Gastric Inhibitory Polypeptide Secretion Research Articles

Highly functional duodenal stent with photosensitizers enables photodynamic therapy for metabolic syndrome treatment: Feasibility and safety study in a porcine model.

Duodenal mucosal resurfacing (DMR) by thermal ablation of the duodenal mucosa is a minimally invasive endoscopic procedure for controlling metabolic syndrome (MS). However, thermal energy can cause adverse effects due to deep mucosal injury, necessitating an additional mucosal lifting process, which complicate the procedures. Therefore, we aimed to develop a similar procedure using non-thermal photodynamic therapy (PDT) for DMR using a highly functional metal stent covered with photosensitizers (PSs) to minimize the potential risks of thermal ablation injury. We developed a novel PS stent enabling the controlled release of radical oxygen species with specific structures to prevent stent migration and duodenal stricture after ablation and performed an animal study (n = 8) to demonstrate the feasibility and safety of PDT for DMR. The stents were placed for 7 days to prevent duodenal strictures after PDT. To confirm PDT efficacy, we stained for gastric inhibitory polypeptide (GIP) and glucose transporter isoform 1. The PS stents were deployed, and PDT was applied without evidence of duodenal stricture, pancreatitis, or hemorrhage in any of the pigs. Microscopic evaluation indicated apoptosis of the mucosal cells in the irradiated duodenum on days 7 and 14, which recovered after day 28. Immunohistochemistry revealed suppressed GIP expression in the mucosal wall of the irradiated duodenum. Endoscopic PDT for DMR using PS stents could be applied safely in a porcine model and may result in decreased GIP secretion, which is a crucial mechanism in MS treatment. Further clinical studies are required to explore its safety and efficacy in patients with MS.

Lipid photosensitizers for suppression of gastric inhibitory polypeptide in obese with type 2 diabetes

“K-cell targeted photodynamic therapy (K-cell targeted PDT)” with a minimally invasive procedure was investigated to reduce the secretion of gastric inhibitory polypeptide (GIP), an incretin hormone secreted from enteroendocrine K-cells in the duodenum that is suspected to be strongly correlated with obesity. Oleic acid-poly (ethylene glycol)-chlorin e6 (OA-PEG-Ce6, OPC) was designed for PDT because it targets K-cells through the interaction of OA in OPC with a G protein-coupled receptor (GPR 119) that is overexpressed on K-cells and mediates fatty acid sensing. OPC interacted with duodenal cells (HUTU-80) expressing GPR 119 and HEK 293 cells transfected with human GPR 119 to mimic K-cells in vitro. The intracellular intensity and cytotoxicity of OPC on HUTU-80 cells increased 5- and 3-fold compared to PEG-Ce6, respectively. In particular, its intensity on HEK 293 cells overexpressing GPR 119 showed 7.8-fold higher than that of PEG-Ce6. Moreover, in high fat-diet animal models, OPC induced endocrine cell death through PDT, resulting in a decrease in the plasma GIP level and a reduction their weight (80% less than on the day of PDT initiation). Therefore, K-cell targeted PDT presents a new direction of future minimally invasive anti-obesity treatment to replace conventional methods such as bariatric surgery and radiofrequency ablation.

1948-P: Secretion of the Short-Form Gastric Inhibitory Polypeptide in Nondiabetic and Diabetic Subjects

