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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.

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.

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

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

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)

Silent lacunar infarcts (SLI) are often incidentally found on brain MRI scans in asymptomatic elderly people, and are associated with the future onset of stroke and dementia. However, the risk factors for SLI have not been fully elucidated yet. We recently found that reduced muscle strength is a risk factor for SLI. Systemic insulin sensitivity (IS) that reflects the metabolic function of muscles could also be a risk factor for SLI; however, interactive effect of IS and muscle strength on SLI is totally unknown. Here, we evaluated SLI, recently established index of IS (PREDIM) and knee extensor muscle strength by MRI, oral glucose tolerance test, and dynamometer, respectively on 1,531 elderly people aged 65-84 years living in an urban area of Tokyo. The subjects were categorized into 3 groups based on the standard deviation of PREDIM and the tertiles of muscle strength, respectively, then categorized into 9 groups by their combination, then we estimated odd ratios for SLI by logistic regression analysis. Among the study subjects, we found 251 (16.4%) subjects had silent lacunar infarcts. IS was weakly correlated to muscle strength (r=0.185, p=0.001). Impaired IS [High; 1.00 (reference), Medium; 1.53 (95%CI: 0.94-2.48), Low; 1.85 (95%CI: 1.02-3.38), p for trend 0.047] and reduced muscle strength [High; 1.00 (reference), Medium; 1.42 (95%CI: 0.99-2.04), Low; 1.51 (95%CI: 1.05-2.16), p for trend 0.034] were independently associated with increased risk for SLI in the fully adjusted model. In terms of interactive association, subjects categorized in the lowest IS and muscle strength had 4.4 fold (95%CI: 1.67-11.64) higher risk for SLI compared with those categorized in both are the highest. In summary, reduced muscle strength and IS were independently associated with higher risk for SLI in elderly subjects, and combination of both was synergistically elevated the risk for SLI. Disclosure Y. Someya: 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. D. Sugimoto: None. S. Kadowaki: None. R. Suzuki: 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); Japan Society for the Promotion of Science (18H03184); Mizuno Sports Promotion Foundation; Mitsui Life Social Welfare Foundation

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 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.

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 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.

Nocturnal hypoglycemia is a serious problem in the management of diabetes mellitus (DM). The average daily risk range (ADRR) was the value created to access blood glucose variability. ADRR can be calculated using self-monitoring blood glucose (SMBG) values and is reported to be sensitive to both hyperglycemia and hypoglycemia. However, the usefulness of ADRR in Asian type 1 patients with DM (T1DM) to detect nocturnal hypoglycemia has not been elucidated yet. In this study, we recruited 28 Japanese T1DM. All patients wore outpatient continuous glucose monitoring (CGM) for 6 days and performed SMBG, 3 times/day (before breakfast and dinner, and 2 hours after dinner) for 14 days. Based on these SMBG data, we calculated ADRR and assessed the correlation of ADRR with glucose kinetics. There were no significant correlations of ADRR with hypoglycemic and hyperglycemic frequencies during nighttime. However, there were significant correlations of ADRR with Standard Deviation (SD) (r=0.53, p = 0.003), and Coefficient of Variation (CV) (r=0.46, p = 0.015) of mean glucose during nighttime. In addition, although ADRR showed no significant correlation with hypoglycemic frequency during daytime, ADRR showed significant correlation with hyperglycemic frequency (r=0.47, p=0.012), mean glucose (r=0.40, p=0.033), SD (r=0.56, p = 0.002) and CV (r=0.39, p = 0.041) during daytime. In conclusion, ADRR could be useful to detect glycemic variability during nighttime, however, it is useless to estimate risks of hypoglycemia and hyperglycemia during nighttime. Our data showed only limited usefulness of ADRR in clinical setting in Japanese T1DM. Disclosure F. Ikeda: None. A. Kanazawa: Speaker's Bureau; Self; Sanofi K.K., Kissei Pharmaceutical Co., Ltd.. M. Iida: None. H. Kaga: None. N. Takayanagi: None. T. Shimizu: None. C. Shirakawa: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.

