Reduced gray matter volume in the default-mode network associated with insulin resistance.

Insulin resistance may lead to structural and functional abnormalities of the human brain. However, the mechanism by which insulin resistance impairs the brain remains elusive. In this study, we used two large neuroimaging databases to investigate the brain regions where insulin resistance was associated with the gray matter volume and to examine the resting-state functional connectivity between these brain regions and each hypothalamic nucleus. Insulin resistance was associated with reduced gray matter volume in the regions of the default-mode and limbic networks in the cerebral cortex in older adults. Resting-state functional connectivity was prominent between these networks and the paraventricular nucleus of the hypothalamus, a hypothalamic interface connecting functionally with the cerebral cortex. Furthermore, we found a significant correlation in these networks between insulin resistance-related gray matter volume reduction and network paraventricular nucleus of the hypothalamus resting-state functional connectivity. These results suggest that insulin resistance-related gray matter volume reduction in the default-mode and limbic networks emerged through metabolic homeostasis mechanisms in the hypothalamus.

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.

Neuroimaging findings related to glymphatic system alterations in older adults with metabolic syndrome.

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Reduced glymphatic flow has been observed in rat models of type 2 diabetes and hypertension, indicating the role of vascular risk factors in the glymphatic system. However, little is known about how vascular risk factors affect the human glymphatic system. The present study aims to assess the relationships between metabolic syndrome (MetS), a cluster of vascular risk factors, and the glymphatic system function using diffusion magnetic resonance imaging (MRI)-based measures of water diffusivity in the glymphatic compartments, including the brain interstitial space and perivascular spaces around the deep medullary vein. We hypothesized that vascular risk factors are associated with glymphatic dysfunction, leading to cognitive impairment in older adults. METHODS: This cross-sectional study assessed 61 older adults (age range, 65-82 years) who had participated in the Bunkyo Health Study, including 15 healthy controls (mean age, 70.87 ± 4.90 years) and 46 individuals with MetS (mean age, 71.76 ± 4.61 years). Fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. RESULTS: After adjusting for age, sex, years of education, total Fazekas scale, Pittsburgh sleep quality index (PSQI) score, and intracranial volume (ICV), a significantly (P = 0.030; Cohen's d = 1.01) higher FW was observed in individuals with MetS than in the healthy controls. Furthermore, individuals with MetS had a significantly (P = 0.031; Cohen's d = 0.86) lower ALPS index than the healthy controls, with age, sex, years of education, total Fazekas scale, PSQI score, ICV, fractional anisotropy, and mean diffusivity included as confounding factors. Higher FW was significantly associated with lower ALPS index (r = -0.37; P = 0.004). Multiple linear regression (MLR) with backward elimination analyses showed that higher diastolic blood pressure (BP; standardized ß = 0.33, P = 0.005) was independently associated with higher FW, whereas higher fasting plasma glucose levels (standardized ß = -0.63, P = 0.002) or higher Brinkman index of cigarette consumption cumulative amount (standardized ß = -0.27, P = 0.022) were associated with lower ALPS index. The lower ALPS index (standardized ß, 0.28; P = 0.040) was associated with poorer global cognitive performance, which was determined using the Japanese version of the Montreal Cognitive Assessment (MOCA-J) scores. Finally, partial correlation analyses showed a significant correlation between higher FW and lower MOCA-J scores (r = -0.35; P = 0.025) and between higher FW and higher diastolic BP (r = 0.32, P = 0.044). CONCLUSION: The present study shows the changes in diffusion MRI-based measures reflected by the higher FW and lower ALPS index in older adults with MetS, possibly due to the adverse effect of vascular risk factors on the glymphatic system. Our findings also indicate the associations between the diffusion MRI-based measures and elevated diastolic BP, hyperglycemia, smoking habit, and poorer cognitive performance. However, owing to the limitations of this study, the results should be cautiously interpreted.

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.

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.

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.

Ectopic fat, insulin resistance and metabolic disease in non-obese Asians: investigating metabolic gradation.

