Sex-specific impact of GCKR rs1260326 polymorphism on metabolic traits in an older Japanese population: the Bunkyo Health Study.

Background: Metabolic syndrome involves health problems influenced by aging and genetics. The glucokinase regulatory protein (GCKR) rs1260326 polymorphism (Leu446) is associated with metabolic traits. This study explores the impact of the GCKR rs1260326 polymorphism on metabolic traits in older Japanese with focusing on sex-specific differences. Methods: This cross-sectional study from the Bunkyo Health Study in Tokyo, Japan, examined 883 participants aged 65-84 years. Participants were excluded with diabetes, or on drug treatment for diabetes or dyslipidemia. The GCKR P446L polymorphism was analyzed and compared their characteristics of physical activity, dietary intake, body composition, and metabolic parameters. Results: Study participants with GCKR rs1260326 genotypes (C/C 20.7%, C/T 47.6%, T/T 31.7%) had a median age of 72 years, and 60.4% were women. Men with the T/T genotype, as compared to the C/C genotype, had a lower body weight, body mass index (BMI), and skeletal mass index. This genotype also associated with lower fasting insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), and higher Matsuda index, but not after adjustment for age, BMI, and physical activity. In contrast, women with the T/T genotype, compared to the C/C genotype, showed higher C-reactive protein, fibroblast growth factor 21, and Matsuda index. They also had lower fasting insulin, insulin area under the curve, and HOMA-IR; with these associations being independent of age, BMI, and physical activity. Conclusion: The GCKR rs1260326 genotype-affected metabolic traits differentially by sex in older Japanese. This highlights the need to consider sex differences in GCKR-related metabolic outcomes.

How a certain gene change affects health differently for older men and women in Japan: a study from Bunkyo This study looks into how a certain genetic change affects the health of older Japanese people, focusing on whether there are differences between men and women. It involves participants aged 65 to 84 from Tokyo who are not taking medication for diabetes or dyslipidemia. The findings indicate that this genetic variation impacts men and women differently. Men with a specific version of this genetic change tend to have lower body weight, body mass index (BMI), and less skeletal mass. They also show lower insulin levels and resistance, but these associations weaken when considering age, BMI, and physical activity. On the other hand, women with this genetic variation showed higher levels of markers indicating inflammation and metabolic health, alongside better insulin sensitivity. These relationships held even after adjusting for age, BMI, and activity levels. From this research, it's clear that the effects of this genetic change on health vary between older Japanese men and women. This suggests the importance of considering gender differences when studying how genes influence our health, underlining the need for personalized approaches in understanding and managing health issues.

Rationale and Design of the Study to Investigate the Metabolic Action of Imeglimin on Patients with Type 2 Diabetes Mellitus (SISIMAI).

INTRODUCTION: Imeglimin is a first-in-class, novel, oral glucose-lowering agent for the treatment of type 2 diabetes mellitus. The efficacy and safety of imeglimin as an antidiabetic agent have been investigated in clinical trials. However, its metabolic effects in humans have not yet been fully elucidated. METHODS: The Study to InveStIgate the Metabolic Action of Imeglimin on patients with type 2 diabetes mellitus (SISIMAI) is a single-arm intervention study. In this study, we have recruited 25 patients with type 2 diabetes to receive 2000 mg/day imeglimin for 20 weeks. We perform a 75-g oral glucose tolerance test (OGTT) with double-glucose tracers, a two-step hyperinsulinemic-euglycemic clamp with glucose tracer, ectopic fat measurement by proton magnetic resonance spectroscopy, visceral/subcutaneous fat area measurement by magnetic resonance imaging, muscle biopsy, and evaluation of fitness level by cycle ergometer before and after imeglimin administration. PLANNED OUTCOMES: The primary outcome is the change in area under the curve of glucose levels during the OGTT after 20 weeks of imeglimin treatment. We also calculate the endogenous glucose production, rate of oral glucose appearance, and rate of glucose disappearance from the data during the 75-g OGTT and compare them between pre- and post-treatment. Additionally, we will compare other parameters, such as the changes in tissue-specific insulin sensitivity, ectopic fat accumulation, visceral/subcutaneous fat area accumulation, and fitness level between each point. This is the first study to investigate the organ-specific metabolic action of imeglimin in patients with type 2 diabetes mellitus using the 75-g OGTT with the double tracer method. The results of this study are expected to provide useful information for drug selection based on the pathophysiology of individual patients with type 2 diabetes mellitus. TRIAL REGISTRATION: jRCTs031210600.