Previous studies reported that the shape of glucose response curve during an oral glucose tolerance test (OGTT) could be a marker of insulin sensitivity in obese subjects. The biphasic response curve was defined by a second rise in glucose concentration of >4.5mg/dl after the decline in glucose during OGTT and subjects with biphasic response curve were insulin sensitive and had low risk of type 2 diabetes compared with subjects with monophasic response curve. While type 2 diabetes is often developed in non-obese Asians, it is still unclear whether the subjects with biphasic response curve are also insulin sensitive in non-obese healthy men. To clarify this, we studied 49 non-obese (BMI In conclusion, biphasic glucose response curve is a marker of elevated muscle insulin sensitivity with less visceral fat in non-obese Japanese healthy men. Disclosure H. Kaga: None. Y. Tamura: None. K. Takeno: None. S. Kakehi: None. Y. Someya: None. R. Suzuki: None. S. Kadowaki: None. D. Sugimoto: None. Y. Furukawa: None. T. Funayama: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.

Increased plasma free fatty acid (FFA) level is reported to be an important cause of obesity-associated insulin resistance in muscle and liver. Increased plasma FFA level in obesity is induced by insufficient suppression of plasma FFA by insulin and this is defined as impaired insulin sensitivity in adipose tissue (Adipo-IS). However, significance of impaired Adipo-IS in non-obese healthy subjects is totally unknown. To clarify this, we studied 49 non-obese (BMI< 25kg/m2) apparently healthy Japanese men without any cardiometabolic risk factors (mean age; 40.2±5.3 y.o, mean BMI; 23.1±1.0 kg/m²). We performed a 2-step hyperinsulinemic euglycemic clamp test (10 and 20 mU/m2 per min, 3h for each) to measure insulin sensitivity in muscle and liver. In addition, plasma FFA levels were also measured at fasting and 2nd step during the glucose clamp. Ectopic fat levels in muscle and liver and visceral fat area (VFA) were measured by 1H-MRS and MRI, respectively. The plasma FFA level was decreased from 530.6±139.1μEq/l to 62.4±64.2μEq/l during hyperinsulinemic euglycemic clamp. Thus, the mean Adipo-IS, defined as %FFA suppression during glucose clamp, was 88.8±10.3%; however, there was a large individual variations in Adipo-IS. Interestingly, Adipo-IS was positively correlated to insulin sensitivity in muscle (r=0.60, p Disclosure D. Sugimoto: None. Y. Tamura: None. K. Takeno: None. H. Kaga: None. Y. Someya: None. R. Suzuki: None. S. Kadowaki: None. T. Funayama: None. Y. Furukawa: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.

Japanese women have substantially lower BMI than women in other developed countries and the prevalence of underweight (BMI In conclusion, the present study suggested that main cause of hyperglycemia in underweight women with IGT was decreased Rd. In addition, decreased insulin secretion may partly contribute to the decreased Rd in those IGT subjects. Disclosure R. Suzuki: None. Y. Tamura: None. Y. Someya: None. H. Kaga: None. D. Sugimoto: None. S. Kadowaki: None. S. Kakehi: None. K. Takeno: None. T. Funayama: None. Y. Furukawa: None. J. Sato: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Novo Nordisk Inc., Novartis Pharmaceuticals Corporation, Sanofi, Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd.. R. Kawamori: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.

Metabolic diseases easily develop in non-obese Asians. We recently found that insulin resistance (IR) in muscle is closely associated with metabolic abnormalities in non-obese Japanese men and muscle IR is correlated well with both visceral fat accumulation (VFA) and fatty liver (FL). However, VFA and FL are correlated well with each other, thus it is unclear which is a better marker of muscle IR.To clarify this, we studied 87 nondiabetic non-obese middle-aged Japanese men. Using a two-step hyperinsulinemic euglycemic clamp, we evaluated insulin sensitivity (IS) in muscle and liver. Intrahepatic lipid (IHL) and visceral fat area are measured by 1H-MRS and MRI, respectively. According to the generally accepted definition, subject was divided into 4 groups by the presence or absence of VFA (visceral fat area 100cm2) and FL (IHL 5%); control (non-VFA non-FL; n=54), VFA alone (n=18), FL alone (n=7), VFA+FL (n=8). Hepatic-IS was similar among the groups. On the other hand, muscle-IS was significantly lower in groups of FL alone and VFA+FL than the control group. Interestingly, muscle-IS of VFA alone group was comparable to the control group, and it was significantly higher than FL alone group (Figure). These differences were still significant after adjustment for confounders. These data suggested that FL is a better marker than VFA in nondiabetic non-obese men in terms of sensitivity to detect muscle IR. Disclosure S. Kadowaki: None. Y. Tamura: None. Y. Someya: None. K. Takeno: None. T. Funayama: None. Y. Furukawa: None. S. Kakehi: None. H. Kaga: None. R. Suzuki: None. D. Sugimoto: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson & Johnson Diabetes Institute, LLC., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.