Decreased arterial distensibility and postmeal hyperinsulinemia in young Japanese women with family history of diabetes.

INTRODUCTION: To assess vascular function and characterize insulin secretion using a physiological approach in Japanese women with family history of type 2 diabetes (FHD). RESEARCH DESIGN AND METHODS: Standardized mixed-meal tests were performed with multiple postprandial glucose, insulin and free fatty acids (FFA) measurements over a 30-120 min period in 31 Japanese women aged 21-24 years. Arterial distensibility was assessed as well. RESULTS: Fasting glucose, triglyceride and insulin averaged <90 mg/dL, <60 mg/dL and <5 µU/mL, respectively, and did not differ cross-sectionally between 10 with (FHD+) and 21 without FHD (FHD-). FHD+ showed higher insulin responses not only during the first 30 min (p=0.005) but also during the second hour (60-120 min, p<0,05) in spite of identical postprandial suppression of FFA and identical fasting and postprandial glucose and FFA concentrations, except for higher 60 min FFA in FHD+. Further, FHD+ had decreased arterial distensibility (p=0.003). On multivariate regression analysis, arterial distensibility emerged as the only significant independent predictor of FHD+. Endurance training in FHD+ did not alter decreased arterial distensibility whereas it abolished postprandial hyperinsulinemia. CONCLUSIONS: FHD was associated with decreased arterial distensibility and postprandial hyperinsulinemia despite nearly identical postprandial glycemia and postprandial FFA suppression, suggesting that impaired vascular insulin sensitivity may precede glucose and lipid dysmetabolism in normal weight Japanese women aged 22 years.

Higher circulating orosomucoid and lower early-phase insulin secretion in midlife Japanese with slower glucose disposal during oral glucose tolerance tests.

OBJECTIVE: We examined whether serum orosomucoid, an acute phase protein as with C-reactive protein, in addition to insulin resistance and beta-cell dysfunction, was involved in glucose disposal during oral glucose tolerance tests. RESEARCH DESIGN AND METHODS: 124 midlife Japanese (65 women, 66% with normal glucose tolerance) received dual-energy X-ray absorptiometry and 75 g oral glucose tolerance tests with multiple postload glucose and insulin measurements. Subjects were divided based on the relationship between postload and fasting glucose. Obesity measures, insulin resistance, insulin secretion, serum orosomucoid and adiponectin were cross-sectionally analyzed by analysis of variance and then Bonferroni's multiple comparison procedure. RESULTS: In 10 subjects (group A) and 19 subjects (group B), postload glucose fell below fasting glucose at 1 h and 2 h, respectively. In the remaining 95 subjects (group C), postload glucose never fell below fasting glucose. The insulinogenic index was lower and area under the glucose curve was higher in groups B and C as compared to group A (both p<0.05), whereas the Matsuda index, the homeostasis model assessment of insulin resistance, adipose insulin resistance (the product of fasting free fatty acid and insulin) and area under the insulin curve did not differ. Although there was no difference in fat mass index, trunk/leg fat ratio and adiponectin, orosomucoid was higher in group C as compared to group A (p<0.05). CONCLUSIONS: Lower early-phase insulin secretion and low-grade inflammation were associated with slower glucose disposal during an oral glucose tolerance test in midlife Japanese. The rate of glucose disposal was not related to adiposity and insulin resistance.

Association between socioeconomic status and small-for-gestational-age in Japan: A single center retrospective cohort study.

