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Background: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5‐fluorouracil (5‐FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5‐FU with Lut in PDACs. Methods and Results: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5‐FU. The xenograft tumors of DPYD‐overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA‐seq analysis of the DPYD‐overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity—MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5‐FU on DPYD‐overexpressing xenograft tumors and PDAC of Pdx1‐Cre; LSL‐KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5‐FU nor Lut showed significant inhibitory effects; however, the combined administration of 5‐FU and Lut exhibited a significant tumor‐suppressive effect in both the xenograft tumors and KPPC models. Conclusion: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5‐FU resistance, in PDACs. The combination therapy of Lut and 5‐FU holds the potential for enhanced efficacy against PDACs. [ABSTRACT FROM AUTHOR]

Context Older adults with sarcopenic obesity are at high risk for type 2 diabetes mellitus (T2DM). However, few East Asians have sarcopenic obesity. Since many East Asians have insulin resistance (IR) without obesity, it is possible that older East Asians with sarcopenia and IR might be at high risk for T2DM. However, this relationship has not been studied. Methods This cross-sectional study included 1629 older adults aged 65 to 84 years registered in the Bunkyo Health Study. All underwent a 75-g oral glucose tolerance test and handgrip strength measurement. Participants were classified into 4 groups by possible sarcopenia (handgrip strength <28 kg in men and <18 kg in women) and IR status (triglyceride glucose [TyG] index ≥8.79 for men and ≥8.62 for women [third quartile]). Modified Poisson regression was used to estimate relative risk (RR) and 95% CIs for T2DM with adjustment for confounding factors. Results The mean age was 73.1 ± 5.4 years. T2DM was diagnosed in 212 (13.0%) participants. After adjusting for age, sex, body mass index, use of lipid-lowering medications, hypertension, and cardiovascular disease, possible sarcopenia and IR were associated with T2DM, with their coexistence showing a notably stronger association (control: RR, 1.00 [Reference]; possible sarcopenia: RR, 1.55 [95% CI, 1.04-2.30]; IR: RR, 2.69 [95% CI, 1.99-3.65]; and IR possible sarcopenia: RR, 4.76 [95% CI, 3.34-6.79]). Conclusion Possible sarcopenia based on low handgrip strength and IR based on the TyG index are independently associated with T2DM in older Japanese individuals. Their coexistence shows a particularly strong association with T2DM. [ABSTRACT FROM AUTHOR]

Context Older adults have a high prevalence of new-onset diabetes, often attributed to age-related decreases in insulin sensitivity and secretion. It remains unclear whether both insulin sensitivity and secretion continue to deteriorate after age 65. Objective To investigate the effects of aging on glucose metabolism after age 65 and to identify its determinants. Methods This cross-sectional study involved 1438 Japanese older adults without diabetes. All participants underwent a 75-g oral glucose tolerance test (OGTT). Body composition and fat distribution were measured with dual-energy X-ray absorptiometry and magnetic resonance imaging. Participants were divided into 4 groups by age (65-69, 70-74, 75-79, and 80-84 years) to compare differences in metabolic parameters. Results Mean age and body mass index were 73.0 ± 5.4 years and 22.7 ± 3.0 kg/m2. The prevalence of newly diagnosed diabetes increased with age. Fasting glucose, fasting insulin, the area under the curve (AUC)-insulin/AUC-glucose and insulinogenic index were comparable between groups. AUC-glucose and AUC-insulin during OGTT were significantly higher and Matsuda index and disposition index (Matsuda index · AUC-insulin/AUC-glucose) were significantly lower in the age 80-84 group than in the age 65-69 group. Age-related fat accumulation, particularly increased visceral fat area (VFA), and elevated free fatty acid (FFA) levels were observed. Multiple regression revealed strong correlations of both Matsuda index and disposition index with VFA and FFA. Conclusion Glucose tolerance declined with age in Japanese older adults, possibly due to age-related insulin resistance and β-cell deterioration associated with fat accumulation and elevated FFA levels. [ABSTRACT FROM AUTHOR]

A short-term high-calorie high-fat diet (HCHFD) impairs insulin sensitivity in non-obese South Asian but not Caucasian men; however, the effect of short-term HCHFD on insulin sensitivity in East Asians is unknown. We recruited 21 healthy non-obese Japanese men to evaluate metabolic parameters and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus a 45% energy excess with dairy fat supplementation. We evaluated tissue-specific insulin sensitivity and metabolic clearance rate of insulin (MCRI) using a two-step hyperinsulinemic euglycemic clamp, glucose tolerance using the glucose tolerance test, and measured ectopic fat in muscle and the liver using ¹H-magnetic resonance spectroscopy. The primary outcome of this study was insulin sensitivity measured by the clamp study. The secondary/exploratory outcomes were other metabolic changes. After HCHFD, levels of circulating lipopolysaccharide binding protein (LBP), a marker of endotoxemia, increased by 14%. In addition, intramyocellular lipid levels in the tibialis anterior and soleus and intrahepatic lipid levels increased by 47%, 31%, and 200%, respectively. Insulin sensitivity decreased by 4% in muscle and 8% in liver. However, even with reduced insulin sensitivity, glucose metabolism was maintained by increased serum insulin concentrations due to lower MCRI and higher endogenous insulin secretion during the clamp. Glucose levels during the meal tolerance test were comparable before and after HCHFD. In conclusion, short-term HCHFD impaired insulin sensitivity in the muscle and livers of non-obese Japanese men with increased LBP and ectopic fat accumulation. Elevated insulin levels from modulated insulin secretion and clearance might contribute to the maintenance of normal glucose metabolism during the clamp and meal tolerance test. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether changes in endogenous glucose production (EGP) and insulin and glucagon levels are elicited by the decrease in plasma glucose (PG) levels induced by the sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor tofogliflozin. Materials and Methods: We evaluated EGP in 12 Japanese patients with type 2 diabetes under the conditions of no drugs administered (CON), single administration of the SGLT2 inhibitor tofogliflozin (TOF), and single administration of TOF with adjustment of PG levels with exogenous glucose infusion to mimic changes in PG levels observed with CON (TOF + G). We evaluated changes in EGP and levels of C‐peptide and glucagon from baseline to 180 minutes after drug administration. Results: Endogenous glucose production decreased in the CON (−0.22 ± 0.11 mg/kg·min) and TOF + G experiments (−0.31 ± 0.24 mg/kg·min), but not in the TOF experiment (+0.08 ± 0.19 mg/kg·min). The decrease in C‐peptide was significantly greater in the TOF experiment (−0.11 ± 0.06 nmol/L) than in the CON (−0.03 ± 0.06 nmol/L) and the TOF + G experiments (−0.01 ± 0.11 nmol/L), while the increase in glucagon was significantly greater in the TOF experiment (+11.1 ± 6.3 pmol/L), but not in the TOF + G experiment (+8.6 ± 7.6 pmol/L) compared to the CON experiment (+5.1 ± 4.3 pmol/L). Conclusions: These results indicate that the decrease in PG levels induced by SGLT2 inhibitor administration is required for the increase in EGP and decrease in insulin secretion. [ABSTRACT FROM AUTHOR]

