Background and aims: To prospectively investigate associations of plasma sphingolipids with insulin sensitivity, 8 -cell function, and incident diabetes in the Japanese American Community Diabetes Study. Methods and results: Baseline plasma samples from adults without diabetes (n = 349; mean age 56.7 years, 51 % men) were assayed for circulating ceramide and sphingomyelin species. Adjusted regression models examined cross-sectional and longitudinal associations with insulin sensitivity (HOMA2-%S), 8 -cell function (oral disposition index: DIo) and with incident diabetes over 5 years follow-up. Concentrations of four species (Ceramide C16:0, C18:0, C20:0, and C22:0) were inversely associated with HOMA2-%S at baseline (all P values < 0.05, Q values < 0.05) and change in HOMA2-%S over 5 years (all P values < 0.05, Q values < 0.05). No sphingolipids were associated with baseline or change in DIo. Of the four species associated with HOMA2-%S, only Ceramide C18:0 was significantly and positively associated with incident diabetes (RR/1SD 1.44, 95 % CI 1.10-1.80, P = 0.006, Q = 0.024). The association of plasma Ceramide C18:0 with the risk of diabetes was partially mediated by change in HOMA2-%S between baseline and 5 years (mediation proportion: 61.5 %, 95 % CI 21.1%-212.5 %). Conclusion: Plasma Ceramide C18:0 was associated with higher risk of incident diabetes which was partially mediated through a decrease in insulin sensitivity between baseline and five years. Circulating Ceramide C18:0 could be a potential biomarker for identifying those at risk of developing diabetes. (c) 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Aims: Visceral fat predicts the development of metabolic syndrome (MetS), but it is not known whether the visceral to subcutaneous fat area ratio (VSR) measured using imaging predicts MetS risk as well or better. Thus, we aimed to examine if VSR predicted future risk of MetS over 10-years. Methods: We followed 329 participants in the longitudinal Japanese American Community Diabetes Study without MetS at baseline for its development over 10 years. Intra-abdominal (VFA) and subcutaneous abdominal (SFA) fat areas were measured at baseline and 10-years and used to calculate VSR. Logistic regression was used to estimate the odds of incident MetS by baseline and 10-year change in VSR and other adipose depots with and without adjustment for baseline MetS features. Areas under ROC curves were calculated in predicting the development of MetS. Results: 99 participants developed MetS over 10-years. Logistic regression models showed a higher odds of incident MetS with greater VSR and 10-year VSR change (OR = 1.67, 95 % CI 1.11-2.51; OR = 1.46, 95 % CI 1.06-2.01, respectively) adjusting for age, sex, and MetS features at baseline. However, VSR alone performed poorly at discriminating (AUROC 0.5807) compared to VFA (AUROC 0.6970, p < 0.001) or a logistic model incorporating VFA and SFA (AUROC 0.7221, p = 0.001). Conclusions: VSR and VFA predict 10-year MetS risk in Japanese Americans, confirming the importance of relatively greater fat distribution in the visceral depot in the development of MetS. However, VSR is a weaker predictor of MetS development and provides less information compared to VFA alone, and its further use in predicting metabolic abnormalities is not recommended.

Background Both intra-abdominal fat (IAF) and high-density lipoprotein cholesterol (HDL-C) are known to be associated with cardiometabolic health. We evaluated whether the accumulation of computed tomography (CT)-measured IAF over 5 years was related to baseline HDL-C concentration in a prospective cohort study. Methods All participants were Japanese-Americans between the ages of 34 and 74 years. Plasma HDL-C concentration and CT measurements of IAF, abdominal subcutaneous fat (SCF), and thigh SCF cross-sectional areas were assessed at baseline and at 5-year follow-up visits. Results A total of 397 subjects without diabetes were included. The mean±standard deviation HDL-C concentration was 51.6±13.0 mg/dL in men and 66.0±17.0 mg/dL in women, and the IAF was 91.9±48.4 cm2 in men and 63.1±39.5 cm2 in women. The baseline plasma concentration of HDL-C was inversely associated with the change in IAF over 5 years using multivariable regression analysis with adjustment for age, sex, family history of diabetes, weight change over 5 years, and baseline measurements of body mass index, IAF, abdominal SCF, abdominal circumference, thigh SCF, and homeostatic model assessment for insulin resistance. Conclusion These results demonstrate that HDL-C concentration significantly predicts future accumulation of IAF over 5 years independent of age, sex, insulin sensitivity, and body composition in Japanese-American men and women without diabetes.

