Yasuki Higaki

Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice

Physical exercise promotes glucose uptake into skeletal muscle and makes the working muscles more sensitive to insulin. To understand the role of insulin receptor (IR) signaling in these responses, we studied the effects of exercise and insulin on skeletal muscle glucose metabolism and insulin signaling in mice lacking insulin receptors specifically in muscle. Muscle-specific insulin receptor knockout (MIRKO) mice had normal resting 2-deoxy-glucose (2DG) uptake in soleus muscles but had no significant response to insulin. Despite this, MIRKO mice displayed normal exercise-stimulated 2DG uptake and a normal synergistic activation of muscle 2DG uptake with the combination of exercise plus insulin. Glycogen content and glycogen synthase activity in resting muscle were normal in MIRKO mice, and exercise, but not insulin, increased glycogen synthase activity. Insulin, exercise, and the combination of exercise plus insulin did not increase IR tyrosine phosphorylation or phosphatidylinositol 3-kinase activity in MIRKO muscle. In contrast, insulin alone produced a small activation of Akt and glycogen synthase kinase-3 in MIRKO mice, and prior exercise markedly enhanced this insulin effect. In conclusion, normal expression of muscle insulin receptors is not needed for the exercise-mediated increase in glucose uptake and glycogen synthase activity in vivo. The synergistic activation of glucose transport with exercise plus insulin is retained in MIRKO mice, suggesting a phenomenon mediated by nonmuscle cells or by downstream signaling events.

Insulin Receptor Substrate-2 Is Not Necessary for Insulin- and Exercise-stimulated Glucose Transport in Skeletal Muscle

Insulin receptor substrate-2-deficient (IRS2−/−) mice develop type 2 diabetes. The purpose of this study was to determine whether there is a defect in basal, insulin-, and exercise-stimulated glucose transport in the skeletal muscle of these animals. IRS2−/− and wild-type (WT) mice (male, 8–10 weeks) exercised on a treadmill for 1 h or remained sedentary. 2-Deoxyglucose (2DG) uptake was measured in isolated soleus muscles incubated in vitro in the presence or absence of insulin. Resting blood glucose concentration in IRS2−/−mice (10.3 mm) was higher than WT animals (4.1 mm), but there was a wide range among the IRS2−/− mice (3–25 mm). Therefore, IRS2−/− mice were divided into two subgroups based on blood glucose concentrations (IRS2−/−L < 7.2 mm, IRS2−/−H > 7.2 mm). Only IRS2−/−H had lower basal, exercise-, and submaximally insulin-stimulated 2DG uptake, while maximal insulin-stimulated 2DG uptake was similar among the three groups. The ED50 for insulin to stimulate 2DG uptake above basal in IRS2−/−H was higher than WT and IRS2−/−L mice, suggesting insulin resistance in the skeletal muscle from the IRS2−/− mice with high blood glucose concentrations. Furthermore, resting blood glucose concentrations from all groups were negatively correlated to submaximally insulin-stimulated 2DG uptake (r 2 = 0.33, p < 0.01). Muscle GLUT4 content was significantly lower in IRS2−/−H mice compared with WT and IRS2−/−L mice. These results demonstrate that the IRS2 protein in muscle is not necessary for insulin- or exercise-stimulated glucose transport, suggesting that the onset of diabetes in the IRS2−/− mice is not due to a defect in skeletal muscle glucose transport; hyperglycemia may cause insulin resistance in the muscle of IRS2−/− mice.