Objective: In Japan, while it is known that underweight women over the age of 40 years have a high risk for type 2 diabetes, there is a lack of clarity on the association between glucose tolerance and underweight in younger women. Accordingly, we investigate the prevalence and features of impaired glucose tolerance (IGT) in young underweight Japanese women.Designs and Methods: In this cross-sectional study, we recruited 56 normal weight and 98 underweight young Japanese women and evaluated their glucose tolerance levels using an oral glucose tolerance test. Then, we compared the clinical characteristics associated with normal glucose tolerance (NGT) and IGT in the underweight women. Insulin secretion, whole-body insulin sensitivity, and adipose tissue insulin resistance values were measured using the insulinogenic index, whole-body insulin sensitivity index (Matsuda index), and adipose insulin resistance index (Adipo-IR), respectively. Fitness level (peak VO2) was measured using an ergometer.Results: The prevalence of IGT was higher in the underweight women than the normal weight women (13.3% vs 1.8%). The underweight women with IGT showed a lower insulinogenic index, lower peak VO2, and Matsuda index and a higher fasting free fatty acid level and Adipo-IR than those with NGT. The whole-body composition was comparable between the NGT and IGT groups.Conclusions: The prevalence of IGT was higher in young Japanese women with underweight than those with a normal weight. The underweight women with IGT showed impaired early-phase insulin secretion, low fitness levels, and reduced whole-body and adipose tissue insulin sensitivity levels. [ABSTRACT FROM AUTHOR]

Aims/Introduction: As a low‐carbohydrate diet and the use of sodium–glucose transporter‐2 inhibitors are both known to increase D‐beta‐hydroxybutyrate levels, the effect of these levels on glucose metabolism has attracted attention. We investigated the acute effects of ketone monoester (KM) ingestion on blood glucose levels during the 75‐g oral glucose tolerance test (OGTT) in participants with impaired glucose tolerance. Materials and Methods: Nine Japanese adults aged 48–62 years (4 men, 5 women) with impaired glucose tolerance participated in this study. After participants fasted overnight, we carried out OGTT for 180 min with and without KM ingestion on two separate days in a randomized cross‐over design. We compared the area under the curve (AUC) of D‐beta‐hydroxybutyrate, glucose, insulin, C‐peptide, glucagon and free fatty acids during OGTT. Results: The AUC of D‐beta‐hydroxybutyrate during OGTT was significantly higher with KM than without KM (KM 5995.3 ± 1257.1 mmol/L·h; without KM 116.1 ± 33.9 mmol/L·h, P < 0.0001), and the AUC of glucose with KM was significantly lower than that without KM (KM 406.6 ± 70.6 mg/dL·h; without KM 483.2 ± 74.3 mg/dL·h, P < 0.0001). This improved glucose excursion was associated with enhanced AUC of insulin during the first half (0–90 min) of OGTT, even though the AUC of C‐peptide during this period was unchanged. In contrast, the AUC of insulin, C‐peptide, glucagon and free fatty acids during 180 min of OGTT were similar in both conditions. Conclusion: The ingestion of KM decreased the AUC of glucose during 75‐g OGTT in Japanese individuals with impaired glucose tolerance, and the mechanism might involve elevated levels of circulating early phase insulin. [ABSTRACT FROM AUTHOR]

Elevated 1‐h plasma glucose (1h‐PG; ≥155 mg/dL) during an oral glucose tolerance test is a risk factor for type 2 diabetes. However, the metabolic characteristics of non‐obese Asians with elevated 1h‐PG are unknown. Thus, we studied 59 non‐obese Japanese men with normal glucose tolerance. We divided study participants into the Low 1h‐PG group (<155 mg/dL) and the High 1h‐PG group (≥155 mg/dL). We compared the metabolic characteristics of the groups, including tissue‐specific insulin sensitivity measured using a two‐step hyperinsulinemic‐euglycemic clamp. Insulinogenic index and adiponectin levels were significantly lower in the High 1h‐PG group than in the Low 1h‐PG group. Other characteristics, including insulin sensitivity, adiposity and ectopic fat accumulation, were similar between the groups. In conclusion, non‐obese Japanese men with high 1h‐PG have impaired early‐phase insulin secretion and lower adiponectin levels. Insulin resistance and abnormal fat distribution were not evident in this population. [ABSTRACT FROM AUTHOR]

