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The volumes of intracranial tissues of 40 healthy volunteers acquired from 0.3- and 3-T scanners were compared using intraclass correlation coefficients, correlation analyses, and Bland-Altman analyses. We found high intraclass correlation coefficients, high Pearson's correlation coefficients, and low percentage biases in all tissues and most of the brain regions, although small differences were observed in some areas. These findings may support the validity of brain volumetry with low-field magnetic resonance imaging.

Background: Estimating the nutritional content of food is essential for self-management in people with type 2 diabetes mellitus, but it is a difficult skill to learn. The aim of this study was to investigate how diabetes management was impacted by the ability of patients to search for items they ate from a database of 26,300 different foods, and to visualize nutritional intake using the Japanese mobile application (app) "Calomeal." Methods: This was a single-arm, single-center, pilot study. Eighteen outpatients with type 2 diabetes mellitus used the "Calomeal" app for 3 months. The primary endpoint was change in hemoglobin A1c (HbA1c). Secondary endpoints were changes in body weight (BW), lipid parameters, and quality of life scores. Results: The baseline characteristics of the study subjects were as follows: age: 53.4 ± 7.8 years; male/female ratio: 11/7; HbA1c: 7.9 (7.58 - 8.23)%; and body mass index (BMI): 25.17 (21.63 - 28.59) kg/m 2 . Significant reductions in HbA1c and BMI were observed over 3 months (HbA1c: 7.9 (7.58 - 8.23)% to 7.6 (7.3 - 8.23)%, P = 0.0410; BMI: 25.17 (21.63 - 28.59) to 24.54 (21.57 - 27.81) kg/m 2 , P = 0.0057). Reductions in HbA1c and BMI both correlated with decreased carbohydrate intake estimated by the mobile app. Conclusions: Japanese patients who used their smartphones to visualize their nutritional intake using the "Calomeal" app demonstrated improved short-term glycemic control and BMI. Although the validity of the results should be tested in future randomized controlled trials, this approach may be a clinical option for improving self-management in Japanese patients with type 2 diabetes mellitus. J Clin Med Res. 2021;13(8):425-433 doi: https://doi.org/10.14740/jocmr4558

Background Among former Olympic-level athletes, engagement in different sport disciplines has been associated with mortality risk in subsequent years. However, limited evidence is available on whether engagement in different sport disciplines at a young age is associated with locomotive syndrome (LS) risk later in life. This study examined the relationship between engagement in different sport disciplines during university years and LS risk in older age among former university athletes. Methods Participants were 274 middle-aged and 294 older men alumni who graduated from a school of physical education in Japan. LS risk was defined as answering “yes” to any of the Loco-check questions. Data on university sports club membership were collected using questionnaires. University clubs were classified into three groups of cardiovascular intensity (low, moderate, high), following the classification system of sport disciplines by the American College of Cardiology. This classification considers the static and dynamic components of an activity, which correspond to the estimated percent of maximal voluntary contraction reached and maximal oxygen uptake achieved, respectively. University clubs were grouped based on the risk of bodily collision (no, yes) and extent of physical contact (low, moderate, high). Relationships between engagement in different sport disciplines and LS risk were analyzed using Cox proportional hazards models, and adjusted for age, height, weight, joint disease, habitual exercise, and smoking and drinking status. Results Adjusted hazard ratios and 95% confidence intervals associated with the low, moderate, and high cardiovascular intensity sports were 1.00 (reference), 0.48 (0.22–1.06, P = 0.070), and 0.44 (0.20–0.97, P = 0.042) in older men, respectively; however, there was no significant association between these parameters among middle-aged men. Engagement in sports associated with physical contact and collision did not affect LS risk in either group. Conclusions Engagement in sports associated with high cardiovascular intensity during university years may reduce the risk of LS in later life. Encouraging young people to participate in such activities might help reduce LS prevalence among older populations.