Although metabolic abnormalities commonly occur in non-obese Asians, their pathogenesis is not fully understood. Proton magnetic resonance spectroscopy has been used to analyze intracellular lipids in humans, and results suggest that ectopic fat accumulation in muscle and liver may induce insulin resistance in each tissue independently of obesity. Thus, measurement of ectopic fat currently plays an important role in the study of insulin resistance in non-obese Asians. In addition, studies using 2-step hyperinsulinemic euglycemic clamp with a glucose tracer may clarify how tissue-specific insulin resistance in muscle, liver, and adipose tissue contributes to the development of metabolic disease in non-obese Japanese. Although numerous studies have elucidated the pathophysiology of insulin resistance in obese subjects, research on "metabolic gradation," defined as the gradual transition from an insulin-sensitive to an insulin-resistant state, is less common, especially in terms of early metabolic changes. This review addresses a simple question: when and how is insulin resistance induced in non-obese East Asians? Several studies revealed that impaired insulin clearance and hyperinsulinemia not only compensated for insulin resistance, but also secondarily facilitated insulin resistance and weight gain. In this regard, we recently found that impaired insulin clearance and hyperinsulinemia could occur in apparently healthy subjects without significant insulin resistance, suggesting that this change may be an initial trigger that drives subsequent insulin resistance and weight gain. Further research is required to clarify the pathogenesis of metabolic gradation in non-obese Asians.

Functional subdivisions of the hypothalamus using areal parcellation and their signal changes related to glucose metabolism.

The hypothalamus consists of numerous nuclei, and is regarded as the highest center for various autonomic functions. Although each hypothalamic nucleus implements a distinct function, it remains difficult to investigate the human hypothalamus at the nucleus level. In the present high-resolution functional MRI study, we utilized areal parcellation to discriminate individual nuclei in the human hypothalamus based on areal profiles of resting-state functional connectivity. The areal parcellation detected ten foci that were expected to represent hypothalamic nuclei, and the locations of the foci were consistent with those of the hypothalamic nuclei identified in previous histological studies. Regions of interest (ROI) analyses revealed contrasting brain activity changes following glucose ingestion: decrease in the ventromedial hypothalamic nucleus and increase in the lateral hypothalamic area in parallel with blood glucose increase. Moreover, decreased brain activity in the arcuate nucleus predicted future elevation of blood insulin during the first 10 min after glucose ingestion. These results suggest that the hypothalamic nuclei can putatively be determined using areal parcellation, and that the ROI analysis of the human hypothalamic nuclei is useful for future scientific and clinical investigations into the autonomic functions.

Myocardial triglyceride content in patients with left ventricular hypertrophy: comparison between hypertensive heart disease and hypertrophic cardiomyopathy.

Proton magnetic resonance spectroscopy (1H-MRS) enables the assessment of myocardial triglyceride (TG) content, which is reported to be associated with cardiac dysfunction and morphology accompanied by metabolic disorder and cardiac hemodynamic status. The clinical usefulness of myocardial TG content measurements in patients with left ventricular hypertrophy (LVH) has not been fully investigated. We examined whether myocardial TG content assessed by 1H-MRS was useful for diagnosis in patients with LVH. To quantify myocardial TG content, we conducted 1H-MRS in 35 subjects with LVH. Left ventricular function was measured by cardiac magnetic resonance imaging. Patients were assigned to a hypertensive heart disease (HHD, n = 10) or hypertrophic cardiomyopathy (HCM, n = 25) group based on the histology and/or late gadolinium enhancement pattern. The myocardial TG content was significantly higher in the HHD group than in the HCM group (2.14 ± 1.29 vs. 1.09 ± 0.72 %, P < 0.001). Myocardial TG content were significantly and negatively correlated with LV mass (r = -0.41, P < 0.04) and stroke volume (r = -0.64, P < 0.05) in the HCM group and HHD group, respectively. In a multivariate analysis, LV mass volume and diagnosis of HCM or HHD were independent factors of the myocardial TG content. The results suggest that myocardial metabolism may differ between HCM and HHD patients and that measurement of myocardial TG content by 1H-MRS may be useful for evaluating the myocardial metabolic features of LVH.

[Aging and homeostasis. Aging of skeletal muscle.]

With aging, insulin resistance and sarcopenia in skeletal muscle are induced, resulting in skeletal muscle aging. It is suggested that the former is one of the reasons that mitochondrial function decreases with aging, and the latter is due to endocrinologic dysfunction, neurological mechanism, nutritional deficiency and inactivity such as waste are complicatedly involved. Also, as sarcopenia progresses, the amount of physical activity further decreases, and it is also assumed that insulin resistance and sarcopenia progress synergistically. It is suggested that exercise enhances the activity and amount of mitochondria and works preventively against insulin resistance in skeletal muscle accompanying aging and it also works for prevention and amelioration of sarcopenia. On the other hand, as for nutritional supplementation, it has been reported that it works for improving sarcopenia by amino acid ingestion.

Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet.

