Lkb

Metformin

AMPK activity

AMPK activity

FIGURE 3 Mechanisms of metformin action on lipid and carbohydrate metabolism in adipose tissue, liver, and skeletal muscle. Abbreviations: ACC1, acetyl-CoA carboxylase 1; AMPK, AMP-kinase; FAS, fatty acid synthase; FFA, free fatty acids; GLUT1, glucose transporter 1; GLUT4, glucose transporter 4; G6Pase, glucose-6-phos-phatase; IRS 1, HSL, hormone-sensitive lipase; insulin receptor substrate 1; LKB1, tumor suppressor gene; PEPCK, phosphoenolpyruvate carboxylase; SREBP1, sterol regulatory element-binding protein 1; TG, triglycerides.

Glucose |

Glucose |

FIGURE 3 Mechanisms of metformin action on lipid and carbohydrate metabolism in adipose tissue, liver, and skeletal muscle. Abbreviations: ACC1, acetyl-CoA carboxylase 1; AMPK, AMP-kinase; FAS, fatty acid synthase; FFA, free fatty acids; GLUT1, glucose transporter 1; GLUT4, glucose transporter 4; G6Pase, glucose-6-phos-phatase; IRS 1, HSL, hormone-sensitive lipase; insulin receptor substrate 1; LKB1, tumor suppressor gene; PEPCK, phosphoenolpyruvate carboxylase; SREBP1, sterol regulatory element-binding protein 1; TG, triglycerides.

assessment (HOMA), but not insulin-stimulated glucose disposal or glucose oxidation (41). In this study both fasting glucose and insulin decreased significantly. In android obese subjects with IGT increased insulin sensitivity (using an intravenous glucose tolerance) was observed after only 2 days of metformin treatment (1700mg/day) (42). In obese women with the polycystic ovarian syndrome (PCOS) 6 months treatment with metformin also significantly improved insulin-stimulated glucose disposal (43,44). In another study in obese women with PCOS the decrease in serum insulin levels was associated with an increased ovulatory response to clomiphene (45). Glucose production was not assessed in the latter study. These apparent discrepancies could be explained by differences in the type of insulin resistance. In the highly selected group of lean, first-degree relatives and women with PCOS mechanisms may contribute to insulin resistance, which are different than those in garden-variety type 2 diabetes where insulin resistance is predominantly the result of obesity and longstanding hyperglycemia. Moreover, the reduction in endogenous glucose production after metformin treatment may only be seen in subjects in whom it was increased to begin with, such as patients with type 2 diabetes. The latter is supported by observations showing that metformin alone does not cause hypoglycemia or lowers blood glucose in nondiabetic subjects (46,47). The effect of metformin on endogenous glucose production in nondiabetic humans has not been studied yet.

FIGURE 4 Summary of the effect of metformin on basal hepatic glucose production in type 2 diabetic patients. Abbreviations: HGP, hepatic glucose production. Source: From Ref. 30.

FIGURE 5 Summary of the effect of metformin on insulin-stimulated glucose disposal in type 2 diabetic patients. Source: From Ref. 30.

Additional evidence for improved insulin action comes from studies combining insulin therapy and metformin. It was shown that requirements of exogenous insulin are reduced (by ~30%) by addition of metformin in obese patients with type 2 diabetes (48-50) and in some patients with type 1 diabetes in whom glycemic control was unaltered (51-53).

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