Aims/Introduction There are few studies to investigate the relationship between macronutrients and longitudinal changes in arterial stiffness in patients with type 2 diabetes mellitus. This exploratory study sought to determine whether macronutrients were correlated with increased arterial stiffness independently of conventional atherosclerotic risk factors. Materials and Methods The study participants comprised 733 type 2 diabetes outpatients who had no apparent history of cardiovascular diseases. The dietary schedule was assessed with a validated, brief, self‐administered diet history questionnaire. At baseline and at years 2 and 5, brachial‐ankle pulse wave velocity was measured. A multivariable linear mixed‐effects model was used to determine the predictive values of macronutrients and atherosclerotic risk factors for longitudinal changes in brachial‐ankle pulse wave velocity. Results There was a significant increase in brachial‐ankle pulse wave velocity values over the 5‐year follow‐up period. In a multivariable linear mixed‐effects model that adjusted for age and sex, lower saturated fatty acid intake was significantly correlated with persistently higher brachial‐ankle pulse wave velocity, independently of other atherosclerotic risk factors. Lower intake of dairy products in particular showed this correlation. Conclusions Our data showed that lower saturated fatty acids intake was correlated with persistently higher brachial‐ankle pulse wave velocity in type 2 diabetes patients. Among food sources of saturated fatty acids, lower dairy products specifically were correlated with elevated brachial‐ankle pulse wave velocity. This might be because the consumption of dairy products in Japan is much lower than in Western countries., A lower percentage of total calories from SFAs was an independent predictive factor for persistently higher baPWV, in addition to several conventional risk factors.

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.

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.

Background Physical fitness and motor ability are associated with the incidence of locomotive syndrome (LS) in older adults. The relationships between physical fitness and motor ability at a young age to LS risk in later life remain unclear. This study examined the association between physical fitness and motor ability among university students and their risk of LS in middle and old age. Methods The participants were 231 male alumni aged 48–65 years from the Department of Physical Education of a university in Japan. Physical fitness and motor ability test results during their fourth year at the university were used. Physical fitness tests included the side-step test, vertical jump test, back muscle, grip strength, trunk lift, standing trunk flexion, and step-test. Motor ability was tested using the 50-m and 1500-m run, running long jump, hand-ball throw, and pull-up test. LS risk was assessed using a seven-question standardized self-administered Loco-check questionnaire. Participants were divided into three groups (low, medium, and high) based on physical fitness and motor ability test results at young age, and LS risk was assessed at an older age across the three groups using Cox proportional hazards models. Results From the 2017 follow-up survey, the median follow-up period was 37 years (interquartile range, 33–41), and LS risk was suspected for 31 (13.4%) participants. Better performance on the side-step test was associated with the reduced risk of LS (hazard ratio 0.32; 95% confidence interval, 0.101–0.983, P = 0.047). Conclusions Good agility (side-step test) at a young age may reduce the future risk of LS among middle-aged and older men.

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, Ketone monoester lowers glucose level during the oral glucose tolerance test in individuals with impaired glucose tolerance. This improvement was associated with decreased insulin clearance and elevated early phase insulin level.

