A decrease in plasma glucose levels is required for increased endogenous glucose production with a single administration of a sodium-glucose co-transporter-2 inhibitor tofogliflozin.

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.

Adipose tissue insulin resistance in young Japanese women is associated with metabolic abnormalities and dehydroepiandrosterone-sulfate.

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

Low Handgrip Strength (Possible Sarcopenia) With Insulin Resistance Is Associated With Type 2 Diabetes Mellitus.

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

Fat Accumulation and Elevated Free Fatty Acid Are Associated With Age-Related Glucose Intolerance: Bunkyo Health Study.

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

Motivation to Decrease Discharge Cost Results in Improper Discharge of Regulated Medical Wastes from Small Clinics: Inspectional and Statistical Evidence in the Tokyo Metropolitan Area.

Introduction: Regulated medical waste (RMW) management, particularly, improper discharges of RMW from small-scale medical institutions (less than 20 sickbeds), has drawn attentions. This study investigated improper discharges of RMW containers from small clinics to analyze improper discharge mechanisms. Methods: Inspectional survey categorized improper discharges into improper sealing, container deformation, overweight, container contamination, container damaging, etc. The inspection surveys were performed from April 2018 to March 2019. In total, 2364 containers were inspected, which was equivalent to 64317 Litters in container volume and around 13.19 Mg in weight. Results: About 38% of RMW containers were categorized to improper discharges. They consist mainly of improper sealing (67.0%), container deformation (24.6%), and overweight (6.31%). It was hypothesized that frequent RMW discharges allow short interval of container discharge, which prevents clinic staff from human errors due to forgetting and might reduce improper discharges. However, the inspection results rejected this hypothesis. The survey proposes that improper discharges were likely not sporadic events, which possibly occurred in any clinics, but repeated events in certain clinics. It was also hypothesized that saving discharge cost likely induced overpacking of RMW to containers, particularly larger volume containers, and caused improper sealing, container deformation, and eventually overweight. The inspection results and statistical analyses validated this hypothesis. This study also validated one more hypothesis that large compressive force required for complete sealing might cause improper sealing. The measurement results rejected it. However, they also suggest that gender and age of clinic staff might be partially associated with improper sealing. Conclusions: Improper discharges of RMW containers seem to be non-random events. Specific clinics likely repeat improper discharges using larger volume containers. It is proposed that decreasing discharge cost induces overpacking of RMW to containers, and causes subsequent problems like container deformation.

A Short-Term High-Fat Diet Worsens Insulin Sensitivity with Changes in Metabolic Parameters in Non-Obese Japanese Men.

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

Prediabetes is an independent risk factor for sarcopenia in older men, but not in older women: the Bunkyo Health Study.

BACKGROUND: Sarcopenia is a major cause of disability in the elderly. Although type 2 diabetes is a risk factor for increased sarcopenia, the relationship between prediabetes and sarcopenia has not been elucidated. We aimed to examine the relationship between sarcopenia and prediabetes. METHODS: The design of this study is a cross-sectional study. We evaluated glucose metabolism using the 75-g oral glucose tolerance test and glycated haemoglobin, appendicular skeletal muscle mass, and hand grip strength in 1629 older adults living in an urban area of Tokyo, Japan. We investigated the frequency of sarcopenia in participants with normal glucose tolerance (NGT), prediabetes and diabetes. A multivariable logistic regression model was used to analyse the association between glucose tolerance and the prevalence of sarcopenia. RESULTS: The mean age of participants was 73.1 ± 5.4 years. In men, 44.3% had NGT, 26.6% had prediabetes, and 29.1% had diabetes. In women, the distribution was 56.1%, 28.8% and 15.2%. The prevalence of sarcopenia was 12.7% in men and 11.9% in women. Logistic regression revealed that prediabetes and diabetes are independent risk factors for sarcopenia in men (prediabetes, odds ratio [OR] = 2.081 [95% confidence interval {CI}: 1.031-4.199]; diabetes, OR = 2.614 [95% CI: 1.362-5.018]) and diabetes, but not prediabetes, is an independent risk factor for sarcopenia in women (prediabetes, OR = 1.036 [95% CI: 0.611-1.757]; diabetes, OR = 2.099 [95% CI: 1.146-3.844]). In both sexes, higher age (men, OR = 1.086 [95% CI: 1.028-1.146]; women, OR = 1.195 [95% CI: 1.142-1.251]), higher body fat percentage (men, OR = 1.346 [95% CI: 1.240-1.461]; women, OR = 1.218 [95% CI: 1.138-1.303]) and lower body mass index (men, OR = 0.371 [95% CI: 0.299-0.461]; women, OR = 0.498 [95% CI: 0.419-0.593]) were independent risk factors for sarcopenia. CONCLUSIONS: Although we confirmed that diabetes mellitus is associated with sarcopenia in both sexes, prediabetes is associated with sarcopenia in men, but not in women.