Background and Aim. Although many epidemiologic studies have shown that Helicobacter pylori eradication has prophylactic effects on gastric cancer, it does not completely eliminate the risk of gastric cancer. We aimed to investigate the changes in histological gastritis in patients receiving rebamipide treatment after H. pylori eradication. Methods. 206 patients who had undergone H. pylori eradication were evaluated. Of these, 169 patients who achieved successful eradication were randomly allocated to 2 groups: the rebamipide group (n = 82) and the untreated group (n = 87). The primary endpoints were histopathological findings according to the updated Sydney system at the start of the study and after 1 year. Results. Final assessment for histological gastritis was possible in 50 cases from the rebamipide group and 53 cases from the untreated group. The activity and atrophy improved in both the rebamipide and untreated groups, and no significant intergroup differences were observed. Chronic inflammation affecting the lesser curvature of the corpus was significantly improved in the rebamipide group compared to in the untreated group (1.12±0.08 versus 1.35±0.08; P = 0.043). Conclusions. Rebamipide treatment after H. pylori eradication alleviated chronic inflammation in the lesser curvature of the corpus compared to that in the untreated group. This trial is registered with UMIN000002369. [ABSTRACT FROM AUTHOR]

Background and Aim: Although mucoprotective agents are commonly used against gastric and duodenal lesions in Japan, their availability as agents for non-steroidal anti-inflammatory drug (NSAID)-induced gastrointestinal damage has not been clarified. To investigate the effect of irsogladine maleate (IM) on gastric mucosal blood flow (GMBF) reduction induced by diclofenac sodium, a NSAID commonly used in Japan, by laser Doppler flowmetry (LDF) and ultrasonography (US) in canine stomach. Methods: GMBF was measured by LDF and contrast-enhanced US in 15 beagles. US was performed employing real-time harmonic imaging under low acoustic power after intravenous contrast injection using Definity™ (60 mg/kg). 60 min after insertion of a diclofenac sodium suppository (1.0 mg/kg) into the rectum, LDF and contrast-enhanced US were repeated. The examination was done in a crossover, single-blinded fashion. Results: The mean extent of the change in GMBF in the IM group and in the placebo group was +29.3 and –38%, respectively. Conclusions: IM alleviates the reduction of GMBF induced by diclofenac sodium. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Functional dyspepsia (FD) is a clinical syndrome involving upper abdominal symptoms, the causes of which cannot be identified by conventional diagnostic evaluation. Many pathophysiological factors, such as gastric acid, gastroduodenal motility, gastric accommodation, sensory disturbance, stress and Helicobacter pylori infection, may play a role in the pathogenesis of FD. Dysmotility of the upper gastrointestinal tract has been implicated in the symptoms of FD. In previous studies, antral hypomotility and delayed gastric emptying have been reported as major pathogenetic factors in patients with FD. Although a number of methods have been applied to evaluate gastroduodenal motility in humans, many of them have technical limitations and are too expensive or complex to use in daily clinical practice. Recent technical developments enable one to evaluate gastroduodenal motility by using ultrasonography. Ultrasonography is a simple, noninvasive modality for the assessment of gastric emptying and antral motility in either a liquid or solid meal, along with the examination of duodenogastric reflux. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Decreased insulin clearance could be a relatively upstream abnormality in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Previous studies have shown that sodium-glucose cotransporter 2 inhibitor (SGLT2i) increases insulin–C-peptide ratio, a marker of insulin clearance, and improves metabolic parameters. We evaluated the effects of the SGLT2i tofogliflozin on metabolic clearance rate of insulin (MCRI) with a hyperinsulinemic euglycemic clamp study, the gold standard for measuring systemic insulin clearance. Methods: Study participants were 12 Japanese men with type 2 diabetes. We evaluated MCRI and tissue-specific insulin sensitivity with a hyperinsulinemic euglycemic clamp (insulin infusion rate, 40 mU/m2·min) before and immediately after a single dose (n = 12) and 8 weeks (n = 9) of tofogliflozin. We also measured ectopic fat in muscle and liver and the abdominal fat area using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively, before and after 8 weeks of tofogliflozin. Results: MCRI did not change after a single dose of tofogliflozin (594.7 ± 67.7 mL/min·m2 and 608.3 ± 90.9 mL/min·m2, p = 0.61) or after 8 weeks (582.5 ± 67.3 mL/min·m2 and 602.3 ± 67.0 mL/min·m2, p = 0.41). The 8-week treatment significantly improved glycated hemoglobin and decreased body weight (1.7%) and the subcutaneous fat area (6.4%), whereas insulin sensitivity and ectopic fat in muscle and liver did not change significantly. Conclusions: MCRI did not change after a single dose or 8 weeks of tofogliflozin. Increased MCRI does not precede a decrease in body fat or improved glycemic control. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article I A decrease in plasma glucose levels is required for increased endogenous glucose production with a single administration of a sodium-glucose co-transporter-2 inhibitor tofogliflozin i by Nozomu Yamasaki et al., https://doi.org/10.1111/dom.14312. [Extracted from the article]

