Glucose-dependent insulinotropic polypeptide deficiency reduced fat accumulation and insulin resistance, but deteriorated bone loss in ovariectomized mice.
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ABSTRACT:
SUBMITTER: Shimazu-Kuwahara S
PROVIDER: S-EPMC6626948 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We aim to validate the effects of glucose-dependent insulinotropic polypeptide (GIP) on fat distribution and glucose metabolism in Han Chinese populations.We genotyped six tag single-nucleotide polymorphisms (SNPs) of GIP and four tag SNPs of glucose-dependent insulinotropic polypeptide receptor (GIPR) among 2884 community-based individuals from Han Chinese populations. Linear analysis was applied to test the associations of these variants with visceral fat area (VFA) and subcutaneous fat area (SFA) quantified by magnetic resonance imaging as well as glucose-related traits.We found that the C allele of rs4794008 of GIP tended to increase the VFA and the VFA/SFA ratio in all subjects (P=0.050 and P=0.054, respectively), and rs4794008 was associated with the VFA/SFA ratio in males (P=0.041) after adjusting for the BMI. The VFA-increasing allele of rs4794008 was not related to any glucose metabolism traits. However, rs9904288 of GIP was associated with the SFA in males as well as glucose-related traits in all subjects (P range, 0.004-0.049), and the GIPR variants displayed associations with both fat- and glucose-related traits.The results could provide the evidence that GIP might modulate visceral fat accumulation via incretin function or independent of incretin.
| S-EPMC5518809 | biostudies-literature
Project description:ObjectiveTo evaluate the glucose dependency of glucose-dependent insulinotropic polypeptide (GIP) effects on insulin and glucagon release in 10 healthy male subjects ([means ± SEM] aged 23 ± 1 years, BMI 23 ± 1 kg/m(2), and HbA(1c) 5.5 ± 0.1%).Research design and methodsSaline or physiological doses of GIP were administered intravenously (randomized and double blinded) during 90 min of insulin-induced hypoglycemia, euglycemia, or hyperglycemia.ResultsDuring hypoglycemia, GIP infusion caused greater glucagon responses during the first 30 min compared with saline (76 ± 17 vs. 28 ± 16 pmol/L per 30 min, P < 0.008), with similar peak levels of glucagon reached after 60 min. During euglycemia, GIP infusion elicited larger glucagon responses (62 ± 18 vs. -11 ± 8 pmol/L per 90 min, P < 0.005). During hyperglycemia, comparable suppression of plasma glucagon (-461 ± 81 vs. -371 ± 50 pmol/L per 90 min, P = 0.26) was observed with GIP and saline infusions. In addition, during hyperglycemia, GIP more than doubled the insulin secretion rate (P < 0.0001).ConclusionsIn healthy subjects, GIP has no effect on glucagon responses during hyperglycemia while strongly potentiating insulin secretion. In contrast, GIP increases glucagon levels during fasting and hypoglycemic conditions, where it has little or no effect on insulin secretion. Thus, GIP seems to be a physiological bifunctional blood glucose stabilizer with diverging glucose-dependent effects on the two main pancreatic glucoregulatory hormones.
| S-EPMC3219957 | biostudies-literature
Project description:Obesity is a global epidemic associated with a higher risk of cardiovascular disease and metabolic disorders, such as type 2 diabetes. Previous studies demonstrated that chronic feeding of steamed wheat bran (WB) decreases obesity. To clarify the underlying mechanism and the responsible component for the anti-obesity effects of steamed WB, we investigated the effects of dietary steamed WB and arabinoxylan on postprandial energy metabolism and blood variables. Overnight-fasted male C57BL/6J mice were fed an isocaloric diet with or without steamed WB (30%). Energy metabolism was evaluated using an indirect calorimeter, and plasma glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) levels were measured for 120 min after feeding. We similarly investigated the effect of arabinoxylan, a major component of steamed WB. Mice fed the WB diet had higher postprandial fat oxidation and a lower blood GIP response compared with mice fed the control diet. Mice fed the arabinoxylan diet exhibited a dose-dependent postprandial blood GIP response; increasing the arabinoxylan content in the diet led to a lower postprandial blood GIP response. The arabinoxylan-fed mice also had higher fat oxidation and energy expenditure compared with the control mice. In conclusion, the findings of the present study revealed that dietary steamed WB increases fat oxidation in mice. Increased fat oxidation may have a significant role in the anti-obesity effects of steamed WB. The postprandial effects of steamed WB are due to arabinoxylan, a major component of WB. The reduction of the postprandial blood GIP response may be responsible for the increase in postprandial fat utilization after feeding on a diet containing steamed WB and arabinoxylan.
