Liver enzymes as a predictor for incident diabetes in a Japanese population: the Hisayama study

Objective: We studied the relationship between liver enzymes and the development of diabetes in a general Japanese population. Research Methods and Procedures: A total of 1804 non‐diabetic subjects 40 to 79 years of age were followed‐up prospectively for a mean of 9.0 years. Results: During the follow‐up, 135 subjects developed diabetes. In both sexes, the age‐adjusted cumulative incidence of diabetes increased significantly with elevating quartiles of serum γ‐glutamyltransferase (GGT) and alanine aminotransferase (ALT) levels. This pattern was also observed in aspartate aminotransferase (AST) quartiles for men but not for women. In multivariate analyses after adjusting for comprehensive risk factors and other liver enzymes, the risk of developing diabetes was significantly higher in the highest GGT quartile than in the lowest quartile [odds ratio (OR), 2.54; 95% confidence interval (CI), 1.03 to 6.26 for men; OR, 5.73; 95% CI, 1.62 to 20.19 for women]. Similar results were observed in ALT quartiles (OR, 2.32; 95% CI, 0.91 to 5.92 for men; OR, 4.40; 95% CI, 1.38 to 14.06 for women) but not in AST quartiles in either sex. Significant positive associations of GGT and ALT with diabetes were seen within each stratified category of risk factors, namely fasting insulin, BMI, waist‐to‐hip ratio, high‐sensitivity C‐reactive protein, and alcohol consumption. In receiver operating characteristic analyses, the areas under the receiver operating characteristic curve of GGT and ALT were significantly larger than that of AST, fasting insulin, waist‐to‐hip ratio, or C‐reactive protein. Discussion: Our findings suggest that serum GGT and ALT concentrations are strong predictors of diabetes in the general population, independent of known risk factors.     

Adiponectin Levels during Low‐ and High‐Fat Eucaloric Diets in Lean and Obese Women

Objective: Adiponectin influences insulin sensitivity (S_I) and fat oxidation. Little is known about changes in adiponectin with changes in the fat content of eucaloric diets. We hypothesized that dietary fat content may influence adiponectin according to an individual's S_I. Research Methods and Procedures: We measured changes in adiponectin, insulin, glucose, and leptin in response to high‐fat (HF) and low‐fat (LF) eucaloric diets in lean (n = 10) and obese (n = 11) subjects. Obese subjects were further subdivided in relation to a priori S_I. Results: We found significantly higher insulin, glucose, and leptin and lower adiponectin in obese vs. lean subjects during both HF and LF. The mean group values of these measurements, including adiponectin (lean, HF 21.9 ± 9.8; LF, 20.8 ± 6.6; obese, HF 10.0 ± 3.3; LF, 9.5 ± 2.3 ng/mL; mean ± SD), did not significantly change between HF and LF diets. However, within the obese group, the insulin‐sensitive subjects had significantly higher adiponectin during HF than did the insulin‐resistant subjects. Additionally, the change in adiponectin from LF to HF diet correlated positively with the obese subjects’ baseline S_I. Discussion: Although in lean and obese women, group mean values for adiponectin did not change significantly with a change in fat content of a eucaloric diet, a priori measured S_I in obese subjects predicted an increase in adiponectin during the HF diet; this may be a mechanism that preserves S_I in an already obese group.     

Brassica rapa Polysaccharides Ameliorate CCl4‐Induced Acute Liver Injury in Mice through Inhibiting Inflammatory Apoptotic Response and Oxidative Stress

