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

Abstract

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 approximately 5.3 mmol/l, insulin approximately 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.

Fig. 1

Glucose, insulin, C-peptide and glucagon concentrations during infusion of Intralipid and heparin (white circles) or glycerol (black circles). Studies were performed before (a, c, e, g, i, k, m, o) and after (b, d, f, h, j, l, n, p) 4 months of treatment with pioglitazone (a–h) or metformin (i–p). Infusion of insulin, somatostatin and glucagon was started at time zero

Fig. 1

Glucose, insulin, C-peptide and glucagon concentrations during infusion of Intralipid and heparin (white circles) or glycerol (black circles). Studies were performed before (a, c, e, g, i, k, m, o) and after (b, d, f, h, j, l, n, p) 4 months of treatment with pioglitazone (a–h) or metformin (i–p). Infusion of insulin, somatostatin and glucagon was started at time zero

Fig. 2

Plasma NEFA (a, b) and glycerol (c, d) concentrations during infusion of Intralipid and heparin (white bars) or glycerol (black bars) before (basal) and during (clamp) a hyperinsulinaemic–euglycaemic clamp. Studies were performed before (left panels) and after (right panels) 4 months of treatment with pioglitazone (a, c) or metformin (b, d). *p<0.05 vs glycerol study day

Fig. 2

Plasma NEFA (a, b) and glycerol (c, d) concentrations during infusion of Intralipid and heparin (white bars) or glycerol (black bars) before (basal) and during (clamp) a hyperinsulinaemic–euglycaemic clamp. Studies were performed before (left panels) and after (right panels) 4 months of treatment with pioglitazone (a, c) or metformin (b, d). *p<0.05 vs glycerol study day

Fig. 3

Rates of glucose disappearance (R_d) before (basal) and during (clamp) a hyperinsulinaemic–euglycaemic clamp during infusion of Intralipid and heparin (white bars) or glycerol (black bars). Studies were performed before (left panels) and after (right panels) 4 months of treatment with pioglitazone (a) or metformin (b). *p<0.05, **p<0.01 vs glycerol study day; ^†p<0.01, ^‡p<0.001

Fig. 4

Rates of endogenous glucose production (R_a) before (basal) and during (clamp) a hyperinsulinaemic–euglycaemic clamp during infusion of Intralipid and heparin (white bars) or glycerol (black bars). Studies were performed before (left panels) and after (right panels) 4 months of treatment with pioglitazone (a) or metformin (b). *p< 0.05, **p<0.01 vs glycerol study day; ^†p<0.05, ^‡p<0.01

Fig. 5

Rates of gluconeogenesis (GN) before (basal) and during (clamp) a hyperinsulinaemic–euglycaemic clamp during infusion of Intralipid and heparin (white bars) or glycerol (black bars). Studies were performed before (left panels) and after (right panels) 4 months of treatment with pioglitazone (a) or metformin (b). *p<0.05, **p<0.01 vs glycerol study day; ^†p<0.05, ^‡p<0.01

Fig. 6

Rates of glycogenolysis (GL) before (basal) and during (clamp) a hyperinsulinaemic–euglycaemic clamp during infusion of Intralipid and heparin (white bars) or glycerol (black bars). Studies were performed before (left panels) and after (right panels) 4 months of treatment with pioglitazone (a) or metformin (b). *p<0.05 vs glycerol study day; ^†p<0.05