Abnormalities of GIP in Spontaneous Syndromes of Obesity and Diabetes in Mice

Abstract

The role of GIP in the pathogenesis of spontaneous syndromes of obesity-diabetes was examined in ob/ob mice of the Aston stock and db/db mice of the C57BL/KsJ background. Compared with lean controls, fed adult ob/ob and db/db mice, respectively, exhibited 1.8-fold and 2.1-fold increases in body weight, 1.8-fold and 2.8-fold elevations of plasma glucose, and 15.4-fold and 5.6-fold elevations of plasma insulin. As indicated by the relative magnitude of the hyperglycemia and hyperinsulinemia, db/db mice displayed a particularly severe form of diabetes. Plasma GIP concentrations of ob/ob and db/db mice were elevated 15.1-fold and 6.2-fold, respectively; the increments closely corresponded with the degrees of hyperinsulinemia. Small intestinal weight was increased 1.4-fold and 1.8-fold in ob/ob and db/db mice, respectively, but the intestinal GIP content expressed as microgram/g intestine or microgram/intestine was raised only in ob/ob mice (1.9-fold and 2.8-fold, respectively). Since glucose stimulation of insulin release is defective in both mutant strains, the results strongly implicate pathologically raised GIP concentrations in the hyperinsulinemia and related metabolic abnormalities of the obesity-diabetes syndromes. It is suggested that hypersecretion of GIP results in part from loss of normal feedback inhibition by endogenous insulin.

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

“…The particularly potent stimulation of GIP secretion after high-fat feeding [27] suggests a role for GIP in fat metabolism [20]. Consistent with this, plasma GIP concentrations have been reported to be elevated in obesity-related type 2 diabetes [28] and animals with obesity-related diabetes [29]. Experimental evidence in mice also indicates that inhibition of GIP signalling by genetic knockout of the GIP receptor prevents diet-induced obesity through the preferential use of fat as an energy substrate [30].…”

“…More recently it has been shown that obese diabetic (ob/ob) mice have intestinal K cell hyperplasia, markedly elevated concentrations of intestinal (2.8-fold increase) and circulating GIP (15.1-fold increase) [29,40,41] and display a diminished insulinotropic response to native GIP [11]. Additionally, ob/ob mice genetically manipulated to knock out GIP receptor function displayed significant amelioration of adiposity [30].…”

High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats

“…However, the bridge between high-fat obesitogenic diet and obesity comorbidities is not fully understood. High-fat feeding, such as that used in the present study, allows intestinal K-cell hyperplasia, enhancing GIP gene expression together with intestinal GIP content, ultimately resulting in high basal and feedinginduced circulating levels of GIP [6][7][8][9]. The role played by GIP in mediating the effects of HFD, i.e.…”

“…High-fat feeding induces K cell hyperplasia and glucosedependent insulinotropic polypeptide (GIP) secretion [6][7][8][9] with insulin secretion potentiating effects [10]. Blockade of GIP action by administration of a specific GIP receptor antagonist, (Pro 3 )GIP, reverses the glucose intolerance induced by HFD [11] without affecting circulating insulin concentration.…”

Nutrient-induced secretion and metabolic effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1

“…Animal models of obesity-diabetes syndromes support a role for an overactive EIA in the metabolic disturbance. The genetically-obese (ob/ob) mouse exhibits hyperplasia of intestinal GIP-secreting cells and circulating GIP and insulin levels are raised (Flatt et al 1983). Circulating GLP-1(7-36)amide levels cannot be measured in reasonable blood volumes in these animals, but intestinal levels are elevated when compared with homozygous lean littermates and these animals can respond to exogenous GLP-1(7-36)amide administration .…”