Brassica rapa L., also called NIUMA, is used empirically in Tibetan medicine for its antioxidant, anti‐inflammatory and antiradiation activities. This study explored the hepatoprotective effects of B. rapa polysaccharides (BRPs) on acute liver injury induced by carbon tetrachloride (CCl₄) in mice and the underlying mechanisms. Mice were treated with CCl₄ after the oral administration of BRPs (55, 110 and 220 mg/kg) or bifendate (100 mg/kg) for 7 days. Blood and liver samples of mice were collected for analysis after 24 h. The ALP, ALT and AST levels and the biological activities of SOD, MDA and GSH?Px were measured. Histopathological changes in the liver were determined through hematoxylin and eosin staining. Moreover, TNF‐α, IL‐1β and IL‐6 expression levels were detected by commercial reagent kits. Finally, Western blot analysis was used to check the relative expression levels of caspase‐3, p‐JAK2 and p‐STAT3. The BRP pre‐treatment significantly decreased the enzymatic activities of ALT, ALP and AST in the serum, markedly increased the activities of SOD and GSH?Px in the liver and reduced the MDA concentration in the liver. BRPs alleviated hepatocyte injury and markedly inhibited the expression of TNF‐α, IL‐1β and IL‐6, also downregulating the CCl₄‐induced hepatic tissue expression of caspase‐3. Furthermore, BRPs inhibited the JAK2/STAT3 signaling pathway in a dose‐dependent manner in the liver. This study demonstrated that BRPs exert hepatoprotective effect against the CCl₄‐induced liver injury via modulating the apoptotic and inflammatory responses and downregulating the JAK2/STAT3 signaling pathway. Therefore, B. rapa could be considered a hepatoprotective medicine.     

Association of ADIPOR2 with liver function tests in type 2 diabetic subjects

Objective: Adiponectin protects against liver dysfunction in insulin‐resistant states such as obesity and type 2 diabetes (T2DM), but the role of adiponectin receptors in this disorder is largely unknown. We studied whether common single‐nucleotide polymorphisms (SNPs) in ADIPOR1 and ADIPOR2 are associated with liver function tests (LFTs) in human subjects with various degrees of insulin resistance. Methods and Procedures: Serum alanine (ALT) and aspartate (AST) aminotransferases, homeostasis model assessment of insulin resistance (HOMA‐IR), ?8503 G/A (rs6666089) and +5843 C/T (rs1342387) SNPs in ADIPOR1, ?64,241 T/G (rs1029629) and +33447 C/T (rs1044471) SNPs in ADIPOR2 were assessed in 700 white subjects from a population‐based study. Results: In nondiabetic subjects, the at‐risk alleles for the common ?64,241 T/G and +33447 C/T SNPs in ADIPOR2 were associated with increased circulating adiponectin (P < 0.05 to P < 0.005), but not with LFT. Conversely, in T2DM subjects (who are at risk for liver dysfunction), the same alleles were associated with increased serum ALT and AST (P < 0.05 to P < 0.0001), but not with circulating adiponectin. No significant associations with these parameters were evident for the common ?8503 G/A and +5843 C/T SNPs in ADIPOR1. In a replication study, the ?64,241 T/G and +33447 C/T SNPs in ADIPOR2 were associated with ALT and AST (P < 0.05 to P < 0.0001) in pooled obese and T2DM subjects. Discussion: Common SNPs in ADIPOR2 are associated with LFT in T2DM subjects, which suggests a possible role of this receptor in liver dysfunction associated with insulin resistance.     

Relation of epicardial fat and alanine aminotransferase in subjects with increased visceral fat

