Absence of GIP secretion alleviates age-related obesity and insulin resistance.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP-/-) and heterozygous (GIP+/-) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP-/- mice compared to that in WT and GIP+/- mice from 38 weeks of age, while there was no significant difference between WT and GIP+/- mice. Visceral and s.c. fat mass were also significantly lower in GIP-/- mice compared to those in WT and GIP+/- mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP-/- mice than those in WT and GIP+/- mice. During insulin tolerance test, GIP-/- mice showed higher insulin sensitivity than that of WT and GIP+/- mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP-/- mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.

Medium-chain triglyceride diet stimulates less GIP secretion and suppresses body weight and fat mass gain compared with long-chain triglyceride diet.

Gastric inhibitory polypeptide (GIP) is an incretin secreted from enteroendocrine K cells and potentiates insulin secretion from pancreatic ß-cells. GIP also enhances long-chain triglyceride (LCT) diet-induced obesity and insulin resistance. Long-term intake of medium-chain triglyceride (MCT) diet is known to induce less body weight and fat mass gain than that of LCT diet. However, the effect of MCT diet feeding on GIP secretion and the effect of GIP on body weight and fat mass under MCT diet-feeding condition are unknown. In this study, we evaluated the effect of single MCT oil administration on GIP secretion and compared the effect of long-term MCT and LCT diet on body weight and fat mass gain in wild-type (WT) and GIP-knockout (GIP KO) mice. Single administration of LCT oil induced GIP secretion but that of MCT oil did not in WT mice. Long-term intake of LCT diet induced GIP hypersecretion and significant body weight and fat mass gain compared with that of control fat (CF) diet in WT mice. In contrast, MCT diet did not induce GIP hypersecretion, and MCT diet-fed mice showed smaller increase in body weight and fat mass gain compared with CF diet-fed mice. In GIP KO mice, body weight and fat mass were markedly attenuated in LCT diet-fed mice but not in MCT diet-fed mice. Our results suggest that long-term intake of MCT diet stimulates less GIP secretion and suppresses body weight and fat mass gain compared with that of LCT diet.

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

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

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.

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.

Evaluation of prognosis in patients with respiratory failure requiring venovenous extracorporeal membrane oxygenation (ECMO).

PURPOSE: In this study, we analyzed the respiratory status and the prognosis of patients, including adults with acute respiratory failure requiring venovenous extracorporeal membrane oxygenation (VV ECMO) to maintain respiratory status. We then evaluated the differences between patients who could be removed from VV ECMO and those who could not. PATIENTS AND METHODS: From January 2003 to December 2008, eleven patients in our hospital required VV ECMO for severe acute respiratory failure. All 11 had severe acute respiratory distress syndrome. The age of the patients was 52 ± 24 (range; 8-86) years, and the male/female ratio was 8/3. The acute physiology and chronic health evaluation II (APACHE II) score, ECMO flow, and respiratory parameters, such as PaO2/FiO2 (P/F ratio), pulmonary compliance, and Lung Injury Score (LIS) before and after the introduction of ECMO, were compared among patients in whom ECMO could or could not be removed. RESULTS: ECMO could be removed from six patients (55%, group A), but in five (45%, group B) could not. The duration of ECMO support was significantly shorter in group A than in group B (111 ± 68 hr vs. 380 ± 233 hr, p = 0.011). The pre-ECMO ventilator time was shorter in group A than in group B. Significant differences were found between the two groups in the P/F ratio and LIS from pre-ECMO introduction to 72 hours after. ECMO flow in group A could be weaned for 48 hours after introduction, significantly different compared with group B. CONCLUSION: The early introduction of ECMO may be desirable if the causes of respiratory failure are recoverable. It is presumed that VV ECMO removal will be difficult if the ECMO flow cannot be weaned within 48 hours after ECMO introduction in patients with severe respiratory failure.

Evaluation of respiratory status in patients after thoracic esophagectomy using PiCCO system.

PURPOSE: Thoracic esophagectomy for esophageal cancer is among the most invasive operations, requiring thoracotomy and laparotomy. With regard to postoperative status, the increment of vascular permeability caused by various inflammatory cytokines might influence the postoperative respiratory condition. The PiCCO (pulse contour cardiac output) system (Pulsion Medical Systems AG, Munich, Germany), a new technique based on an arterial thermodilution technique, allows the measurement of extravascular lung water (EVLW). In this study, we hypothesized that EVLW might be a useful parameter to assess the respiratory condition and evaluated respiratory status using values for EVLW after thoracic esophagectomy. PATIENTS AND METHODS: The PiCCO system was established in the intensive care unit (ICU) in 25 patients immediately after thoracic esophagectomy for esophageal cancer. EVLWI (EVLW/body weight, normal range: 3-7 ml/kg) was measured on ICU days (ICUD) 1, 2, and 3. The PaO(2)/FiO(2) (P/F ratio), pulmonary compliance, and lung injury score (LIS) were also calculated, and relationships between EVLWI and those parameters were evaluated. RESULTS: Mean operating time, blood volume, and fluid balance during surgery were 515+/- 16 (395-690) min, 721+/- 91 (167-1,770) ml, and 3,462+/- 292 (1,892-7,300) ml, respectively. The mean ICU stay was 3.4 +/- 0.3 (2-10) days, and all patients were discharged from the ICU without complications. EVLWI gradually increased after surgery with values of 8.6+/- 1.9 ml/kg on ICUD 1, 9.7+/- 2.7 ml/kg on ICUD 2, and 10.0+/- 3.0 ml/kg on ICUD 3. EVLWI was well correlated with P/F ratio (r = -0.358, p = 0.0135), pulmonary compliance (r = -0.625, p = 0.0001), and LIS (r = 0.614, p = 0.0001). CONCLUSION: EVLWI may be a useful parameter for evaluation of the respiratory condition after thoracic esophagectomy.