Effects of metformin on glucose and glucagon regulated gluconeogenesis in cultured normal and diabetic hepatocytes.
The effects of glucose and glucagon on the anti-gluconeogenic action of metformin were investigated in normal and diabetic hepatocytes. Glucose production from lactate was elevated by 88% in hepatocytes from fasted normal rats compared with hepatocytes from fed animals. Diabetes caused 3.5- and 2.1-fold increases in hepatic gluconeogenesis under fasting and fed conditions, respectively. Metformin (250 microM) suppressed glucose production by 37% in normal and by 30% in diabetic hepatocytes from fed rats. This drug was more effective (up to 67%) with increasing concentrations of glucose in the medium. Potentiation by metformin of insulin action on gluconeogenesis was elevated significantly (P < 0.01 to 0.001) by glucose in vitro. Metformin (75-250 microM) also counteracted the effects of glucagon at optimal concentrations in normal (32-68%) as well as diabetic (8-46%) hepatocytes. The findings of this study indicate that (i) the anti-gluconeogenic effect of metformin is enhanced by glucose in vivo and in vitro; and (ii) the suppression of glucagon-induced gluconeogenesis by metformin could play a role in its glucose-lowering effects in diabetic conditions.
Yu
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B
Department of Biochemistry, University of Saskatchewan, Saskatoon, Canada.
Pugazhenthi
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S
Khandelwal
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RL
D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005934:Glucagon / Q000502:physiology*; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005934:Glucagon; D008687:Metformin; D005947:Glucose