AIM: Small-for-gestational-age (SGA) status has negative health consequences in neonates and later life. Low socioeconomic status (SES) is a reported risk factor for adverse birth outcomes, such as SGA and preterm birth (PTB). The present study investigated whether maternal SES is associated with adverse outcomes in Japanese pregnant women. METHODS: Retrospective data were collected for 1970 Japanese women with singleton pregnancies who delivered between January 2007 and December 2011 at a single center: low SES group (n = 197); and controls (n = 1773). Low SES was defined according to the criteria of the Japanese pregnant-childbirth hospitalization support policy system. RESULTS: The low SES group included a significantly higher proportion of young women, women with single marital status, greater parity, pre-pregnancy smoking and a lack of regular employment (P < 0.001, respectively). The crude odds ratio (OR) for the association between low maternal SES and SGA was 1.80 (95% confidence interval [CI] 1.15-2.82, P = 0.010). After adjustment for baseline maternal age, parity, body mass index, smoking and gestational weight gain, the adjusted OR for the association between low maternal SES and SGA was 1.92 (95% CI 1.17-3.17, P = 0.010). No significant association was found between maternal SES and PTB. CONCLUSION: The present results suggest that low maternal SES is associated with SGA births in the Japanese population. Mitigation of low maternal SES could be urgent public health to prevent disadvantage birth outcome.

Associations of ABC (Hemoglobin A1c, Blood Pressure and Low-Density Lipoprotein Cholesterol) Goal Achievement With Chronic Kidney Disease in Type 2 Diabetic Patients With Preserved Kidney Function.

BACKGROUND: We investigated cross-sectional and prospective associations of ABC (hemoglobin A1c (HbA1c), blood pressure and low-density lipoprotein cholesterol) goal attainment with chronic kidney disease. Cross-sectional association with carotid intima-media thickness (IMT) was evaluated as well. METHODS: Prevalence of low estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2) and albuminuria (urinary albumin-to-creatinine ratio (ACR) ≥ 30 mg/g) were assessed at baseline and after a median follow-up of 6.0 years in 168 patients with type 2 diabetes with preserved kidney function (aged 62.3 years, 53.6% men). Carotid IMT was measured at baseline only. RESULTS: At baseline, 47 (28.0%), 45 (26.8%), 63 (37.5%) and 13 (7.7%) patients achieved triple-goal, dual-goal, single-goal and no-goal, respectively. Achieving more ABC targets was associated with lower log ACR (P < 0.01), lower percentage of albuminuria (P = 0.02), and lower carotid IMT (P < 0.01) at baseline. Over 6.0 years, eGFR decreased from 76 ± 16 to 67 ± 18 mL/min/1.73 m2 (P < 0.01) whereas ACR levels did not change. There were 32 patients with incident reduced eGFR, eight with GFR stage progression, 15 with progression of albuminuric stages and five with doubling of ACR within the microalbuminuric range. Achieving more ABC targets decreased the percentage of deterioration of GFR stages (30.8%, 28.6%, 24.4% and 14.9%, respectively, P = 0.01). Achieving two or more (8.9% and 8.5%, respectively) compared with one or less ABC targets (15.4% and 15.9%, respectively) was associated with less deterioration of albuminuria (P < 0.001). Although achieving more ABC targets was associated with lower annual decline in eGFR, the difference was not significant. CONCLUSIONS: ABC goal achievement has shown cross-sectional and prospective associations with deterioration of chronic kidney disease in type 2 diabetic patients with preserved kidney function. Cross-sectional association with carotid IMT has been demonstrated as well. Reaching more ABC treatment targets may be important for preventing adverse renal outcomes.

Association of Age and Anemia With Adiponectin Serum Levels in Normal-Weight Japanese Women.