Background: Increased visceral adipose tissue (VAT) is a risk factor for an unfavorable cardio‐metabolic profile and fatty liver. Individuals with human immunodeficiency virus (HIV) on highly active antiretroviral therapy (HAART) can be associated with metabolic syndrome (MS) and higher visceral fat. However, the potential link between cardiac adiposity, emerging index of visceral adiposity, and fatty liver is still unexplored. Objective: To evaluate whether echocardiographic epicardial adipose tissue, index of cardiac adiposity, could be related to serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, surrogate markers of fatty liver, in HIV‐infected patients with (HIV+MS+) and without HAART‐associated MS (HIV+MS‐). Methods and Procedures: This was a cross‐sectional observational study on 57 HIV+MS+ patients, 52 HIV+MS? and 57 HIV‐negative subjects with MS (HIV?MS+), as control group. Epicardial fat thickness and intra‐abdominal VAT were obtained by echocardiography and magnetic resonance imaging (MRI), respectively. Serum ALT and AST activity, plasma adiponectin levels, and MS biochemical parameters were measured. Results: Echocardiographic epicardial fat thickness was correlated with MRI‐VAT (r = 0.83, P < 0.01), AST/ALT ratio (r = 0.77, P < 0.01), ALT (r = 0.58, P < 0.01), AST (r = 0.56, P < 0.01), and adiponectin (r = ?0.45, P < 0.01) in HIV+MS+. MRI‐VAT and AST/ALT ratio were the best correlates of epicardial fat thickness (r ² = 0.45, P < 0.01). Discussion: This study shows for the first time a clear relationship of epicardial fat, index of cardiac and visceral adiposity, and serum ALT and AST activity, markers of fatty liver, in subjects with increased visceral adiposity and cardio‐metabolic risk. This correlation seems to be independent of overall adiposity and rather function of excess visceral adiposity.     

Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function

Objective: Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures. Methods and Procedures: Forty‐six white and black overweight men and women (BMI = 24.7–31.3 kg/m²) were randomized to “control (CO)” = 100% energy requirements; “CR” = 25%; “caloric restriction and increased structured exercise (CR+EX)”= 12.5% CR + 12.5% increase in energy expenditure through exercise; or “low‐calorie diet (LCD)” = 15% weight loss by liquid diet followed by weight‐maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole‐body inflammation (tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), high‐sensitivity C‐reactive protein (hsCRP)) were measured in fasting blood. Results: At baseline, increased liver lipid content (by MRS) correlated (P < 0.05) with elevated fasting triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high‐density lipoprotein (HDL)‐cholesterol, or markers of whole‐body inflammation. Discussion: CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD.     

Adiposity and β‐Cell Function: Relationships Differ With Ethnicity and Age

The prevalence of type 2 diabetes is higher among African Americans (AA) vs. European Americans (EA), is highest at middle age, and is related to obesity. This study was conducted to test the hypothesis that the association of adiposity (percent body fat (%fat)) with indexes of insulin sensitivity (S_I) and β‐cell function would differ with ethnicity and age. Subjects were 168 healthy, normoglycemic AA and EA girls and women aged 7–12 years, 18–32 years, and 40–70 years. An intravenous glucose tolerance test (IVGTT) was used to assess indexes of insulin secretion and action: S_I, acute C‐peptide secretion (X0); basal, first‐phase, second‐phase, and total β‐cell responsivity to glucose (PhiB, Phi1, Phi2, and Phi_TOT, respectively); and the disposition index (DI = S_I × Phi_TOT). %Fat was assessed with dual energy X‐ray absorptiometrys. Adiposity was significantly associated with S_I among EA (?0.57, P < 0.001) but not AA (?0.20, P = 0.09). Adiposity appeared stimulatory to β‐cell function in the two groups of younger subjects and in EA, but inhibitory in postmenopausal women, particularly AA postmenopausal women. Among AA postmenopausal women, %fat was inversely associated with Phi1 (r = ?0.57, P < 0.05) and Phi_TOT (r = ?0.68, P < 0.01). These results suggest that the impact of adiposity on insulin secretion and action differs with age and ethnicity.     

Effects of β‐carotene on antioxidant status in rats with chronic alcohol consumption

This study examined the effects of β‐carotene on antioxidant status in rats with chronic alcohol consumption. At the beginning of experiment (week 0), according to both the plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, rats (n = 24) were divided into 3 groups and fed with a standard diet (group C), a diet containing ethanol (group E), or a diet containing ethanol and β‐carotene (group E+B). After 10 weeks, plasma AST and ALT, fat accumulation in the liver, antioxidant enzyme activities in erythrocytes and the liver, malondialdehyde (MDA), and α‐tocopherol and retinol in plasma and hepatic samples were analyzed. The chronic alcohol diet significantly increased AST and ALT levels in plasma, and these changes were prevented by supplementing the diet with β‐carotene. Glutathione (GSH) in erythrocytes and in the liver was significantly elevated in rats fed with a diet containing β‐carotene. The results indicate that β‐carotene supplementation can prevent ethanol‐induced liver damage and increase GSH concentrations in erythrocytes and the liver. Copyright © 2009 John Wiley & Sons, Ltd.     