Dietary characteristics of urban community-dwelling older adults with low muscle mass: the bunkyo health study: a cross-sectional study.

BACKGROUND: With the aging of the population worldwide, extending healthy life expectancy is an urgent issue. Muscle mass has been reported to be associated with physical independence and longevity. This study aimed to investigate the characteristics of food intake in urban community-dwelling older adults with low muscle mass. METHODS: This cross-sectional study used baseline data from the Bunkyo Health Study, which included 1618 urban community-dwelling older adults aged 65-84 years. All participants underwent measurement of body composition using bioelectrical impedance analysis and evaluation of nutrient and food intake using the brief-type self-administered diet history questionnaire. Participants were stratified by sex and divided into robust or low skeletal muscle mass index (SMI) groups according to the Asian Working Group for Sarcopenia criteria to compare differences in nutrient and food intake. RESULTS: The mean age and body mass index were 73.1 ± 5.4 years and 22.6 ± 3.1 kg/m2, respectively. The prevalence of low SMI was 31.1% in men and 43.3% in women. In men, all food intake, including total energy intake, was similar between the low SMI group and the robust group. In women, the low SMI group had less total energy intake, and consumed lower amounts of energy-producing nutrients (protein, fat, and carbohydrates), but there were only small differences in the intake of specific foods. CONCLUSIONS: There were sex differences in food intake characteristics between urban community-dwelling older adults with low SMI and those who were robust. Advising women to increase their energy intake may be important in preventing muscle loss, and further research is needed in men.

A genome-wide association study identifies a locus associated with knee extension strength in older Japanese individuals.

Sarcopenia is a common skeletal muscle disease in older people. Lower limb muscle strength is a good predictive value for sarcopenia; however, little is known about its genetic components. Here, we conducted a genome-wide association study (GWAS) for knee extension strength in a total of 3452 Japanese aged 60 years or older from two independent cohorts. We identified a significant locus, rs10749438 which is an intronic variant in TACC2 (transforming acidic coiled-coil-containing 2) (P = 4.2 × 10-8). TACC2, encoding a cytoskeleton-related protein, is highly expressed in skeletal muscle, and is reported as a target of myotonic dystrophy 1-associated splicing alterations. These suggest that changes in TACC2 expression are associated with variations in muscle strength in older people. The association was consistently observed in young and middle-aged subjects. Our findings would shed light on genetic components of lower limb muscle strength and indicate TACC2 as a potential therapeutic target for sarcopenia.

Corrigendum: Playing basketball and volleyball during adolescence is associated with higher bone mineral density in old age: the Bunkyo Health Study.

[This corrects the article DOI: 10.3389/fphys.2023.1227639.].

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.

Playing basketball and volleyball during adolescence is associated with higher bone mineral density in old age: the Bunkyo Health Study.

Introduction: Exercise is beneficial for increasing areal bone mineral density (aBMD) in adolescence and maintaining it in old age. Moreover, high-impact sports are more effective than low-impact sports in increasing aBMD. This study aimed to determine the types of adolescent sports played in school-based sports clubs associated with aBMD in old age. Methods: In total, 1,596 older adults (681 men and 915 women, age: 65-84 years) living in an urban area of Japan were evaluated for the femoral neck and lumbar spine aBMD using dual-energy X-ray absorptiometry. The association between adolescent sports played in sports clubs and aBMD in old age was analyzed using multiple regression analysis, with femoral neck and lumbar spine aBMD as dependent variables, and sports type and participant characteristics such as age, body weight, and serum 25-hydroxyvitamin D [25(OH)D] level, as independent variables. Results: For the femoral neck, basketball was associated with aBMD in older men (ß = 0.079, p < 0.05) and women (ß = 0.08, p < 0.01), whereas current body weight and 25(OH)D level were associated with aBMD in both sexes. For the lumbar spine, volleyball (ß = 0.08, p < 0.01) and swimming (ß = 0.06, p < 0.05) was significantly associated with lumbar spine aBMD, whereas current body weight, 25(OH)D, and diabetes mellitus were associated with aBMD in older women. Conclusion: Both men and women who played basketball in adolescence had higher femoral neck aBMD in old age. Moreover, women who played volleyball in adolescence had higher lumbar spine aBMD in old age.

