The integrated incretin effect is reduced by both glucose intolerance and obesity in Japanese subjects.

Introduction: Incretin-based drugs are extensively utilized in the treatment of type 2 diabetes (T2D), with remarkable clinical efficacy. These drugs were developed based on findings that the incretin effect is reduced in T2D. The incretin effect in East Asians, whose pancreatic ß-cell function is more vulnerable than that in Caucasians, however, has not been fully examined. In this study, we investigated the effects of incretin in Japanese subjects. Methods: A total of 28 Japanese subjects (14 with normal glucose tolerance [NGT], 6 with impaired glucose tolerance, and 8 with T2D) were enrolled. Isoglycemic oral (75 g glucose tolerance test) and intravenous glucose were administered. The numerical incretin effect and gastrointestinally-mediated glucose disposal (GIGD) were calculated by measuring the plasma glucose and entero-pancreatic hormone concentrations. Results and discussion: The difference in the numerical incretin effect among the groups was relatively small. The numerical incretin effect significantly negatively correlated with the body mass index (BMI). GIGD was significantly lower in participants with T2D than in those with NGT, and significantly negatively correlated with the area under the curve (AUC)-glucose, BMI, and AUC-glucagon. Incretin concentrations did not differ significantly among the groups. We demonstrate that in Japanese subjects, obesity has a greater effect than glucose tolerance on the numerical incretin effect, whereas GIGD is diminished in individuals with both glucose intolerance and obesity. These findings indicate variances as well as commonalities between East Asians and Caucasians in the manifestation of incretin effects on pancreatic ß-cell function and the integrated capacity to handle glucose.

High-Density Linkage Maps from Japanese Rice japonica Recombinant Inbred Lines Using Genotyping by Random Amplicon Sequencing-Direct (GRAS-Di).

The genetic dissection of agronomically important traits in closely related Japanese rice cultivars is still in its infancy mainly because of the narrow genetic diversity within japonica rice cultivars. In an attempt to unveil potential polymorphism between closely related Japanese rice cultivars, we used a next-generation-sequencing-based genotyping method: genotyping by random amplicon sequencing-direct (GRAS-Di) to develop genetic linkage maps. In this study, four recombinant inbred line (RIL) populations and their parents were used. A final RIL number of 190 for RIL71, 96 for RIL98, 95 for RIL16, and 94 for RIL91 derived from crosses between a common leading Japanese rice cultivar Koshihikari and Yamadanishiki, Taichung 65, Fujisaka 5, and Futaba, respectively, and the parent plants were subjected to GRAS-Di library construction and sequencing. Approximately 438.7 Mbp, 440 Mbp, 403.1 Mbp, and 392 Mbp called bases covering 97.5%, 97.3%, 98.3%, and 96.1%, respectively, of the estimated rice genome sequence at average depth of 1× were generated. Analysis of genotypic data identified 1050, 1285, 1708, and 1704 markers for each of the above RIL populations, respectively. Markers generated by GRAS-Di were organized into linkage maps and compared with those generated by GoldenGate SNP assay of the same RIL populations; the average genetic distance between markers showed a clear decrease in the four RIL populations when we integrated markers of both linkage maps. Genetic studies using these markers successfully localized five QTLs associated with heading date on chromosomes 3, 6, and 7 and which previously were identified as Hd1, Hd2, Hd6, Hd16, and Hd17. Therefore, GRAS-Di technology provided a low cost and efficient genotyping to overcome the narrow genetic diversity in closely related Japanese rice cultivars and enabled us to generate a high density linkage map in this germplasm.

Usefulness of maximum intensity projection images of non-enhanced CT for detection of hyperdense middle cerebral artery sign in acute thromboembolic ischemic stroke.