BACKGROUND: Adiponectin serum levels are affected by sex, ethnicities, adiposity, age and several pathological conditions such as anemia. The prevalence of hyperadiponectinemia (≥ 20 mg/L) in relation to anemia (hemoglobin < 12 g/dL) was examined in normal-weight Japanese women. METHODS: Serum adiponectin and blood hemoglobin were measured in 311 young women aged 18 - 24 years (A), 148 of their middle-aged mothers aged 39 - 60 years (B) and 322 community-dwelling women aged ≥ 65 years (C) with a mean body mass index (BMI) of 20.4, 22.0 and 22.4 kg/m2, respectively. Elderly women were subdivided into three age groups: between 65 and 74 years (n = 95, X), between 75 and 84 years (n = 176, Y) and older than 85 years (n = 51, Z). RESULTS: The prevalence of hyperadiponectinemia (A: 3.9%, B: 3.4%, C: 22.7%, P < 0.001) was low and serum adiponectin (A: 11.5 ± 4.3 mg/L, B: 11.8 ± 4.9 mg/L, C: 15.3 ± 7.8 mg/L, P < 0.001) did not change until middle-aged but increased thereafter in a stepwise fashion (X: 18.9%, Y: 22.7%, Z: 35.3%, P = 0.07 and X: 13.9 ± 6.9 mg/L, Y: 15.1 ± 7.7 mg/L, Z: 18.7 ± 8.6 mg/L, P = 0.001, respectively). There were inverse associations of adiponectin with age (r = -0.201, P < 0.001) and hemoglobin (r = -0.318, P < 0.001) in elderly women but not even in young and middle-aged women combined. Furthermore, anemia was associated with higher prevalence of hyperadiponectinemia (34.8% vs. 20.6%, P = 0.01) and higher serum adiponectin (18.3 ± 9.4 mg/L vs. 14.5 ± 7.1 mg/L, P < 0.001) in elderly women but not in younger and middle-aged women. CONCLUSIONS: In normal-weight Japanese women, the prevalence of hyperadiponectinemia and serum adiponectin were increased and associated with anemia at 65 years of age and older.

Higher circulating adiponectin and lower orosomucoid were associated with postload glucose ≤70 mg/dL, a possible inverse marker for dysglycemia, in young Japanese women.

Objective: To examine whether serum adiponectin and orosomucoid were associated with postload glucose ≤70 mg/dL during an oral glucose tolerance test (OGTT), termed as postload low glycemia, a possible inverse marker for dysglycemia. Research design and methods: 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30-120 min period in 168 normal-weight Japanese women (18-24 years). Insulin resistance (IR) and ß-cell function inferred from serum insulin kinetics during OGTT, fat mass and distribution by dual-energy X-ray absorptiometry (DXA), serum adiponectin and inflammatory markers were compared cross-sectionally between 39 women with and 129 women without postload low glycemia. Results: Of 168 women, 161 had normal glucose tolerance. Women with as compared with those without postload low glycemia had lower fasting and postload glycemia despite similar fasting and postload insulinemia. They had higher insulinogenic index (p=0.03) and lower adipose IR (a product of fasting free fatty acid and insulin, p=0.01), although DXA-derived general and central adiposity, the Matsuda Index and homeostasis model assessment-IR did not differ. In addition, they had higher adiponectin and lower orosomucoid (both p<0.001). Multivariate logistic regression analyses revealed that adiponectin (OR: 1.14, 95% CI 1.03 to 1.26, p=0.009) and orosomucoid (0.96, 0.93 to 0.97, p=0.008) were associated with postload low glycemia independently of adipose IR and insulinogenic index. Conclusions: Higher adiponectin and lower orosomucoid were associated with 70 or lower mg/dL of postload glucose, a possible inverse marker for dysglycemia, in young women independently of DXA-derived fat mass and distribution, insulin secretion and IR.

