs. 9.2 +/- 1.1 mmol/l; P < 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 < 0.05). The addition of 10(-6)M 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 < 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-[U14C] lactate were also significantly increased in hepatocytes from GTG-obese mice compared with controls. There was no effect of 10(-6)M insulin on glycogen or triacylglycerol glycerol production from lactate by hepatocytes from GTG-obese mice but the addition of 10(-6)M insulin to the incubations of control hepatocytes significantly reduced the amount of lactate converted to glycogen and triacylglycerol glycerol.(ABSTRACT TRUNCATED AT 250 WORDS)
Greenaway
T M
TM
Department of Medicine, University of Sydney, NSW, Australia.
Cooney
G J
GJ
Blair
S C
SC
Caterson
I D
ID
D000818:Animals; D006051:Aurothioglucose; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000032:analysis; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000096:biosynthesis; D006003:Glycogen / Q000032:analysis / Q000096:biosynthesis; D007328:Insulin / Q000494:pharmacology*; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D014280:Triglycerides / Q000096:biosynthesis
D005227:Fatty Acids; D007328:Insulin; D007773:Lactates; D014280:Triglycerides; D006051:Aurothioglucose; D006003:Glycogen; D005947:Glucose