PURPOSE: To compare the sensitivity of the hyperdense middle cerebral artery (MCA) sign between maximum intensity projection (MIP) and conventional averaged images in patients with acute focal neurological deficits with acute thromboembolic MCA occlusion (MCA occlusion group) and patients with acute focal neurological deficits without MCA occlusion (control group). MATERIALS AND METHODS: Initial computed tomography (CT) scans on admission were reconstructed with 5 mm thickness at every 3 mm interval for averaged and MIP images from 1 mm thickness non-contrast axial source images. Images were obtained from 30 cases each in the MCA occlusion and control groups. The CT values in the region of interests (ROIs) on the affected and unaffected sides of the MCA were compared. To compare CT values among subjects, the CT values were normalized by obtaining a ratio on the affected and unaffected sides, and the normalized CT values were analyzed using the receiver operating characteristic (ROC) curve. RESULTS: The hyperdense MCA sign was visually detected on MIP images in 90% cases and on 5 mm averaged images in only 57% cases in the MCA occlusion group. Based on the ROC analysis of the normalized ratio on the affected and unaffected sides, area under the curve of MIP image and averaged image was 0.941 and 0.655, respectively. On MIP images, the optimal threshold of the ratio on the affected and unaffected sides was 1.152 (sensitivity: 90.0%, and specificity: 93.3%). CONCLUSION: The hyperdense MCA sign sensitivity on 5 mm MIP images was significantly higher than that on conventional 5 mm averaged CT images. This could be useful for the early initiation of proper therapy for patients with acute focal neurological deficits.

Women in radiation (WiR)-a perspective for the strengthening of radiation protection.

Gender balance refers to the equitable treatment and access to opportunities for all genders. In order to achieve true gender balance, a variety of proactive approaches developed collaboratively, with insight from multiple perspectives, need to be implemented. With that purpose, the participation of women in professions related to radiation and radiation protection was prioritised and given high visibility by allocating a 'Women in Radiation' (WiR) Special Session at the 15th International Congress of the International Radiation Protection Association (IRPA), hosted by South Korea on 20 January 2021. In this session, various issues related to gender balance and equity/equality were highlighted by the panellists, and further elaborated in a subsequent discussion with attendees. The main goal of the WiR Special Session was to convene women from different organisations, career and age stages, disciplines and countries, in particular to consider the Asian-Oceanic vision and status of gender equality, along with other topics to support a 'Call for Action', with concrete recommendations subsequently provided to IRPA. The discussion stressed the main needs and challenges faced by women working in various radiation fields, along with raising awareness of possible professional and employment opportunities. This paper identifies some steps necessary to encourage, enhance and support the inclusion of more diversity in nuclear professions with specific emphasis on women. In conclusion, gender balance and equality must be at the heart of any strategic plan for the future of the radiological protection profession; international cooperation between relevant bodies is essential for success and could serve as a catalyst for specific policy statements aimed at achieving a balanced representation of women in radiological protection.

Visceral fat obesity is the key risk factor for the development of reflux erosive esophagitis in 40-69-years subjects.

BACKGROUND: Visceral fat obesity can be defined quantitatively by abdominal computed tomography, however, the usefulness of measuring visceral fat area to assess the etiology of gastrointestinal reflux disease has not been fully elucidated. METHODS: A total of 433 healthy subjects aged 40-69 years (234 men, 199 women) were included in the study. The relationship between obesity-related factors (total fat area, visceral fat area, subcutaneous fat area, waist circumference, and body mass index) and the incidence of reflux erosive esophagitis was investigated. Lifestyle factors and stomach conditions relevant to the onset of erosive esophagitis were also analyzed. RESULTS: The prevalence of reflux erosive esophagitis was 27.2% (118/433; 106 men, 12 women). Visceral fat area was higher in subjects with erosive esophagitis than in those without (116.6 cm2 vs. 64.9 cm2, respectively). The incidence of erosive esophagitis was higher in subjects with visceral fat obesity (visceral fat area ≥ 100 cm2) than in those without (61.2% vs. 12.8%, respectively). Visceral fat obesity had the highest odds ratio (OR) among obesity-related factors. Multivariate analysis showed that visceral fat area was associated with the incidence of erosive esophagitis (OR = 2.18), indicating that it is an independent risk factor for erosive esophagitis. In addition, daily alcohol intake (OR = 1.54), gastric atrophy open type (OR = 0.29), and never-smoking history (OR = 0.49) were also independently associated with the development of erosive esophagitis. CONCLUSIONS: Visceral fat obesity is the key risk factor for the development of reflux erosive esophagitis in subjects aged 40-69 years.