Both Subcutaneous and Visceral Adipose Tissue Correlate Highly with Insulin Resistance in African Americans

Objective: The contribution of visceral adipose tissue (VAT) to insulin resistance is well‐established; however, the role of subcutaneous abdominal adipose tissue (SAT) in insulin resistance remains controversial. Sex may determine which of these two components of abdominal obesity is more strongly related to insulin resistance and its consequences. The aim of this study was to determine whether both VAT and SAT contribute to insulin resistance in African Americans and to examine the effects of sex on this relationship. Research Methods and Procedures: This was a cross‐sectional study of 78 nondiabetic African‐American volunteers (44 men, 35 women; age 33.8 ± 7.3 years; BMI 30.9 ± 7.4 kg/m²). VAT and SAT volumes were measured using serial computerized tomography slices from the dome of the diaphragm to the iliac crest. The insulin sensitivity index (S_I) was determined from the minimal model using data obtained from the frequently sampled intravenous glucose tolerance test. Results: In men, both VAT and SAT were negatively correlated with S_I (r for both correlations = ?0.57; p < 0.01). In women, the correlation coefficient between VAT and S_I was ?0.50 (p < 0.01) and between SAT and S_I was ?0.67 (p < 0.01). In women, the correlation coefficient for S_I with SAT was significantly greater than the correlation coefficient with VAT (p = 0.02). Discussion: Both SAT and VAT are strongly correlated with insulin resistance in African Americans. For African‐American women, SAT may have a greater effect than VAT on insulin resistance.     

Bright Liver and Alanine Aminotransferase Are Associated with Metabolic Syndrome in Adults

Objectives: The metabolic syndrome has become a significant health problem worldwide. In this study, we investigated the relationship between the metabolic syndrome, bright liver (BL) by ultrasonography (US), and plasma alanine aminotransferase (ALT) levels among apparently healthy adults. Research Methods and Procedures: A total of 15, 430 nonalcoholic healthy adults without hepatitis B or C were recruited from four nationwide MJ Health Screening Centers in Taiwan in 2000. Metabolic syndrome was defined using the National Cholesterol Education Panel (NCEP) metabolic syndrome criteria or modified NCEP criteria. Based on liver US, subjects were classified into either having BL or not. The relationship between the metabolic syndrome, BL, and ALT levels was examined using multivariate logistic regression analysis. Results: The crude OR of the metabolic syndrome was 13.92 (12.19 using modified NCEP criteria), and the age‐BMI‐sex—adjusted OR was 3.77 (3.71 using modified NCEP criteria) in subjects with BL vs. subjects without BL, respectively. The ORs of the metabolic syndrome were significantly higher in subjects with elevated ALT levels than in those with normal ALT levels. After adjustment for age, sex, and BMI, BL and elevated ALT level were independently associated with increased risk of the metabolic syndrome. Discussion: Presence of BL and elevated plasma ALT level was independently associated with increased risk of the metabolic syndrome in adults. These factors contribute to a list of well‐known risk factors, including obesity, aging, and male sex, and thus can be applied as an additional evaluation for the metabolic syndrome in a clinical setting.     