Sarcopenic obesity is associated with cognitive impairment in community-dwelling older adults: The Bunkyo Health Study.

BACKGROUND & AIMS: Coexistence of obesity and decreased muscle strength, defined as sarcopenic obesity, is often observed in the older adults. The present study investigated whether sarcopenic obesity, defined as reduced handgrip strength and increased body mass index (BMI), is associated with cognitive impairment. METHODS: Study participants include 1615 older adults aged 65-84 years who lived in an urban area of Tokyo, Japan and participated in the Bunkyo Health Study. Mild cognitive impairment (MCI) and dementia were defined based on ≤22 points of Montreal Cognitive Assessment and ≤23 points of the Mine-Mental State Examination, respectively. Handgrip strength was measured using a dynamometer in a standing position. We divided participants into four groups according to their sarcopenia (probable) (handgrip strength <28 kg in men and <18 kg in women) and obesity status (BMI ≥25 kg/m2) as control, obesity, sarcopenia and sarcopenic obesity, and investigated the association between cognitive function, sarcopenia, and obesity status. RESULTS: Mean age was 73.1 ± 5.4 years, and 57.6% of study participants were female. The prevalence of control, obesity, sarcopenia, and sarcopenic obesity was 59.4%, 21.2%, 14.6%, and 4.7%, respectively. The prevalence of MCI and dementia, respectively, was highest in participants with sarcopenic obesity, followed by those with sarcopenia, obesity, and control. After multivariate adjustment, sarcopenic obesity was independently associated with increased odds of MCI and dementia compared with the control (MCI: 2.11 [95% confidence interval, 1.12-3.62]; dementia: 6.17 [2.50-15.27]). CONCLUSIONS: Sarcopenic obesity was independently associated with MCI and dementia among Japanese older adults. Future studies are necessary to clarify the causal relationship.

Ingestion of an exogenous ketone monoester improves the glycemic response during oral glucose tolerance test in individuals with impaired glucose tolerance: A cross-over randomized trial.

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

Insulin resistance and muscle weakness are synergistic risk factors for silent lacunar infarcts: the Bunkyo Health Study.

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.

Short-Term SGLT2 Inhibitor Administration Does Not Alter Systemic Insulin Clearance in Type 2 Diabetes.

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.

Prevalence and Features of Impaired Glucose Tolerance in Young Underweight Japanese Women.

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.

Adipose Insulin Resistance and Decreased Adiponectin Are Correlated With Metabolic Abnormalities in Nonobese Men.

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.

Decreased Muscle Strength of Knee Flexors is Associated with Impaired Muscle Insulin Sensitivity in Non-Diabetic Middle-Aged Japanese Male Subjects.

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 < 0.05; knee extensor muscles: low, medium, and high strength was 7.3 ± 2.5, 7.5 ± 2.2, and 7.8 ± 2.3 mg/kg per minute, respectively, p for trend = 0.73). Knee flexor muscle strength was also identified as an independent determinant of insulin sensitivity in the multiple regression analysis (ß = 0.274, p = 0.036). CONCLUSIONS: Diminished strength of knee flexor muscles, but not knee extensor muscles, was associated with muscle insulin sensitivity in non-diabetic, non-obese Japanese male subjects.