Reduced insulin clearance (IC) and hyperinsulinemia are observed in obesity with insulin resistance and considered as compensatory change against insulin resistance. On the other hand, several animal models showed that enhanced IC by genetic modification suppressed high fat diet induced weight gain and insulin resistance. Recently we found that 3-day low carbohydrate diet increased IC, suggesting low glucose availability may acutely increase IC. Given that SGLT2 inhibitors decrease glucose availability by increasing urinary glucose excretion, we hypothesized that SGLT2 inhibitors may acutely increase IC, and then induce body weight reduction and improve metabolic disorders. To test this hypothesis, we recruited 12 Japanese men with type 2 diabetes mellitus. We evaluated IC and tissue specific insulin sensitivity by hyperinsulinemic euglycemic clamp (insulin infusion rate; 40 mU/m2·min) on baseline, immediately after a single administration (n=12) and after 8-week administration (n=9) of SGLT2 inhibitor (Tofogliflozin). We also measured ectopic fat in muscle and liver and abdominal fat areas by 1H-MRS and MRI, respectively. IC was not altered immediately after a single administration of Tofogliflozin (594.7±67.7ml/min/m2 to 608.3±90.9ml/min/m2, p=0.61). Also, 8 weeks administration of Tofogliflozin did not alter IC (582.5±67.3ml/min/m2 vs. 602.3±67.0ml/min/m2, p=0.41), while body weight and subcutaneous fat area were significantly decreased by 1.7% and 6.4%, respectively. In addition, 8 weeks administration of Tofogliflozin significantly decreased HbA1c and fasting plasma glucose levels and increased fasting endogenous glucose production, while insulin sensitivity and ectopic fat in muscle and liver were not changed. In conclusion, IC was not altered after a single and 8-week administration of Tofogliflozin. Decreased body weight and improved glycemic control by chronic administration of Tofogliflozin may occur independently of IC change. Disclosure: M. Sato: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker's Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. H. Kaga: None. N. Yamasaki: None. M. Kiya: None. R. Suzuki: None. D. Sugimoto: None. S. Kadowaki: None. Y. Furukawa: None. T. Funayama: None. Y. Someya: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding: Kowa Company, Ltd. [ABSTRACT FROM AUTHOR]

Hyperinsulinemia is observed in obese subject. Even in healthy non-obese subjects, intentional small weight gain by a high-calorie, high-fat diet (HCHFD) resulted in hyperinsulinemia which was caused not by increased insulin secretion but by decreased metabolic clearance rate of insulin (MCRI). In addition, it was reported that in the mice with genetic deletion of CEACAM-1, impairment of MCRI induces hyperinsulinemia and subsequently these mice develop obesity and insulin resistance (IR). Therefore, in healthy subjects, reduction of MCRI could be the primary change that induces hyperinsulinemia, obesity and IR. On the other hand, it has been shown that HCHFD induces enhanced gut permeability and endotoxemia and these changes could be a cause of IR. However, it is totally unknown whether gut microbiota and endotoxemia are related to changes in MCRI as well as insulin sensitivity after HCHFD. To address this, we recruited 21 healthy non-obese men and evaluated metabolic changes and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus 45% energy excess by supplementation with dairy fat. Using a 2-step hyperinsulinemic euglycemic clamp, we evaluated MCRI and tissue specific insulin sensitivity. After the HCHFD, MCRI and muscle insulin sensitivity (M-IS) were significantly decreased by 6% and 4%, respectively. In addition, circulating lipopolysaccharide (LPS) binding protein, a marker of endotoxemia, was significantly increased by 14% after the HCHFD. Baseline relative abundance of Bacteroidetes, LPS-producing Gram-negative gut microbiota, was correlated to changes in MCRI (r=-0.57, p=0.009) and M-IS (r=-0.46, p=0.040), respectively. In conclusion, short-term HCHFD decreased MCRI and M-IS and those changes were associated with increased marker of endotoxemia after HCHFD and higher baseline relative abundance of Bacteroidetes in gut microbiota. Disclosure: S. Kadowaki: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker's Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. D. Sugimoto: None. Y. Someya: None. H. Kaga: None. R. Suzuki: None. S. Kakehi: None. N. Yamasaki: None. M. Sato: None. A. Kanazawa: Speaker's Bureau; Self; Novartis Pharma K.K., Sanofi, Takeda Pharmaceutical Company Limited. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding: Ministry of Education, Culture, Sports, Science and Technology of Japan (18H03196) [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that saturated fat intake increases the risk of type 2 diabetes (T2DM) due to reduction of insulin sensitivity. On the other hand, the consumption of dairy fat that predominantly includes saturated fat is reported to be protective against T2DM. However, its underlying mechanism has not been fully understood. To address this, we recruited 21 healthy non-obese men and evaluated metabolic changes before and after 6-day high-calorie, high-fat diet (HCHFD) consisting of a regular diet plus 45% energy excess by supplementation with dairy fat. We measured intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) in tibialis anterior muscle by 1H-MRS and metabolic rate during sleeping by metabolic chamber. One day after the measurement, we performed meal test, and the next day, we measured tissue specific insulin sensitivity by 2-step hyperinsulinemic euglycemic clamp. After the HCHFD, body weight was increased by 0.4 kg, and IMCL and IHL were also increased by 47% and 200%, respectively. On the other hand, hepatic and muscle insulin sensitivity showed only a modest decrease by 8% and 4%, respectively. Consistently, fasting endogenous glucose production elevated by only 3% without altering insulin level; however, unexpectedly, fasting free fatty acid (FFA) greatly decreased by 43%, suggesting increased adipose tissue insulin sensitivity (ATIS), and total ketone body levels was decreased by 53% and glucose oxidation during sleeping was consistently increased. Further, post-prandial glucose rise during the meal test was suppressed after the HCHFD, although insulin secretion was lower during the test. In conclusion, short-term HCHFD by dairy fat supplementation increased ATIS and glucose oxidation, and suppressed post-prandial glucose rise with lowered insulin secretion. These metabolic changes by dairy fat may be beneficial to prevent T2DM. Disclosure: D. Sugimoto: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker's Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. S. Kadowaki: None. Y. Someya: None. H. Kaga: None. R. Suzuki: None. S. Kakehi: None. N. Yamasaki: None. M. Sato: None. A. Kanazawa: Speaker's Bureau; Self; Novartis Pharma K.K., Sanofi, Takeda Pharmaceutical Company Limited. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding: Ministry of Education, Culture, Sports, Science and Technology of Japan (18H03196) [ABSTRACT FROM AUTHOR]