Supplemental digital content is available in the text., Objectives Quantitative synthetic magnetic resonance imaging (MRI) enables the determination of fundamental tissue properties, namely, T1 and T2 relaxation times and proton density (PD), in a single scan. Myelin estimation and brain segmentation based on these quantitative values can also be performed automatically. This study aimed to reveal the changes in tissue characteristics and volumes of the brain according to age and provide age-specific reference values obtained by quantitative synthetic MRI. Materials and Methods This was a prospective study of healthy subjects with no history of brain diseases scanned with a multidynamic multiecho sequence for simultaneous measurement of relaxometry of T1, T2, and PD. We performed myelin estimation and brain volumetry based on these values. We performed volume-of-interest analysis on both gray matter (GM) and white matter (WM) regions for T1, T2, PD, and myelin volume fraction maps. Tissue volumes were calculated in the whole brain, producing brain parenchymal volume, GM volume, WM volume, and myelin volume. These volumes were normalized by intracranial volume to a brain parenchymal fraction, GM fraction, WM fraction, and myelin fraction (MyF). We examined the changes in the mean regional quantitative values and segmented tissue volumes according to age. Results We analyzed data of 114 adults (53 men and 61 women; median age, 66.5 years; range, 21–86 years). T1, T2, and PD values showed quadratic changes according to age and stayed stable or decreased until around 60 years of age and increased thereafter. Myelin volume fraction showed a reversed trend. Brain parenchymal fraction and GM fraction decreased throughout all ages. The approximation curves showed that WM fraction and MyF gradually increased until around the 40s to 50s and decreased thereafter. A significant decline in MyF was first noted in the 60s age group (Tukey test, P < 0.001). Conclusions Our study showed changes according to age in tissue characteristic values and brain volumes using quantitative synthetic MRI. The reference values for age demonstrated in this study may be useful to discriminate brain disorders from healthy brains.

Introduction Reduced muscle strength is a high risk factor for type 2 diabetes mellitus, and this association is especially strong in non-obese male individuals. However, it remains unclear how reduced muscle strength affects susceptibility to diabetes. We have examined whether lower limb muscle strength is associated with insulin resistance in non-obese Japanese male subjects. Methods Measurements from 64 non-diabetic, non-obese, middle-aged Japanese men were analyzed. Insulin sensitivity in muscle was measured using the hyperinsulinemic-euglycemic clamp. Isometric muscle strength of the knee extensor and flexor muscles was evaluated using a dynameter. Results Lower muscle strength of knee flexors, but not knee extensors, was associated with impaired muscle insulin sensitivity (knee flexor muscles: low, medium, and high strength was 6.6 ± 2.2, 7.3 ± 2.0, and 8.8 ± 2.2 mg/kg per minute, respectively, p for trend

Individuals with a monophasic glucose response curve (GRC) during a 75‐g oral glucose tolerance test have a higher risk for type 2 diabetes than those with a biphasic GRC. However, no studies have addressed the association between GRC type and insulin clearance. Thus, we studied 49 healthy non‐obese Japanese men. We divided study participants into the monophasic or biphasic group based on the shape of their GRC. We evaluated tissue‐specific insulin sensitivity and insulin clearance using a two‐step hyperinsulinemic‐euglycemic clamp. The monophasic group had more visceral fat, lower insulin clearance and lower muscle insulin sensitivity than the biphasic group, whereas liver and adipose tissue insulin sensitivity, and insulin secretion were comparable. In conclusion, healthy non‐obese men with a monophasic GRC have lower insulin clearance and muscle insulin sensitivity., A monophasic glucose response curve during 75‐g oral glucose tolerance test in apparently healthy non‐obese men is associated with reduced insulin clearance, lower muscle insulin sensitivity and more visceral fat accumulation compared with a biphasic curve.

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 (, Characteristics of non‐obese Asians with elevated 1‐h plasma glucose are unknown. Individuals with elevated 1‐h plasma glucose have lower insulinogenic index and adiponectin. Insulin sensitivity was similar between the low and high 1‐h plasma glucose groups.

We investigated effects of exercise habits (EHs) in adolescence and old age on osteoporosis prevalence and hip joint and lumbar spine bone mineral density (BMD). Body composition and BMD in 1596 people aged 65–84 years living in Bunkyo-ku, Tokyo, were measured using dual-energy X-ray absorptiometry. We divided participants into four groups by a combination of EHs in adolescence and old age: none in either period (None-None), only in adolescence (Active-None), only in old age (None-Active), and in both periods (Active-Active). Logistic regression models were employed to estimate multivariable-adjusted odds ratios (ORs) for osteoporosis determined by T-score (less than −2.5 SD) using the None-None reference group. In men, the combination of EHs in adolescence and old age was not associated with osteoporosis prevalence. However, the lumbar spine’s BMD was significantly higher in the Active-Active than the None-Active group (p = 0.043). In women, the Active-Active group had lower lumbar spine osteoporosis prevalence than the None-None group (OR 0.65; 95% CI, 0.42–1.00, p = 0.049). Furthermore, hip BMD was significantly higher in the Active-Active group than in the other three groups (p = 0.001). Older women with EHs in adolescence and old age had higher lumbar BMD and lower risk of osteoporosis.

