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Disruption of GIPR/GIP signaling axis correlated with obesity, insulin resistance
The glucose-dependent insulinotropic peptide receptor/glucose-dependent insulinotropic peptide signaling axis appears to play an important role in the pathogenesis of obesity and attendant insulin resistance, according to study results.
Researchers recruited three independent cohorts of participants seen at university-affiliated hospitals in Spain. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) samples were collected from morbidly obese patients undergoing bariatric surgery. The researchers also obtained biobank tissue samples from a nonmorbidly obese control group through surgeries such as hernia repair or cholecystectomy.
The researchers evaluated the expression of glucose-dependent insulinotropic peptide (GIP) and GIP receptor (GIPR) in the tissue samples, with a focus on body size and biochemical variables. The relationship between GIP and insulin sensitivity was assessed in human adipocyte cell lines in environments with normal oxygen concentration, as well as in hypoxic situations.
The results showed a down-regulation of GIPR expression in the SAT of the obese patients, as well as an inverse association between GIPR and BMI, waist circumference, systolic blood pressure, glucose and triglyceride levels. In addition, the following variables were revealed to be strongly correlated with GIPR expression in SAT: homeostasis model assessment of insulin resistance (HOMA-IR), glucose, and G protein-coupled receptor kinase 2 (GRK2).
GIP was found to be an insulin sensitizer incretin through glucose uptake assessments and insulin signaling in fat cells. The results of immunoprecipitation experiments indicated that GIP triggers the interaction of GRK2 and GIPR, and minimizes the interaction of GRK2 and insulin receptor substitute 1 (IRS1). These relationships, noted under circumstances of normal oxygen concentration, were not maintained in fat cells cultured under hypoxic conditions. Consistent with this finding, GIP increased insulin sensitivity in adipose-derived stem cells in lean patients. GIP enhanced the expression of GIPR, which occurred in tandem with the down-regulation of the incretin-inhibiting enzyme DPP-IV. In human fat cells taken from obese patients with decreased GIPR levels, none of the physiological effects of GIP were observed.
“Here, we demonstrate a defective GIP/GIPR signaling axis in obese-derived adipose tissue, which is characterized by decreased GIPR expression in a subcutaneous adipose depot, an inverse relationship to insulin resistance, and a GIP-resistant phenotype in obese-derived adipocytes,” the researchers wrote. “Further investigation will be required to determine if the failure of obese adipose tissue to properly respond to GIP is a consequence of an altered epigenetic regulation of GIPR, originating from the obese environment.”
Disclosure: The researchers report no relevant financial disclosures.