Prevalence and Risk Factors of Elevated Liver Enzymes in Japanese Women With Polycystic Ovary Syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder among reproductive-aged women. While PCOS is associated with an increased risk of obesity and insulin resistance, little is known regarding the prevalence of and risk factors for nonalcoholic fatty liver disease (NAFLD) among Japanese women with PCOS. We estimated the prevalence of and risk factors for elevated liver enzymes, as the index of NAFLD, in Japanese women with PCOS. METHODS: We retrospectively reviewed 102 reproductive-aged women who visited the Department of Gynecology, Kyoto Medical Center in Japan from January 2000 to September 2016. Inclusion criterion was confirmed diagnosis of PCOS using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10) codes. Exclusion criteria were women with a history of liver diseases, missing body mass index (BMI) and serum alanine aminotransferase (ALT) data, and pregnancy. Data regarding age; BMI; and levels of blood glucose, serum lipid, liver enzymes, and sex hormones were obtained from medical records. Elevated liver enzymes was defined as ALT > 19 IU/L. Optimal cutoffs for risk factors for elevated liver enzymes were calculated to determine predictors of elevated liver enzymes using area under the curve (AUC) by receiver-operating characteristics (ROC). RESULTS: The prevalence of elevated liver enzymes was 33.3%. BMI was significantly higher in PCOS patients than in those without elevated liver enzymes (25.3 vs. 20.7 kg/m2, P < 0.05). ROC analyses were performed using BMI and blood glucose and testosterone levels because BMI and blood glucose showed differences between the groups and testosterone is related to fatty liver. AUC of the model including BMI and blood glucose and testosterone levels was 0.861 (sensitivity, 66.7%; specificity, 100%). CONCLUSIONS: These findings suggest that elevated liver enzymes are common in women with PCOS. An algorism using BMI and blood glucose and testosterone levels might be useful to determine elevated liver enzymes in women with PCOS. Our finding may be useful for the study of NAFLD among Japanese women with PCOS since several previous studies have indicated elevated liver enzymes to be related to the potential presence of NAFLD. Further examination, including abdominal ultrasonography and/or liver biopsy data, is required to confirm these results.

Higher Fasting and Postprandial Free Fatty Acid Levels Are Associated With Higher Muscle Insulin Resistance and Lower Insulin Secretion in Young Non-Obese Women.

BACKGROUND: To assess the relationship of the shape of glucose concentration curve during a standardized meal test to serum free fatty acid (FFA) concentrations, insulin resistance and insulin secretion in young non-obese women. METHODS: Thirty-five young women had a standardized meal for breakfast with measurement of glucose, insulin and FFA concentrations at 0 (fasting), 30, 60 and 120 min; the areas under the concentration curves were calculated (AUCg, AUCi and AUCffa, respectively). Meal-induced insulin response (MIR) was calculated as the ratio between the incremental insulin and glucose concentrations during the first 30 min of meal tests. In two women (group A), post-breakfast glucose (PBG) returned to levels below fasting plasma glucose (FPG) at 30 min; in 15 and 11 women, PBG returned to levels below FPG at 60 and 120 min (groups B and C, respectively). In the remaining seven women (group D), PBG never fell below FPG. RESULTS: Despite no difference in fasting insulin and AUCi, fasting FFA, AUCg and AUCffa were the lowest in group A, increased linearly from group B to C and plateaued in group D, whereas MIR might be the highest in group A, decreased from group B to C and plateaued in group D. CONCLUSION: Young women whose PBG returned to FPG more slowly had higher muscle insulin resistance and lower MIR associated with higher fasting and postprandial FFA levels compared with young women whose PBG returned to baseline more quickly.

Elevated serum adiponectin and tumor necrosis factor-α and decreased transthyretin in Japanese elderly women with low grip strength and preserved muscle mass and insulin sensitivity.

OBJECTIVE: To determine if adiponectin levels are associated with low grip strength among the elderly independently of insulin resistance and inflammation. RESEARCH DESIGN AND METHODS: Cross-sectional associations were analyzed by logistic regression between low grip strength and body composition, elevated serum adiponectin (≥20 mg/L), and biomarkers of nutritious stasis, insulin resistance and inflammation in 179 community-living Japanese women. Sarcopenia was evaluated using the Asian criteria. RESULTS: No women had sarcopenia. In bivariate analyses, low grip strength (n=68) was positively associated with age, log tumor necrosis factor-α (TNF-α) and hyperadiponectinemia (n=37) and inversely with body weight, height, skeletal muscle mass, serum albumin, transthyretin (TTR), fat mass, serum zinc and hemoglobin (all p<0.01). In a fully adjusted model, TTR (0.90: 0.83-0.98, p=0.01) in addition to age (p=0.007), height (p=0.004) and skeletal muscle mass (p=0.008) emerged as independent determinants of low grip strength. When TTR was removed from the full model, TNF-α was associated with low grip strength (7.7; 1.3-45.8, p=0.02). Mean waist circumference and high-density lipoprotein cholesterol did not differ between women with and without low grip strength and were within the respective normal range. Women with hyperadiponectinemia had higher percentage of women with low grip strength and lower grip strength (both p<0.01). CONCLUSIONS: Hyperadiponectinemia and elevated TNF-α in addition to decreased TTR, a biomarker of age-related catabolic states, were found in community-living Japanese elderly women with low grip strength and preserved muscle mass and insulin sensitivity.