Insulin resistance and muscle weakness are risk factors for silent lacunar infarcts (SLI), but it is unclear whether they are still independent risk factors when adjusted for each other. In addition, the effect of their combination on SLI is completely unknown. We evaluated SLI, insulin sensitivity, and knee extensor muscle strength by magnetic resonance imaging, PREDIM, and dynamometer, respectively, in 1531 elderly people aged 65–84 years living in an urban area of Tokyo. Among the study subjects, 251 (16.4%) had SLI. Impaired insulin sensitivity (High; 1.00 [reference], Medium; 1.53 [95% confidence interval (CI) 0.94–2.48], Low; 1.86 [1.02–3.39], p for trend 0.047) and reduced muscle strength (High; 1.00 [reference], Medium; 1.40 [0.98–2.02], Low; 1.49 [1.04–2.15], p for trend 0.037) were independently associated with increased risk for SLI in the fully adjusted model. In terms of combined, subjects classified as having the lowest insulin sensitivity and lowest strength were 4.33 times (95% CI 1.64–11.45) more likely to have a SLI than those classified as having the highest insulin sensitivity and highest strength. Impaired insulin sensitivity and reduced muscle strength were independently associated with higher risk of SLI in elderly subjects, and their combination synergistically increased this risk.

Context Circulating C-peptide is generally suppressed by exogenous insulin infusion. However, steady-state serum C-peptide (SSSC) levels during hyperinsulinemic-euglycemic clamp in obese subjects are higher than in healthy subjects, which may contribute to hyperinsulinemia to compensate for insulin resistance. Even in healthy subjects, interindividual variations in SSSC levels are present; however, the characteristics of subjects with high SSSC levels in those populations have not been fully elucidated. Objective To investigate the clinical parameters associated with interindividual variations in SSSC levels in apparently healthy, nonobese Japanese men. Design and Participants We studied 49 nonobese (BMI < 25 kg/m2), healthy Japanese men. We evaluated SSSC and insulin sensitivity using hyperinsulinemic-euglycemic clamp with tracer. Intrahepatic lipid (IHL) was measured using proton magnetic resonance spectroscopy. Results We divided subjects into high and low SSSC groups based on the median SSSC value and compared their clinical parameters. Compared with the low SSSC group, the high SSSC group had IHL accumulation, impaired muscle insulin sensitivity, reduced insulin clearance, and hyperinsulinemia during a 75-g oral glucose tolerance test (OGTT). All of these factors were significantly correlated with SSSC. Conclusions In healthy, nonobese men, higher SSSC was associated with impaired muscle insulin sensitivity, IHL accumulation, and hyperinsulinemia during OGTT. These findings suggest that higher endogenous insulin secretion during hyperinsulinemia, along with reduced insulin clearance, may be an early change to maintain metabolic status in the face of moderate muscle insulin resistance, even in healthy, nonobese men.

