Effect of Pioglitazone on Circulating Adipocytokine Levels and Insulin Sensitivity in Type 2 Diabetic Patients

Abstract

We examined the effect of pioglitazone (PIO) on circulating adipocytokine levels to elucidate the mechanisms by which thiazolidinediones improve insulin resistance in type 2 diabetes mellitus (T2DM). Twenty-three subjects with T2DM (age 54 +/- 2 yr, body mass index 29 +/- 1 kg/m(2)) were randomly assigned to receive placebo (n = 11) or PIO, 45 mg/d (n = 12), for 4 months. Before and after treatment, subjects received a 75-g oral glucose tolerance test (OGTT); euglycemic insulin clamp (40 mU/m(2).min) with 3-(3)H-glucose; determination of fat mass ((3)H(2)O); and measurement of fasting glucose, free fatty acids (FFAs), leptin, adiponectin, and TNFalpha concentrations. After 4 months of PIO, fasting plasma glucose concentration (Delta = -2.7 mol/liter), mean plasma glucose during OGTT (Delta = -3.8 mol/liter), and hemoglobin A(1c) (Delta = 1.7%) decreased (P < 0.05 vs. placebo) without change in fasting or post-OGTT plasma insulin levels. Fasting FFAs (Delta = 168 micromol/liter) and TNFalpha (Delta = 0.7 pg/ml) concentrations decreased (P < 0.05 vs. placebo), whereas adiponectin (Delta = 8.7 microg/ml) increased (P< 0.01 vs. placebo). Despite the increase in body fat mass (Delta = 3.4 kg) after PIO, plasma leptin concentration did not change significantly. No changes in plasma glucose, FFAs, or adipocytokine levels were observed in placebo-treated subjects. During the insulin clamp, endogenous (hepatic) glucose production decreased (Delta = -2.67 micromol/fat-free mass.min, P < 0.05 vs. placebo), whereas metabolic clearance rate of glucose (MCR) increased (Delta = 0.58 ml/fat-free mass.min, P < 0.05 vs. placebo) after PIO. In all subjects, before and after PIO, the decrease in plasma FFA concentration was correlated with the changes in both endogenous (hepatic) glucose production (r = 0.47, P < 0.05) and MCR (r = -0.41, P < 0.05), whereas the increase in plasma adiponectin concentration was correlated with the change in endogenous (hepatic) glucose production (r = -0.70, P < 0.01) and MCR (r = 0.49, P < 0.05). These results suggest that the direct effects of PIO on adipose tissue to decrease plasma FFA levels and increase plasma adiponectin contribute to the improvements in hepatic and peripheral insulin sensitivity and glucose tolerance in patients with T2DM.

Adiponectin is critical in determining susceptibility to depressive behaviors and has antidepressant-like activity

“…Compounds that increase endogenous adiponectin levels may be proven to have beneficial effects on treatment of depression. Administration of peroxisome proliferator-activated receptor-γ (PPARγ) agonists increases plasma levels of adiponectin by two-to threefold (46)(47)(48)(49). Interestingly, it has been recently reported that PPARγ agonists, i.e., pioglitazone and rosiglitazone, produce antidepressant effects (50,51).…”

Long-Term Effects of Pioglitazone on Carotid Atherosclerosis in Japanese Patients with Type 2 Diabetes without a Recent History of Macrovascular Morbidity

“…Indeed, pioglitazone has been shown to reduce neointimal thickening after endothelial injury in animal models of atherosclerosis 10) . Furthermore, pioglitazone can modify systemic inflammatory and coagulation markers 8,9) . Recently, pioglitazone was found to modify the progression of carotid atherosclerosis induced by various genetic risk factors 28) .…”

“…It acts by increasing insulin sensitivity, mediating favorable effects on blood glucose levels and lipid profile 7) . In addition to these metabolic actions, pioglitazone has beneficial effects on systemic inflammatory and coagulation markers, and endothelial cell function 8,9) . Thus, the overall pattern of changes induced by pioglitazone suggests a general improvement of various risk factors for atherosclerosis.…”

Mechanisms by which diabetes increases cardiovascular disease

“…mRNA for VCAM-1 and scavenger receptor class A were significantly reduced in lesions from these mice [50]. Interestingly, PPARγ agonists are known to promote adipocyte differentiation and also to increase adiponectin transcription and serum levels [51]. However, clinical data suggest that PPARγ agonists may rather promote cardiovascular adverse events than be atheroprotective [30].…”