Background/Aim: Greater visceral fat area (VFA) is associated with multiple metabolic conditions. We sought to determine whether plasma amino acid concentrations (AA) predict VFA.Methods: In plasma samples from Japanese American participants in a study of diabetes risk factors, we used mass spectrometry to measure fasting levels of 20 AA in 351 individuals who were free from diabetes (mean age 56 y, 51% male). We measured height, weight, waist circumference (WC), and VFA and subcutaneous fat area (SFA). Using AA that were significantly associated with VFA in univariate analyses, we fitted a multivariable linear regression model to create a VFA prediction index. We calculated area under receiver-operating characteristic curves (AUROC) for ability of AA to discriminate between low vs. high VFA dichotomized at median values (men - 99.3 cm2, women - 65.6 cm2) and compared our AA estimates to WC AUROC.Results: All AA significantly discriminated between high and low VFA as all AUROC significantly exceeded the null value of 0.5 (Table 1). However, WC AUROC was significantly greater than all AA. Our new AA-based VFA prediction index performed better at distinguishing between high and low VFA than a previously reported index (Yamakado M et al., Clin Obesity, 2012, AUROC 0.780 vs. 0.676, p-value <0.005).View largeDownload slideView largeDownload slide Conclusions: Plasma AAs predict VFA in Japanese Americans and may be considered for this purpose when WC is not available.DisclosureA. Tran: None. P. Wander: None. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. S. E. Kahn: Advisory Panel; Self; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Pfizer Inc. W. Y. Fujimoto: None. E. J. Boyko: None.

Objectives: The adipokines leptin and adiponectin are associated with change in body composition and are highly correlated, raising questions about whether they exert independent effects. We investigated whether these two adipokines are independently associated with regional body fat accumulation in a prospective study of Japanese Americans. Methods: Nondiabetic participants between the ages of 34 to 74 years were followed for 5 years to assess change in body composition. Leptin and adiponectin concentrations and single slice CT-measurements of intra-abdominal fat (IAF), abdominal (SCF) and thigh (TF) subcutaneous fat cross-sectional areas were evaluated at baseline and 5 year follow-up study visits. Multiple linear regression analysis was used to estimate the association between leptin and adiponectin and future 5-year accumulation of IAF. Results: 96 men and 95 women without diabetes included in this analysis had the following baseline mean (SD) values: age 45.7 (3.5) years and 46.4 (3.9) years; BMI 25.5 (3.1) kg/m2 and 24.0 (3.9) kg/m2; IAF 78.7 (38.6) cm2 and 62.1 (39.0) cm2; leptin concentration 4.5 (2.3) μg/L and 10.2 (5.2) μg/L; and adiponectin concentration 7.4 (3.2) μg/mL and 10.8 (4.7) μg/mL, respectively. Baseline leptin (β = 1.7722, p=0.014) and adiponectin concentrations (β = -0.4162, p<0.001) were significantly associated with ΔIAF over 5 years in multivariable models adjusting for age, sex, diabetes family history, weight change over 5 years, and baseline measurements of BMI, IAF, abdominal SCF, abdominal circumference, TF, and HOMA-IR. Conclusions: In nondiabetic Japanese Americans, baseline concentrations of leptin and adiponectin were independent predictors of IAF accumulation at 5 years. Higher levels of leptin and adiponectin were associated with greater and lesser accumulation of IAF, respectively. These relationships were independent of age, sex, insulin sensitivity, and body composition. Disclosure S. Song: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. D.L. Leonetti: None. W.Y. Fujimoto: None. E.J. Boyko: None. Funding National Institutes of Health DK31170, HL49293); University of Washington (DK017047, DK035816, RR-000037); VA Puget Sound Health Care System (to E.J.B., S.E.K.)

