Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients

Abstract

We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in patients with type 2 diabetes mellitus. Thirteen type 2 diabetic patients (nine men and four women; age, 52 +/- 3 yr; body mass index, 29.0 +/- 1.1 kg/m(2)), who were being treated with a stable dose of sulfonylurea (n = 7) or with diet alone (n = 6), received pioglitazone (45 mg/d) for 16 wk. Before and after pioglitazone treatment, subjects underwent a 75-g oral glucose tolerance test (OGTT) and two-step euglycemic insulin clamp (insulin infusion rates, 40 and 160 mU/m(2).min) with [(3)H]glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at L4-5. After 16 wk of pioglitazone treatment, fasting plasma glucose (179 +/- 10 to 140 +/- 10 mg/dl; P < 0.01), mean plasma glucose during OGTT (295 +/- 13 to 233 +/- 14 mg/dl; P < 0.01), and hemoglobin A(1c) (8.6 +/- 0.4% to 7.2 +/- 0.5%; P < 0.01) decreased without a change in fasting or post-OGTT insulin levels. Fasting plasma FFA (674 +/- 38 to 569 +/- 31 microEq/liter; P < 0.05) and mean plasma FFA (539 +/- 20 to 396 +/- 29 microEq/liter; P < 0.01) during OGTT decreased after pioglitazone. In the postabsorptive state, hepatic insulin resistance [basal endogenous glucose production (EGP) x basal plasma insulin concentration] decreased from 41 +/- 7 to 25 +/- 3 mg/kg fat-free mass (FFM).min x microU/ml; P < 0.05) and suppression of EGP during the first insulin clamp step (1.1 +/- 0.1 to 0.6 +/- 0.2 mg/kg FFM.min; P < 0.05) improved after pioglitazone treatment. The total body glucose MCR during the first and second insulin clamp steps increased after pioglitazone treatment [first MCR, 3.5 +/- 0.5 to 4.4 +/- 0.4 ml/kg FFM.min (P < 0.05); second MCR, 8.7 +/- 1.0 to 11.3 +/- 1.1 ml/kg FFM(.)min (P < 0.01)]. The improvement in hepatic and peripheral tissue insulin sensitivity occurred despite increases in body weight (82 +/- 4 to 85 +/- 4 kg; P < 0.05) and fat mass (27 +/- 2 to 30 +/- 3 kg; P < 0.05). After pioglitazone treatment, sc fat area at L4-5 (301 +/- 44 to 342 +/- 44 cm(2); P < 0.01) increased, whereas visceral fat area at L4-5 (144 +/- 13 to 131 +/- 16 cm(2); P < 0.05) and the ratio of visceral to sc fat (0.59 +/- 0.08 to 0.44 +/- 0.06; P < 0.01) decreased. In the postabsorptive state hepatic insulin resistance (basal EGP x basal immunoreactive insulin) correlated positively with visceral fat area (r = 0.55; P < 0.01). The glucose MCRs during the first (r = -0.45; P < 0.05) and second (r = -0.44; P < 0.05) insulin clamp steps were negatively correlated with the visceral fat area. These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin.

MANAGEMENT OF ENDOCRINE DISEASE: Morbidity in polycystic ovary syndrome

“…Peroxisome proliferator-activated receptor gamma (PPARγ) agonist treatment is associated with decreased peripheral adipocyte lipolysis, decreased free fatty acid levels and fat redistribution toward peripheral fat (93). In PCOS, PPARγ agonist treatment increased insulin sensitivity, improved ovulatory function and decreased inflammatory markers without significant effects on testosterone levels (94).…”

Pioglitazone for Secondary Stroke Prevention

“…Pioglitazone is a peroxisome proliferator-activated receptor γ agonist that, in addition to its primary effect on glycemic control, exerts potential beneficial effects on inflammation, fat distribution, lipid and protein metabolism, and vascular endothelial function. [12][13][14][15] The IRIS trial (Insulin Resistance Intervention After Stroke) found that among patients without diabetes mellitus who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of combined stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo, but differences in recurrent stroke alone did not reach statistical significance. 16 The objective of this study was to use the totality of the published literature to qualitatively and quantitatively evaluate the risk of recurrent stroke in stroke patients with abnormal glucose metabolism receiving pioglitazone therapy, by conducting a systematic review and meta-analysis of randomized controlled trials.…”

ISL1 Regulates Peroxisome Proliferator-Activated Receptor γ Activation and Early Adipogenesis via Bone Morphogenetic Protein 4-Dependent and -Independent Mechanisms

“…In a defined serum-free medium, PPAR␥ agonists markedly enhance the differentiation of preadipocytes isolated from SF but not of preadipocytes from VF of same individuals (54). In vivo, subcutaneous but not visceral fat expands in response to PPAR␥ agonists (55,56). The mechanisms by which SF and VF have different sensitivities to PPAR␥ agonists are still unknown.…”