Physical inactivity induces insulin resistance in plantaris muscle through protein tyrosine phosphatase 1B activation in mice.

Inactivity causes insulin resistance in skeletal muscle and exacerbates various lifestyle-related diseases. We previously found that 24-h hindlimb cast immobilization (HCI) of the predominantly slow-twitch soleus muscle increased intramyocellular diacylglycerol (IMDG) and insulin resistance by activation of lipin1, and HCI after a high-fat diet (HFD) further aggravated insulin resistance. Here, we investigated the effects of HCI on the fast-twitch-predominant plantaris muscle. HCI reduced the insulin sensitivity of plantaris muscle by approximately 30%, and HCI following HFD dramatically reduced insulin sensitivity by approximately 70% without significant changes in the amount of IMDG. Insulin-stimulated phosphorylation levels of insulin receptor (IR), IR substrate-1, and Akt were reduced in parallel with the decrease in insulin sensitivity. Furthermore, tyrosine phosphatase 1B (PTP1B), a protein known to inhibit insulin action by dephosphorylating IR, was activated, and PTP1B inhibition canceled HCI-induced insulin resistance. In conclusion, HCI causes insulin resistance in the fast-twitch-predominant plantaris muscle as well as in the slow-twitch-predominant soleus muscle, and HFD potentiates these effects in both muscle types. However, the mechanism differed between soleus and plantaris muscles, since insulin resistance was mediated by the PTP1B inhibition at IR in plantaris muscle.

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.

Effects of exercise habits in adolescence and older age on sarcopenia risk in older adults: the Bunkyo Health Study.

BACKGROUND: Sarcopenia, defined as an age-associated loss of skeletal muscle mass and function, is a major risk factor for requiring long-term care. Because physical activity in adolescence and older age enhances peak muscle function in youth and prevents muscle function decline in older age, older adults with exercise habits during both periods may be at a lower risk for sarcopenia. We investigated the relationship between exercise habits in adolescence and older age and sarcopenia and its components in community-dwelling older Japanese adults. METHODS: This study included 1607 community-dwelling individuals (aged 65-84, medians 73 years, 679 men and 928 women) with complete health examinations, including measurements of skeletal muscle index, handgrip strength and gait speed, who were enrolled in the Bunkyo Health Study. We divided the participants into four groups according to exercise habits in adolescence and older age: no exercise in either period (none-none; NN), exercise only in adolescence (active-none; AN), exercise only in older age (none-active; NA) and exercise in both periods (active-active; AA). Multivariate-adjusted logistic regression models were used to estimate the odds ratios (ORs) and associated 95% confidence intervals (CIs) in each group for the prevalence of sarcopenia, defined as low muscle mass and low muscle performance, as compared with the NN group. Low muscle performance was defined as low muscle strength and/or low gait speed. RESULTS: The total prevalence of sarcopenia was 6.6% (45/679) in men and 1.7% (16/928) in women, the total prevalence of low muscle mass was 14.3% (97/679) in men and 5.2% (48/928) in women, and the total prevalence of low muscle performance was 25.6% (174/679) in men and 19.6% (182/928) in women. In men, the ORs (95% CIs) for sarcopenia, low muscle mass and low muscle performance were significantly lower in the AA group (sarcopenia: 0.29 [0.09-0.95], P = 0.041; low muscle mass: 0.21 [0.09-0.52], P = 0.001; and low muscle performance: 0.52 [0.28-0.97], P = 0.038). In women, the OR (95% CI) for low muscle performance was significantly lower in the AA group than in the other groups (0.48 [0.27-0.84], P = 0.010), whereas none of the ORs for sarcopenia and low muscle mass were significant. CONCLUSIONS: Older men with exercise habits in both adolescence and older age were at a lower risk of sarcopenia, low muscle mass and low muscle performance, whereas older women with exercise habits at both time periods were at a lower risk of low muscle performance.

A chronic high-fat diet does not exacerbate muscle atrophy in fast-twitch skeletal muscle of aged mice.