Background: Greater visceral fat area (VFA) is associated with cardiometabolic outcomes. We sought to identify cross-sectional and longitudinal associations between amino acid (AA) levels and VFA in Japanese-Americans. Methods: From the cohort of 342 Japanese-American participants (51% men) in a study of diabetes risk factors who were free from diabetes, we measured levels of 20 AA by mass spectrometry, height, weight, waist circumference (WC), VFA, subcutaneous fat area by single-slice CT at the umbilicus. Using AA significantly associated with VFA in univariate analyses, we created a VFA prediction index, termed the 4A index. We compared area under receiver-operating characteristic curve (AUROC) of the 4A index to WC and an existing AA index (Yamakado et al. Clin Obes 2012) in classifying VFA at different cutoff values. We fit age-adjusted linear regression models to evaluate associations between AA levels and change in VFA over 5 years. Results: All 20 AA levels significantly detected VFA excess, but WC was better. The 4A index performed better than Yamakado index at classifying VFA 0.0033) and VFA sex-specific median values (0.797, 0.786 vs. 0.676, 0.629 for men and women, p < 0.0017). AA significantly associated with change in VFA over 5 years were asparagine, glutamate, glutamine, glycine, methionine, proline, threonine in men; and histidine, isoleucine, tyrosine in women (p < 0.05). Conclusions: The 4A index can serve as a biomarker for VFA in Japanese-Americans and be considered for this purpose when WC is not available.

Leptin and adiponectin are two major adipocytokines reported to be associated with type 2 diabetes. However, it is unknown whether their associations with the risk of incident type 2 diabetes are independent of visceral adiposity and liver fat in a prospective cohort study. We included 787 Japanese men aged 28 to 77 years without type 2 diabetes at baseline. The subjects were classified into four groups based on leptin-adiponectin profile at baseline, with the median concentration value as the cut-off point (median levels of leptin and adiponectin were 4.8 ng/dL and 5.7 µg/mL, respectively): low-high, low-low, high-high, and high-low group. Visceral fat was measured by computed tomography (CT) as intra-abdominal fat area at the umbilicus level. Liver fat was assessed by liver-to-spleen attenuation ratio measured by CT. Type 2 diabetes was diagnosed as fasting plasma glucose level ≥126 mg/dL, HbA1c ≥6.5%, or taking oral hypoglycemic medications or insulin. Cox proportional hazard models were used to estimate hazard ratios (HR) for developing type 2 diabetes. During 5215 person-years of follow-up, 72 subjects developed type 2 diabetes. Incidence rates of type 2 diabetes per 1000 person-years were 3.2, 9.2, 18.6, and 26.1 for the low-high, low-low, high-high, and high-low group, respectively. After adjustment for age, smoking status, alcohol consumption, regular physical activity, family history of diabetes, visceral fat, and liver fat, multiple-adjusted HRs (95% CI) of incident type 2 diabetes were 1.87 (0.63-5.50), 2.90 (1.02-8.21), and 3.41 (1.23-9.47) for the low-low, high-high, and high-low group compared with the low-high group. In conclusion, leptin and adiponectin were associated with incident type 2 diabetes independent of both visceral fat and liver fat. Disclosure I. Shibata: None. W. Y. Fujimoto: None. E. J. Boyko: None. T. Hayashi: None. M. Shibata: None. K. K. Sato: None. S. Uehara: None. N. Nishida: None. K. Okamura: None. Y. Yuyama: None. H. Koh: None. Y. Hikita: None.

Physicians must recognize and treat adrenal crisis that may occur with acute viral illnesses such as influenza in women with Sheehan’s syndrome that has been undiagnosed and hence untreated, sometimes for many years, after postpartum hemorrhage.

