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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gastrointestinal hormone, gastric inhibitory polypeptide (GIP), is synthesized and released from the duodenum and proximal jejunum postprandially. Its release depends upon several factors including meal content and pre-existing health status (ie. obesity, diabetes, age, etc.). It was initially discovered and named for its gastric acid inhibitory properties. However, its more physiologically relevant role appears to be as an insulinotropic agent with a stimulatory effect on insulin release and synthesis. Accordingly, it was later renamed glucose-dependent insulinotropic polypeptide because its action on insulin release depends upon an increase in circulating levels of glucose. GIP is considered to be one of the principle incretin factors of the enteroinsular axis. The GIP receptor is a G-protein-coupled receptor belonging to the family of secretin/VIP receptors. GIP receptor mRNA is widely distributed in peripheral organs, including the pancreas, gut, adipose tissue, heart, adrenal cortex, and brain, suggesting it may have other functions in addition to the ones mentioned above. An overactive enteroinsular axis has been suggested to play a role in the pathogenesis of diabetes and obesity. In addition to stimulating insulin release, GIP has been shown to amplify the effect of insulin on target tissues. In adipose tissue, GIP has been reported to (1) stimulate fatty acid synthesis, (2) enhance insulin-stimulated incorporation of fatty acids into triglycerides, (3) increase insulin receptor affinity, and (4) increase sensitivity of insulin-stimulated glucose transport. In addition, although controversial, lipolytic properties of GIP have been proposed. The mechanism of action of GIP-induced effects on adipocytes is unknown, and it is unclear whether these effects of GIP on adipocytes are direct or indirect. However, there is now evidence that GIP receptors are expressed on adipocytes and that these receptors respond to GIP stimulation. Given the location of its release and the timing of its release, GIP is an ideal anabolic agent and expanding our understanding of its physiology will be needed to determine its exact role in the etiology of diabetes mellitus and obesity.
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PMID:GIP biology and fat metabolism. 1066 5

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.
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PMID:Inhibition of gastric inhibitory polypeptide signaling prevents obesity. 1206 90

Gastric inhibitory polypeptide (GIP, also called glucose-dependent insulinotropic polypeptide) and glucagon-like peptide-1 (GLP-1) are peptide hormones from the gut that enhance nutrient-stimulated insulin secretion (the 'incretin' effect). Judging from experiments in mice with targeted deletions of GIP and GLP-1 receptors, the incretin effect is essential for normal glucose tolerance. In patients with type 2 diabetes mellitus it turns out that the incretin effect is severely impaired or abolished. The explanation seems to be that both the secretion of GLP-1 and the effect of GIP are impaired (whereas both the secretion of GIP and the effect of GLP-1 are near normal). The impaired GLP-1 secretion is probably a consequence of diabetic metabolic disturbances. The known genetic variations in the GIP receptor sequence are not associated with type 2 diabetes mellitus, but a defective insulinotropic effect of GIP may be found in first degree relatives of the patients, suggesting a genetic background for the defect. The molecular nature of the defect is not known and given the close similarity of the two receptors and their signalling, the dissociation of their effects is remarkable. Whereas GLP-1 and its analogues are attractive as therapeutic agents for type 2 diabetes mellitus, analogues of GIP are unlikely to be effective. On the other hand, GIP seems to play an important role in lipid metabolism, promoting the disposal of ingested lipids, and mice with a targeted deletion of the GIP receptor do not become obese when exposed to a high-fat diet. Therefore, antagonistic analogues of GIP may be speculated to have a role in the pharmaceutical management of obesity.
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PMID:Gastric inhibitory polypeptide analogues: do they have a therapeutic role in diabetes mellitus similar to that of glucagon-like Peptide-1? 1210 45

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that is released during a meal and facilitates the disposal of both glucose and fat. Because of the insulinotropic action of GIP, this hormone has been considered as a potential therapy of type 2 diabetes, where insulin secretion is inadequate. However, a recent study using GIP receptor knockout mice suggests that inhibition of GIP signalling might be a new target for anti-obesity drugs.
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PMID:GIP or not GIP? That is the question. 1262 51

Glucose-dependent insulinotropic polypeptide (GIP or gastric inhibitory polypeptide) is a gastrointestinal hormone, which modulates physiological insulin secretion. Due to its insulinotropic activity, there has been a considerable increase of interest in utilising the hormone as a potential therapy for type 2 diabetes. One of the difficulties in attempting to harness the insulinotropic activity of GIP into an effective therapeutic agent is its short biological half-life in the circulation. However, recent years have witnessed the development of a substantial number of designer enzyme-resistant 'super GIP' molecules with potent insulinotropic and anti-diabetic properties. In addition, observations in transgenic GIP receptor deficient mice indicate that GIP directly links overnutrition to obesity, therein playing a crucial role in the development of obesity and related metabolic disorders. The present review aims to highlight the rapidly emerging potential therapeutic applications of GIP, and especially, enzyme-resistant GIP analogues.
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PMID:Glucose-dependent insulinotropic polypeptide (GIP): anti-diabetic and anti-obesity potential? 1460 2

