Effects of Pioglitazone on Glucose-Dependent Insulinotropic Polypeptide–Mediated Insulin Secretion and Adipocyte Receptor Expression in Patients With Type 2 Diabetes

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 downregulation of β-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator–activated receptor γ (PPARγ) response elements (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 expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPARγ binding to GIP-R PPREs. These results show PPARγ agonists 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 PPARγ agonists.

How May GIP Enhance the Therapeutic Efficacy of GLP-1?

“…The GIPR is found at low levels in preadipocytes, but its expression increases throughout differentiation and is associated with markers of adipocyte development [50,51]. PPARγ (peroxisome proliferator-activated receptor γ) is a master regulator of WAT generation, GIPR is a downstream PPARγ target, and PPARγ ligands increase its expression whereas PPARγ knockdown decreases GIPR levels [52,53]. Similarly, GIP enhances adipocyte Box…”

Coordinated regulation of gene expression and microRNA changes in adipose tissue and circulating extracellular vesicles in response to pioglitazone treatment in humans with type 2 diabetes

“…To test our hypothesis, we used archived plasma and subcutaneous adipose tissue samples from a 3-month randomized, controlled trial (NCT00656864) (13). Participants included 24 subjects with T2D who were well-controlled (HbA1c ≤ 7.0%) with diet/exercise or metformin.…”

“…Clinical trial design and subjects. Interventional study, ClinicalTrials.gov ID: NCT00656864 (33). Twenty-four participants with well-controlled type 2 diabetes (T2D) (HbA1C<7%) on diet and exercise or a stable dose of metformin were recruited for a randomized, double-blind, and placebocontrolled study.…”

“…Data from the IVGTT were used to calculate insulin sensitivity (Si), acute insulin response to glucose (AIRg), and glucose effectiveness (Sg) using the Minimal Model method of Bergman (MINMOD-Millennium,© R. Bergman (34)). The IVGTT consisted of an intravenous bolus of 0.3 g dextrose/kg body weight followed by an insulin bolus (0.06 IU/kg body weight) 20 min later (33). Administration of the insulin bolus during the IVGTT circumvent the need for endogenous insulin secretion and permits the application of minimal model analysis in people with diabetes (35).…”

Quality Improvement in Diabetes Care: A Review of Initiatives and Outcomes in the T1D Exchange Quality Improvement Collaborative

“…Initiatives to improve CGM use included investing in new staff roles to support CGM uptake and creating patient navigator positions dedicated to helping patients navigate insurance coverage, industry forms, and CGM training sessions. In another collaborative project focused on diabetes devices, five T1DX-QI sites deployed QI interventions to expand insulin pump use, with a 10% overall increase from a baseline of 46 to 56% for the entire cohort ( 43 ). Successful interventions to expand pump use included redesigning clinic workflows, developing mobile technology classes, and coaching patients to take insulin before meals.…”