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 ∼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 NEFAinduced extrahepatic insulin resistance, it does not protect against NEFA-induced hepatic insulin resistance.

Transaldolase exchange and its effects on measurements of gluconeogenesis in humans

“…In theory, high rates of hepatic lypolysis combined with incomplete equilibration at the level of the triose isomerase reaction could generate sufficient unlabeled dihydroxyacetone phosphate to disproportionately decrease labeling of C3 relative to C4 (26). However, we doubt whether this is the cause of the lower C3/C4 ratio in the current studies since equilibration of the triose isomerase reaction is nearly complete and lipolysis is not high following an overnight fast and is presumably further suppressed by infusion of insulin (3,13,33,35).…”

“…We demonstrated recently that the ratio of [1,2,3-13 C 3 ]glucose to [4,5,6-13 C 3 ]glucuronide isotopomers derived from gluconeogenic metabolism of [U-13 C]glycerol is altered by transaldolase exchange activity (23). On this basis, the ratio of "top" to "bottom" glucose triose isotopomers (e.g., [3][4][5][6][7][8][9][10][11][12][13] C]-to [4-13 C]glucose) allows the fraction of unlabeled glucose 6-phosphate that has participated in transaldolase exchange to be calculated (23). Therefore, in the present experiments, enrichment of glucose from [1-13 C]acetate and 2 H 2 O was measured simultaneously using 13 C and 2 H nuclear magnetic resonance (NMR) spectroscopy, allowing calculation of the contribution of transaldolase exchange to incorporation of deuterium on position 5 of glucose following 2 H 2 O ingestion.…”

Sex-different hepatic glycogen content and glucose output in rats

“…In the post-absorptive state, plasma concentrations of NEFA are lower whereas glucose and insulin levels are higher in men than in women [80]. Furthermore, men have been shown to utilize less fat and more carbohydrates and amino acids during endurance exercise [81,82].…”

Effect of liraglutide on estimates of lipolysis and lipid oxidation in obese patients with stable coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial

“…Metformin treatment has been shown to induce lipoprotein lipase activity in muscles 9 and prevents NEFAinduced extrahepatic IR but not NEFA-induced hepatic IR. 10 Based on the present results we speculate that the effects of liraglutide on lipid metabolism could be counteracted, in some instances, by metformin; that is, metformin increases indices of lipid oxidation, in opposition to the effect of liraglutide). However, concerning other metabolic pathways, for example, glucose metabolism, the effect of metformin and liraglutide could be additive.…”

“…Both lipolysis and lipid oxidation during the 180‐minute test were reduced by liraglutide‐metformin treatment but increased with placebo‐metformin (Figure S3). Metformin treatment has been shown to induce lipoprotein lipase activity in muscles and prevents NEFA‐induced extrahepatic IR but not NEFA‐induced hepatic IR …”