Both higher fitness level and higher current physical activity level may be required for intramyocellular lipid accumulation in non-athlete men.

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.

Characteristics associated with elevated 1-h plasma glucose levels during a 75-g oral glucose tolerance test in non-obese Japanese men.

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

Shape of the glucose response curve during an oral glucose tolerance test is associated with insulin clearance and muscle insulin sensitivity in healthy non-obese men.

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.

Stereochemical study of a novel tautomeric furanone, homofuraneol.

A mixture of tautomers with unique keto-enol structures, 5-ethyl-4-hydroxy-2-methylfuran-3(2H)-one and 2-ethyl-4-hydroxy-5-methylfuran-3(2H)-one (EHMF, homofuraneol, 1a and 1b), comprises four structural isomers including their enantiomers. The four isomers were successfully separated by chromatographic optical resolution, and their odor evaluation was performed. Determination of the absolute chemistry of 1a and 1b were accomplished for the first time by direct measurement of the VCD spectra of their methyl ether derivatives 4a and 4b compared with the calculated ones as well as chemical relay reaction. The relationship between odor characteristics and stereochemistry was also examined.

Three days of a eucaloric, low-carbohydrate/high-fat diet increases insulin clearance in healthy non-obese Japanese men.

Metabolic clearance rate of insulin (MCRI) is thought to help maintain glucose homeostasis even in healthy subjects. However, the effect of a low carbohydrate/high fat (LCHF) diet on MCRI in healthy subject remains unclear. To investigate the effect of a 3-day eucaloric LCHF diet on MCRI in healthy subjects, we studied 42 healthy non-obese Japanese men. Each subject consumed a eucaloric LCHF diet for 3 days. Before and after the LCHF diet, intramyocellular lipid (IMCL) levels were measured using 1H-magnetic resonance spectroscopy, and glucose infusion rate (GIR) and MCRI were evaluated with a euglycemic hyperinsulinemic clamp. The LCHF diet increased MCRI by 10% and decreased steady state serum insulin (SSSI) and GIR during glucose clamp by 10% and 6%, respectively. To further investigate the role of MCRI, we divided subjects into high-responder (HR) and low-responder (LR) groups based on the median %change in MCRI. The LCHF diet increased IMCL and decreased SSSI during glucose clamp in the HR group, while those were not altered in the LR group. Our results suggested that a 3-day eucaloric LCHF diet increases MCRI in healthy non-obese Japanese men. This change seemed to be beneficial in terms of maintaining euglycemia during low carbohydrate availability.

Clinical Features of Nonobese, Apparently Healthy, Japanese Men With Reduced Adipose Tissue Insulin Sensitivity.

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 <25 kg/m2), Japanese men. METHODS: We studied 52 nonobese Japanese men without cardiometabolic risk factors. Using a two-step hyperinsulinemic euglycemic clamp with a glucose tracer, we evaluated the insulin sensitivity in muscle, liver, and adipose tissue. ATIS was calculated as the percentage of free fatty acid (FFA) suppression/insulin concentration during the first step of the glucose clamp. RESULTS: Using the median ATIS value, the subjects were divided into low- and high-FFA suppression groups. The low-FFA suppression group had moderate fat accumulation in the abdominal subcutaneous adipose tissue and liver. Compared with the high-FFA group, they also had a lower fitness level, decreased insulin clearance, impaired insulin sensitivity in muscle, moderately elevated triglycerides, and lowered high-density lipoprotein cholesterol levels. All these factors correlated significantly with ATIS. Hepatic insulin sensitivity was comparable between the two groups. CONCLUSIONS: In nonobese, apparently healthy, Japanese men, reduced ATIS was associated with moderate fat accumulation in subcutaneous fat and liver, lower insulin clearance, muscle insulin resistance, and moderate lipedema. These data suggest that reduced ATIS can occur early in the development of the metabolic syndrome, even in nonobese, apparently healthy, men.