Decreased muscle strength in lower extremities is a major cause of disability in elderly. It has been shown that type 2 diabetes (DM) is a risk factor for reduced muscle strength; however, it remains unclear whether impaired glucose tolerance (IGT) as well as DM is also a risk factor for reduced muscle strength. To address this, we evaluated hand grip strength and knee extensor and flexor muscle strengths in 1,629 older adults living in an urban area of Tokyo, Japan. The reduced muscle strength of hand grip was defined by sarcopenia criteria, and the reduced muscle strength in knee extensor and flexor muscle strengths was defined as mean value -1 SD or less. Adjustments for potential confounders were performed by age, physical activity, BMI, smoking, hypertension and dyslipidemia. The mean age of subjects was 73.1±5.4 years. In men, 43.5% was normal glucose tolerance (NGT), 38.1% was IGT, and 18.3% was DM, and in women, those were 55.8%, 35.2% and 8.9%, respectively. In men, after multivariate adjustment, the odds ratio for the reduced muscle strength of hand grip was higher in DM compared to NGT (NGT;1.00 (reference), IGT; 1.38 (95%CI: 0.88-2.16), DM; 1.87 (95%CI: 1.08-3.22)), while the odds ratios for muscle weakness of knee extensor and flexor were not elevated in DM and IGT compared to NGT. In women, the odds ratios for the reduced muscle strength in hand grip and knee extensor were higher in DM compared to NGT (Hand grip; NGT;1.00, IGT; 0.96 (0.64-1.46), DM; 2.69 (1.52-4.75), Knee extensor; NGT;1.00, IGT; 1.00 (0.66-1.51), DM; 1.93 (1.06-3.53)), while the odds ratio for the reduced muscle strength of knee flexor was higher in both IGT and DM compared to NGT (NGT;1.00, IGT;1.63 (1.15-2.31), DM;1.88(1.08-3.26)). In conclusion, DM is an independent risk factor for reduced muscle strength of handgrip, knee extensor and flexor in elderly women, but not in elderly men. In elderly women, IGT is also an independent risk factor for reduced muscle strength in knee flexor. Disclosure: H. Kaga: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker's Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. Y. Someya: None. S. Kadowaki: None. D. Sugimoto: None. R. Suzuki: None. M. Sato: None. N. Yamasaki: None. M. Kiya: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding: Strategic Research Foundation at Private Universities (S1411006); Ministry of Education, Culture, Sports, Science and Technology of Japan (18H03184); Mizuno Sports Promotion Foundation; Mitsui Life Social Welfare Foundation [ABSTRACT FROM AUTHOR]

Both reduced circulating adiponectin (AN) and impaired adipose tissue insulin sensitivity (ATIS) are observed in obese subjects with insulin resistance (IR). While Asians easily develop metabolic disease featured with IR without obesity, we found that both reduced AN and impaired ATIS are individually associated with muscle IR and accumulation of intrahepatic lipid (IHL) in non-obese Japanese men. However, it is entirely unclear whether the coexistence of reduced AN and impaired ATIS is associated with metabolic abnormality.To clarify this, we studied 94 non-obese Japanese men. We evaluated tissue specific insulin sensitivity by 2-step hyperinsulinemic euglycemic clamp and calculated ATIS as a degree of insulin-mediated suppression of circulating free fatty acid. IHL was measured by 1H-MRS. Then, we divided the subjects into 4 groups based on their median AN and ATIS and assessed the effect of AN and ATIS on the parameters related to muscle IR. As shown in Figure, the levels of IHL in the patients with both reduced AN and impaired ATIS were higher than other groups. The similar tendency was also observed regarding the serum triglyceride level and muscle IR. These results suggested that coexistence of reduced AN and impaired ATIS increases the risk of metabolic abnormality due to muscle IR in non-obese Japanese men. Disclosure: M. Kiya: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker's Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. K. Takeno: None. Y. Someya: None. S. Kakehi: None. M. Sato: None. N. Yamasaki: None. S. Kadowaki: None. R. Suzuki: None. Y. Furukawa: None. D. Sugimoto: None. H. Kaga: None. T. Funayama: None. H. Satoh: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding: High Technology Research Center; Strategic Research Foundation at Private Universities; Japan Ministry of Education, Culture, Sports, Science and Technology (23680069, 26282197, 17K19929); Japan Diabetes Foundation; Suzuken Memorial Foundation; Mitsukoshi Welfare Foundation; Diabetes Masters Conference [ABSTRACT FROM AUTHOR]