We previously reported that the short-form gastric inhibitory polypeptide (GIP) 1-30 is released from islet alpha cells and promotes insulin secretion in a paracrine manner in vitro. However, the role played by GIP 1-30 in glucose metabolism in vivo remains unclear. We developed an enzyme-linked immunosorbent assay (ELISA) specific for GIP 1-30 and measured GIP 1-30 secretion in nondiabetic subjects (ND, n = 8) and patients with type 2 diabetes (T2D, n = 9). We developed a sandwich ELISA by combining a novel antibody to the GIP C-terminus with the N-terminal anti-GIP 1-42 antibody that is already available. We explored cross-reactivities with incretins and glucagon-related peptides. We next subjected ND and T2D subjects to the cookie meal test (CMT: carbohydrates 75 g, lipids 28.5 g, proteins 8.5 g) and measured GIP 1-30 blood levels. Absorbance increased in a dose-dependent manner on addition of the GIP 1-30 amide but not GIP 1-42, GLP-1, or glucagon. Post-CMT loading, GIP 1-30 concentrations increased in both ND and T2D subjects; however, in ND subjects, the increases were much lower than those of GIP 1-42 (GIP 1-30, before loading: 1.4 ± 0.5 pmol/L, after: 1.9 ± 0.6 pmol/L; GIP 1-42, before: 8.2 ± 0.1 pmol/L, after: 204.0 ± 35.2 pmol/L, P<0.05). In T2D patients, the GIP 1-30 levels, as assessed by the areas under the curves, tended to be lower than those in ND patients. The DPP-4 inhibitor significantly increased both GIP 1-30 and GIP 1-42 secretion in T2D patients. In conclusion, we developed a novel ELISA that is highly specific for GIP 1-30, the secretion of which was promoted by a mixed meal to a blood level lower than that of GIP 1-42. As is also true of the incretins, GIP 1-30 levels increased upon administration of DPP-4 inhibitor; GIP 1-30 secretion may differ between ND and T2D subjects. Disclosure Y. Takeda: None. Y. Fujita: None. T. Yanagimachi: None. N. Maruyama: Employee; Self; Immuno-Biological Laboratoties Co.,Ltd. R. Bessho: None. H. Sakagami: None. M. Haneda: None. T. Ota: None. Funding Japan Society for the Promotion of Science

Free fatty acid receptors, Gprotein-coupled receptor120 and Gprotein-coupled receptor40, are essential for oil-induced gastric inhibitory polypeptide secretion.

Aims/IntroductionIncretin hormone glucose‐dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) plays a key role in high‐fat diet‐induced obesity and insulin resistance. GIP is strongly secreted from enteroendocrine K cells by oil ingestion. G protein‐coupled receptor (GPR)120 and GPR40 are two major receptors for long chain fatty acids, and are expressed in enteroendocrine K cells. In the present study, we investigated the effect of the two receptors on oil‐induced GIP secretion using GPR120‐ and GPR40‐double knockout (DKO) mice.Materials and MethodsGlobal knockout mice of GPR120 and GPR40 were crossbred to generate DKO mice. Oral glucose tolerance test and oral corn oil tolerance test were carried out. For analysis of the number of K cells and gene expression in K cells, DKO mice were crossbred with GIP‐green fluorescent protein knock‐in mice in which visualization and isolation of K cells can be achieved.ResultsDouble knockout mice showed normal glucose‐induced GIP secretion, but no GIP secretion by oil. We then investigated the number of K cells and gene characteristics in K cells isolated from GIP‐green fluorescent protein knock‐in mice. Deficiency of both receptors did not affect the number of K cells in the small intestine or expression of GIP messenger ribonucleic acid in K cells. Furthermore, there was no significant difference in the expression of the genes associated with lipid absorption or GIP secretion in K cells between wild‐type and DKO mice.ConclusionsOil‐induced GIP secretion is triggered by the two major fatty acid receptors, GPR120 and GPR40, without changing K‐cell number or K‐cell characteristics.

Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion.