Epigenetic changes precede the development of diabetes by many years, providing clues to its pathogenesis. We explored whether the epigenetic markers, circulating microRNAs (miRNAs), were associated with incident diabetes in Japanese Americans. We conducted a pilot study (n = 10) using plasma from age- and sex-matched participants who did or did not develop diabetes in the Japanese American Community Diabetes Study, an observational study of diabetes risk factors. Extraction and high-throughput sequencing of miRNAs were performed using samples collected at baseline. Regression models were fit comparing circulating miRNAs (N = 1640) among individuals who did or did not develop incident diabetes at 10-year follow-up. Participants averaged 51.7 years of age at baseline; 60% were male. We identified 36 miRNAs present at different (10 higher and 26 lower) levels in individuals who developed diabetes compared to those who did not (log2fold change ≥1.25 and false discovery rate ≤5%). These included miRNAs with functions in skeletal muscle insulin metabolism (miR-106b and miR-20b-5p) and miRNAs with functions in both skeletal muscle insulin metabolism and cell cycle regulation in endocrine pancreas (miR-15a and miR-17). Circulating miRNAs were associated with subsequent development of diabetes among Japanese Americans over 10 years of follow-up. Results are preliminary. Large-scale miRNA sequencing studies could inform our understanding of diabetes pathogenesis and development of therapies, based on gene expression regulation, that target diabetes.

Background High plasma apolipoprotein B (apoB) levels have been shown to be associated with hypertension, central obesity, and insulin resistance in cross-sectional research. However, it is unclear whether apoB levels predict future hypertension independent of body composition and insulin sensitivity. Therefore, we prospectively investigated whether plasma apoB concentrations independently predicted the risk of hypertension in a cohort of Japanese Americans. Methods A total of 233 normotensive Japanese Americans (77 men, 156 women; mean age, 46.4±11.0 years) were followed over 10 years to monitor them for the development of hypertension. Fasting plasma concentrations of apoB, glucose, and insulin were measured at baseline. Insulin sensitivity was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). The abdominal visceral and subcutaneous fat areas were measured at baseline using computed tomography. Logistic regression analysis was used to estimate the association between apoB concentrations and the odds of incident hypertension. Results The 10-year cumulative incidence of hypertension was 21.5%. The baseline apoB level was found to be positively associated with the odds of incident hypertension over 10 years after adjustment for age, sex, body mass index, systolic blood pressure, abdominal visceral fat area, abdominal subcutaneous fat area, total plasma cholesterol concentration, diabetes status, and HOMA-IR at baseline (odds ratio and 95% confidence interval for a 1-standard deviation increase, 1.89 [1.06 to 3.37]; P=0.030). Conclusion Higher apoB concentrations predicted greater risks of future hypertension independent of abdominal visceral fat area and insulin sensitivity in Japanese Americans.

Ageing in male adults is typically accompanied by adiposity accumulation and changes in circulating sex hormone concentrations. We hypothesized that an ageing‐associated increase in oestrogens and decrease in androgens would correlate with an increase in adiposity.

Background We describe the association between high density lipoprotein cholesterol (HDL-C) concentration and computed tomography (CT)-measured fat depots. Methods We examined the cross-sectional associations between HDL-C concentration and intra-abdominal (IAF), abdominal subcutaneous (SCF), and thigh fat (TF) areas in 641 Japanese-American men and women. IAF, SCF, and TF were measured by CT at the level of the umbilicus and mid-thigh. The associations between fat area measurements and HDL-C were examined using multivariate linear regression analysis adjusting for age, sex, diabetes family history, homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index (BMI). Non-linearity was assessed using fractional polynomials. Results Mean±standard deviation of HDL-C concentration and IAF in men and women were 1.30±0.34 mg/dL, 105±55.3 cm2, and 1.67±0.43 mg/dL, 74.4±46.6 cm2 and differed significantly by gender for both comparisons (P<0.001). In univariate analysis, HDL-C concentration was significantly associated with CT-measured fat depots. In multivariate analysis, IAF was significantly and non-linearly associated with HDL-C concentration adjusted for age, sex, BMI, HOMA-IR, SCF, and TF (IAF: β=−0.1012, P<0.001; IAF2: β=0.0008, P<0.001). SCF was also negatively and linearly associated with HDL-C (β=−0.4919, P=0.001). Conclusion HDL-C does not linearly decline with increasing IAF in Japanese-Americans. A more complex pattern better fits this association.