It has been shown that a single administration of SGLT2 inhibitor (SGLT2i) to the patients with type 2 diabetes mellitus (T2DM) decreases plasma glucose (PG), but increases endogenous glucose production (EGP); however, its underlying mechanism has been totally unknown. We hypothesized that a single administration of SGLT2i lowers PG, thereby suppresses insulin level and increases glucagon level, which in turn rises EGP. To test this hypothesis, we recruited 12 Japanese patients with type 2 diabetes mellitus without taking any hypoglycemic agents (BMI 24.9±2.5 kg/m2, HbA1c 7.7±0.9%). In each patient, by [6,6-2H2]-glucose infusion, we evaluated basal EGP and EGP under the conditions with: (i) no administration of drugs (CON), (ii) single administration of a SGLT2i, Tofogliflozin (TOF), and (iii) TOF + glucose adjustment (TOF+G) in which we adjusted PG level by exogenous glucose infusion to mimic PG level during CON. In each patient, we measured EGP under three condition at 1-2 week intervals. Also, we evaluated changes in insulin, glucagon and EGP between basal period and after each 3h condition. The decrement of PG during 3h experimental period in TOF was significantly greater than that in CON, and this change was inhibited by glucose infusion (delta PG: CON; -14.6 mg/dl, TOF; -26.4 mg/dl, TOF+G; -15.6 mg/dl). In CON, EGP was decreased by 11.1%, but it was significantly increased by 4.5% in TOF. However, similar to CON, EGP was decreased by 15.7% in TOF+G. In addition, insulin level was decreased by 24% and glucagon level was increased by 36% in TOF; however, these hormonal changes were not observed in CON and TOF+G. In conclusion, acute EGP elevation by a single administration of SGLT2i was disappeared by suppression of glucose lowering effect of SGLT2i. Changes in insulin and glucagon by rapid decline of PG after SGLT2i administration may be a main inducer of EGP elevation. Disclosure: N. Yamasaki: None. Y. Tamura: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Kowa Company, Ltd. Speaker's Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd. H. Kaga: None. M. Sato: None. M. Kiya: None. S. Kadowaki: None. R. Suzuki: None. Y. Furukawa: None. D. Sugimoto: None. T. Funayama: None. Y. Someya: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; Abbott, Ajinomoto, Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Fuji Film, Janssen Pharmaceuticals, Inc., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Research Support; Self; Astellas Pharma Inc., Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Yakult. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Bayer Yakuhin, Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding: Kowa Company, Ltd. [ABSTRACT FROM AUTHOR]

It has been shown that subjects with normal glucose tolerance (NGT) but elevated 1-hour glucose level ≧155 mg/dl during a 75g oral glucose tolerance test (75g OGTT) is an independent risk factor for type 2 diabetes. In Caucasian, subjects with elevated 1-h glucose were characterized by adiposity with lower insulin sensitivity and impaired beta-cell function. While type 2 diabetes in Asians is frequently affected in non-obese (BMI<25 kg/m2) subjects, the characteristics of non-obese Asians with elevated 1-h glucose are totally unknown. Here, we studied 59 non-obese Japanese men with NGT. Based on the level of 1-hour glucose level during 75g OGTT, we divided the subjects into Low-1 hour group (< 155mg/dl) and High-1 hour group (≧155mg/dl). We measured ectopic fat in muscle and liver and subcutaneous and viscera fat areas by 1H-MRS and MRI, respectively. We also measured tissue specific insulin sensitivity by 2 step hyperinsulinemic-euglycemic clamp. Insulinogenic index (0.66±0.30 vs. 1.41±1.21ΔInsulin0-30 min/ΔGlucose 0-30min, p=0.02) was significantly lower and area under the curve of glucose and insulin during 75g OGTT were significantly higher in High-1 hour group than Low-1 hour group (Figure). However, other parameters including insulin sensitivity and ectopic fat in muscle and liver, subcutaneous and viscera fat areas were comparable between the groups. These data suggest that non-obese Japanese men with High-1 hour glucose are characterized by impaired early-phase insulin secretion and subsequent hyperinsulinemia. Insulin resistance and abnormal fat distribution are not evident in this population. Disclosure: M. Sato: None. Y. Tamura: None. H. Kaga: None. Y. Someya: None. S. Kakehi: None. N. Yamasaki: None. D. Sugimoto: None. S. Kadowaki: None. R. Suzuki: None. Y. Furukawa: None. K. Takeno: None. T. Funayama: None. R. Kawamori: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited. [ABSTRACT FROM AUTHOR]

Accumulation of intramyocellular lipid (IMCL) is observed not only in insulin resistant obese subjects with low peak oxygen consumption (VO2peak), but also in insulin sensitive endurance athletes with high VO2peak (athlete's paradox). While the relationship among intramyocellular lipid, peak oxygen consumption and insulin resistance is variable among the different subjects, its relation within non-obese non-athlete subject has not been elucidated yet. To investigate this relation, we studied 61 non-obese (BMI<25kg/m2) non-athlete Japanese men. We evaluated muscle insulin sensitivity (M-IS) by a 2-step hyperinsulinemic euglycemic clamp. We divided the subjects into 4 groups based on the median value of VO2 peak (31.4 ml/kg per min) and the IMCL in soleus muscles (14.3 s-fat/Cre), then we compared M-IS. Compared with Low-VO2peak/High-IMCL group, M-IS was significantly higher in High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group (Fig). On the other hand, M-IS was comparable between High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group. These results suggest that in non-obese non-athlete Japanese men, VO2peaklevel is an important determinant of muscle insulin sensitivity in IMCL accumulated subjects. In addition, IMCL accumulation is not an important determinant of muscle insulin sensitivity in subjects with high VO2peak. Disclosure: N. Yamasaki: None. Y. Tamura: None. K. Takeno: None. S. Kakehi: None. Y. Someya: None. T. Funayama: None. Y. Furukawa: None. H. Kaga: None. R. Suzuki: None. D. Sugimoto: None. S. Kadowaki: None. M. Sato: None. R. Kawamori: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited. [ABSTRACT FROM AUTHOR]