Carbonic anhydrase 8 (CAR8) negatively regulates GLP-1 secretion from enteroendocrine cells in response to long-chain fatty acids.

Glucagon-like peptide-1 (GLP-1) is an incretin secreted from enteroendocrine preproglucagon (PPG)-expressing cells (traditionally known as L cells) in response to luminal nutrients that potentiates insulin secretion. Augmentation of endogenous GLP-1 secretion might well represent a novel therapeutic target for diabetes treatment in addition to the incretin-associated drugs currently in use. In this study, we found that PPG cells substantially express carbonic anhydrase 8 (CAR8), which has been reported to inhibit inositol 1,4,5-trisphosphate (IP3) binding to the IP3 receptor and subsequent Ca2+ efflux from the endoplasmic reticulum in neuronal cells. In vitro experiments using STC-1 cells demonstrated that Car8 knockdown increases long-chain fatty acid (LCFA)-stimulated GLP-1 secretion. This effect was reduced in the presence of phospholipase C (PLC) inhibitor; in addition, Car8 knockdown increased the intracellular Ca2+ elevation caused by α-linolenic acid, indicating that CAR8 exerts its effect on GLP-1 secretion via the PLC/IP3/Ca2+ pathway. Car8wdl null mutant mice showed significant increase in GLP-1 response to oral corn oil administration compared with that in wild-type littermates, with no significant change in intestinal GLP-1 content. These results demonstrate that CAR8 negatively regulates GLP-1 secretion from PPG cells in response to LCFAs, suggesting the possibility of augmentation of postprandial GLP-1 secretion by CAR8 inhibition.NEW & NOTEWORTHY This study focused on the physiological significance of carbonic anhydrase 8 (CAR8) in GLP-1 secretion from enteroendocrine preproglucagon (PPG)-expressing cells. We found an inhibitory role of CAR8 in LCFA-induced GLP-1 secretion in vitro and in vivo, suggesting a novel therapeutic approach to diabetes and obesity through augmentation of postprandial GLP-1 secretion by CAR8 inhibition.

WAM to SeeSaw model for cancer therapy - overcoming LQM difficulties.

PURPOSE: The assessment of biological effects caused by radiation exposure has been currently carried out with the linear-quadratic (LQ) model as an extension of the linear non-threshold (LNT) model. In this study, we suggest a new mathematical model named as SeaSaw (SS) model, which describes proliferation and cell death effects by taking account of Bergonie-Tribondeau's law in terms of a differential equation in time. We show how this model overcomes the long-standing difficulties of the LQ model. MATERIALS AND METHODS: We construct the SS model as an extended Wack-A-Mole (WAM) model by using a differential equation with respect to time in order to express the dynamics of the proliferation effect. A large number of accumulated data of such parameters as α and ß in the LQ based models provide us with valuable pieces of information on the corresponding parameter b1 and the maximum volume Vm of the SS model. The dose rate b1 and the notion of active cell can explain the present data without introduction of ß, which is obtained by comparing the SS model with not only the cancer therapy data but also with in vitro experimental data. Numerical calculations are presented to grasp the global features of the SS model. RESULTS: The SS model predicts the time dependence of the number of active- and inactive-cells. The SS model clarifies how the effect of radiation depends on the cancer stage at the starting time in the treatment. Further, the time dependence of the tumor volume is calculated by changing individual dose strength, which results in the change of the irradiation duration for the same effect. We can consider continuous irradiation in the SS model with interesting outcome on the time dependence of the tumor volume for various dose rates. Especially by choosing the value of the dose rate to be balanced with the total growth rate, the tumor volume is kept constant. CONCLUSIONS: The SS model gives a simple equation to study the situation of clinical radiation therapy and risk estimation of radiation. The radiation parameter extracted from the cancer therapy is close to the value obtained from animal experiment in vitro and in vivo. We expect the SS model leads us to a unified description of radiation therapy and protection and provides a great development in cancer-therapy clinical-planning.