The accumulation of intramyocellular lipid (IMCL) is recognized as an important determinant of insulin resistance, and is increased by a high-fat diet (HFD). However, the effects of HFD on IMCL and insulin sensitivity are highly variable. The aim of this study was to identify the genes in muscle that are related to this inter-individual variation. Fifty healthy men were recruited for this study. Before and after HFD for 3 days, IMCL levels in the tibialis anterior were measured by (1)H magnetic resonance spectroscopy, and peripheral insulin sensitivity was evaluated by glucose infusion rate (GIR) during the euglycemic-hyperinsulinemic clamp. Subjects who showed a large increase in IMCL and a large decrease in GIR by HFD were classified as high responders (HRs), and subjects who showed a small increase in IMCL and a small decrease in GIR were classified as low responders (LRs). In five subjects from each group, the gene expression profile of the vastus lateralis muscle was analyzed by DNA microarray analysis. Before HFD, gene expression profiles related to lipid metabolism were comparable between the two groups. Gene Set Enrichment Analysis demonstrated that five gene sets related to lipid metabolism were upregulated by HFD in the HR group but not in the LR group. Changes in gene expression patterns were confirmed by qRT-PCR using more samples (LR, n = 9; HR, n = 11). These results suggest that IMCL accumulation/impaired insulin sensitivity after HFD is closely associated with changes in the expression of genes related to lipid metabolism in muscle.

Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle.

A single bout of exercise is known to increase the insulin sensitivity of skeletal muscle; however, the underlying mechanism of this phenomenon is not fully understood. Because a single bout of exercise induces a transient increase in blood interleukin-6 (IL-6) level, we hypothesized that the enhancement of insulin sensitivity after a single bout of exercise in skeletal muscle is mediated at least in part through IL-6-dependent mechanisms. To test this hypothesis, C57BL6J mice were intravenously injected with normal IgG or an IL-6 neutralizing antibody before exercise. Twenty-four hours after a single bout of exercise, the plantaris muscle was harvested to measure insulin sensitivity and glucose transporter (GLUT)-4 expression levels by ex-vivo insulin-stimulated 2-deoxyglucose (2-DG) uptake and Western blotting, respectively. Compared with sedentary mice, mice that performed exercise showed enhanced IL-6 concentration, insulin-stimulated 2-DG uptake, and GLUT-4 expression in the plantaris muscle. The enhanced insulin sensitivity and GLUT4 expression were canceled by injection of the IL-6 neutralizing antibody before exercise. In addition, IL-6 injection increased GLUT4 expression, both in the plantaris muscle and the soleus muscle in C57BL6J mice. Furthermore, a short period of incubation with IL-6 increased GLUT4 expression in differentiated C2C12 myotubes. In summary, these results suggested that IL-6 increased GLUT4 expression in muscle and that this phenomenon may play a role in the post-exercise enhancement of insulin sensitivity in skeletal muscle.

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.

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.

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.

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.].

Myelin Changes in Poor Sleepers: Insights into Glymphatic Clearance Function and Regional Circadian Clock Gene Expression.

Sleep is essential for maintaining brain myelin integrity. Emerging evidence suggests that poor sleep quality compromises the glymphatic system, a perivascular network crucial for brain waste clearance, leading to the accumulation of neuroinflammatory and toxic proteins, which may affect myelin integrity. Furthermore, poor sleep quality results in alterations in gene expression within the brain. We evaluated the associations among poor sleep quality, brain myelin integrity, and glymphatic clearance function as well as the impact of circadian clock gene expression on regional cortical myelin content. 50 poor sleepers (average age 71.08 ± 4.69 years; Pittsburgh Sleep Quality Index [PSQI] &;gt 5) and 50 good sleepers (average age 73.04 ± 5.80 years; PSQI ≤ 5) were assessed. Myelin volume fraction (MVF) was quantified using magnetization transfer saturation imaging, and glymphatic function was noninvasively examined using diffusion tensor imaging along the perivascular space. Circadian gene expression was analyzed using postmortem brain tissue from the Allen Human Brain Atlas. Magnetic resonance imaging measures were correlated with cognitive and depression scores. Lower MVF was observed in the fronto-temporo-parietal and limbic regions as well as in major white matter tracts in poor sleepers compared with that in good sleepers. This reduction was linked to lower cognitive function scores and higher depressive scores. Poor sleepers also exhibited lower diffusivity along the perivascular spaces, mediating the relationship between poor sleep quality and demyelination. Regions with higher expression of CLOCK, CRY2, PER1, and PER2 exhibited greater MVF disparities between good and poor sleepers, whereas lower expression of CRY1 was associated with more pronounced differences. Poor sleep quality was associated with lower brain myelin integrity, correlating with reduced cognitive performance and increased depressive symptoms. These changes might be mediated by glymphatic clearance dysfunction and were associated with the differential expression of circadian clock genes.

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.