Adipose tissue interleukin-18 mRNA and plasma interleukin-18: effect of obesity and exercise

Objectives: Obesity and a physically inactive lifestyle are associated with increased risk of developing insulin resistance. The hypothesis that obesity is associated with increased adipose tissue (AT) interleukin (IL)‐18 mRNA expression and that AT IL‐18 mRNA expression is related to insulin resistance was tested. Furthermore, we speculated that acute exercise and exercise training would regulate AT IL‐18 mRNA expression. Research Methods and Procedures: Non‐obese subjects with BMI < 30 kg/m² (women: n = 18; men; n = 11) and obese subjects with BMI >30 kg/m² (women: n = 6; men: n = 7) participated in the study. Blood samples and abdominal subcutaneous AT biopsies were obtained at rest, immediately after an acute exercise bout, and at 2 hours or 10 hours of recovery. After 8 weeks of exercise training of the obese group, sampling was repeated 48 hours after the last training session. Results: AT IL‐18 mRNA content and plasma IL‐18 concentration were higher (p < 0.05) in the obese group than in the non‐obese group. AT IL‐18 mRNA content and plasma IL‐18 concentration was positively correlated (p < 0.05) with insulin resistance. While acute exercise did not affect IL‐18 mRNA expression at the studied time‐points, exercise training reduced AT IL‐18 mRNA content by 20% in both sexes. Discussion: Because obesity and insulin resistance were associated with elevated AT IL‐18 mRNA and plasma IL‐18 levels, the training‐induced lowering of AT IL‐18 mRNA content may contribute to the beneficial effects of regular physical activity with improved insulin sensitivity.     

Relationships between Insulin Sensitivity and Measures of Body Fat in Asymptomatic Men and Women

Objective: To assess whether measures of body fat by DXA scanning can improve prediction of insulin sensitivity (S_I) beyond what is possible with traditional measures, such as BMI, waist circumference, and waist‐to‐hip ratio (WHR). Research Methods and Procedures: Frequently sampled intravenous glucose tolerance tests were performed in 256 asymptomatic non‐Hispanic white subjects from Rochester, MN (age 19‐60 years; 123 men and 133 women) to determine the S_I index by Bergman's minimal model technique. Height, weight, and waist and hip circumferences were measured for calculation of BMI and WHR; DXA was used to determine fat in the head, upper body, abdomen, and lower body. Linear regression was used to assess their relationships with S_I after sex stratification and adjustment for age. Results: After controlling for age, increases in traditional and DXA measures of fat were consistently associated with smaller declines in S_I among women than among men. In men, after controlling for age, all of the predictive information of S_I was provided by waist circumference (additional R² = 0.39, p < 0.001); none of the DXA measures improved the ability to predict S_I. In women, after adjustment for age, BMI, and WHR, the only DXA measure that improved the prediction of S_I was percentage head fat (additional R² = 0.03, p < 0.001). Discussion: Equivalent increases in most measures of body fat had lesser impact on S_I in women than in men. In both sexes, the predictive information provided by DXA measures is approximately equal to, but not additive to, that provided by simpler, traditional measures.     

ERCP术与腹腔镜手术治疗胆总管结石的疗效对比及对血清AST、ALT、ALP的影响

目的:探讨内镜逆行胰胆管造影术(ERCP)与腹腔镜手术治疗胆总管结石的疗效对比及对血清门冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、碱性磷酸酶(ALP)的影响。方法:选择2017年4月到2018年4月我院接诊的胆总管结石患者50例作为研究对象,以随机数表法分为观察组(n=26)和对照组(n=24),对照组使用腹腔镜手术治疗,观察组采用ERCP取石术治疗。比较两组手术时间、术中出血量、术后下床时间、住院时间、血清AST、ALT、ALP水平变化情况、术后胃肠道恢复时间及术后不良反应发生情况。结果:观察组患者手术时间高于对照组,(P0.05),术中出血量、术后下床时间及住院时间均显著低于对照组(P0.05);手术前,两组患者血清AST、ALT、ALP水平无明显差异;治疗后,两组患者血清AST、ALT、ALP水平均明显上升(P0.05),且观察组患者血清AST、ALT、ALP水平显著低于对照组(P0.05);观察组患者肠鸣音恢复时间、排气时间、排便时间均明显低于对照组(P0.05);治疗期间,观察组患者不良反应总发生率为7.69%,显著低于对照组的29.17%(P0.05)。结论:在胆总管结石患者中应用ERCP取石术效果显著,对患者血清血清AST、ALT、ALP影响较小,值得推广与运用。     