Oxidative stress stimulates skeletal muscle glucose uptake through a phosphatidylinositol 3-kinase-dependent pathway

We determined the acute effects of oxidative stress on glucose uptake and intracellular signaling in skeletal muscle by incubating muscles with reactive oxygen species (ROS). Xanthine oxidase (XO) is a superoxide-generating enzyme that increases ROS. Exposure of isolated rat extensor digitorum longus (EDL) muscles to Hx/XO (Hx/XO) for 20 min resulted in a dose-dependent increase in glucose uptake. To determine whether the mechanism leading to Hx/XO-stimulated glucose uptake is associated with the production of H2O2, EDL muscles from rats were preincubated with the H2O2 scavenger catalase or the superoxide scavenger superoxide dismutase (SOD) prior to incubation with Hx/XO. Catalase treatment, but not SOD, completely inhibited the increase in Hx/XO-stimulated 2-deoxyglucose (2-DG) uptake, suggesting that H2O2 is an intermediary leading to Hx/XO-stimulated glucose uptake with incubation. Direct H2O2 also resulted in a dose-dependent increase in 2-DG uptake in isolated EDL muscles, and the maximal increase was threefold over basal levels at a concentration of 600 micromol/l H2O2. H2O2-stimulated 2-DG uptake was completely inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, but not the nitric oxide inhibitor NG-monomethyl-l-arginine. H2O2 stimulated the phosphorylation of Akt Ser473 (7-fold) and Thr308 (2-fold) in isolated EDL muscles. H2O2 at 600 micromol/l had no effect on ATP concentrations and did not increase the activities of either the alpha1 or alpha2 catalytic isoforms of AMP-activated protein kinase. These results demonstrate that acute exposure of muscle to ROS is a potent stimulator of skeletal muscle glucose uptake and that this occurs through a PI3K-dependent mechanism.

Long-period accelerometer monitoring shows the role of physical activity in overweight and obesity

CONTEXT:Physical activity (PA) plays an important role in obesity. A new accelerometer has been developed to assess total energy expenditure as well as PA.OBJECTIVE:To investigate the association of PA with overweight and obesity in Japanese men and women, a large cross-sectional study was performed using a single-axis accelerometer.DESIGN, SETTING AND PARTICIPANTS:Population-based cross-sectional study of Japanese 18–84 y of age. Height, body weight and PA were measured in 400 male and 388 female Japanese volunteers from 1999 to 2000. The outcome measurements were overweight and obesity, which are defined as a body mass index ≥25 kg/m2. PA was measured for 1 to 4 weeks and was then categorized into three activity levels, which were defined as light, moderate and vigorous PA.RESULTS:Prevalence of overweight and obesity was 22.3%. Number of steps and time spent in moderate and vigorous PA per day were lower in overweight and obese individuals. No difference was found in time spent in light PA. Individuals who are in the 4th and 5th quintile of moderate and vigorous PA showed a significantly lower body mass index. When odd ratios (ORs) of overweight and obesity estimated by logistic regression were used as effect measures, overweight and obesity were negatively associated with vigorous PA (ORs=0.91).CONCLUSION:These results indicate that overweight and obese individuals have a lower step rate and are spending less time for moderate to vigorous PA. Participation in vigorous PA is an important predictor of overweight and obesity.

Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case‐control study in Japan

Coffee use has consistently been associated with lower serum liver enzyme levels and a reduced risk of liver cirrhosis. A limited number of cohort and case‐control studies also suggest a decreased risk of hepatocellular carcinoma (HCC) among coffee drinkers, but mostly without consideration of hepatitis virus infection. In the present case‐control study, we recruited 209 incident HCC cases and three different controls (1308 community controls, 275 hospital controls, and 381 patients with chronic liver disease [CLD] without HCC), all of whom were aged 40–79 years and residents of Saga Prefecture, Japan. A questionnaire survey elicited information on coffee use during the last 1–2 years and 10 years before, and plasma hepatitis B surface antigen and antibodies to hepatitis C virus were tested for all but community controls. After adjustment for sex, age, heavy alcohol use, smoking status and hepatitis virus markers (except for community controls), coffee use during the last 1–2 years was associated with a decreased risk against any control group. For coffee use 10 years before, comparison between HCC cases and either community controls or CLD patients revealed a decreased risk; adjusted odds ratios for occasional use, 1–2 cups/day and ≥3 cups/day compared with no use were 0.33, 0.27 and 0.22 (P trend < 0.001), respectively, against community controls, and 0.86, 0.62 and 0.53 (P trend = 0.05), respectively, against CLD patients. These results suggest that coffee may protect against the development of HCC, yet further elaborate studies (hopefully, intervention studies) are warranted to corroborate these findings. (Cancer Sci 2007; 98: 214–218)

Long-term trends in cardiorespiratory fitness and the incidence of type 2 diabetes.

