Abstract

Incretin hormone dysregulation contributes to reduced insulin secretion and hyperglycemia in patients with Type 2 Diabetes Mellitus (T2DM). Resistance to glucose dependent insulinotropic polypeptide (GIP) action may occur through desensitization or down-regulation of β-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferation-activated receptor-γ (PPARγ) response elements (PPRE). Whether this occurs in humans is unknown. To test this, we conducted a randomized, double-blind, placebo-controlled trial of pioglitazone therapy on GIP-mediated insulin secretion and adipocyte GIP-R expression in subjects with well controlled T2DM. Insulin sensitivity improved, but the insulinotropic effect of infused GIP was unchanged following 12 weeks of pioglitazone treatment. In parallel, we observed increased GIP-R mRNA expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPARγ binding to GIP-R PPRE. These results show PPARγ agonists regulate GIP-R expression through PPRE in human adipocytes, but suggests this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Since GIP has anti-lipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPARγ agonists.