Effects of vitamin B6 supplementation in rats during lactation on vitamin B6 concentration and transaminase activities in the offspring

The aim of the present investigation was to study the effect of a varying maternal vitamin B₆ supplementation during lactation period on vitamin B₆ levels in blood, liver and total body, and on the activity of two transaminase enzymes in the offspring. Therefore, eighty female Sprague‐Dawley rats were fed a semi‐synthetic diet (0.2 mg vitamin B₆ per kg) which was supplemented during gravidity with 5 mg vitamin B₆ per kg diet. During the following lactation period the rats were assigned to one of 10 vitamin B₆ treatment groups (supplementation of 0, 3, 6, 9, 12, 15, 18, 36, 360, 3600 mg vitamin B₆ per kg diet). At day 14 of lactation the pubs of all dams were decapitated and blood, liver, and carcass were used for analysis of vitamin B₆ concentration, activities of two transaminases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in plasma, erythrocytes, and liver, and of haematological parameters.

While the liver and total body wet weights as well as the haematological parameters (red blood cells, haemoglobin concentration, hematocrit, middle corpuscular cell volume, middle corpuscular haemoglobin, middle corpuscular haemoglobin concentration) did not differ within the experimental groups, the present data clearly show that in blood, liver and total body of the offspring exists a slight dose‐response relationship between the maternal dietary vitamin B₆ supplementation and the vitamin B₆ concentration. Concerning the activities of the transaminases a dietary supplementation above 3mg vitamin B₆ per kg diet had no influence on the AST and ALT activities in offspring plasma. In the erythrocytes no statistical significant influence of the vitamin B₆ supplementation during lactation on the activities of AST and ALT was found. The activities of ALT and AST in liver were not consistently altered by the vitamin B₆ supplementation of the dams during lactation. In conclusion these results indicate that a minimal maternal dietary vitamin B₆ supply of 3.1 mg per kg diet is necessary with regard to health and development of their offspring. But not all of the analysed parameters as the liver and total body weights, the activities of AST and ALT in the erythrocytes, and the haematological parameters were influenced by a deficient maternal dietary vitamin B₆ supply.     

Racial Differences in Insulin Secretion and Sensitivity in Prepubertal Children: Role of Physical Fitness and Physical Activity

Objective: To investigate in prepubertal children whether physical fitness and/or physical activity are: 1) associated with insulin secretion and sensitivity and 2) account for racial differences in insulin secretion and sensitivity. Research Methods and Procedures: Subjects included 34 African American and 34 white nondiabetic children aged 5 to 11 years. Data were divided into two sets according to the availability of VO_2max and physical activity data. Body composition was measured by dual‐energy X‐ray absorptiometry. Subcutaneous abdominal adipose tissue and intra‐abdominal adipose tissue were examined by computed tomography. Insulin sensitivity (S_I) and acute insulin response (AIR) were determined by a frequently sampled intravenous glucose tolerance test. An all‐out, progressive treadmill exercise test was used for measuring VO_2max. Physical activity data were collected by questionnaire. Results: African American children had lower S_I and higher AIR than white children, after adjusting for total body fat mass. African Americans reported higher levels of physical activity (hours/wk) than whites, but had a lower VO_2max. In multiple linear regression analysis, hours/wk of activity and hours/wk of vigorous activity, but not moderate activity, were independently related to S_I and AIR after adjusting for race, total body fat mass or fat distribution, and total lean tissue mass. VO_2max was not related to AIR, and was inversely related to S_I, after adjusting for body composition. Race remained significantly associated with both S_I and AIR, even after adjusting for body composition, fat distribution, and hours/wk of activity or hours/wk of vigorous activity. Discussion: In summary, overall physical activity and, especially, vigorous activity were associated with insulin secretion and sensitivity. However, neither physical activity nor VO_2max explained the racial difference in insulin secretion (higher in African Americans) and sensitivity (lower in African Americans). Thus, racial (African American to white) differences in aspects of insulin action seem to be due to factors other than body composition, fat distribution, cardiovascular fitness, and amount of physical activity.     