Objective: The proportion of young Japanese women who are underweight is exceptionally high. We previously showed that the prevalence of impaired glucose tolerance (IGT) was high in underweight young Japanese women, and that IGT was characterized by high free fatty acid levels and adipose tissue insulin resistance (ATIR). As the next step, this study aimed to explore factors associated with elevated ATIR in this population., Participants: Ninety-eight young, healthy, underweight women participated in this study., Design: To investigate the relationship between ATIR and metabolic parameters, participants were divided into three groups (Low, Medium, and High) according to ATIR level. Body composition examination, oral glucose tolerance testing, and blood biochemical analysis were performed; Adipo-IR and the Matsuda index were used as indices of ATIR and systemic insulin sensitivity, respectively., Results: Participants in the High ATIR group had the highest prevalence of IGT (25%), and significantly higher body fat percentage, whole-body insulin resistance, and levels of insulin-like growth factor-1 and dehydroepiandrosterone sulfate (DHEA-S) than the other two groups. They were also significantly younger and had higher systolic blood pressure than the Low ATIR group. Multiple regression analysis showed that DHEA-S, which is known to enhance lipolysis in adipose tissue, was an independent correlate of ATIR., Conclusions: Underweight Japanese women with high ATIR had impaired metabolism, a higher prevalence of IGT, higher systemic insulin resistance, and higher systolic blood pressure. DHEA-S was a determinant of high ATIR levels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sato, Tamura, Kaga, Yamasaki, Kadowaki, Sugimoto, Nakagata, Someya, Nishida, Kawamori and Watada.)

Context: Older adults have a high prevalence of new-onset diabetes, often attributed to age-related decreases in insulin sensitivity and secretion. It remains unclear whether both insulin sensitivity and secretion continue to deteriorate after age 65., Objective: To investigate the effects of aging on glucose metabolism after age 65 and to identify its determinants., Methods: This cross-sectional study involved 1438 Japanese older adults without diabetes. All participants underwent a 75-g oral glucose tolerance test (OGTT). Body composition and fat distribution were measured with dual-energy X-ray absorptiometry and magnetic resonance imaging. Participants were divided into 4 groups by age (65-69, 70-74, 75-79, and 80-84 years) to compare differences in metabolic parameters., Results: Mean age and body mass index were 73.0 ± 5.4 years and 22.7 ± 3.0 kg/m 2 . The prevalence of newly diagnosed diabetes increased with age. Fasting glucose, fasting insulin, the area under the curve (AUC)-insulin/AUC-glucose and insulinogenic index were comparable between groups. AUC-glucose and AUC-insulin during OGTT were significantly higher and Matsuda index and disposition index (Matsuda index · AUC-insulin/AUC-glucose) were significantly lower in the age 80-84 group than in the age 65-69 group. Age-related fat accumulation, particularly increased visceral fat area (VFA), and elevated free fatty acid (FFA) levels were observed. Multiple regression revealed strong correlations of both Matsuda index and disposition index with VFA and FFA., Conclusion: Glucose tolerance declined with age in Japanese older adults, possibly due to age-related insulin resistance and β-cell deterioration associated with fat accumulation and elevated FFA levels., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: In Japan, while it is known that underweight women over the age of 40 years have a high risk for type 2 diabetes, there is a lack of clarity on the association between glucose tolerance and underweight in younger women. Accordingly, we investigate the prevalence and features of impaired glucose tolerance (IGT) in young underweight Japanese women., Designs and Methods: In this cross-sectional study, we recruited 56 normal weight and 98 underweight young Japanese women and evaluated their glucose tolerance levels using an oral glucose tolerance test. Then, we compared the clinical characteristics associated with normal glucose tolerance (NGT) and IGT in the underweight women. Insulin secretion, whole-body insulin sensitivity, and adipose tissue insulin resistance values were measured using the insulinogenic index, whole-body insulin sensitivity index (Matsuda index), and adipose insulin resistance index (Adipo-IR), respectively. Fitness level (peak VO2) was measured using an ergometer., Results: The prevalence of IGT was higher in the underweight women than the normal weight women (13.3% vs 1.8%). The underweight women with IGT showed a lower insulinogenic index, lower peak VO2, and Matsuda index and a higher fasting free fatty acid level and Adipo-IR than those with NGT. The whole-body composition was comparable between the NGT and IGT groups., Conclusions: The prevalence of IGT was higher in young Japanese women with underweight than those with a normal weight. The underweight women with IGT showed impaired early-phase insulin secretion, low fitness levels, and reduced whole-body and adipose tissue insulin sensitivity levels., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Adipose tissue dysfunction is characterized by decreased adiponectin (AN) levels and impaired adipose tissue insulin sensitivity (ATIS) and is associated with metabolic disorders. While Asians readily develop metabolic disease without obesity, it remains unclear how decreased AN level and impaired ATIS affect metabolic abnormalities in nonobese Asians., Design and Setting: To investigate the relationships between decreased AN level, impaired ATIS, and metabolic abnormalities, we studied 94 Japanese men whose body mass index was less than 25 kg/m2. We divided the subjects into 4 groups based on their median AN level and ATIS, the latter calculated as the degree of insulin-mediated suppression of free fatty acids during hyperinsulinemic euglycemic clamp, and compared the metabolic parameters in the 4 groups., Results: The High-ATIS/High-AN group (n = 29) showed similar anthropometric data to the High-ATIS/Low-AN group (n = 18). In contrast, both the Low-ATIS/High-AN (n = 18) and Low-ATIS/Low-AN (n = 29) groups showed significantly lower muscle insulin sensitivity than the High-ATIS groups. The intrahepatic lipid level in the Low-ATIS/Low-AN group was significantly higher than that in the High-ATIS groups. In addition, the Low-ATIS/Low-AN group had a significantly higher fasting serum triglyceride level and significantly lower high-density lipoprotein cholesterol level than the other 3 groups., Conclusions: In nonobese Japanese men with high ATIS, the AN level was not associated with metabolic characteristics. On the other hand, subjects with low ATIS showed reduced muscle insulin sensitivity, and those with a decreased AN level demonstrated multiple metabolic abnormalities, represented by fatty liver and dyslipidemia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Functional dyspepsia (FD) is a subcategory of the functional gastrointestinal disorders according to the Rome III classification of functional gastroduodenal disorders. FD is characterized by the presence of symptoms that are believed to be associated with gastroduodenal lesions, particularly epigastric pain or burning, postprandial fullness, or early satiation, without the evidence of organic disease likely to explain the onset of these symptoms. Generally, multiple factors are considered to be involved in the onset of dyspeptic symptoms in patients with FD. Among these factors, acid is thought to be more important because proton pump inhibitors (PPIs) and histamine 2 (H2)-receptor antagonists have been proposed to be effective therapies for a subset of patients with FD. Although manometric methods, scintigraphic methods, electrogastrography and ultrasonography have been used to evaluate enterokinesis, a practical method for evaluating duodenal hypersensitivity to acid has not been reported. Recently, we attempted to evaluate duodenal hypersensitivity to acid and gastric motility by duodenal acidification using transnasal endoscopy. Using this method, we could simultaneously evaluate both dyspeptic symptoms and gastric motility in healthy volunteers. Furthermore, we evaluated duodenal hypersensitivity to acid in healthy volunteers and in patients with FD, and we reported that duodenal acidification induced dyspeptic symptoms more significantly in patients with FD than in healthy volunteers.