GRAS-Di system facilitates high-density genetic map construction and QTL identification in recombinant inbred lines of the wheat progenitor Aegilops tauschii.

Due to large and complex genomes of Triticeae species, skim sequencing approaches have cost and analytical advantages for detecting genetic markers and building linkage maps. Here, we develop a high-density linkage map and identify quantitative trait loci (QTLs) for recombinant inbred lines of Aegilops tauschii, a D-genome donor of bread wheat, using the recently developed genotyping by Random Amplicon Sequencing-Direct (GRAS-Di) system, which facilitates skimming of the large and complicated genome and generates a large number of genetic markers. The deduced linkage groups based on the GRAS-Di genetic markers corresponded to the chromosome number of Ae. tauschii. We successfully identified stable QTLs for flowering time and spikelet shape-related traits. Genotype differences of RILs at the QTL-linked markers were significantly associated with the trait variations. In particular, one of the QTL-linked markers for flowering time was mapped close to VRN3 (also known as FLOWERING LOCUS T), which controls flowering. The GRAS-Di system is, therefore, an efficient and useful application for genotyping and linkage mapping in species with large and complex genomes, such as Triticeae species.

Study of mutation from DNA to biological evolution.

Purpose: This is a paper based on a talk given in the BER2018 conference by M. Bando. We first emphasize the importance of collaborations among scientists in various fields for the low dose/dose-rate effects on biological body. We make comparisons of quantitative estimations of mutation caused by the radiation exposure on various animals and plants using one mathematical model. We derive the importance of the spontaneous mutation at the DNA level, which provides the key to understand the biological evolution. We try to make a guide map to solve this problem and find that the mutation is an important stage of the pathway from the DNA damage to the macroscopic biological evolution. Materials and methods: We construct a mathematical model for the mutation, named as 'WAM' model, which takes into account the recovery effect. The model setting is regarded as an extension of the survival and the hazard functions. The WAM model is used to reproduce accumulated data of mutation frequency of animals and plants. Especially the model analysis shows that the dose-rate dependence is important to understand various mutation data. Results and conclusions: The WAM model is successful in reproducing various mutation data of animals and plants. We find that the inclusion of the dose rate is important to understand all the mutation data. Hence, we are able to develop the 'scaling law' to make the cross-species comparison of mutation frequency data. With this finding, we can extract the dominant effect on the mutation to be caused by the spontaneous mutation, and quantify this amount. We are able to write then the artificial radiation frequency by subtracting the spontaneous mutation. With this success, we estimate the origin of the spontaneous mutation as due to ROS, the order of which agrees to the spontaneous mutation.

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 ß-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.

Verification of a dose rate-responsive dynamic equilibrium model on radiation-induced mutation frequencies in mice.

Purpose: We have proposed a mathematical model (WAM model) expressing increment of the dose-rate dependent mutation frequency caused by artificial radiations. In this model, it is defined that the pool of mutant cells in dynamic equilibrium in organisms. We verified the accuracy of the WAM prediction of mutation frequency in mice. Materials and methods: The theoretical values calculated by the WAM model were compared with the experimental values obtained from the large mouse genetics program at the Oak Ridge National Laboratory (ORNL). Results: Most of all the theoretical values in acute and chronic irradiation conditions nearly coincided with the experimental values. However, the theoretical value of the chronic conditions at the dose-rate of 0.8 R/min was significantly higher than its experimental value. This discordance was able to be minimized in the WAM assumption, when the period from the end of exposure to start mating was two weeks longer. Conclusions: As a result of comparison between experimental and theoretical data, the certainty of the WAM model was confirmed in mice and it was shown that the genetic influence varies depending on the dose-rate.

Transcriptional factor Pdx1 is involved in age-related GIP hypersecretion in mice.

