Pioneer Study: PPARγ Activation Results in Overall Improvement of Clinical and Metabolic Markers Associated with Insulin Resistance Independent of Long-term Glucose Control

Abstract

New scores and biochemical markers have recently been published for diagnosis of insulin resistance and beta-cell dysfunction (such as intact proinsulin, adiponectin, IRISII-score). One goal of this 6-month prospective controlled study was to evaluate the impact of pioglitazone (45 mg) vs. glimepiride (1-6 mg, in the intend to optimize therapy) on these markers. Observation parameters were: IRIS-II score, HOMA-score, ATP III score, HbA (1c), fasting glucose, lipids, intact proinsulin, adiponectin, and adverse events. The study was completed by 173 patients (66 female, 107 male, age +/- STD: 63 +/- 8 years, disease duration: 7.2 +/- 7.2 years, HbA (1c): 7.53 +/- 0.85 %, pioglitazone arm: 89 patients). The groups were not different for any of the observation parameters at baseline, and a similar reduction in HbA (1c) was seen in both groups (p < 0.001). In the pioglitazone group, reductions were observed for the IRIS-II and HOMA scores (p < 0.001 vs. glimepiride at endpoint) fasting glucose (p < 0.001), insulin (p < 0.001), LDL/HDL ratio (p < 0.001), hsCRP (p < 0.05), intact proinsulin (p < 0.001), and an increase was seen in HDL (p < 0.001), adiponectin (p < 0.001) and BMI (p < 0.001). In conclusion, treatment with pioglitazone resulted in an improvement of markers for insulin resistance and beta-cell dysfunction, independent from blood glucose control. Adiponectin, intact proinsulin, and the IRIS-II score may be suitable parameters for monitoring of these additional beneficial therapeutic effects.

Elevated Intact Proinsulin Levels are Indicative of Beta-Cell Dysfunction, Insulin Resistance, and Cardiovascular Risk: Impact of the Antidiabetic Agent Pioglitazone

“…In contrast to insulinsensitizing strategies, sulfonylureas have been reported not to change or to increase plasma proinsulin values. 26,28,31,36,38,41,[48][49][50] Preliminary studies revealed that the fasting proinsulin serum concentration was significantly higher in T2DM patients treated with sulfonylureas than in a well-matched group receiving insulin only. 49 One of our studies explored the immediate effect of supplementary insulin treatment on beta-cell function in 20 T2DM patients with glimepiride monotherapy.…”

“…No such effects were observed in the glimepiride group. 28 Another analysis of the PIONEER data substantiated that measurement of intact proinsulin enables an estimation of atherosclerotic risk.…”

Association of high-sensitive C-reactive protein with advanced stage β-cell dysfunction and insulin resistance in patients with type 2 diabetes mellitus

“…However, prospective studies using the same diagnostic markers as used in our current analysis have provided evidence of a beneficial impact of other therapeutic interventions compared to sulfonylurea therapy. Treatment of insulin resistance, e.g., using PPARg agonists seems to be an effective measure for decreasing cardiovascular and metabolic risk (29)(30)(31)(32).…”

Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions

“…In addition to decreasing insulin resistance and ␤-cell dysfunction (47), increasing serum HDL cholesterol and decreasing serum triglycerides levels (25), improving the procoagulant state and endothelial dysfunction in diabetes, and reducing "nontraditional" inflammatory cytokines (12), thiazolidinediones have been shown to reduce myocardial infarct size (IS) in the rat (35,61,66,67). However, the specific underlying mechanisms for myocardial protection by thiazolidinediones are still unknown.…”