Insulin-dependent actions of pioglitazone in newly diagnosed, drug na⟨ve patients with type 2 diabetes

The aim of this study was to study the effects of pioglitazone on several diabetic parameters with subjects possessing distinct levels of insulin. Treatment naive patients with type 2 diabetes received 15-30 mg/day pioglitazone monotherapy. At 3 months, levels of insulin, C-peptide, HbA1c, HOMA-R, HOMA-B and BMI were compared with those at baseline between the low (below 5.9 mu U/ml, n = 48), medium (11.9-6 mu U/ml n = 39) and high (above 12 mu U/ml, n = 33) insulin groups. At baseline, differences existed in the levels of HbA1c, insulin, C-peptide, HOMA-R, HOMA-B, and BMI between these groups. In the high-insulin group significant reductions of insulin/C-peptide levels were observed, while in the low-insulin group significant increases of insulin/C-peptide were observed. In the medium-insulin group, no significant changes were observed. In contrast, the HbA1c levels significantly and similarly decreased in all the groups. Significant correlations between the changes of insulin/C-peptide levels with pioglitazone and the baseline insulin/C-peptide levels were observed. HOMA-R showed greater reductions in the high-insulin group, while HOMA-B showed greater increases in the low-insulin group in comparison to other groups. Multiple regression analysis revealed that the baseline insulin level is the predominant determinant of the changes of insulin levels with pioglitazone. These results suggest that pioglitazone appears to have two effects: to reduce insulin resistance (and lower insulin) and to improve beta-cell function (and increase insulin). The predominance of these effects appears to be determined by the insulin levels. Based on these data, a novel physiological model showing that pioglitazone may shift the natural history of diabetes toward an earlier stage (rejuvenation of beta-cell function) will be presented.