GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet

Abstract

McClean PL, Irwin N, Cassidy RS, Holst JJ, Gault VA, Flatt PR. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet. Am J Physiol Endocrinol Metab 293: E1746-E1755, 2007. First published September 11, 2007; doi:10.1152/ajpendo.00460.2007.-The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, (Pro 3 )GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of (Pro 3 )GIP over 50 days significantly decreased body weight compared with salinetreated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. (Pro 3 )GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in (Pro 3 )GIP-treated high-fat-fed mice. (Pro 3 )GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro 3 )GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet.gastric inhibitory polypeptide; antagonist; high-fat feeding GASTRIC INHIBITORY POLYPEPTIDE (GIP) is an important gastrointestinal hormone secreted from intestinal K cells in response to feeding (35). Together with the sister incretin hormone glucagon-like peptide-1 (GLP-1), GIP comprises the hormonal arm of the enteroinsular axis involved in postprandial nutrient homeostasis (7). The most widely accepted physiological role for GIP is glucose-dependent potentiation of insulin secretion (33). The importance of pancreatic ␤-cells as a target for GIP is further illustrated by the ability of the hormone to stimulate the neogenesis, differentiation, and proliferation of insulinsecreting ␤-cells (10, 43). These various actions have given rise to GIP being implicated as a potentially important player in both the pathogenesis and potential treatment of type 2 diabetes (7,17,48).In addition to the classical ␤-cell target, the GIP receptor is expressed on various extrapancreatic tissues, including bone, intestine, heart, stomach, brain, and adipose tissue (46,49). The significance of GIP action at these sites is largely unknown, but the particularly potent and prolonged stimulation of GIP secretion after high-fat feeding (35) draws attention ...

Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion

“…The findings of Flatt and colleagues [23,25,26] in rodents provide an interesting parallelism with our results in humans. Genetic knockout of the GIP receptor and blockade of GIP action were both associated with a large improvement in insulin resistance and diabetes [25,26].…”

Preparation and in vivo evaluation of insulin-loaded biodegradable nanoparticles prepared from diblock copolymers of PLGA and PEG

“…To investigate conformational stability and sensitivity of insulin encapsulated in PEG-PLGA, Swiss TO mice with diet-induced obesity-diabetes (type II) were used. This diabetic animal model is closely aligned to diabetic obesity found increasingly in humans consuming high-fat and energy-rich diets (McClean et al, 2007). The high-fat diet resulted in glucose intolerance and impaired insulin sensitivity in animals used in this study (Bailey et al, 1986;Flatt et al, 1990).…”

Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT

“…Levels of ALT were not measured in that study, but along with the increase in GIP, an increase in aspartate aminotransferase, another marker of liver fat accumulation, was reported (47). In animal models, long-term administration of a GIP receptor antagonist decreased adipose tissue mass and triglyceride deposition in liver and muscle (23). So the notion of GIP adversely related to lipid metabolism and fatty liver is in line with earlier findings, but the mechanisms underlying increased fasting GIP levels warrant further study.…”

“…In contrast, GIP receptors are thought to promote fat deposition and fatty acid synthesis in adipose tissue (22). Administration of a GIP receptor antagonist reverses obesity and insulin resistance in high-fat-fed mice (23). In humans, the beneficial effects of bariatric surgery in curing diabetes among obese persons were accompanied by a rapid decrease in GIP, suggesting that lowering GIP levels may play a role in the metabolic effects of such a surgery (24).…”