OBJECTIVE Whereas single assessments of cardiorespiratory fitness have been shown to predict lower incidence of type 2 diabetes, there are no data on long-term trends in fitness and risk. We investigated the relationship between long-term trends in fitness and the incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS A cohort of 4,187 Japanese men free of diabetes completed annual health checkups and fitness tests for estimated maximal oxygen uptake at least four times over 7 years (1979–1985). We modeled the trend in fitness over 7 years for each man using simple linear regression. Men were then divided into quartiles based on the regression coefficient (slope) from the model. During the follow-up period (1985–1999), 274 men developed diabetes. Hazard ratios (HRs) and 95% CIs for the incidence of diabetes were obtained using the Cox proportional hazards model. RESULTS Men in the lowest quartile of the distribution decreased in fitness over the 7 years (median slope −1.25 ml/kg/min), whereas men in the highest quartile increased in fitness (median slope 1.33 ml/kg/min). With adjustment for age, initial fitness level, BMI, systolic blood pressure, cigarette smoking, alcohol intake, and a family history of diabetes and use of the lowest quartile, the HRs (95% CI) for the second through fourth quartiles were 0.64 (0.46–0.89), 0.40 (0.27–0.58), and 0.33 (0.21–0.50), respectively (Ptrend < 0.001). CONCLUSIONS These results indicate that the long-term trend in fitness is a strong predictor of the incidence of type 2 diabetes in Japanese men.

Effects of a 12-Month Multicomponent Exercise Program on Physical Performance, Daily Physical Activity, and Quality of Life in Very Elderly People With Minor Disabilities: An Intervention Study

Background Although studies suggest that exercise training improves physical performance and health-related quality of life (HRQOL) among elderly people, most of these studies have investigated relatively healthy persons. The objective of the present study was to determine the effects of a 12-month multicomponent exercise program on physical performance, daily physical activity, and HRQOL among very elderly people with minor disabilities. Methods The subjects consisted of 65 elders (median age: 84 years) who were certified to receive long-term care in the form of support only or Level 1 care (the lowest level of care required); 31 were allocated to the intervention group and 34 to the control group. The intervention group participated in supervised exercises once a week for 12 months and in home-based exercises. The exercise program consisted of various exercises related to flexibility, muscle strength, balance, and aerobic performance. Results After 12 months of exercise training, the intervention group had significant improvements in lower-limb strength and on the sit-and-reach test; these effects were not observed in the control group. The control group had significant decreases in grip strength, 6-minute walking distance, walking speed, and stride length; these decreases were not observed in the intervention group. No clear differences in HRQOL measurements or changes in physical activity were detected between groups. Conclusions The 12-month multicomponent exercise program may effectively improve and maintain the physical performance of very elderly individuals with minor disabilities.

Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population.

Although alcohol intake as well as hepatitis viruses has been associated with hepatocellular carcinoma (HCC), gene–alcohol interactions on HCC risk remain to be elucidated. We conducted a case‐control study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake. ADH2 and ALDH2 genotyping was performed by a duplex polymerase chain reaction with confronting two‐pair primers in 209 newly diagnosed HCC cases and 2 different controls [275 hospital controls and 381 patients with chronic liver disease (CLD)]. Multiple logistic regression analyses revealed that heavy drinkers consuming ≥3 “go”s/day of sake (69 g of ethanol/day) showed an increased risk of HCC based on comparison of HCC cases with hospital controls [adjusted odds ratio (OR) = 13.5; 95% confidence interval (CI) 3.3–54.3] or CLD patients (adjusted OR = 7.0; 95% CI 2.5–19.2), whereas the overall risk was not elevated among light to moderate drinkers consuming <3 “go”s/day. Interestingly, light to moderate drinking was associated with an increased risk among those with ALDH2*1/*2 (adjusted OR = 4.5 or 2.0), but not among those with ALDH2*1/*1 (adjusted OR = 0.8 or 1.0; p interaction = 0.03 or 0.13). However, this gene–alcohol interaction was not observed for heavy drinking. Among light to moderate drinkers, people with the combination of ALDH2*1/*2 and ADH2*2/*2 revealed the highest risk of HCC. These findings indicate that the ALDH2 polymorphism may modify HCC risk among light to moderate drinkers.