NEW FINDINGS: What is the central question of this study? Ageing leads to a loss of mass in skeletal muscle, but the effect of obesity on ageing-related muscle wasting is unclear. In this study, we aimed to demonstrate the specific effect of obesity on fast-twitch skeletal muscle in ageing. What is the main finding and its importance? Our findings show that the obesity induced by long-term ingestion of a high-fat diet does not aggravate muscle wasting in fast-twitch skeletal muscle of aged mice, indicating that the present study provides morphological characteristics for skeletal muscle of sarcopenic obesity. ABSTRACT: Obesity and ageing reduce muscle mass and lead to deficits in muscle maintenance, but it is not known whether obesity accelerates muscle wasting additively in the setting of ageing. We investigated morphological characteristics in fast-twitch extensor digitorum longus (EDL) muscle of mice fed a low-fat diet (LFD) or a high-fat diet (HFD) for 4 or 20 months. The fast-twitch EDL muscle was harvested, and the muscle fibre-type composition, individual muscle cross-sectional area and myotube diameter were measured. We found an increase in the percentage of type IIa and IIx myosin heavy chain fibres in the whole EDL muscle, but a decrease in type IIB myosin heavy chain in both HFD protocols. The cross-sectional area and myofibre diameter were lower in both groups of aged mice (after 20 months of LFD or HFD) compared with young mice (after 4 months of the diets), but there were no differences between mice fed LFD or HFD for 20 months. These data suggest that long-term feeding of HFD does not aggravate muscle wasting in fast-twitch EDL muscle of male mice.

Association of ALDH2 Genotypes and Alcohol Intake with Dietary Patterns: The Bunkyo Health Study.

Dietary habits are associated with various diseases and assessed by dietary patterns (DPs). Since the ALDH2 genotype is correlated with alcohol and several food preferences, this genotype is probably associated with DPs. In this cross-sectional study of 1612 elderly adults, we investigated the effects of the ALDH2 genotype on DPs and the mediating role of alcohol intake. We identified the ALDH2 genotype and conducted a dietary history survey, then used principal component analysis to determine DPs for each gender. We performed multiple regression analysis to determine the independent contribution of the ALDH2 genotype and alcohol intake to DP scores. We identified three DPs: the "Japanese side dish type" (DP1), the "Japanese dish with alcohol type" (DP2), and the "Western dish with alcohol type" (DP3). In men, the single nucleotide polymorphism ALDH2 rs671 was significantly associated with all DP scores. When alcohol intake was added as a covariate, ALDH2 rs671 was still significantly correlated with the DP2 score but not with the DP1 or DP3 score, and alcohol intake was significantly correlated with all DP scores. In women, ALDH2 rs671 was significantly associated with the DP2 and DP3 scores; however, after adding alcohol intake as a covariate, these associations disappeared, and alcohol intake significantly correlated with all DP scores. In conclusion, the ALDH2 genotype was associated with several DPs in elderly adults, but most associations were mediated by alcohol intake.

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.

Impaired fatigue resistance, sarcoplasmic reticulum function, and mitochondrial activity in soleus muscle of db/db mice.

Type 2 diabetes mellitus (T2DM) is characterized by reduced exercise tolerance due to increased fatigability in skeletal muscle. In this study, we investigated muscle fatigue resistance of soleus (SOL) muscle in obese type 2 diabetic model mice (db/db). No differences in muscle volume, absolute force, or specific force in SOL muscle were observed between db/db mice and control mice (db/+), while fatigue resistance evaluated by repeated tetanic contractions was significantly lower in db/db mice (30th tetani, db/+: 63.7 ± 4.7%, db/db: 51.3 ± 4.8%). The protein abundance related to Ca2+ release from the sarcoplasmic reticulum (SR) in SOL muscle was not different between db/db mice and db/+ mice, while SR Ca2+ -ATPase (Ca2+ reuptake to SR) protein was decreased in db/db mice compared to db/+ mice (db/+: 1.00 ± 0.17, db/db: 0.60 ± 0.04, relative units). In addition, mitochondrial oxidative enzyme activity (succinate dehydrogenase) was decreased in the SOL muscle of db/db mice (p < 0.05). These data suggest that fatigue resistance in slow-twitch dominant muscle is impaired in mice with T2DM. Decreased mitochondrial oxidative enzyme activity and impairment of Ca2+ uptake to SR, or both might be involved in the mechanisms.