| S-EPMC5614337 | biostudies-literature
Project description:Gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) is one of the incretins, which are gastrointestinal hormones released in response to nutrient ingestion and potentiate glucose-stimulated insulin secretion. Single fat ingestion stimulates GIP secretion from enteroendocrine K cells; chronic high-fat diet (HFD) loading enhances GIP secretion and induces obesity in mice in a GIP-dependent manner. However, the mechanisms of GIP secretion from K cells in response to fat ingestion and GIP hypersecretion in HFD-induced obesity are not well understood. We generated GIP-green fluorescent protein knock-in (GIP (gfp/+)) mice, in which K cells are labeled by enhanced GIP-green fluorescent protein. Microarray analysis of isolated K cells from GIP (gfp/+) mice showed that both fatty acid-binding protein 5 and G protein-coupled receptor 120 are highly expressed in K cells. Single oral administration of fat resulted in significant reduction of GIP secretion in both fatty acid-binding protein 5- and G protein-coupled receptor 120-deficient mice, showing that fatty acid-binding protein 5 and G protein-coupled receptor 120 are involved in acute fat-induced GIP secretion. Furthermore, the transcriptional factor, regulatory factor X6 (Rfx6), is highly expressed in K cells. In vitro experiments using the mouse enteroendocrine cell line, STC-1, showed that GIP messenger ribonucleic acid levels are upregulated by Rfx6. Expression levels of Rfx6 messenger ribonucleic acid as well as that of GIP messenger ribonucleic acid were augmented in the K cells of HFD-induced obese mice, in which GIP content in the small intestine is increased compared with that in lean mice fed a control diet. These results suggest that Rfx6 is involved in hypersecretion of GIP in HFD-induced obese conditions by increasing GIP gene expression.
| S-EPMC4854500 | biostudies-other
Project description:Our data mark GIP as a beneficial immunoregulator during obesity and suggest a novel untapped therapeutic potential for specific targeted GIP analogs. Emerging studies suggest that glucose-dependent insulin tropic polypeptide (GIP) affect obesity-associated inflammation. Yet, whether GIP can directly regulate immune cell activity and the respective metabolic consequences remained unknown. Here, we targeted GIP-receptor-deficiency to immune cells using bone marrow (BM) chimerism approach and the reconstituted chimeric mice were subjected to a high fat diet (HFD) regimen. Mice reconstituted with Gipr-/- BM gained significantly more weight, despite similar food consumption. This was accompanied by increased epididymal adipose tissue (epiWAT) mass, adipocyte hypertrophy, enhanced hepatic steatosis, insulin resistance and significant myelopoiesis in the circulation, epiWAT and inguinal adipose tissue (ingWAT). In accordance these mice also exhibited reduced energy expenditure and ingWAT beiging. Mechanistically, impaired GIP-governed regulation of S100A8/9 in myeloid cells was responsible for the perturbed energy homeostasis, increased insulin resistance and intensified inflammatory response under nutrient overload. Collectively, our results outline a beneficial immunoregulatory role for GIP in immune cells during obesity.
2019-01-02 | GSE109371 | GEO
Project description:In mammals, glucose-dependent insulinotropic polypeptide (GIP) is synthesized predominately in the small intestine and functions in conjunction with insulin to promote nutrient deposition. However, little is known regarding GIP expression and function in early vertebrates like the zebrafish, a model organism representing an early stage in the evolutionary development of the compound vertebrate pancreas. Analysis of GIP and insulin (insa) expression in zebrafish larvae by RT-PCR demonstrated that although insa was detected as early as 24 h postfertilization (hpf), GIP expression was not demonstrated until 72 hpf, shortly after the completion of endocrine pancreatic development but prior to the commencement of independent feeding. Furthermore, whole mount in situ hybridization of zebrafish larvae showed expression of GIP and insa in the same tissues, and in adult zebrafish, RT-PCR and immunohistochemistry demonstrated GIP expression in both the intestine and the pancreas. Receptor activation studies showed that zebrafish GIP was capable of activating the rat GIP receptor. Although previous studies have identified four receptors with glucagon receptor-like sequences in the zebrafish, one of which possesses the capacity to bind GIP, a functional analysis of these receptors has not been performed. This study demonstrates interactions between the latter receptor and zebrafish GIP, identifying it as a potential in vivo target for the ligand. Finally, food deprivation studies in larvae demonstrated an increase in GIP and proglucagon II mRNA levels in response to fasting. In conclusion, the results of these studies suggest that although the zebrafish appears to be a model of an early stage of evolutionary development of GIP expression, the peptide may not possess incretin properties in this species.
| S-EPMC2803629 | biostudies-literature
Project description:Aims/introductionThe involvement of glucose-dependent insulinotropic polypeptide (GIP) on inflammation was explored in atherosclerosis and adipose tissue. Periodontal disease is a chronic inflammatory disease, and is considered one of the diabetic complications. In the present study, to examine the effect of GIP on periodontitis, we induced experimental periodontitis in glucose-dependent insulinotropic polypeptide receptor-knockout mice (GIPRKO). We also investigated the anti-inflammatory effect of GIP in a culture system.Materials and methodsExperimental periodontitis was induced by ligature wire in GIPRKO and C57BL/C mice. Two weeks after the ligature, immunohistological evaluation and inflammatory messenger ribonucleic acid expression in the gingiva was examined. To elucidate the role of GIP in inflammation, the effects of GIP on lipopolysaccharide-induced gene expressions in THP-1 cells were evaluated.ResultsPeriodontitis increased inflammatory cell infiltration, macrophage accumulation and tumor necrosis factor-? and nitric oxide synthase gene expressions in the gingiva. Periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue. Mac-1-positive macrophages and the inflammatory gene expressions were significantly increased in periodontitis in GIPRKO compared with C57BL/C mice periodontitis. Immunohistochemical staining confirmed that GIP receptors were expressed in residual and infiltrated Mac-1-positive macrophages. The in vitro study showed that GIP suppressed lipopolysaccharide-induced tumor necrosis factor-? and nitric oxide synthase gene expression in a dose-dependent manner. Furthermore, the inhibitory effect of GIP on lipopolysaccharide-induced inflammatory gene expressions was at least partially through cyclic adenosine monophosphate/protein kinase A pathway.ConclusionsThese results suggest the beneficial effects of GIP on periodontal disease. In diabetic patients, GIP is expected to have a direct anti-inflammatory effect on periodontitis in addition to its glucose-lowering effect.
