Effects of Pioglitazone on Glucose-Dependent Insulinotropic Polypeptide–Mediated Insulin Secretion and Adipocyte Receptor Expression in Patients With Type 2 Diabetes William G. Tharp, 1 Dhananjay Gupta, 2 Olga Sideleva, 2 Carolyn F. Deacon, 3 Jens J. Holst, 4 Dariush Elahi, 4 and Richard E. Pratley 5 Diabetes 2020;69:146–157 | https://doi.org/10.2337/db18-1163 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 oc- cur through desensitization or downregulation of b-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator–activated receptor g (PPARg) response ele- ments (PPREs). 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 expres- sion in subcutaneous abdominal adipocytes from sub- jects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPARg binding to GIP-R PPREs. These results show PPARg ago- nists regulate GIP-R expression through PPREs in human adipocytes, but suggest this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Because GIP has antilipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPARg agonists. Obesity and type 2 diabetes mellitus (T2DM) are growing global public health crises. Worldwide, .650 million people are obese, and .422 million are affected by T2DM (1). The pathophysiology of T2DM is complex, with multiple metabolic abnormalities, including defects in incretin secretion and action, contributing to hyperglycemia in those with estab- lished disease. The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypep- tide (GIP) are secreted by enteroendocrine cells following nutrient ingestion and are responsible for stimulating .50% of postprandial insulin secretion (2). Both GLP-1 and GIP are rapidly degraded by dipeptidyl peptidase 4 (DPP-4) following secretion into the circulation. The secretion and clearance of GLP-1 and GIP are largely normal in those with T2DM; however, the insulinotropic effect to these hormones is markedly diminished (3,4). Blunted insuli- notropic responses to GLP-1 can be overcome by infu- sions that achieve supraphysiologic levels; however, even supraphysiologic GIP levels fail to stimulate insu- lin secretion in most patients with T2DM (5–7). As a con- sequence, the development of incretin-based therapies for the treatment of T2DM has largely focused on the creation of GLP-1 analogs and inhibitors of DPP-4 action (8,9). The incretin hormones act through specific G-protein– coupled membrane receptors that are widely expressed 1 Department of Anesthesiology, University of Vermont Medical Center, Larner College of Medicine, University of Vermont, Burlington, VT 2 Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 3 Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark 4 Cardiovascular Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 5 AdventHealth Translational Research Institute for Metabolism and Diabetes, Orlando, FL Corresponding author: Richard E. Pratley, richard.pratley@flhosp.org Received 26 October 2018 and accepted 13 November 2019 Clinical trial reg. no. NCT00656864, clinicaltrials.gov This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db18-1163/-/DC1. © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals .org/content/license. 146 Diabetes Volume 69, February 2020 METABOLISM Downloaded from http://diabetesjournals.org/diabetes/article-pdf/69/2/146/431768/db181163.pdf by guest on 22 April 2023