Nonalcoholic Fatty Liver Disease in University Rugby Football Players.

Physical activity improves various metabolic disturbances. The effect of physical activity on non-alcoholic fatty liver disease (NAFLD) has not been defined, particularly in athletes who are able to consume a diet to increase body mass. The aim of this study was to evaluate the prevalence of NAFLD and associated factors of NAFLD among male university rugby football players [n = 69, 37 forwards (FW) and 32 backs (BK)], relative to age-matched controls (CON; n = 29). For FW players exercise consists of physical contact play, such as ruck, mall, scrum, and tackle. For BK players exercise consists of sprints and endurance running. Liver function tests and bioimpedance analysis to assess body composition were performed. Subjects consuming ≤ 20 g/day of ethanol and exhibiting an aspartate transaminase (AST) level ≥ 33 U/L, and/or alanine transaminase (ALT) level ≥ 43 U/L, were considered to have NAFLD. The PNPLA3 and MTP genotypes were determined using real-time polymerase chain reaction (PCR). The body mass index, body fat mass, and lean body mass were significantly higher in the FW group than in the BK and CON groups (P < 0.05). The total cholesterol, low-density lipoprotein cholesterol, triglyceride, AST, ALT, and alkaline phosphatase levels were significantly higher in the FW group than in the CON group (P < 0.05). The prevalence of NAFLD was significantly higher in the FW group than in the BK group and CON group (18.9, 8.6, and 0.0%, respectively), whereas there were non-significant between-group differences in the frequency of the PNPLA3 and MTP genotypes. These findings indicate that rugby football players, especially those in the FW position, are at higher risk of developing NAFLD, which emphasizes the role of diet and exercise in the development of NAFLD.

Association of serum orosomucoid with 30-min plasma glucose and glucose excursion during oral glucose tolerance tests in non-obese young Japanese women.

OBJECTIVE: Inflammatory markers are elevated in insulin resistance (IR) and diabetes. We tested whether serum orosomucoid (ORM) is associated with postload glucose, ß-cell dysfunction and IR inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30-120 min period in 168 non-obese Japanese women (aged 18-24 years). OGTT responses, serum adiponectin and high-sensitivity C reactive protein (hsCRP) were cross-sectionally analyzed by analysis of variance and then Bonferroni's multiple comparison procedure. Stepwise multivariate linear regression analyses were used to identify most important determinants of ORM. RESULTS: Of 168 women, 161 had normal glucose tolerance. Postload glucose levels and the area under the glucose curve (AUCg) increased in a stepwise fashion from the first through the third ORM tertile. In contrast, there was no or modest, if any, association with fat mass index, trunk/leg fat ratio, adiponectin, hsCRP, postload insulinemia, the Matsuda index and homeostasis model assessment IR. In multivariable models, which incorporated the insulinogenic index, the Matsuda index and HOMA-IR, 30 min glucose (standardized ß: 0.517) and AUCg (standardized ß: 0.495) explained 92.8% of ORM variations. CONCLUSIONS: Elevated circulating orosomucoid was associated with elevated 30 min glucose and glucose excursion in non-obese young Japanese women independently of adiposity, IR, insulin secretion, adiponectin and other investigated markers of inflammation. Although further research is needed, these results may suggest a clue to identify novel pathways that may have utility in monitoring dysglycemia within normal glucose tolerance.

Appendicular muscle mass and fasting triglycerides predict serum liver aminotransferases in young female collegiate athletes.