Our previous study demonstrated that sphingosine kinase 1-interacting protein (SKIP, or Sphkap) is expressed in pancreatic β-cells, and depletion of SKIP enhances glucose-stimulated insulin secretion. We find here that SKIP is also expressed in intestinal K- and L-cells and that secretion of gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) as well as insulin are significantly increased, and blood glucose levels are decreased in SKIP-deficient (SKIP-/-) mice compared with those in wild-type mice. Plasma triglyceride (Tg), LDL cholesterol, and mRNA levels of proinflammatory cytokines in adipose tissues, livers, and intestines were found to be significantly decreased in SKIP-/- mice. The phenotypic characteristics of SKIP-/- mice, including adiposity and attenuation of basal inflammation, were abolished by genetic depletion of GIP. The improvement of glucose tolerance and lipid profiles in SKIP-/- mice were cancelled by GLP-1 receptor antagonist exendin-(9-39) treatment. In summary, depletion of SKIP ameliorates glucose tolerance by enhancing secretion of insulin and incretins, improves lipid metabolism, and reduces basal inflammation levels. Thus, inhibition of SKIP action may emerge as a new option for treatment of type 2 diabetes mellitus with metabolic dysfunction.-Liu, Y., Harashima, S., Wang, Y., Suzuki, K., Tokumoto, S., Usui, R., Tatsuoka, H., Tanaka, D., Yabe, D., Harada, N., Hayashi, Y., Inagaki, N. Sphingosine kinase 1-interacting protein is a dual regulator of insulin and incretin secretion.

Daily consumption of monoglucosyl-rutin prevents high-fat diet-induced obesity by suppressing gastric inhibitory polypeptide secretion in mice

Background: Alpha monoglucosyl-rutin (4G-α-D-glucopyranosyl rutin, αMR) has been shown to stimulate antioxidant defenses and anti-glycation. We evaluated the effects of αMR on body weight gain in mice.Methods: Male C57BL/6J mice were divided into four groups: Control low-fat diet, low-fat diet + 0.5% αMR, high-fat diet, and high-fat diet + 0.5% αMR. Blood chemistry, hepatic lipids, and serum metabolic hormones and cytokines were evaluated after 4 and 13 weeks.Results: After 6 weeks, the high-fat diet group gained more weight than the low-fat diet group. Supplementing the high-fat diet with αMR suppressed weight gain by week 13. Visceral fat weight was higher in the high-fat diet group on weeks 4 and 13, while αMR supplementation inhibited increase on week 13 but not on week 4. Serum levels of gastric inhibitory polypeptide were higher in the high-fat-diet group than in the low-fat-diet group. αMR supplementation inhibited this elevation and regulated levels of serum leptin and hepatic triglycerides.Conclusion: For the first time, we demonstrated how daily consumption of αMR inhibits diet-induced visceral fat accumulation by regulating the secretion of gastric inhibitory polypeptide, which thereby prevents excess weight gain. Therefore, αMR may be a promising potential functional food.Keywords: Anti-obesity; gastric inhibitory polypeptide; mouse; alpha monoglucosyl-rutin; quercetin

Glycemic, insulinemic and incretin responses after oral trehalose ingestion in healthy subjects

BackgroundTrehalose is hydrolyzed by a specific intestinal brush-border disaccharidase (trehalase) into two glucose molecules. In animal studies, trehalose has been shown to prevent adipocyte hypertrophy and mitigate insulin resistance in mice fed a high-fat diet. Recently, we found that trehalose improved glucose tolerance in human subjects. However, the underlying metabolic responses after trehalose ingestion in humans are not well understood. Therefore, we examined the glycemic, insulinemic and incretin responses after trehalose ingestion in healthy Japanese volunteers.MethodsIn a crossover study, 20 fasted healthy volunteers consumed 25 g trehalose or glucose in 100 mL water. Blood samples were taken frequently over the following 3 h, and blood glucose, insulin, active gastric inhibitory polypeptide (GIP) and active glucagon-like peptide-1 (GLP-1) levels were measured.ResultsTrehalose ingestion did not evoke rapid increases in blood glucose levels, and had a lower stimulatory potency of insulin and active GIP secretion compared with glucose ingestion. Conversely, active GLP-1 showed higher levels from 45 to 180 min after trehalose ingestion as compared with glucose ingestion. Specifically, active GIP secretion, which induces fat accumulation, was markedly lower after trehalose ingestion.ConclusionsOur findings indicate that trehalose may be a useful saccharide for good health because of properties that do not stimulate rapid increases in blood glucose and excessive secretion of insulin and GIP promoting fat accumulation.

