The thiazolidinediones improve peripheral insulin action not only in patients with type 2 diabetes, but also in other insulin resistant states like impaired glucose tolerance (IGT), polycystic ovary disease, previous gestational diabetes and Werner's syndrome (28-31).
In studies using either the hyperinsulinemic-euglycemic clamp study which is currently considered the "gold standard" to evaluate peripheral insulin sensitivity, or other less direct methods like the frequently sampled intravenous glucose tolerance test, the insulin tolerance test, the oral glucose tolerance test and the HOMA (S), the thiazolidinediones consistently improve insulin-mediated peripheral glucose utilization in obese and lean insulin-resistant, type 2 diabetes patients by approximately 30% to 100% (32). In all these studies, the improvements in insulin sensitivity with the thiazolidinediones has consistently resulted in improved glycemia, lower HbA1c levels and in the case of insulin-resistant IGT/impaired fasting glucose (IFG) subjects, regression from IGT/IFG to normoglycemia, besides improvement in the lipid profile and other cardiovascular risk markers (33).
In one study, 29 diet-treated diabetic patients were randomly assigned to either rosiglitazone, 8 mg/day or placebo (34). After 12 weeks, rosiglitazone improved the FPG (195-150 mg/dL) and HbA1c (8.7-7.4%), significantly suppressed endogenous glucose production by 13% and increased whole-body glucose uptake (measured by the insulin clamp technique) by 37%. Other beneficial changes included a decrease in FFA levels which occurred despite an increase in both body weight and total fat mass of 4 kg. There were significant correlations between measures of insulin sensitivity and plasma FFA levels and the authors concluded that rosiglitazone increases hepatic and peripheral (muscle) tissue insulin sensitivity and reduces FFA turnover despite increased total body fat mass and suggest that the beneficial effects of rosiglitazone on glycemic control are mediated, in part, by the drug's effect on FFA metabolism (34).
Pioglitazone has also been shown to improve peripheral insulin sensitivity. In a large, international study in 205 patients with recently diagnosed, treatment-naive type 2 diabetes, after 24 weeks, pioglitazone was comparable to metformin in improving glycemic control and FPG (decreases in HbA1c of ~ 1.3% and FPG of ~ 54 mg/dL, respectively) (35). However, insulin sensitivity (assessed by HOMA-S) increased significantly by 17.4% in the pioglitazone group as compared with an increase of only 8.9% in the metformin group.
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