Pioglitazone improves insulin resistance and decreases blood pressure in adult patients with congenital adrenal hyperplasia

ContextPatients with congenital adrenal hyperplasia (CAH) are chronically treated with supraphysiological doses of glucocorticoids, which are known to induce insulin resistance. Thiazolidinediones might reverse this effect and improve insulin sensitivity.ObjectivesTo assess insulin sensitivity in CAH patients and the effect of pioglitazone treatment on insulin sensitivity in CAH patients. Secondary objectives were the effects of treatment with pioglitazone on blood pressure, body fat distribution, lipid, and steroid profiles.DesignRandomized placebo controlled crossover trial.ParticipantsTwelve CAH patients and 12 body mass and age-matched control subjects.InterventionSixteen-week treatment with pioglitazone (45 mg/day) or placebo.Main outcome measureInsulin sensitivity measured by euglycemic clamp and oral glucose tolerance test. Further measures were 24-h blood pressure profiles, body fat distribution measured by magnetic resonance imaging, dual energy x-ray absorptiometry (DEXA) and bioimpedance procedures, liver fat by magnetic resonance spectroscopy, lipid, and steroid profiles.ResultsCAH patients were insulin resistant compared with healthy controls. Treatment with pioglitazone significantly improved insulin sensitivity in CAH patients (glucose infusion rate (GIR) from 28.5±11.6 to 38.9±11.0 μmol/kg per min, P=0.000, GIR in controls 46.2±23.4 μmol/kg per min, P<0.05 versus CAH). Treatment with pioglitazone decreased blood pressure (systolic: 124.0±13.6 vs 127.0±14.9 mmHg, P<0.001, diastolic: 72.8±11.5 vs 77.4±12.6 mmHg, P<0.001). No changes in body fat distribution, lipid, and steroid profiles were observed.ConclusionsCAH patients are insulin resistant compared with matched control subjects. Treatment with pioglitazone improves insulin sensitivity and decreases blood pressure in CAH patients.

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Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1416412112 ◽

2015 ◽

Vol 112 (14) ◽

pp. 4363-4368 ◽

Cited By ~ 37

Author(s):

James E. N. Minchin ◽

Ingrid Dahlman ◽

Christopher J. Harvey ◽

Niklas Mejhert ◽

Manvendra K. Singh ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Body Fat ◽

Fat Distribution ◽

Body Fat Distribution ◽

High Fat ◽

Type V ◽

Visceral Adipose

Genome-wide association studies have implicated PLEXIN D1 (PLXND1) in body fat distribution and type 2 diabetes. However, a role for PLXND1 in regional adiposity and insulin resistance is unknown. Here we use in vivo imaging and genetic analysis in zebrafish to show that Plxnd1 regulates body fat distribution and insulin sensitivity. Plxnd1 deficiency in zebrafish induced hyperplastic morphology in visceral adipose tissue (VAT) and reduced lipid storage. In contrast, subcutaneous adipose tissue (SAT) growth and morphology were unaffected, resulting in altered body fat distribution and a reduced VAT:SAT ratio in zebrafish. A VAT-specific role for Plxnd1 appeared conserved in humans, as PLXND1 mRNA was positively associated with hypertrophic morphology in VAT, but not SAT. In zebrafish plxnd1 mutants, the effect on VAT morphology and body fat distribution was dependent on induction of the extracellular matrix protein collagen type V alpha 1 (col5a1). Furthermore, after high-fat feeding, zebrafish plxnd1 mutant VAT was resistant to expansion, and excess lipid was disproportionately deposited in SAT, leading to an even greater exacerbation of altered body fat distribution. Plxnd1-deficient zebrafish were protected from high-fat-diet-induced insulin resistance, and human VAT PLXND1 mRNA was positively associated with type 2 diabetes, suggesting a conserved role for PLXND1 in insulin sensitivity. Together, our findings identify Plxnd1 as a novel regulator of VAT growth, body fat distribution, and insulin sensitivity in both zebrafish and humans.

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