Background: Previous studies showed that insulin resistance and reduced muscle strength are risk factors for silent lacunar infarcts, but it is unclear whether they are still independent risk factors when adjusted for each other. In addition, the effect of their combination on silent lacunar infarcts is completely unknown.Methods: We evaluated silent lacunar infarcts, insulin sensitivity, and knee extensor muscle strength by magnetic resonance imaging, PREDIM (an index for insulin sensitivity), and dynamometer, respectively, in 1531 elderly people aged 65–84 years living in an urban area of Tokyo. Results: Among the study subjects, 251 (16.4%) had silent lacunar infarcts. Impaired insulin sensitivity (High; 1.00 [reference], Medium; 1.53 [95% confidence interval (CI): 0.94-2.48], Low; 1.86 [95%CI: 1.02-3.39], p for trend 0.047) and reduced muscle strength (High; 1.00 [reference], Medium; 1.40 [95%CI: 0.98-2.02], Low; 1.49 [95%CI: 1.04-2.15], p for trend 0.037) were independently associated with increased risk for silent lacunar infarcts in the fully adjusted model. In terms of combined, subjects classified as having the lowest insulin sensitivity and lowest strength were 4.33 times (95%CI: 1.64-11.45) more likely to have a silent lacunar infarct than those classified as having the highest insulin sensitivity and highest strength.Conclusions: Impaired insulin sensitivity and reduced muscle strength were independently associated with higher risk of silent lacunar infarcts in elderly subjects, and their combination synergistically increased this risk.

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.

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

Background: The estimation of nutrient content is difficult, but important for self-management of people with type 2 diabetes mellitus (T2DM). In Japan, food-log app has not been penetrated as a treatment tool yet. That could be because Japanese food is diverse and consists of various ingredients. In this study, we investigated the efficacy of app “Calomeal” that enables the patients to search for what they eat among the database of 26300 kinds of foods and to visualize the nutrients using smartphone. Method: We recruited 20 people with T2DM in Juntendo University. They used this app for 3 months on the regular treatment. The blood and urine exams were performed monthly. At the beginning and the end of the study, the estimation of food was also assessed by the dietitian and the questionnaires about QOL (DTSQ/PAID) were performed. Results: 2 were dropped out. 18 participants were 52.3±9.2 y.o., male/female 12/8, BMI 25.8±4.7 kg/m2, and HbA1c 8.1±0.4%. At the end of study, significant reduction was observed in HbA1c and BMI (7.92±0.4 to 7.75±0.5%[p=0.0410], 25.69±5.0 to 25.10±4.8 kg/m2 [p=0.0057]). Reduction of HbA1c and BMI were both correlated to the reduction of carbohydrate (r=0.5018 [p=0.0338], r =0.5542 [p=0.0170]). High correlation was also observed between the reduction of carbohydrate and calorie (r=0.8167 [p Conclusion: Visualizing nutrients via Calomeal improved glycemic control and BMI by reducing over intake. It is of note that in some Japanese people, the adjusting nutrient intake by raising the calorie may contribute to their QOL. Disclosure A. Tsunemi: None. J. Sato: Research Support; Self; Sanofi. Speaker’s Bureau; Self; Daiichi Sankyo, Medtronic, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. M. Enomoto: None. Y. Iwagaki: None. S. Sugimoto: None. Y. Someya: None. M. Kiya: None. E. Matsuhashi: None. Y. Wakabayashi: None. T. Funayama: None. T. Uchida: None. T. Miyatsuka: None. K. Azuma: None. T. Shimizu: None. H. Satoh: None. A. Kanazawa: Speaker’s Bureau; Self; Novartis Pharma K.K., Sanofi, Takeda Pharmaceutical Company Limited. 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.

CONTEXT Adipose tissue insulin resistance has been observed in obese subjects and is considered an early metabolic defect that precedes insulin resistance in muscle and liver. Although Asians can readily develop metabolic disease without obesity, the clinical features of nonobese, apparently healthy, Asians with reduced adipose tissue insulin sensitivity (ATIS) have not been elucidated. OBJECTIVE To investigate the clinical parameters associated with reduced ATIS in nonobese, apparently healthy (body mass index