Aims: We compared 20 previously reported indices of insulin sensitivity derived from samples during an oral glucose tolerance test (OGTT) to determine which was best in predicting incident type 2 diabetes. Methods: We prospectively followed 418 Japanese Americans without diabetes for 10-11 years. We compared ability to predict incident diabetes of 20 insulin sensitivity indices-9 based on fasting samples, 7 based on 2-h and/or fasting samples, and 4 based on multiple samples (0, 30, 60,120 min) during an OGTT-by integrated discrimination improvement, category free net reclassification improvement, and area under the receiver operator characteristic curve. Results: There were 95 incident cases of diabetes. The Cederholm and Gutt indices, requiring more than only fasting samples, were the best to predict incident diabetes as judged by integrated discrimination improvement (0.187, 0.184), category free net reclassification improvement (0.962, 1.030), and area under the receiver operator characteristic curve (0.864, 0.863, respectively). Fasting indices were clearly inferior to both the Cederholm and Gutt indices. Conclusions: Among the 20 indices, the Cederholm and Gutt indices predicted diabetes best but the Gutt index may be preferable because it requires fewer samples during an OGTT. (c) 2020 Elsevier Inc. All rights reserved.

IMPORTANCE The prevalence of diabetes among Hispanic and Asian American subpopulations in the United States is unknown. OBJECTIVE To estimate racial/ethnic differences in the prevalence of diabetes among US adults 20 years or older by major race/ethnicity groups and selected Hispanic and non-Hispanic Asian subpopulations. DESIGN, SETTING, AND PARTICIPANTS National Health and Nutrition Examination Surveys, 2011-2016, cross-sectional samples representing the noninstitutionalized, civilian, US population. The sample included adults 20 years or older who had self-reported diagnosed diabetes during the interview or measurements of hemoglobin A(1c) (HbA(1c)), fasting plasma glucose (FPG), and 2-hour plasma glucose (2hPG). EXPOSURES Race/ethnicity groups: non-Hispanic white, non-Hispanic black, Hispanic and Hispanic subgroups (Mexican, Puerto Rican, Cuban/Dominican, Central American, and South American), non-Hispanic Asian and non-Hispanic Asian subgroups (East, South, and Southeast Asian), and non-Hispanic other. MAIN OUTCOMES AND MEASURES Diagnosed diabetes was based on self-reported prior diagnosis. Undiagnosed diabetes was defined as HbA1c 6.5% or greater, FPG 126 mg/dL or greater, or 2hPG 200 mg/dL or greater in participants without diagnosed diabetes. Total diabetes was defined as diagnosed or undiagnosed diabetes. RESULTS The study sample included 7575 US adults (mean age, 47.5 years; 52% women; 2866 [65%] non-Hispanic white, 1636 [11%] non-Hispanic black, 1952 [15%] Hispanic, 909 [6%] non-Hispanic Asian, and 212 [3%] non-Hispanic other). A total of 2266 individuals had diagnosed diabetes; 377 had undiagnosed diabetes. Weighted age- and sex-adjusted prevalence of total diabetes was 12.1% (95% CI, 11.0%-13.4%) for non-Hispanic white, 20.4% (95% CI, 18.8%-22.1%) for non-Hispanic black, 22.1% (95% CI, 19.6%-24.7%) for Hispanic, and 19.1%(95% CI, 16.0%-22.1%) for non-Hispanic Asian adults (overall P < .001). Among Hispanic adults, the prevalence of total diabetes was 24.6%(95% CI, 21.6%-27.6%) for Mexican, 21.7%(95% CI, 14.6%-28.8%) for Puerto Rican, 20.5%(95% CI, 13.7%-27.3%) for Cuban/Dominican, 19.3%(95% CI, 12.4%-26.1%) for Central American, and 12.3%(95% CI, 8.5%-16.2%) for South American subgroups (overall P < .001). Among non-Hispanic Asian adults, the prevalence of total diabetes was 14.0%(95% CI, 9.5%-18.4%) for East Asian, 23.3%(95% CI, 15.6%-30.9%) for South Asian, and 22.4%(95% CI, 15.9%-28.9%) for Southeast Asian subgroups (overall P = .02). The prevalence of undiagnosed diabetes was 3.9% (95% CI, 3.0%-4.8%) for non-Hispanic white, 5.2%(95% CI, 3.9%-6.4%) for non-Hispanic black, 7.5%(95% CI, 5.9%-9.1%) for Hispanic, and 7.5%(95% CI, 4.9%-10.0%) for non-Hispanic Asian adults (overall P < .001). CONCLUSIONS AND RELEVANCE In this nationally representative survey of US adults from 2011 to 2016, the prevalence of diabetes and undiagnosed diabetes varied by race/ethnicity and among subgroups identified within the Hispanic and non-Hispanic Asian populations.

