Effects of pioglitazone and metformin on NEFA-induced insulin resistance in type 2 diabetes

Aims/hypothesis: We sought to determine whether pioglitazone and metformin alter NEFA-induced insulin resistance in type 2 diabetes and, if so, the mechanism whereby this is effected. Methods: Euglycaemic-hyperinsulinaemic clamps (glucose ∼5.3 mmol/l, insulin ∼200 pmol/l) were performed in the presence of Intralipid-heparin (IL/H) or glycerol before and after 4 months of treatment with pioglitazone (n=11) or metformin (n=9) in diabetic participants. Hormone secretion was inhibited with somatostatin in all participants. Results: Pioglitazone increased insulin-stimulated glucose disappearance (p<0.01) and increased insulin-induced suppression of glucose production (p<0.01), gluconeogenesis (p<0.05) and glycogenolysis (p<0.05) during IL/H. However, glucose disappearance remained lower (p<0.05) whereas glucose production (p<0.01), gluconeogenesis (p<0.05) and glycogenolysis (p<0.05) were higher on the IL/H study day than on the glycerol study day, indicating persistence of NEFA-induced insulin resistance. Metformin increased (p<0.001) glucose disappearance during IL/H to rates present during glycerol treatment, indicating protection against NEFA-induced insulin resistance in extrahepatic tissues. However, glucose production and gluconeogenesis (but not glycogenolysis) were higher (p<0.01) during IL/H than during glycerol treatment with metformin, indicating persistence of NEFA-induced hepatic insulin resistance. Conclusions/interpretation: We conclude that pioglitazone improves both the hepatic and the extrahepatic action of insulin but does not prevent NEFA-induced insulin resistance. In contrast, whereas metformin prevents NEFA-induced extrahepatic insulin resistance, it does not protect against NEFA-induced hepatic insulin resistance.