Accumulation of intramyocellular lipid (IMCL) is observed in individuals with insulin resistance as well as insulin-sensitive endurance athletes with high peak oxygen consumption (VO2peak), which is called the athlete’s paradox. It remains unclear whether non-athletes with higher fitness levels have IMCL accumulation and higher insulin sensitivity in general. In this study, we investigated the association between IMCL accumulation and muscle insulin sensitivity (M-IS) in subjects with high or low VO2peak. We studied 61 nonobese (BMI, 23 to 25 kg/m2), non-athlete Japanese men. We divided the subjects into four groups based on the median value of VO2peak and IMCL in the soleus muscle. We evaluated M-IS using a two-step hyperinsulinemic-euglycemic clamp. Among subjects with higher VO2peak (n = 32), half of those (n = 16) had lower IMCL levels. Both High-VO2peak groups had higher M-IS than the Low-VO2peak groups. On the other hand, M-IS was comparable between the High-VO2peak/High-IMCL and High-VO2peak/Low-IMCL groups, whereas the High-VO2peak/High-IMCL group had IMCL levels that were twice as high as those in the High-VO2peak/Low-IMCL group. On the other hand, the High-VO2peak/High-IMCL group had significantly higher physical activity levels (approximately 1.8-fold) than the other three groups. In conclusion, in nonobese, non-athlete Japanese men, subjects with higher VO2peak and higher IMCL had higher physical activity levels. IMCL accumulation is not associated with insulin resistance in individuals with higher or lower fitness levels.

Objective We aimed to clarify the onset of diabetes. Design Data from 27,392 nondiabetic health examinees were retrospectively analyzed for a mean of 5.3 years. Trajectories of fasting plasma glucose (FPG), body mass index (BMI), and the single point insulin sensitivity (Si) estimator (SPISE), an index of Si, 10 years before diagnosis of prediabetes (PDM; n = 4781) or diabetes (n = 1061) were separately assessed by a mixed effects model. Diabetes and PDM were diagnosed by the American Diabetes Association definition on the basis of FPG and glycosylated hemoglobin A1c values. Results In individuals who developed diabetes, mean FPG and BMI were significantly higher (P < 0.01 each) and SPISE lower than those who did not at −10 years: FPG 101.5 mg/dL vs 94.5 mg/dL, BMI 24.0 kg/m2 vs 22.7 kg/m2, and SPISE 7.32 vs 8.34, P < 0.01 each. These measurements, in subjects who developed prediabetes, were slightly but definitely different from those who did not, already at −10 years: FPG 91.8 mg/dL vs 89.6 mg/dL, BMI 22.6 kg/m2 vs 22.1 kg/m2, and SPISE 8.44 vs 8.82, P < 0.01 each. In both cases, the differences were progressively greater toward year 0, the time of diabetes, or PDM diagnosis. Conclusions FPG was significantly elevated in those who developed diabetes at least 10 years before diagnosis of diabetes, and this was also the case in those who developed PDM. Glucose dysregulation precedes diagnosis of diabetes at least for 20 years., FPG already increased at 10 years before diagnosis of diabetes and also at 10 years before diagnosis of prediabetes. Diabetes may begin at least >20 years before its diagnosis.

Context Japanese women have substantially lower body mass index (BMI) than women in other developed countries. The BMI of Japanese women has steadily decreased over time. However, glucose metabolism in underweight Japanese women has not been fully characterized. Objective The aim of this study was to investigate glucose metabolism and the physical characteristics of underweight Japanese women. Design and Participants We recruited 31 young (20 to 29 years of age) and 30 postmenopausal (50 to 65 years of age) underweight women. We also recruited young normal-weight women (n = 13) and postmenopausal normal-weight women (n = 10) to serve as references. We administered an oral glucose tolerance test (OGTT) and evaluated intramyocellular lipid (IMCL) levels and body composition using 1H-magnetic resonance spectroscopy and dual-energy X-ray absorptiometry, respectively. Results Young underweight women had similar glucose tolerance as young normal-weight women. However, postmenopausal underweight women had a higher area under the curve (AUC) for glucose during OGTT than postmenopausal normal-weight women. In postmenopausal underweight women, 2-hour glucose levels during OGTT were negatively correlated with lean body mass (r = −0.55, P < 0.01) and insulinogenic index (r = −0.42, P = 0.02) and were positively correlated with IMCL levels (r = 0.40, P = 0.03). Compared with young underweight women, postmenopausal underweight women had a higher AUC for glucose during OGTT and a lower insulinogenic index and AUC for insulin during OGTT. Conclusions Postmenopausal underweight women had more impaired glucose tolerance than young underweight women. In postmenopausal underweight women, the degree of glucose tolerance impairment was associated with decreased lean body mass, increased IMCL accumulation, and impaired insulin secretion., In underweight Japanese women, worsening glucose tolerance was observed after menopause. The degree of glucose intolerance is associated with decreased muscle mass/quality and insulin secretion.