OBJECTIVE: We test the hypothesis that aspartate aminotransferase (AST) may be associated inversely with serum triglycerides (TG) and positively with high density lipoprotein (HDL) cholesterol in young athletes because athletes have larger amounts of muscle mass. RESEARCH DESIGN AND METHODS: Pearson's correlation coefficients were calculated between serum AST and alanine aminotransferase (ALT) and body composition identified by dual-energy X-ray absorptiometry, markers of insulin resistance, serum lipids, lipoproteins, apolipoproteins, adiponectin and leptin in 174 female collegiate athletes (18-22 years). Multivariate linear regression analyses were used to identify independent determinants of the aminotransferases. RESULTS: AST and ALT showed positive correlation with appendicular skeletal muscle mass (ASM) and height-adjusted ASM. In addition, ALT as well as AST showed inverse, not positive, association with fasting TG. Further, both AST and ALT showed positive associations with HDL cholesterol and apolipoprotein AI, a major apolipoprotein of HDL particles. Multivariate analysis revealed that height-adjusted ASM and TG (inverse) were independent determinants for AST and ALT. Further, fat mass index (inverse) and resting heart rate (inverse) predicted AST and apolipoprotein AI predicted ALT. CONCLUSIONS: In young female collegiate athletes, both serum AST and ALT showed inverse association with fasting TG and positive association with apoAI, both of which may be mediated through positive association between the aminotransferases and ASM. The association between ALT and TG is opposite in direction in young athletes (inverse) and in the general population (positive).

The Cluster of Abnormalities Related to Metabolic Syndrome Is Associated With Reduced Glomerular Filtration Rate and Raised Albuminuria in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: As association of metabolic syndrome (MS) with chronic kidney disease (CKD) has not been extensively studied in patients with type 2 diabetes, we addressed these issues. METHODS: Intrapersonal means of 12 measurements of waist circumference, blood pressure and high-density lipoprotein (HDL) cholesterol and those of six measurements of fasting triglycerides during 12 months were calculated in a cohort of 168 previously reported Japanese patients with type 2 diabetes. Based on these means, MS was diagnosed according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of abdominal obesity. CKD was defined as the presence of low estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2), albuminuria (urinary albumin/creatinine ratio (ACR) ≥ 30 mg/g) or both. RESULTS: Of 168 patients, 77 patients (46 %) had MS and 67 (40 %) had CKD. As the number of MS components increased from 1 through 5, the prevalence of albuminuria (9%, 38%, 30%, 41%, and 50%, P < 0.001), low eGFR (0%, 10%, 24%, 22%, and 50%, P < 0.001) and consequently, CKD increased (9%, 41%, 48%, 52%, and 75%, P < 0.001). Urinary ACR increased and eGFR decreased as a function of the number of MS components. As compared to patients without MS, prevalence of low eGFR (26% vs. 7%, P = 0.001) and CKD (52% vs. 30%, P = 0.005) was higher in patients with MS but prevalence of albuminuria did not differ (36% vs. 27%, P = 0.2). CONCLUSION: In Japanese patients with type 2 diabetes, the cluster of abnormalities related to MS was associated not only with higher prevalence of albuminuria, reduced kidney function and hence the increase in CKD but also with corresponding changes in urinary ACR and eGFR.

Post-Prandial Plasma Glucose Less Than or Equal to 70 mg/dL Is Not Uncommon in Young Japanese Women.

BACKGROUND: Post-breakfast/post-challenge plasma glucose (PG) concentrations were studied less in young normal weight Japanese women. We addressed these issues. METHODS: Two separate groups of female collegiate athletes and female untrained students underwent either a standardized meal test or a standard 75-g oral glucose tolerance test, but not both. Frequency of women whose post-breakfast/post-load PG fell to 70 mg/dL or lower (termed as low glycemia) was compared between athletes and non-athletes, who also underwent measurements of serum adipokines, markers of insulin resistance and inflammation and dual-energy X-ray absorptiometry. Insulin secretion, insulin sensitivity/resistance and serum adipokines were compared between women with and without post-breakfast low glycemia. The same comparison was done between women whose post-breakfast PG returned to levels below the fasting PG and women whose post-breakfast PG never fell below the fasting PG. RESULTS: There was no difference between athletes and non-athletes in frequency of post-breakfast low glycemia (47% (8/17) and 44% (8/18)) and post-challenge low glycemia (24% (12/50) and 23% (27/118)). As compared to seven women whose post-breakfast PG never fell below the fasting PG, 28 women whose post-breakfast PG returned to levels below the fasting PG had higher meal-induced insulin responses (283 ± 366 vs. 89 ± 36 µU/mg, P = 0.014). However, two groups did not differ in body composition, markers of insulin resistance and serum adiponectin. No significant difference was also observed in any of these variables between women with and without post-breakfast low glycemia. CONCLUSION: Post-prandial PG ≤ 70 mg/dL is not uncommon in young normal weight Japanese women and may not be a pathological condition. The underlying mechanisms for this finding need further exploration.

Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability Is an Independent Determinant of Carotid Intima-Media Thickness in Patients With Type 2 Diabetes.

BACKGROUND: Studies demonstrated that visit-to-visit variability in low-density lipoprotein cholesterol (LDLC) is an independent predictor of cardiovascular events in subjects with coronary artery disease. Whether visit-to-visit variability in LDLC levels affects subclinical atherosclerosis is unknown. This study sought to evaluate the role of visit-to-visit variability in LDLC levels on subclinical atherosclerosis. METHODS: We evaluated 162 type 2 diabetic patients with measurement of carotid intima-media thickness (IMT). Intrapersonal mean and standard deviation (SD) of six measurements of LDLC during 12 months were calculated. Multivariate linear regressions assessed the independent correlates of carotid IMT. RESULTS: The mean and SD of LDLC were 112 ± 22 and 15 ± 10 mg/dL, respectively, and 43.2% of patients were on hypolipidemic drugs. Age (standardized ß = 0.355, P < 0.001), male sex (standardized ß = 0.234, P = 0.002) and SD-LDLC (standardized ß = 0.201, P = 0.009) emerged as independent determinants of carotid maximum IMT independently of mean LDLC levels, body mass index (BMI), waist circumference, duration and treatment of diabetes, means and SDs of glycemic and other lipid variables, and uses of hypolipidemic and anti-hypertensive medications (R2 = 0.15). Results did not change when mean IMT was used instead of maximum IMT. After controlling for age and sex, maximum IMT was thicker in patients with the highest compared to those with other three quartiles of SD-LDLC combined (1.14 ± 0.04 (SE) vs. 1.01 ± 0.02 mm, P = 0.01). Independent determinants of SD-LDLC were mean LDLC, use of hypolipidemic drugs, fasting triglyceride and visit-to-visit variability in HbA1c. CONCLUSIONS: Consistency of LDLC levels may be important to subclinical atherosclerosis in real-world patients with type 2 diabetes. It may be important for patients on lipid-lowering drugs to prevent non-compliance.

Association of Whole Blood Viscosity With Metabolic Syndrome in Type 2 Diabetic Patients: Independent Association With Post-Breakfast Triglyceridemia.

BACKGROUND: Associations of whole blood viscosity (WBV) with metabolic syndrome (MS) have not been extensively studied in patients with type 2 diabetes. METHODS: Intrapersonal means of 12 measurements of waist circumference, blood pressure (BP) and high-density lipoprotein cholesterol and those of six measurements of fasting and post-breakfast triglycerides (TG) during 12 months were calculated in a cohort of 168 patients with type 2 diabetes. Based on these means, MS was diagnosed according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of abdominal obesity. WBV was calculated from hematocrit and total serum protein concentrations by a validated formula. RESULTS: Diabetes patients with MS (n = 77) had higher WBV as compared to those without MS (6.38 ± 0.06 vs. 6.10 ± 0.07 cP, P = 0.004). As the number of MS components increased, WBV increased (component number 1: 6.12 ± 0.10, 2: 6.09 ± 0.10, 3: 6.37 ± 0.08, 4: 6.42 ± 0.10, 5: 6.30 ± 0.15 cP, P for trends = 0.001). Multiple regression analysis revealed that male gender, diastolic BP and post-breakfast TG were determinants of WBV independent of fasting TG, body mass index (BMI) and waist circumference (R2 = 0.258). CONCLUSIONS: Both the presence of MS and the number of MS components were associated with higher WBV in patients with type 2 diabetes. Physicians need to perform a close follow-up of type 2 diabetes patients with MS on inhibitors of sodium-glucose co-transporters 2, which may increase stroke risk associated with an increase in hematocrit and therefore blood viscosity. Post-breakfast TG was an independent determinant of WBV. Elevated WBV may represent an important confounder of the relationship between MS, postprandial hyperlipidemia and elevated cardiovascular risk in this population.