Acute insulin secretion as a predictor of weight gain in healthy humans

Objective: We sought to determine the role of the acute insulin secretory response to glucose (AIRg) in predicting weight gain in normoglycemic persons with no family history of diabetes, who are at low risk for development of disease. Research Methods and Procedures: One hundred five individuals (64 men and 41 women) who underwent measures of weight and AIRg and insulin sensitivity index (S_I) by intravenous glucose tolerance test between 1963 and 1983 were surveyed again for weight between 1994 and 1999, with a mean follow‐up of 26 ± 4 years. Results: Mean change in weight was 8 ± 10 kg. Annualized weight change was calculated as change in kilograms divided by change in year and averaged 0.27 ± 0.04 kg/yr. Dividing the cohort by either median AIRg or median S_I demonstrated no association of either AIRg or S_I with total or annualized weight gain. Subgroup analysis by ideal body weight or gender did not alter the association. Furthermore, no association between AIRg and weight gain rate was seen within insulin‐sensitive or ‐resistant subgroups, although younger age at entry was associated with greater rates of weight gain. Discussion: Our data suggest that neither AIRg nor S_I plays a role in predicting weight gain in normoglycemic individuals with no family history of diabetes.     

Smad3 gene C‐terminal phosphorylation site mutation aggravates CCl4‐induced inflammation in mice

The expression of C‐terminal phosphorylated Smad3 (pSmad3C) is down‐regulated with the progression of liver disease. Thus, we hypothesized that pSmad3C expression may be negatively related to liver disease. To develop novel therapeutic strategies, a suitable animal model is required that will allow researchers to study the effect of Smad3 domain‐specific phosphorylation on liver disease progression. The current study aimed to construct a new mouse model with the Smad3 C‐terminal phosphorylation site mutation and to explore the effects of this mutation on CCl₄‐induced inflammation. Smad3 C‐terminal phosphorylation site mutant mice were generated using TetraOne? gene fixed‐point knock‐in technology and embryonic stem cell microinjection. Resulting mice were identified by genotyping, and the effects on inflammation were explored in the presence or absence of CCl₄. No homozygous mice were born, indicating that the mutation is embryonic lethal. There was no significant difference in liver phenotype and growth between the wild‐type (WT) and heterozygous (HT) mice in the absence of reagent stimulation. After CCl₄‐induced acute and chronic liver damage, liver pathology, serum transaminase (ALT/AST) expression and levels of inflammatory factors (IL‐6/TNF‐α) were more severely altered in HT mice than in WT mice. Furthermore, pSmad3C protein levels were lower in liver tissue from HT mice. These results suggest that Smad3 C‐terminal phosphorylation may have a protective effect during the early stages of liver injury. In summary, we have generated a new animal model that will be a novel tool for future research on the effects of Smad3 domain‐specific phosphorylation on liver disease progression.     

Associations of Free Fatty Acids With Insulin Secretion and Action Among African‐American and European‐American Girls and Women

Ethnic differences in insulin secretion and action between African Americans (AAs) and European Americans (EAs) may influence mobilization of free fatty acids (FFAs). We tested the hypotheses that FFA concentrations would be associated with measures of insulin secretion and action before and during a glucose challenge test. Subjects were 48 prepubertal girls, 60 premenopausal women, and 46 postmenopausal women. Fasting insulin (insulin₀), the acute insulin response to glucose (AIR_g), the insulin sensitivity index (S_I), basal and nadir FFA (FFA₀, FFA_nadir), and nadir time (TIME_nadir) were determined during an intravenous glucose tolerance test (IVGTT). Stepwise multiple linear regression (MLR) analysis was conducted to identify associations of FFA₀, FFA_nadir, and TIME_nadir with ethnicity, age group, insulin measures, indexes of body composition from dual‐energy X‐ray absorptiometry, and measures of fat distribution from computed tomography scan. In this population, insulin₀ and AIR_g were higher among AAs vs. EAs, whereas S_I was lower, independent of age group. MLR analyses indicated that FFA₀ was best predicted by lean tissue mass (LTM), leg fat mass, ethnicity (lower in AAs), S_I, and insulin₀. FFA_nadir was best predicted by FFA₀, age group, and intra‐abdominal adipose tissue (IAAT). TIME_nadir was best predicted by leg fat mass, AIR_g, and S_I. In conclusion, indexes of insulin secretion and action were associated with FFA dynamics in healthy girls and women. Lower FFA₀ among AAs was independent of insulin₀ and S_I. Whether lower FFA₀ is associated with substrate oxidation or risk for obesity remains to be determined.     

