Pioglitazone Improves Fat Distribution, the Adipokine Profile and Hepatic Insulin Sensitivity in Non-Diabetic End-Stage Renal Disease Subjects on Maintenance Dialysis: A Randomized Cross-Over Pilot Study

Abstract

BackgroundFat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity.Trial DesignThis was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects.MethodsAt the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored.ResultsFour months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63×10−3 to 0.76×10−3. This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP.Conclusions/LimitationsPioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation.Trial RegistrationClinicalTrial.gov NCT01253928

Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence

“…Pioglitazone is well-tolerated in patients with CKD [219]. Indeed, pioglitazone improved the visceral-to-subcutaneous fat deposition, adipokine profile, hepatic insulin sensitivity, and circulating CRP in non-diabetic patients on dialysis [220]. Similar improvements in adiponectin and CRP were also found in obese, diabetic, or insulin-resistant patients with end-stage renal failure (NCT01301027).…”

Treatment with direct-acting antivirals improves peripheral insulin sensitivity in non-diabetic, lean chronic hepatitis C patients

“…Insulin sensitivity was assessed by performing a two-step hyperinsulinemic euglycemic clamp (0.3 mU · kg−1 · min−1 and 1 mU · kg−1 · min−1 for 90 min each) with non-radioactive tracers ([6,6]- 2 H 2 -glucose and 2 H 5 -glycerol, Cambridge Isotope Laboratories, Innerberg, Switzerland) [37] (S1 Fig). Blood samples were collected at 30 min intervals for the analysis of tracers, non-esterified fatty acids (NEFA), glucose and insulin and every 5 min during the clamp to control plasma glucose concentration, which was maintained constant at ∼5 mmol/L by infusing a 20% (w/v) glucose solution.…”

Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug

“…Pioglitazone treatment is associated with an increase in insulin sensitivity in diabetic subjects, notwithstanding its neutral [ 157 ] or increasing effect in body weight of about 2.5–3 kg [ 158 ]. This is due to a change in adipose tissue distribution with reduced visceral fat in favour of subcutaneous fat [ 157 , 159 – 161 ]; in non-diabetic individuals it promotes an increase in total body fat content with preferential accumulation in the lower body parts and reduction in waist-to-hip ratio [ 162 ]. Both in animals [ 163 ] and humans [ 161 , 162 , 164 ], pioglitazone increases the number and the activity of small adipocytes promoting differentiation of preadipocytes to adipocytes in visceral and subcutaneous adipose tissue stimulating glucose uptake, storage, and metabolism [ 165 , 166 ].…”