Associations of Exercise Habits in Adolescence and Old Age with Risk of Osteoporosis in Older Adults: The Bunkyo Health Study.

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.

Short-term physical inactivity induces diacylglycerol accumulation and insulin resistance in muscle via lipin1 activation.

Physical inactivity impairs muscle insulin sensitivity. However, its mechanism is unclear. To model physical inactivity, we applied 24-h hind-limb cast immobilization (HCI) to mice with normal or high-fat diet (HFD) and evaluated intramyocellular lipids and the insulin signaling pathway in the soleus muscle. Although 2-wk HFD alone did not alter intramyocellular diacylglycerol (IMDG) accumulation, HCI alone increased it by 1.9-fold and HCI after HFD further increased it by 3.3-fold. Parallel to this, we found increased protein kinase C ε (PKCε) activity, reduced insulin-induced 2-deoxyglucose (2-DOG) uptake, and reduced phosphorylation of insulin receptor ß (IRß) and Akt, key molecules for insulin signaling pathway. Lipin1, which converts phosphatidic acid to diacylglycerol, showed increase of its activity by HCI, and dominant-negative lipin1 expression in muscle prevented HCI-induced IMDG accumulation and impaired insulin-induced 2-DOG uptake. Furthermore, 24-h leg cast immobilization in human increased lipin1 expression. Thus, even short-term immobilization increases IMDG and impairs insulin sensitivity in muscle via enhanced lipin1 activity.NEW & NOTEWORTHY Physical inactivity impairs muscle insulin sensitivity. However, its mechanism is unclear. To model physical inactivity, we applied 24-h hind-limb cast immobilization to mice with normal or high-fat diet and evaluated intramyocellular lipids and the insulin signaling pathway in the soleus muscle. We found that even short-term immobilization increases intramyocellular diacylglycerol and impairs insulin sensitivity in muscle via enhanced lipin1 activity.

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.

ALDH2 rs671 Is Associated With Elevated FPG, Reduced Glucose Clearance and Hepatic Insulin Resistance in Japanese Men.

CONTEXT: A recent meta-analysis of genome-wide association studies data from East Asians identified aldehyde dehydrogenase 2 (ALDH2) rs671 as a susceptibility variant for type 2 diabetes in males. OBJECTIVE: To investigate the association between ALDH2 rs671 and metabolic characteristics. METHODS: We studied 94 nonobese, nondiabetic, Japanese men. Using a 2-step hyperinsulinemic-euglycemic clamp, we evaluated insulin sensitivity in muscle and liver. Intrahepatic lipid and fat distribution were measured using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively. We divided participants into a risk-carrying group with ALDH2 rs671 G/G (n = 53) and a nonrisk-carrying group with ALDH2 rs671 G/A or A/A (n = 41). RESULTS: The risk-carrying group had significantly higher levels of alcohol consumption (18.4 [interquartile range, IQR, 10.4-48.9]) vs 12.1 (IQR, 1.3-29.0) g/day; P = .003), elevated fasting plasma glucose (FPG) (97.5 ±â€…7.9 vs 93.5 ±â€…6.2 mg/dL; P = .010), lower hepatic insulin sensitivity (61.7 ±â€…20.5% vs 73.1 ±â€…15.9%; P = .003), and lower fasting glucose clearance (0.84 ±â€…0.8 dL·m-2·min-1 vs 0.87 ±â€…0.09 dL·m-2·min-1; P = .047) than the nonrisk-carrying group, while insulin resistance in muscle and body fat distribution were similar. The single linear correlation analysis revealed significant correlations between alcohol consumption and hepatic insulin sensitivity (r = -0.262, P = .011), fasting glucose clearance (r = -0.370, P < .001), or FPG (r = 0.489, P < .001). The multiple regression analysis revealed that both ALDH2 rs671 G/G genotype and alcohol consumption were significant independent correlates for hepatic insulin sensitivity, whereas only alcohol consumption was a significant independent correlate for fasting glucose clearance. CONCLUSION: Our data suggest that high-alcohol intake-dependent and independent hepatic insulin resistance and reduced fasting glucose clearance due to high alcohol intake could be a relatively upstream metabolic abnormality in ALDH2 rs671 G/G carriers.