Glucose-dependent insulinotropic polypeptide deficiency reduced fat accumulation and insulin resistance, but deteriorated bone loss in ovariectomized mice.

Given the established roles of glucose-dependent insulinotropic polypeptide (GIP) in promoting fat storage and bone formation, we assessed the contribution of GIP to obesity and osteopenia in ovariectomized mice with a gene encoding green fluorescent protein (GFP) inserted into the GIP locus, in which GIP was either reduced (GIPgfp/+ ) or absent (GIPgfp/gfp ). In GIPgfp/gfp mice, weight gain, subcutaneous and visceral fat mass were reduced, and glucose intolerance was improved compared with wild-type mice with the same magnitude of insulin responses. Cancellous bone mineral density and bone cortical thickness were reduced in GIPgfp/gfp mice compared with wild-type mice. In GIPgfp/+ mice, weight gain, glucose intolerance and cancellous bone mineral density were not different from that of wild-type mice. These results indicate that the total elimination of GIP ameliorates weight gain and adiposity in ovariectomized mice, but it enhances osteopenia, particularly in cancellous bone by partly suppressing bone formation.

Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength.

UNLABELLED: A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone--and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology. INTRODUCTION: The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice. METHODS: Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively. RESULTS: As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy. CONCLUSIONS: This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.

Effective surgical treatment of obesity may be mediated by ablation of the lipogenic gut hormone gastric inhibitory polypeptide (GIP): evidence and clinical opportunity for development of new obesity-diabetes drugs?

Roux-en-Y bypass surgery is increasingly used for treatment of gross obesity due to the general inability of lifestyle change and existing drug treatments to counter the obesity epidemic. This common form of bariatric surgery involves bypass of the small intestine with significant reduction of body of weight that is independent of malabsorption. Strikingly, obesity-related diabetes is also cured by the procedure but prior to body weight loss. This is due to rapid improvement of insulin resistance and associated pancreatic beta-cell function. Several hypotheses have been proposed to account for this phenomenon, but the most attractive concerns surgical ablation of gastric inhibitory polypetide (GIP)-secreting intestinal K-cells. Thus, circulating GIP levels are decreased after Roux-en-Y bypass surgery and GIP is known to play a key role in lipid metabolism and fat deposition. Further, both genetic and chemical ablation of GIP in animal models has been shown to protect against obesity and associated metabolic disturbances. These observations in animals and man suggest that GIP receptor antagonism may afford an alternative therapeutic option for treatment of obesity-diabetes.

Gastric inhibitory polypeptide as an endogenous factor promoting new bone formation after food ingestion.

Calcium plays a fundamental role as second messenger in intracellular signaling and bone serves as the body's calcium reserve to tightly maintain blood calcium levels. Calcium in ingested meal is the main supply and inadequate calcium intake causes osteoporosis and bone fracture. Here, we describe a novel mechanism of how ingested calcium is deposited on bone. Meal ingestion elicits secretion of the gut hormone gastric inhibitory polypeptide (GIP) from endocrine K cells in the duodenum. Bone histomorphometrical analyses revealed that bone formation parameters in the mice lacking GIP receptor (GIPR(-/-)) were significantly lower than those of wild-type (GIPR(+/+)) mice, and that the number of osteoclasts, especially multinuclear osteoclasts, was significantly increased in GIPR(-/-) mice, indicating that GIPR(-/-) mice have high-turnover osteoporosis. In vitro examination showed the percentage of osteoblastic cells undergoing apoptosis to be significantly decreased in the presence of GIP. Because GIPR(-/-) mice exhibited an increased plasma calcium concentration after meal ingestion, GIP directly links calcium contained in meal to calcium deposition on bone.

[GIP receptor knockout mice].

Gastric inhibitory polypeptide(GIP) is a gastrointestinal peptide hormone, which is secreted from duodenal endocrine K cells after absorption of glucose or fat. It is well known as an incretin. To determine the further role of GIP in vivo, we generated GIP receptor-knockout mice. The mice showed higher blood glucose levels with impaired initial insulin response after oral glucose load. Even after high-fat diet, knockout mice lack compensatory insulin secretion, and showed no hyper-insulinemia. Moreover, knockout mice fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Therefore, GIP directly links glucose tolerance and over-nutrition to obesity and it is a potential target for the treatment for the metabolic syndrome.

Inhibition of gastric inhibitory polypeptide signaling prevents obesity.

Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr(-/-)) fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice (Gipr(-/-), Lep(ob)/Lep(ob)) generated by crossbreeding Gipr(-/-) and obese ob/ob (Lep(ob)/Lep(ob)) mice gained less weight and had lower adiposity than Lep(ob)/Lep(ob) mice. The Gipr(-/-) mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs.

Influence of gastric inhibitory polypeptide antiserum on glucose-induced insulin secretion in rats.

The action of gastric inhibitory polypeptide (GIP) antiserum on glucose tolerance and insulin secretion after an intraduodenal glucose load (600 mg/kg) was examined in anesthetized rats. In control experiments the insulin secretion was nearly doubled when glucose was administered intraduodenally, as compared to an iv glucose load to simulate the blood glucose curve after the intraduodenal glucose administration. After injection of GIP antiserum, the glucose curve resulting from the intraduodenal glucose load was slightly elevated and the insulin response was significantly reduced. No free GIP could be measured in the plasma of antibody-treated rats. However, the GIP antiserum did not offset the incretin effect of the intraduodenal glucose load completely. In control experiments the same amount of GIP antibody completely blocked the insulinotropic effect of exogenous porcine GIP (0.6 microgram/kg . h). In nonanesthetized rats serial oral glucose tolerance tests were performed for 14 days after injection of the GIP antiserum. Despite the blockage of endogenous GIP, the glucose tolerance did not change significantly in the antibody-treated group of rats as compared to a control group. These data indicate that GIP is not the exclusive incretin and that additional gut factors with insulinotropic activity exist.

Depression of insulin release by anti-GIP serum after oral glucose in rats.

An oral glucose tolerance test (OGTT), an OGTT after infusion of anti-gastric inhibitory polypeptide (GIP) serum, and an intravenous glucose infusion were performed in unrestrained and unanesthetized rats. In the rats treated with anti-GIP serum the insulin release was significantly depressed. This finding supports the concept that GIP is a physiologically important 'glucose-dependent insulin-releasing peptide'.

Lack of a gastrointestinal mediator of insulin action in maturity-onset diabetes.

It is suggested that hepatic uptake of orally ingested glucose depends not only on insulin secretion but also on the release of a gastrointestinal factor which mediates insulin action on the liver. In maturity-onset diabetes characterised by hyperinsulinaemia and insulin resistance, deficiency of this gastrointestinal factor may be the primary pathogenetic event leading to postprandial hyperglycaemia. Postprandial hyperglycaemia brings about an increase in insulin secretion; and hyperinsulinaemia, in turn, results in decreased binding of insulin to its receptor and in peripheral (extrahepatic) resistance to insulin.