Fat accumulation with aging is a serious problem; glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is an incretin that plays an important role in fat accumulation. GIP receptor knockout mice show reduced fat mass and improved insulin sensitivity associated with aging. Therefore, GIP is involved in fat accumulation and insulin resistance with aging. However, age-related changes of GIP secretion remain unclear. The present study aimed to elucidate age-related changes of GIP secretion and enteroendocrine K cells using GIP reporter [GIP-green fluorescent protein (GFP) knock-in heterozygous (GIPgfp/+)] mice. Aged 1-yr-old GIPgfp/+ mice exhibited a phenotype of fat accumulation, insulin resistance, and GIP hypersecretion compared with young (3-4 mo old) GIPgfp/+ mice. In aged mice, K-cell number in the small intestine and the mRNA expression levels of GIP and transcriptional factor pancreatic and duodenal homeobox-1 (Pdx1) in K cells were increased. K-cell number, GIP mRNA expression and content in small intestine, and GIP secretion were decreased after posteriori suppression of Pdx1 using intestine-specific gene transfer. Thus, Pdx1 positively regulates GIP mRNA and K-cell number in small intestine. Increased Pdx1 expression might be involved in GIP hypersecretion with aging. NEW & NOTEWORTHY Age-related changes of glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) secretion and K cells were investigated. We found that K-cell number and GIP and pancreatic and duodenal homeobox-1 (Pdx1) expression in K cells were increased in aged mice, which showed greater GIP secretion compared with young mice. In addition, we have succeeded in posteriori suppression of Pdx1 in small intestine using the method of intestine-specific gene transfer, and showed that K-cell number, GIP expression, and GIP secretion were decreased in the Pdx1-knockdown intestine.

Glucose-dependent insulinotropic polypeptide is required for moderate high-fat diet- but not high-carbohydrate diet-induced weight gain.

Both high-fat (HFD) and high-carbohydrate (ST) diets are known to induce weight gain. Glucose-dependent insulinotropic polypeptide (GIP) is secreted mainly from intestinal K cells upon stimuli by nutrients such as fat and glucose, and it potentiates glucose-induced insulin secretion. GIP is well known to contribute to HFD-induced obesity. In this study, we analyzed the effect of ST feeding on GIP secretion and metabolic parameters to explore the role of GIP in ST-induced weight gain. Both wild-type (WT) and GIP receptor deficient ( GiprKO) mice were fed normal chow (NC), ST, or moderate (m)HFD for 22 wk. Body weight was measured, and then glucose tolerance tests were performed. Insulin secretion from isolated islets also was analyzed. WT mice fed ST or mHFD displayed weight gain concomitant with increased plasma GIP levels compared with WT mice fed NC. WT mice fed mHFD showed improved glucose tolerance due to enhanced insulin secretion during oral glucose tolerance tests compared with WT mice fed NC or ST. GiprKO mice fed mHFD did not display weight gain. On the other hand, GiprKO mice fed ST showed weight gain and did not display obvious glucose intolerance. Glucose-induced insulin secretion was enhanced during intraperitoneal glucose tolerance tests and from isolated islets in both WT and GiprKO mice fed ST compared with those fed NC. In conclusion, enhanced GIP secretion induced by mHFD-feeding contributes to increased insulin secretion and body weight gain, whereas GIP is marginally involved in weight gain induced by ST-feeding.

Distribution and hormonal characterization of primary murine L cells throughout the gastrointestinal tract.