Fatty acid-binding protein 5 regulates diet-induced obesity via GIP secretion from enteroendocrine K cells in response to fat ingestion.

Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K cells in response to nutrient intake, especially fat. GIP is one of the contributing factors inducing fat accumulation that results in obesity. A recent study shows that fatty acid-binding protein 5 (FABP5) is expressed in murine K cells and is involved in fat-induced GIP secretion. We investigated the mechanism of fat-induced GIP secretion and the impact of FABP5-related GIP response on diet-induced obesity (DIO). Single oral administration of glucose and fat resulted in a 40% reduction of GIP response to fat but not to glucose in whole body FABP5-knockout (FABP5(-/-)) mice, with no change in K cell count or GIP content in K cells. In an ex vivo experiment using isolated upper small intestine, oleic acid induced only a slight increase in GIP release, which was markedly enhanced by coadministration of bile and oleic acid together with attenuated GIP response in the FABP5(-/-) sample. FABP5(-/-) mice exhibited a 24% reduction in body weight gain and body fat mass under a high-fat diet compared with wild-type (FABP5(+/+)) mice; the difference was not observed between GIP-GFP homozygous knock-in (GIP(gfp/gfp))-FABP5(+/+) mice and GIP(gfp/gfp)-FABP5(-/-) mice, in which GIP is genetically deleted. These results demonstrate that bile efficiently amplifies fat-induced GIP secretion and that FABP5 contributes to the development of DIO in a GIP-dependent manner.

Free fatty acid receptor GPR120 is highly expressed in enteroendocrine K cells of the upper small intestine and has a critical role in GIP secretion after fat ingestion.

Gastric inhibitory polypeptide (GIP) is an incretin secreted from enteroendocrine K cells in response to meal ingestion. Recently free fatty acid receptor G protein-coupled receptor (GPR) 120 was identified as a lipid sensor involved in glucagon-like peptide-1 secretion. However, Gpr 120 gene expression and its role in K cells remain unclear, partly due to difficulties in separation of K cells from other intestinal epithelial cells. In this study, we purified K cells using GIP-green fluorescent protein (GFP) knock-in mice, in which K cells can be visualized by GFP fluorescence. GFP-positive cells (K cells) were observed in the small intestine but not in the stomach and colon. K cell number and GIP content in K cells were significantly higher in the upper small intestine than those in the lower small intestine. We also examined the expression levels of several free fatty acid receptors in K cells. Among free fatty acid receptors, GPR120 was highly expressed in the K cells of the upper small intestine compared with the lower small intestine. To clarify the role of GPR120 on K cells in vivo, we used GPR120-deficient mice (GPR120(-/-)). GPR120(-/-) exhibited significantly lower GIP secretion (75% reduction, P < .01) after lard oil ingestion compared with that in wild-type mice. Consistently, pharmacological inhibition of GPR120 with grifolic acid methyl ether in wild-type mice significantly attenuated lard oil-induced GIP secretion. In conclusion, GPR120 is expressed abundantly in K cells of the upper small intestine and plays a critical role in lipid-induced GIP secretion.

Targeting development of incretin-producing cells increases insulin secretion.

Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing the number of intestinal L cells, which produce GLP-1, is an alternative strategy to augment insulin responses and improve glucose tolerance. Blocking the NOTCH signaling pathway with the γ-secretase inhibitor dibenzazepine increased the number of L cells in intestinal organoid-based mouse and human culture systems and augmented glucose-stimulated GLP-1 secretion. In a high-fat diet-fed mouse model of impaired glucose tolerance and type 2 diabetes, dibenzazepine administration increased L cell numbers in the intestine, improved the early insulin response to glucose, and restored glucose tolerance. Dibenzazepine also increased K cell numbers, resulting in increased gastric inhibitory polypeptide (GIP) secretion. Using a GLP-1 receptor antagonist, we determined that the insulinotropic effect of dibenzazepine was mediated through an increase in GLP-1 signaling. Together, our data indicate that modulation of the development of incretin-producing cells in the intestine has potential as a therapeutic strategy to improve glycemic control.