The β-cell plays a major role in type 2 diabetes (T2DM). HOMA-β reflects fasting β-cell activity. Insulin responses during an OGTT reflect β-cell activity during glucose loading, which has two phases, early and late. HOMA-β, early, and late β-cell activity have different pathophysiologies. However, no research has examined whether HOMA-β and early and late phase β-cell activity during an OGTT are independently associated with the risk of T2DM. In a prospective cohort study, 415 nondiabetic Japanese-American men and women were followed for 10-11 years. β-cell activity was assessed by HOMA-β [fasting insulin × 360/(fasting glucose − 63)] as fasting activity, the insulinogenic index (IGI) [?insulin (30-0 min)/?glucose (30-0 min)] during an OGTT as early phase activity, and (area under the curve (AUC) of insulin 60-120 min)/(AUC glucose 60-120 min) as late phase activity. Insulin sensitivity was estimated by Matsuda index [10000/square root of ((fasting glucose) × (fasting insulin) × (AUC glucose 0-120 min/120) × (AUC insulin 0-120 min/120))]. T2DM was diagnosed as fasting plasma glucose level ≥126 mg/dL, 2-hour glucose level ≥200 mg/dL, or taking glucose-lowering medications. During the 10-11 year follow-up, 95 cases of T2DM occurred. HOMA-β, IGI, and late phase β-cell activity were all independently associated with the risk of T2DM. Multiple-adjusted odds ratios of T2DM for tertile 1, 2, and 3 of HOMA-β were 1.00 (reference), 0.25 (95% CI, 0.11-0.57), and 0.14 (0.05-0.37), respectively; those of IGI were 1.00, 0.35 (0.17-0.75), and 0.19 (0.07-0.47), respectively; and those of late phase β-cell activity were 1.00, 0.34 (0.14-0.82), and 0.16 (0.05-0.53), respectively, in the model that included HOMA-β, IGI, late phase β-cell activity, Matsuda index, age, BMI, sex, and family history of T2DM. In conclusion, higher β-cell activity while fasting and in both the early and late phase during an OGTT were all independently associated with a lower risk of T2DM. Disclosure T. Shimojo: None. C. Izumi: None. K.K. Sato: None. D.L. Leonetti: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. W.Y. Fujimoto: None. E.J. Boyko: None. T. Hayashi: None.

BACKGROUND:This study investigated the relationship between smoking and hearing loss and deafness (HLD) and whether the relationship is modified by genetic variation. Data for these analyses was from the subset of Japanese American families collected as part of the American Diabetes Association Genetics of Non-insulin Dependent Diabetes Mellitus study. Logistic regression with generalized estimating equations assessed the relationship between HLD and smoking. Nonparametric linkage analysis identified genetic regions harboring HLD susceptibility genes and ordered subset analysis was used to identify regions showing evidence for gene-smoking interactions. Genetic variants within these candidate regions were then each tested for interaction with smoking using logistic regression models.RESULTS:After adjusting for age, sex, diabetes status and smoking duration, for each pack of cigarettes smoked per day, risk of HLD increased 4.58 times (odds ratio (OR) = 4.58; 95% Confidence Interval (CI): (1.40,15.03)), and ever smokers were over 5 times more likely than nonsmokers to report HLD (OR = 5.22; 95% CI: (1.24, 22.03)). Suggestive evidence for linkage for HLD was observed in multiple genomic regions (Chromosomes 5p15, 8p23 and 17q21), and additional suggestive regions were identified when considering interactions with smoking status (Chromosomes 7p21, 11q23, 12q32, 15q26, and 20q13) and packs-per-day (Chromosome 8q21).CONCLUSIONS:To our knowledge this was the first report of possible gene-by-smoking interactions in HLD using family data. Additional work, including independent replication, is needed to understand the basis of these findings. HLD are important public health issues and understanding the contributions of genetic and environmental factors may inform public health messages and policies.