AIMS/INTRODUCTION: Glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L cells is an incretin that potentiates insulin secretion and is already applied in therapies for type 2 diabetes. However, detailed examination of L cells throughout the gastrointestinal tract remains unclear, because of difficulties in purifying scattered L cells from other cells. In the present study, we identified characteristics of L cells of the upper small intestine (UI), the lower small intestine (LI) and the colon using glucagon-green fluorescent protein-expressing mice that express GFP driven by the proglucagon promoter. MATERIALS AND METHODS: The localization and density of primary L cells were evaluated by anti-green fluorescent protein antibody reactivity. GLP-1 content, messenger ribonucleic acid (mRNA) expression levels and secretion in purified L cells were measured. RESULTS: The number of L cells significantly increased toward the colon. In contrast, the GLP-1 content and secretion from L cells were higher in the UI than in the LI and colon. L cells from the UI and LI expressed notably high mRNA levels of the transcription factor, islet 1. The mRNA expression levels of peptide YY in L cells were higher in the LI than in the UI and colon. The mRNA expression levels of gastric inhibitory polypeptide in L cells from the UI were significantly higher compared with those from the LI and colon. CONCLUSIONS: L cells show different numbers and characteristics throughout the gut, and they express different mRNA levels of transcription factors and gastrointestinal hormones. These results contribute to the therapeutic application of promoting GLP-1 release from L cells for the treatment of type 2 diabetes.

Long-Chain Free Fatty Acid Receptor GPR120 Mediates Oil-Induced GIP Secretion Through CCK in Male Mice.

Free fatty acid receptors GPR120 and GPR40 are involved in the secretion of gut hormones. GPR120 and GPR40 are expressed in enteroendocrine K cells, and their activation induces the secretion of the incretin glucose-dependent insulinotropic polypeptide (GIP). However, the role of these receptors in fat-induced GIP secretion in vivo and the associated mechanisms are unclear. In this study, we investigated corn oil-induced GIP secretion in GPR120-knockout (GPR120-/-) and GPR40-knockout (GPR40-/-) mice. Oil-induced GIP secretion was reduced by 50% and 80% in GPR120-/- and GPR40-/- mice, respectively, compared with wild-type mice. This was not associated with a significant difference in K-cell number or GIP content in K cells, nor messenger RNA levels of the lipid receptor GPR119, nor bile acid receptors TGR5 and farnesoid X receptor. GPR120-/- and GPR40-/- mice also exhibited substantially decreased levels of cholecystokinin (CCK), a hormone from I cells that promotes bile and pancreatic lipase secretion, and this decrease was associated with impaired gallbladder contraction. Notably, treatment with a CCK analog resulted in recovery of oil-induced GIP secretion in GPR120-/- mice but not in GPR40-/- mice. These results indicate that corn oil-induced GIP secretion from K cells involves both GPR120 and GPR40 signaling pathways, and GPR120-induced GIP secretion is indirectly mediated by CCK.

Inhibition of Gastric Inhibitory Polypeptide Receptor Signaling in Adipose Tissue Reduces Insulin Resistance and Hepatic Steatosis in High-Fat Diet-Fed Mice.

Gastric inhibitory polypeptide receptor (GIPR) directly induces energy accumulation in adipose tissue in vitro. However, the importance of the direct effect of GIPR signaling on adipose tissue in vivo remains unclear. In the current study, we generated adipose tissue-specific GIPR knockout (GIPRadipo-/-) mice and investigated the direct actions of GIP in adipose tissue. Under high-fat diet (HFD)-fed conditions, GIPRadipo-/- mice had significantly lower body weight and lean body mass compared with those in floxed GIPR (GIPRfl/fl) mice, although the fat volume was not significantly different between the two groups. Interestingly, insulin resistance, liver weight, and hepatic steatosis were reduced in HFD-fed GIPRadipo-/- mice. Plasma levels of interleukin-6 (IL-6), a proinflammatory cytokine that induces insulin resistance, were reduced in HFD-fed GIPRadipo-/- mice compared with those in HFD-fed GIPRfl/fl mice. Suppressor of cytokine signaling 3 (SOCS3) signaling is located downstream of the IL-6 receptor and is associated with insulin resistance and hepatic steatosis. Expression levels of SOCS3 mRNA were significantly lower in adipose and liver tissues of HFD-fed GIPRadipo-/- mice compared with those of HFD-fed GIPRfl/fl mice. Thus, GIPR signaling in adipose tissue plays a critical role in HFD-induced insulin resistance and hepatic steatosis in vivo, which may involve IL-6 signaling.

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

AIMS/INTRODUCTION: A 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 METHODS: We 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. RESULTS: GFO 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. CONCLUSIONS: These 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.

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.