Enteral supplementation with glutamine, fiber, and oligosaccharide modulates incretin and glucagon-like peptide-2 secretion.

Aims/IntroductionA dietary supplementation product enriched with glutamine, dietary fiber and oligosaccharide (GFO) is widely applied for enteral nutrition support in Japan. The aim of the present study was to evaluate the effects of GFO ingestion on secretion of incretins, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2).Materials and MethodsWe carried out a cross-over study involving 20 healthy Japanese volunteers. The participants received GFO or 17 g of glucose, the equivalent carbohydrate in GFO as the control. Plasma glucose, serum insulin, and plasma total GIP, total GLP-1 and total GLP-2 levels during GFO or glucose loading were determined.ResultsGFO loading produced significantly higher plasma GLP-1 levels at 30 min and 60 min, area under the curve-GLP-1 value, and area under the curve-GLP-2 value after administration compared with those by glucose loading. In contrast, plasma GIP levels at both 30 and 60 min, and area under the curve-GIP value after glucose loading were significantly higher than those after GFO loading.ConclusionsThese results show that GFO ingestion stimulates GLP-1 and GLP-2 secretion, and reduces GIP secretion compared with glucose ingestion. Therefore, GFO could have an intestinotrophic effect as well as an ameliorating effect on metabolic disorders through modification of release of gut hormones.

High saturated fatty acid intake induces insulin secretion by elevating gastric inhibitory polypeptide levels in healthy individuals

Insulin resistance is central to the etiology of the metabolic syndrome cluster of diseases. Evidence suggests that a high-fat diet is associated with insulin resistance, which may be modulated by dietary fatty acid composition. We hypothesized that high saturated fatty acid intake increases insulin and gastric inhibitory polypeptide (GIP) secretion. To clarify the effect of ingested fatty acid composition on glucose levels, we conducted an intervention study to investigate the insulin and plasma GIP responses in 11 healthy women, including a dietary control. Subjects were provided daily control meals (F-20; saturated fatty acids/monounsaturated fatty acids/polyunsaturated fatty acids [S/M/P] ratio, 3:4:3) with 20 energy (E) % fat, followed by 2 isoenergetic experimental meals for 7 days each. These meals comprised 60 E% carbohydrate, 15 E% protein, and 30 E% fat (FB-30; high saturated fatty acid meal; S/M/P, 5:4:1; F-30: reduced saturated fatty acid meal; S/M/P, 3:4:3). On the second day of the F-20 and the last day of F-30 and FB-30, blood samples were taken before and 30, 60, and 120 minutes after a meal tolerance test. The plasma glucose responses did not differ between F-20 and FB-30 or F-30. However, insulin levels were higher after the FB-30 than after the F-20 (P < .01). The GIP response after the FB-30 was higher than that after the F-30 (P < .05). In addition, the difference in the incremental GIP between FB-30 and F-30 correlated significantly and positively with that of the insulin. These results suggest that a high saturated fatty acid content stimulates postprandial insulin release via increased GIP secretion.

Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions

Gastric inhibitory polypeptide (GIP) exhibits potent insulinotropic effects on β-cells and anabolic effects on bone formation and fat accumulation. We explored the impact of reduced GIP levels in vivo on glucose homeostasis, bone formation, and fat accumulation in a novel GIP-GFP knock-in (KI) mouse. We generated GIP-GFP KI mice with a truncated prepro-GIP gene. The phenotype was assessed in heterozygous and homozygous states in mice on a control fat diet and a high-fat diet (HFD) in vivo and in vitro. Heterozygous GIP-GFP KI mice (GIP-reduced mice [GIP(gfp/+)]) exhibited reduced GIP secretion; in the homozygous state (GIP-lacking mice [GIP(gfp/gfp)]), GIP secretion was undetectable. When fed standard chow, GIP(gfp/+) and GIP(gfp/gfp) mice showed mild glucose intolerance with decreased insulin levels; bone volume was decreased in GIP(gfp/gfp) mice and preserved in GIP(gfp/+) mice. Under an HFD, glucose levels during an oral glucose tolerance test were similar in wild-type, GIP(gfp/+), and GIP(gfp/gfp) mice, while insulin secretion remained lower. GIP(gfp/+) and GIP(gfp/gfp) mice showed reduced obesity and reduced insulin resistance, accompanied by higher fat oxidation and energy expenditure. GIP-reduced mice demonstrate that partial reduction of GIP does not extensively alter glucose tolerance, but it alleviates obesity and lessens the degree of insulin resistance under HFD conditions, suggesting a potential therapeutic value.

Alterations of Glucose-Dependent Insulinotropic Polypeptide and Expression of Genes Involved in Mammary Gland and Adipose Tissue Lipid Metabolism during Pregnancy and Lactation

Gastric inhibitory polypeptide (GIP) is a gut derived peptide with multiple emerging physiological actions. Effects of pregnancy and lactation on GIP secretion and related gene expression were studied in Wistar rats. Pregnancy moderately increased feeding (p<0.05), whilst lactation substantially increased food intake (p<0.01 to p<0.001). Circulating GIP was unchanged during pregnancy, but non-fasting plasma glucose was significantly (p<0.01) decreased and insulin increased (p<0.05). Lactation was associated with elevated circulating GIP concentrations (p<0.001) without change of glucose or insulin. Oral glucose resulted in a significantly (p<0.001) decreased glycaemic excursion despite similar glucose-induced GIP and insulin concentrations in lactating rats. Pregnant rats had a similar glycaemic excursion but exhibited significantly lowered (p<0.05) GIP accompanied by elevated (p<0.001) insulin levels. Pregnant rats exhibited increased (p<0.001) islet numbers and individual islet areas were enlarged (p<0.05). There were no significant differences in islet alpha-cell areas, but all groups of rats displayed co-expression of glucagon and GIP in alpha-cells. Lactating rats exhibited significantly (p<0.01) increased intestinal weight, whereas intestinal GIP stores were significantly (p<0.01) elevated only in pregnant rats. Gene expression studies in lactating rats revealed prominent (p<0.01 to p<0.001) increases in mammary gland expression of genes involved in energy turnover, including GIP-R. GIP was present in intestines and plasma of 17 day old foetal rats, with substantially raised circulating concentrations in neonates throughout the period of lactation/suckling. These data indicate that changes in the secretion and action of GIP play an important role in metabolic adaptations during pregnancy and especially lactation.

Transcriptional Regulatory Factor X6 (Rfx6) Increases Gastric Inhibitory Polypeptide (GIP) Expression in Enteroendocrine K-cells and Is Involved in GIP Hypersecretion in High Fat Diet-induced Obesity

Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K-cells in response to nutrient ingestion. GIP potentiates glucose-stimulated insulin secretion and induces energy accumulation into adipose tissue, resulting in obesity. Plasma GIP levels are reported to be increased in the obese state. However, the molecular mechanisms of GIP secretion and high fat diet (HFD)-induced GIP hypersecretion remain unclear, primarily due to difficulties in separating K-cells from other intestinal epithelial cells in vivo. In this study, GIP-GFP knock-in mice that enable us to visualize K-cells by enhanced GFP were established. Microarray analysis of isolated K-cells from these mice revealed that transcriptional regulatory factor X6 (Rfx6) is expressed exclusively in K-cells. In vitro experiments using the mouse intestinal cell line STC-1 showed that knockdown of Rfx6 decreased mRNA expression, cellular content, and secretion of GIP. Rfx6 bound to the region in the gip promoter that regulates gip promoter activity, and overexpression of Rfx6 increased GIP mRNA expression. HFD induced obesity and GIP hypersecretion in GIP-GFP heterozygous mice in vivo. Immunohistochemical and flow cytometry analysis showed no significant difference in K-cell number between control fat diet-fed (CFD) and HFD-fed mice. However, GIP content in the upper small intestine and GIP mRNA expression in K-cells were significantly increased in HFD-fed mice compared with those in CFD-fed mice. Furthermore, expression levels of Rfx6 mRNA were increased in K-cells of HFD-fed mice. These results suggest that Rfx6 increases GIP expression and content in K-cells and is involved in GIP hypersecretion in HFD-induced obesity.

Abstract 18394: Gastric Inhibitory Polypeptide is Associated with Metabolic Disorder and Cardiovascular Disease Independent of Glucose in Humans

Background - Emerging animal studies have reported the beneficial effect of interrupting gastric inhibitory polypeptide (GIP) receptor signaling in metabolic disorders including extreme fat deposition with insulin resistance and glucose intolerance. These results propose the hypothesis that hyper GIP secretion may contribute to the development of cardiovascular disease (CVD) in humans. However, most studies have focused on incretin responses to glucose loading, and the association between endogenous GIP levels and cardiometabolic disorders has not been well defined in humans. Methods and Results - To examine the association between fasting GIP and cardiometabolic disorders or CVD independent of plasma glucose (PG) levels, we analysed 300 non-diabetic subjects. Furthermore we performed in vitro functional analysis using human macrophage cells. Simple regression analysis demonstrated that the fasting total GIP was correlated with cardiometabolic disorders such as waist to hip ratio, hyperinsulinemia, and HOMA-IR. ANCOVA and logistic analysis after adjustment for age, gender, BMI, smoking, HOMA-IR, hypertension, LDL cholesterol, HDL cholesterol, eGFR and PG, revealed that fasting GIP was increased in the subjects with CVD than non-CVD (53.7 ± 32.2 v.s. 28.2 ± 18.1, p &lt;0.01), and each tertile increase in fasting GIP was associated with the prevalence of CVD (odds ratio 3.12 per tertile, 95% CI 1.73 to 5.62; p &lt;0.01). Furthermore, molecular analysis revealed that GIP receptor was present in human monocyte/macrophage, T-lymphocyte, and human carotid atherosclerotic lesion. In vitro analysis revealed that GIP stimulation up-regulated gene expression of interleukin 6, CC chemokine receptor (CCR) 2, CCR5, and scavenger receptor type A in human THP-1 macrophages. Conclusions - These results suggest that oversecretion of GIP may contribute to cardiometabolic disorder, resulting in the development of CVD independent of PG in humans.

Role of sodium-glucose transporters in glucose uptake of the intestine and kidney.

Role of sodium-glucose transporters in glucose uptake of the intestine and kidney.

Effects of glucose and meal ingestion on incretin secretion in Japanese subjects with normal glucose tolerance.

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the major incretins; their secretion after various nutrient loads are well-evaluated in Caucasians. However, little is known of the relationship between incretin secretion and differing nutritional loading in Japanese subjects. In the present study, we evaluated GIP and GLP-1 secretion in Japanese subjects with normal glucose tolerance (NGT) after glucose loading (75 g glucose and 17 g glucose) and meal ingestion. A total of 10 Japanese NGT subjects participated in 75 g oral glucose tolerance test (OGTT), 17 g OGTT and meal tolerance test (MTT). Plasma glucose (PG), serum insulin (IRI), serum C-peptide (CPR), plasma total GIP, and plasma total GLP-1 levels during OGTT and MTT were determined. Area under the curve (AUC)-GIP was increased in proportion to the amount of glucose, and was highest in MTT, showing that GIP secretion is also stimulated by nutrients other than glucose, such as lipid. In contrast, although the larger glucose load tended to induce a larger GLP-1 release, AUC-GLP-1 was not significantly different among the three loading tests (75 g OGTT, 17 g OGTT, MTT) irrespective of the kind or amount of nutrition load. Our results suggest that nutritional composition might have a greater effect on GIP secretion than that on GLP-1 secretion in Japanese NGT subjects. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00143.x, 2012).

