Predominant Role of GIP in the Development of a Metabolic Syndrome-like Phenotype in Female Wistar Rats Submitted to Forced Catch-up Growth

Abstract

Catch-up growth has been associated with the appearance of metabolic dysfunctions such as obesity and type 2 diabetes in adulthood. Because the entero-insular axis is critical to glucose homeostasis control, we explored the relevance of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the development of these pathologies. Offspring of rat dams fed ad libitum (control [C]) or 65% food-restricted during pregnancy and suckling time (undernourished [U]) were weaned onto a high-fat (HF) diet (CHF and UHF, respectively) to drive catch-up growth. Both male and female UHF rats showed an obese phenotype characterized by hyperphagy, visceral fat accumulation, and adipocyte hypertrophy. High-fat diet induced deterioration of glucose tolerance in a sex-dependent manner. Female UHF rats experienced much more severe glucose intolerance than males, which was not compensated by insulin hypersecretion, suggesting insulin resistance, as shown by homeostatic model assessment of insulin resistance values. Moreover, female, but not male, UHF rats displayed enhanced GIP but not GLP-1 secretion during oral glucose tolerance test. Administration of the GIP receptor antagonist (Pro3)GIP to UHF female rats over 21 days markedly reduced visceral fat mass and adipocyte hypertrophy without variations in food intake or body weight. These changes were accompanied by improvement of glucose tolerance and insulin sensitivity. In conclusion, the exacerbated production and secretion of GIP after the catch-up growth seems to represent the stimulus for insulin hypersecretion and insulin resistance, ultimately resulting in derangement of glucose homeostasis. Overall, these data evidence the role of GIP as a critical link between catch-up growth and the development of metabolic disturbances. (Endocrinology 155: 3769 -3780, 2014)

Novel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

“…1c, suggest that (Pro3)GIP is in fact an antagonist of the human GIPR. Our findings coincide with a large body of research demonstrating the antagonistic effects of (Pro3)GIP at the GIPR (Gault et al, 2002; Gault et al, 2003; De Toro-Martin et al, 2014). The summation of these results, as well as previous data demonstrating the efficacy of twincretin at both receptors in vivo (Finan et al, 2013) suggests that twincretin almost certainly induces significant cAMP production via both receptors in neural cells.…”

The programming effects of nutrition‐induced catch‐up growth on gut microbiota and metabolic diseases in adult mice

“…In this study, we showed that impaired nutrient supply during perinatal growth-induced adaptive changes, leading to metabolic disorders, such as obesity, impaired glucose tolerance, insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease when the organism was challenged with increased caloric intake. Our results are consistent with previous studies showing that maternal imbalanced nutrition-induced detrimental consequences on glucose and lipid homeostasis (Claycombe et al 2013;Baik et al 2014;De Toro-Martin et al 2014;Sellayah et al 2014). Therefore, maternal undernutrition results in lower birth weight that is accompanied by the development of chronic metabolic diseases in later life.…”

Species‐specific action of (Pro3)GIP – a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors

“…Recently, a promising GIP receptor antibody, Gipg013, with a K i of 6.8 nM was reported (Ravn et al ., ). Based on the numerous rodent studies that displayed promising improvements in the diabetic and/or obese state, (Pro3)GIP showed potential to fill the role as a promising antagonist in the context of GIP physiology (Gault et al ., ; Irwin et al ., ; McClean, ; De Toro‐Martin et al ., ). In ob / ob mice, chronic treatment with (Pro3)GIP improved glucose tolerance and insulin sensitivity (Irwin et al ., ), while treatment in mice previously on a high‐fat diet resulted in weight loss, improved insulin sensitivity and glucose tolerance (McClean, ).…”