Variant in the 3′ Region of the IκBα Gene Associated With Insulin Resistance in Hispanic Americans: The IRAS Family Study

The IKKβ/NF‐κB pathway is known to play an important role in inflammatory response and has also recently been implicated in the process of insulin resistance. We hypothesized that one or more variants in the IκBα gene (NFKBIA) or surrounding untranslated regions would be associated with insulin sensitivity (S_I) in Hispanic‐American families. We tested for association between 25 single‐nucleotide polymorphisms (SNPs) in and near NFKBIA and S_I in 981 individuals in 90 Hispanic‐American families from the Insulin Resistance Atherosclerosis (IRAS) Family Study. SNP rs1951276 in the 3′ flanking region of NFKBIA was associated with S_I in the San Antonio (SA) sample after adjusting for age, gender, and admixture (uncorrected P = 1.69 × 10^?5; conservative Bonferroni correction P = 3.38 × 10^?4). Subjects with at least one A allele for NFKBIA rs1951276 had ～29% lower S_I compared to individuals homozygous for the G allele in the SA sample. Although not statistically significant, the effect was in the same direction in the San Luis Valley (SLV) sample alone (P = 0.348) and was significant in the combined SA and SLV samples (P = 5.37 × 10^?4; presence of A allele associated with ～20% lower S_I). In SA, when adjusted for subcutaneous adipose tissue area (SAT, cm²), the association was modestly attenuated (P = 1.25 × 10^?3), but the association remained highly significant after adjustment for visceral adipose tissue area (VAT, cm²; P = 4.41 × 10^?6). These results provide corroborating evidence that the NF‐κB/IKKβ pathway may mediate obesity‐induced insulin resistance in humans.     

Greater Omentectomy Improves Insulin Sensitivity in Nonobese Dogs

Visceral adiposity is strongly associated with insulin resistance; however, little evidence directly demonstrates that visceral fat per se impairs insulin action. Here, we examine the effects of the surgical removal of the greater omentum and its occupying visceral fat, an omentectomy (OM), on insulin sensitivity (S_I) and β‐cell function in nonobese dogs. Thirteen male mongrel dogs were used in this research study; animals were randomly assigned to surgical treatment with either OM (n = 7), or sham‐surgery (SHAM) (n = 6). OM failed to generate measurable changes in body weight (+2%; P = 0.1), or subcutaneous adiposity (+3%; P = 0.83) as assessed by magnetic resonance imaging (MRI). The removal of the greater omentum did not significantly reduce total visceral adipose volume (?7.3 ± 6.4%; P = 0.29); although primary analysis showed a trend for OM to increase S_I when compared to sham operated animals (P = 0.078), further statistical analysis revealed that this minor reduction in visceral fat alleviated insulin resistance by augmenting S_I of the periphery (+67.7 ± 35.2%; P = 0.03), as determined by the euglycemic‐hyperinsulinemic clamp. Insulin secretory response during the hyperglycemic step clamp was not directly influenced by omental fat removal (presurgery 6.82 ± 1.4 vs. postsurgery: 6.7 ± 1.2 pmol/l/mg/dl, P = 0.9). These findings provide new evidence for the deleterious role of visceral fat in insulin resistance, and suggest that a greater OM procedure may effectively improve insulin sensitivity.