Plasma gastric inhibitory polypeptide and glucagon-like peptide-1 levels after glucose loading are associated with different factors in Japanese subjects.

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins that potentiate insulin secretion from pancreatic β-cells. The factors responsible for incretin secretion have been reported in Caucasian subjects, but have not been thoroughly evaluated in Japanese subjects. We evaluated the factors associated with incretin secretion during oral glucose tolerance test (OGTT) in Japanese subjects with normal glucose tolerance (NGT). We measured plasma GIP and GLP-1 levels during OGTT in 17 Japanese NGT subjects and evaluated the factors associated with GIP and GLP-1 secretion using simple and multiple regression analyses. GIP secretion (AUC-GIP) was positively associated with body mass index (P < 0.05), and area under the curve (AUC) of C-peptide (P < 0.05) and glucagon (P < 0.01), whereas GLP-1 secretion (AUC-GLP-1) was negatively associated with AUC of plasma glucose (P < 0.05). The insulinogenic index was most strongly associated with GIP secretion (P < 0.05); homeostasis model assessment β-cell was the most the strongly associated factor in GLP-1 secretion (P < 0.05) among the four indices of insulin secretion and insulin sensitivity. Several distinct factors might be associated with GIP and GLP-1 secretion during OGTT in Japanese subjects. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00078.x, 2011).

Carriers of the TCF7L2 rs7903146 TT genotype have elevated levels of plasma glucose, serum proinsulin and plasma gastric inhibitory polypeptide (GIP) during a meal test

The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele associates with type 2 diabetes in several populations, possibly mediated via decreased incretin secretion and/or action and altered beta and alpha cell function. We aimed to study circulating levels of glucose, proinsulin, insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and gastric inhibitory polypeptide (GIP) among individuals carrying the high-risk rs7903146 TT genotype and low-risk CC genotype following a meal test. A meal challenge was performed in 31 glucose-tolerant men (age 54 ± 7 years and BMI 26 ± 3 kg/m²) with rs7903146 TT genotype and 31 glucose-tolerant age- and BMI-matched men with CC genotype (age 53 ± 6 years and BMI 26 ± 3 kg/m²). Serum proinsulin, insulin, C-peptide and plasma glucose, glucagon, GLP-1, GLP-2 and GIP were obtained 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 210, and 240 min after ingestion of a standardised breakfast meal. An elevated incremental AUC for plasma glucose was observed among TT genotype carriers (CC carriers 21.8 ± 101.9 mmol/l × min vs TT carriers 97.9 ± 89.2 mmol/l × min, p = 0.001). TT carriers also had increased AUCs for proinsulin (CC carriers 6,030 ± 3,001 pmol/l × min vs TT carriers 6,917 ± 4,820 pmol/l × min, p = 0.03), C-peptide (CC carriers 397.6 ± 131.9 nmol/l × min vs TT carriers 417.1 ± 109.3 nmol/l × min, p = 0.04) and GIP (CC carriers 12,310 ± 3,840 pmol/l × min vs TT carriers 14,590 ± 5,910 pmol/l × min, p = 0.004). Middle-aged normoglycaemic individuals carrying the rs7903146 TCF7L2 risk TT genotype show early signs of dysregulated glucose metabolism, decreased processing of proinsulin and elevated GIP secretion following a meal challenge.