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.
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PMID:[GIP receptor knockout mice]. 1520 44

A much greater insulin response is observed after oral glucose load than after intravenous injection of glucose. The hormonal factor(s) implicated as transmitters of signals from the gut to pancreatic beta-cells was referred to incretin; gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide (GIP) is identified as one of the incretins. GIP exerts its effects by binding to its specific receptor, the GIP receptor, which is expressed in various tissues including pancreatic islets, adipose tissue, and brain. However, the physiological role of GIP has been generally thought to stimulate insulin secretion from pancreatic beta-cells, and the other actions of GIP have received little attention. We have bred and characterized mice with a targeted mutation of the GIP receptor gene. From these studies, we now know that GIP not only mediates early insulin secretion by acting on pancreatic beta-cells, but also links overnutrition to obesity by acting on adipocytes.
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PMID:Physiology of GIP--a lesson from GIP receptor knockout mice. 1565 7

Glucose-dependent insulinotropic polypeptide (GIP) is released from K-cells in the gut after meal ingestion, and acts in concert with glucagon-like peptide 1 (GLP-1) to augment glucose-stimulated insulin secretion. While derivatives of GLP-1 are under active investigation for the treatment of type 2 diabetes, the case is different for GIP. Indeed, the insulinotropic effect of GIP is almost absent in patients with type 2 diabetes. In addition, the unfavourable pharmacokinetic profile of native GIP obviates its clinical application. Different analogues of GIP exhibiting prolonged stability and enhanced biological potency have been generated in order improve the anti-diabetic properties of GIP. However, glucose-normalisation, as is typically observed during the intravenous administration of GLP-1 in patients with type 2 diabetes, has not yet been achieved with GIP or its derivatives. Since GIP appears to play a role in lipid physiology and elevated levels of GIP have been associated with obesity, antagonising GIP action has been proposed as a therapeutic strategy for obesity. This concept has recently been reinforced by the observation that GIP receptor knock-out mice are protected from high-fat diet-induced obesity. However, eliminating the effect of endogenous GIP may at the same time impair postprandial insulin secretion, thereby severely disturbing glucose homeostasis. Therefore, therapeutic strategies based on either augmenting or antagonising GIP action are far from being established alternatives for the future therapy of type 2 diabetes or obesity.
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PMID:GIP as a potential therapeutic agent? 1565 20

The glucoincretins, glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), are intestinal peptides secreted in response to glucose or lipid intake. Data on isolated intestinal tissues, dietary treatments and knockout mice strongly suggest that GIP and GLP-1 secretion requires glucose and lipid metabolism by intestinal cells. However, incretin secretion can also be induced by non-digestible carbohydrates and involves the autonomic nervous system and endocrine factors such as GIP itself and cholecystokinin. The classical pharmacological approach and the recent use of knockout mice for the incretin receptors have shown that a remarkable feature of incretins is the ability to stimulate insulin secretion in the presence of hyperglycaemia only, hence avoiding any hypoglycaemic episode. This important role is the basis of ongoing clinical trials using GLP-1 analogues. Since most of the data concern GLP-1, we will focus on this incretin. In addition, GLP-1 is involved in glucose sensing by the autonomic nervous system of the hepato-portal vein controlling muscle glucose utilization and indirectly insulin secretion. GLP-1 has been shown to decrease glucagon secretion, food intake and gastric emptying, preventing excessive hyperglycaemia and overfeeding. Another remarkable feature of GLP-1 is its secretion by the brain. Recently, elegant data showed that cerebral GLP-1 is involved in cognition and memory. Experiments using knockout mice suggest that the lack of the GIP receptor prevents diet-induced obesity. Consequently, macronutrients controlling intestinal glucose and lipid metabolism would control incretin secretion and would consequently be beneficial for health. The control of incretin secretion represents a major goal for new therapeutic as well as nutrition strategies for treating and/or reducing the risk of hyperglycaemic syndromes, excessive body weight and thus improvement of well-being.
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PMID:The incretins: a link between nutrients and well-being. 1587 88

Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P < 0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P < 0.05) and insulin (1.5-fold; P < 0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P < 0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P < 0.05) and partially corrected the obesity-related islet hypertrophy and beta-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes.
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PMID:Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3)GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes. 1604 12


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