Background: Impaired gastric accommodation of the proximal stomach is one of the major pathophysiological mechanisms in functional dyspepsia (FD). However, no useful method exists for the clinical evaluation of this phenomenon., Aim: The aim of the present study was to establish a simple and non-invasive method for evaluating the accommodation reflex of the proximal stomach., Methods: Nine healthy subjects received up to 1,700 mL water (stepwise administration in 100-mL increments) using a nasogastric tube while they were in a supine position. To assess the meal-induced gastric accommodation reflex, we measured the cross-sectional area of the proximal stomach via ultrasonography (US) at 3-min intervals after administration of water. We also measured the pressure of the water column using the same tube. Then, we administrated up to 400 mL of water in 100-mL increments and measured the area of the proximal stomach in 44 FD patients with early satiation (the measurements were performed at intervals of 3-min), and we compared the results with those for 44 healthy subjects., Results: The incremental changes in the area of the proximal stomach corresponded well with the amount of water administered. The area of the proximal stomach increased, but the antral area and the intragastric pressure remained relatively stable. After administration of more than 100 ml water, the area of the proximal stomach in healthy subjects was significantly greater than that in FD patients., Conclusion: US can be used to assess the isotonic expansion of the proximal stomach. We were able to distinguish FD patients with impaired accommodation reflex from healthy individuals by using this simple and easy method.

The (13)C-octanoic acid breath test is widely used for evaluating gastric emptying of solids. Since the results of this test are influenced by multiple factors such as the time required to grind the solid meal into smaller particles, the gastroduodenal transport time of the ground meal, and the time required for bowel drug absorption and drug dispersion, the administration of a test meal by the oral route alone cannot result in an accurate measurement of the complicated process of emptying the stomach of solids. The aim of the present study was to evaluate each phase of gastric emptying of solids by varying the administration route of the test meal. Six healthy male volunteers (mean age: 33.2 yr) participated in the study. The test meal consisted of a bowl of rice topped with a mixture of boiled chicken and eggs admixed with 100 mg of (13)C-octanoic acid (total: 273 kcal). All subjects were given the test meal by each of the following three methods: 1. Normal oral intake of the test meal, 2. Feeding of the ground test meal through a nasogastric tube, 3. Feeding of the ground test meal through a duodenal tube. For each set of examinations, the mean residence time (MRT), half-emptying time (T(1/2)), gastric emptying coefficient (GEC), lag phase (L-breath), and measured maximum (13)C excretion time (Tmax-measured) were calculated. The data was analyzed to determine the time for each phase of gastric emptying as follows: mean grinding time (MGT) = MRT(oral) - MRT(nasogastric), mean gastroduodenal transport time (MGDTT) = MRT(nasogastric) - MRT (nasoduodenal). Data was expressed as the mean +/- SE. The values of the parameters of MGT were 0.82 +/- 0.50 hr (MRT), 0.64 +/- 0.18 hr (T(1/2)), 0.51 +/- 0.24 hr (L-breath), -0.45 +/- 0.30 hr (GEC), and 49.2 +/- 8.0 min (Tmax-measured). The values of the parameters of MGDTT were 0.87 +/- 0.38 hr (MRT), 0.26 +/- 0.29 hr (T(1/2)), 0.92 +/- 0.36 hr (L-breath), 0.55 +/- 0.23 hr (GEC), and 63.33 +/- 8.16 min (Tmax-measured). The times required for the drug absorption and disposition were 1.60 0.20 hr (MRT), 1.03 +/- 0.24 hr (T(1/2)), 0.10 +/- 0.08 hr (L-breath), 3.72 +/- 0.46 hr (GEC), and 19.67 +/- 2.11 min (Tmax-measured). By varying the administration route of a test meal containing (13)C-octanoic acid, we may be able to assess each phase of the emptying of gastric solids in detail, thus leading to a better understanding of gastroduodenal motility.