Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure

Abstract

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) control glucose homeostasis through well-defined actions on the islet β cell via stimulation of insulin secretion and preservation and expansion of β cell mass. We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r -/-, Gipr -/-, and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor-1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist [D-Ala 2 ]GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the β cell via control of adipokine secretion and energy expenditure.

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

“…Circulating adipokines were not appreciably affected by (Pro 3 )GIP, with only a small possibly beneficial decrease in resistin observed. This does not indicate a significant GIPergic adipokine generation in ob/ob mice and questions their recently postulated role in alleviating insulin sensitivity in GIP receptor knockout mice [43]. The abnormal lipid profile also persisted in ob/ob mice treated with (Pro 3 )GIP, but there were significant improvements in triacylglycerol and LDL-cholesterol.…”

Actions of exendin-4 therapy on cognitive function and hippocampal synaptic plasticity in mice fed a high-fat diet

“…1 Differences in food intake induced by exendin-4 therapy may have made a contribution to these effects, but additional experiments are required to single out direct effects of peptide administration on brain function. The reason why bodyweight did not change with exendin-4 treatment may point to an effect of GLP-1 on physical activity and energy expenditure as observed in knockout mice, 11 however, further studies are necessary to confirm this. However, the object recognition test clearly showed that mice fed a high-fat diet exhibited notable impairments in cognitive performance as they failed to discriminate between the familiar and the novel object.…”

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

“…A DPP‐4 inhibitor is used for treating patients with type 2 diabetes. The main mechanism for its anti‐diabetic effect is to inhibit DPP‐4, a degradative enzyme of incretin hormones such as GLP‐1 and glucose‐dependent insulinotropic polypeptide 36. Incretin has been known to exert pleiotropic effects on the central nervous system, the liver, cardiovascular, lung, kidney, or skeletal muscle.…”