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β-cell dysfunction is major risk factor for type 2 diabetes. As HOMA-β reflects fasting β-cell function and insulinogenic index reflects early phase insulin response during an oral glucose tolerance test (OGTT), these two indices represent different aspects of insulin and glucose metabolism. It is not known whether HOMA-β and insulinogenic index are independently associated with type 2 diabetes risk. In a prospective cohort study, 415 nondiabetic Japanese-American men and women were followed for 10-11 years. Insulin sensitivity was assessed by HOMA-IR. β-cell activity was assessed by HOMA-β [fasting plasma insulin (μU/mL) × 360/(fasting plasma glucose (mg/dL) - 63)] and the insulinogenic index [Δinsulin (30-0 min) (μU/mL)/Δglucose (30-0 min) (mg/dL)] obtained during a 75-g OGTT. Type 2 diabetes was diagnosed as fasting plasma glucose level ≥126 mg/dL, 2-hour glucose level ≥200 mg/dL, or taking glucose-lowering medications. Logistic regression analysis was used to estimate odds ratios (OR) of incident diabetes. A total of 95 participants developed type 2 diabetes over 10-11 years. Insulinogenic index and HOMA-β were independently associated with the risk of type 2 diabetes. In multiple-adjusted models that included insulinogenic index, HOMA-β, HOMA-IR, age, BMI, gender, and family history of diabetes, OR of future type 2 diabetes for tertile 2 and 3 of insulinogenic index were 0.43 (95% CI, 0.22-0.85) and 0.31 (0.14-0.67), respectively, compared to tertile 1, and those for tertile 2 and 3 of HOMA-β were 0.31 (0.14-0.69) and 0.25 (0.10-0.63), respectively, compared to tertile 1. HOMA-IR was also associated with the risk of type 2 diabetes independent of these two indices. OR of tertile 2 and 3 of HOMA-IR were 1.75 (0.82-3.74) and 9.17 (3.78-22.28), respectively, compared to tertile 1. In conclusion, both higher insulinogenic index and HOMA-β were independently associated with a lower risk of type 2 diabetes independent of insulin sensitivity. Disclosure K.K. Sato: None. T. Hayashi: None. S. Uehara: None. Y. Onishi: None. D.L. Leonetti: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. W.Y. Fujimoto: None. E.J. Boyko: None.

Aims: We examined the longitudinal association between change in body composition directly measured by computed tomography (CT) and future insulin sensitivity. Methods: This was a prospective study with 10 years of follow-up with 297 JapaneseAmerican without diabetes. Intra-abdominal fat area (IAFA) and abdominal subcutaneous fat area (SCFA), and thigh SCFA were measured by CT. Insulin sensitivity was calculated by HOMA-IR and the Matsuda index. Results: Baseline and change in IAFA were significantly and independently associated with change in HOMA-IR and Matsuda index during follow-up. In multivariate analysis, IAFA and 10-year change in IAFA (D IAFA) was significantly and positively associated with 10year HOMA-IR (p < 0.001) and significantly and negatively associated with 10-year Matsuda index (p < 0.001). The association with Matsuda index though was non-linear and best modeled as a quadratic function (D IAFA + D IAFA2). No significant associations in multivariate analyses were seen between thigh SCFA and insulin sensitivity or abdominal SCFA and HOMA-IR but an increase in abdominal SCFA was associated with diminished insulin sensitivity measured by the Matsuda index. Conclusions: An increase in visceral adiposity predicts diminished insulin sensitivity over 10 years of follow-up independent of the size of this adipose depot at baseline. (C) 2019 Elsevier B.V. All rights reserved.