| S-EPMC4931199 | biostudies-literature
Project description:Glucose-dependent insulinotropic polypeptide (GIP) was established as a gut hormone more than 40 years ago, and there is good experimental support for its role as an incretin hormone although deletion of the GIP receptor or the GIP cells or GIP receptor mutations have only minor effects on glucose metabolism. Unlike the related hormone, GLP-1, GIP stimulates the secretion of glucagon, which in healthy individuals may help to stabilize glucose levels, but in people with type 2 diabetes may contribute to glucose intolerance. A role in lipid metabolism is supported by numerous indirect observations and by resistance to diet-induced obesity after deletion of the GIP receptor. However, a clear effect on lipid clearance could not be identified in humans, raising doubt about its importance. The GIP receptor is widely expressed in the body and also appears to be expressed on bone cells, and experimental studies in rodent point to effects on bone metabolism. Recent studies revealed pronounced inhibitory effects of GIP on bone resorption markers in humans and suggest that GIP may be (one of the) gastrointestinal regulators of bone turn-over. In support of this, a loss-of-function GIP receptor mutation in humans is associated with a marked increase in fracture risk. The lack of a reliable GIP receptor antagonist contributes to the uncertainty regarding the physiological role of GIP.
| S-EPMC4854498 | biostudies-literature
Project description:Mutations in the HNF4A gene cause MODY1 and are associated with an increased risk of Type 2 diabetes mellitus. On the other hand, incretins are hormones that potentiate reductions in blood glucose levels. Given the established role of incretin-based therapy to treat diabetes and metabolic disorders, we investigated a possible regulatory link between intestinal epithelial HNF4α and glucose-dependent insulinotropic polypeptide (GIP), an incretin that is specifically produced by gut enteroendocrine cells. Conditional deletion of HNF4α in the whole intestinal epithelium was achieved by crossing Villin-Cre and Hnf4αloxP/loxP C57BL/6 mouse models. GIP expression was measured by qPCR, immunofluorescence and ELISA. Gene transcription was assessed by luciferase and electrophoretic mobility shift assays. Metabolic parameters were analyzed by indirect calorimetry and dual-energy X-ray absorptiometry. HNF4α specific deletion in the intestine led to a reduction in GIP. HNF4α was able to positively control Gip transcriptional activity in collaboration with GATA-4 transcription factor. Glucose homeostasis and glucose-stimulated insulin secretion remained unchanged in HNF4α deficient mice. Changes in GIP production in these mice did not impact nutrition or energy metabolism under normal physiology but led to a reduction of bone area and mineral content, a well described physiological consequence of GIP deficiency. Our findings point to a novel regulatory role between intestinal HNF4α and GIP with possible functional impact on bone density.
| S-EPMC6414548 | biostudies-literature
Project description:The incretin hormones, glucose-dependent insulinotropic peptide and glucagon-like peptide-1, are secreted from intestinal K- and L cells, respectively, with the former being most abundant in the proximal small intestine, whereas the latter increase in number towards the distal gut. Although an overlap between K- and L cells can be observed immunohistochemically or in murine models expressing fluorescent markers under the control of the two hormone promoters, the majority (>80%) of labeled cells seems to produce only one of these hormones. Transcriptomic analysis showed a close relationship between small intestinal K- and L cells, and glucose sensing mechanisms appear similar in both cell types with a predominant role of electrogenic glucose uptake through sodium-coupled glucose transporter 1. Similarly, both cell types produce the long-chain fatty acid sensing G-protein-coupled receptors, FFAR1 (GPR40) and FFAR4 (GPR120), but differ in the expression/functionality of other lipid sensing receptors. GPR119 and FFAR2/3, for example, have clearly documented roles in glucagon-like peptide-1 secretion, whereas agonists for the endocannabinoid receptor type 1 have been found to show largely selective inhibition of glucose-dependent insulinotropic peptide secretion. In conclusion, although K- and L cell populations overlap and share key molecular nutrient-sensing mechanisms, subtle differences between the responsiveness of the different cell types might be exploited to differentially modulate glucose-dependent insulinotropic peptide or glucagon-like peptide-1 secretion.
| S-EPMC4854499 | biostudies-literature