Association Between Dietary Pattern and Serum C-Reactive Protein in Japanese Men and Women

Background Dietary pattern may influence the risks of cardiovascular disease, atherosclerosis, type 2 diabetes, and metabolic syndrome through its effects on inflammation. We evaluated the association between dietary pattern and serum high-sensitivity C-reactive protein (hs-CRP) in a Japanese population. Methods In this cross-sectional analysis, we used baseline data from 3905 men and 5640 women (age 40–69 years) who participated in a population-based cohort study between November 2005 and December 2007. Participants with possible inflammation-related diseases, current analgesic use, high hs-CRP levels (≥3000 ng/mL) or extreme dietary energy intake were excluded. We used 46 items from a validated short food frequency questionnaire and examined major dietary patterns by factor analysis. Results We identified 5 dietary patterns: healthy (high in vegetables and fruit), Western (high in meat and fried foods), seafood (high in shellfish, squid, fish, etc.), bread (high in bread and low in rice), and dessert (high in confections and fruit). After adjustment for age, alcohol use, smoking, physical activity, and body mass index, hs-CRP levels in men were inversely associated with the healthy, bread, and dessert patterns (P-trend: 0.01, 0.06, and <0.01, respectively) and positively associated with the seafood pattern (P-trend = 0.02). In women, hs-CRP levels were inversely associated with the healthy pattern (P-trend = 0.06) and positively associated with the Western pattern (P-trend = 0.06). Conclusions The healthy dietary pattern may be associated with suppressed inflammation in Japanese men and women, independently of body mass index and other factors. The sex-specific associations of hs-CRP with other dietary patterns (eg, the seafood pattern) require further study.

Overexpression of lipoprotein lipase improves insulin resistance induced by a high-fat diet in transgenic rabbits

Aims/hypothesisDysfunctions of lipoprotein lipase (LPL) have been found to be associated with dyslipidaemias, atherosclerosis, obesity and insulin resistance. There are two conflicting hypotheses regarding the roles of LPL in glucose metabolism and insulin resistance. Whether systemically increased LPL activity would be beneficial or detrimental to insulin sensitivity is yet to be resolved. To address this issue, we studied transgenic rabbits overexpressing human LPL transgene.MethodsLPL transgenic and control rabbits were fed a 10% high-fat diet (HFD) for 16 weeks. To evaluate glucose metabolism, we compared plasma levels of glucose and insulin in transgenic rabbits with control rabbits and performed an intravenous glucose tolerance test. In addition, we measured adipose tissue accumulation in HFD-fed rabbits.ResultsIncreased LPL activity in transgenic rabbits resulted in a significant reduction of plasma triglycerides and non-esterified fatty acids, but not in basal levels of glucose and insulin. HFD feeding induced an elevation of plasma glucose levels accompanied by hyperinsulinaemia in control rabbits, but was significantly inhibited in transgenic rabbits. The intravenous glucose tolerance test showed that transgenic rabbits had faster glucose clearance associated with lower levels of insulin secretion than control rabbits. In addition, there was a significant reduction of body adipose tissue in transgenic rabbits compared with in control rabbits fed an HFD. Scanning electron microscopic examination revealed that adipocytes in transgenic rabbits were predominately small cells.Conclusions/interpretationOur results showed that systemically increased LPL activity improves insulin resistance and reduces adipose accumulation in transgenic rabbits, indicating that systemic elevation of LPL may have potential benefits for the treatment of insulin resistance and obesity.