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.

Muscle strengthening activity and high muscle strength were reported to protect against the development of type 2 diabetes in middle age. On the other hand, the reported prevalence of type 2 diabetes is higher in former top-level power sports athletes compared to healthy non-athlete men. High muscle strength may be a risk factor for type 2 diabetes. However, it is not clear whether high muscle strength can predict the future development of type 2 diabetes. This study examined the relationship between muscle strength at a young age and the future development of type 2 diabetes in former Japanese college athletes by a historical cohort study. Subjects were male alumni who graduated from the Physical Education School of Juntendo University. Hand-grip strength at college age (1971-1991) and type 2 diabetes history, as determined by follow-up questionnaires (2007-2009, and 2011), were collected. Relationships between hand-grip strength and new cases of type 2 diabetes were analyzed by Cox proportional hazards models and adjusted for relative risks. Data of hand-grip strength and medical history of 617 subjects were collected. The median follow-up period was 27 years, and 29 men developed type 2 diabetes. There was no relationship between incidence of type 2 diabetes and muscle strength level after adjustment for potential risk factors. The adjusted hazard ratios (HRs) and 95% confidence intervals of the low, medium, and high muscle strength categories were 1.00 (reference), 1.12 (0.46-2.70) and 0.70 (0.25-1.92), respectively. We concluded that muscle strength at a young age does not predict the future development of type 2 diabetes in Japanese male athletes.

PurposeThe proportion of elderly individuals (age ≥65 years) in Japan reached 27.7% in 2017, the highest in the world. A serious social problem in a super-aged society is the rise in the number of elderly people who need long-term care (LTC), which is mainly due to cerebrovascular disease, dementia, age-related frailty, falls and fractures, and joint disease. We hypothesised that decreased muscle mass, muscle strength and insulin sensitivity are the common risk factors for these diseases related to needing LTC. We developed a prospective cohort study of elderly subjects in an urban community to test this hypothesis. The primary objective is to prospectively investigate associations between muscle mass, muscle strength, and insulin sensitivity and incidence of main disease and risk factors of needing LTC. The primary outcomes are the incidence of cerebrovascular disease and cognitive decline.ParticipantsParticipants were 1629 people aged 65–84 years living in 13 communities in an urban area (Bunkyo-ku, Tokyo, Japan). Average age was 73.1±5.4 years.Findings to dateWe obtained baseline data on cognitive function, cerebral small vessel disease (SVD) determined by brain MRI, body composition, bone mineral density, arteriosclerosis, physical function, muscle mass, muscle strength and insulin sensitivity. Mild cognitive impairment and dementia were observed in 18.1% and 3.3% of participants, respectively. The prevalence of cerebral SVD was 24.8%. These characteristics are similar to those previously reported in elderly Japanese subjects.Future plansWe will ask participants about their health status, including incidence of cerebrovascular disease, falls, fractures and other diseases every year by mail. We plan to re-evaluate cognitive function, brain MRI parameters and other parameters at 5 and 10 years after the baseline evaluation. We will evaluate whether low muscle function (muscle mass, muscle strength or insulin sensitivity) is a risk factor for cognitive decline or cerebrovascular disease.

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.