Increased Adipose and Muscle Insulin Sensitivity Without Changes in Serum Adiponectin in Young Female Collegiate Athletes.

BACKGROUND: Effects of endurance training on adipose insulin sensitivity in association with body composition, circulating adipokines, and markers of inflammation have been studied less in young Asian subjects. METHODS: Adipose insulin sensitivity/resistance was compared between 170 female Japanese collegiate athletes and 311 nonathletes (18-24 years), who underwent measurements of serum adipokines, markers of insulin sensitivity, inflammation, and dual-energy X-ray absorptiometry. Two separate subsamples of two groups of women underwent either a 75-gram oral glucose tolerance test or a standardized meal test, but not both. RESULTS: As compared with nonathletes, athletes, characterized by higher skeletal muscle mass and lower percentage of body fat (both P < 0.001), had lower adipose insulin resistance (IR) (a product of fasting insulin and nonesterified fatty acid (NEFA) and lower leptin/adiponectin ratio (both P < 0.001). Although athletes had lower postmeal/postglucose insulinemia (P = 0.009 and 0.01, respectively), the two groups did not differ in postmeal percentage NEFA suppression and postmeal/postglucose glycemia, suggesting increased insulin sensitivity in adipose tissue and skeletal muscle, respectively. Serum leptin (P < 0.001) and tumor necrosis factor-α (P = 0.01) were lower in athletes, whereas adiponectin and homeostasis model assessment IR did not differ. CONCLUSIONS: Endurance training was associated with increased insulin sensitivity in adipose tissue as well as skeletal muscle without changes in circulating adiponectin even in young, normal-weight Japanese women.

Novel effect of ezetimibe to inhibit the development of non-alcoholic fatty liver disease in Fatty Liver Shionogi mouse.

AIM: Several studies using experimental non-alcoholic fatty liver disease (NAFLD) models have shown that ezetimibe, an inhibitor of cholesterol absorption mainly in the intestine, not only protects against diet-induced hyperlipidemia, but also attenuates liver steatosis. The aim of this study was to clarify whether ezetimibe inhibits the development of NAFLD and to elaborate the mechanism of ezetimibe to inhibit the development of NAFLD using Fatty Liver Shionogi (FLS) mice, a spontaneous model of NAFLD/non-alcoholic steatohepatitis. METHODS: Male FLS mice at 20 weeks of age were divided into two groups (n = 7 in each group). Mice fed a normal laboratory chow, CRF-1 or CRF-1 containing 0.005% w/w ezetimibe (7 mg/kg per day) for 4 weeks. After 4-week treatment with ezetimibe, the livers of each group of mice were subjected to histological as well as molecular evaluation. RESULTS: Ezetimibe administration for 4 weeks was associated with improvement of steatosis and fibrosis of the liver in normal diet-fed FLS mice. Ezetimibe reduced hepatic reactive oxygen species generation and prevented ubiquitination and protein degradation of microsomal triglyceride transfer protein (MTP), a key molecule for very low-density lipoprotein assembly and export, via downregulation of the protein expression of Skp2 and CDC20. CONCLUSION: Ezetimibe not only reduced lipid synthesis in the liver, but also promoted lipid discharge from the liver by preventing post-translational degradation of MTP via a reduction of hepatic reactive oxygen species generation, leading to inhibition of the development of NAFLD.