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Ni Hms 24200 | Diabetes Mellitus Type 2 | Insulin Resistance

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  Insulin Sensitivity and Insulin Secretion Determined byHomeostasis Model Assessment (HOMA) and Risk of Diabetes ina Multiethnic Cohort of Women: The Women’s Health InitiativeObservational Study Yiqing Song, MD, SCD 1, JoAnn E. Manson, MD, DRPH 1,2, Lesley Tinker, PHD, RD 3, BarbaraV. Howard, PHD 4, Lewis H. Kuller, MD, DRPH 5, Lauren Nathan, MD 6, Nader Rifai, PHD 7, and Simin Liu, MD, SCD 1,2,8,9 1  Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts  2  Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts  3  Public Health Division, Fred Hutchinson Cancer Research Center, Seattle, Washington  4  MedStar Research Institute, Washington, D.C   5  Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania 6   Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California 7   Children’s Hospital, Boston, Massachusetts 8  Department of Epidemiology, University of California, Los Angeles, School of Public Health, Los Angeles,California  9  David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California  Abstract OBJECTIVE— The homeostasis model assessment (HOMA), based on plasma levels of fastingglucose and insulin, has been widely validated and applied for quantifying insulin resistance and β -cell function. However, prospective data regarding its relation to diabetes risk in ethnically diverse populations are limited. RESEARCH DESIGN AND METHODS— Among 82,069 women who were aged 50–79 years,free of cardiovascular disease or diabetes, and participating in the Women’s Health InitiativeObservational Study, we conducted a nested case-control study to prospectively examine the relationsof HOMA of insulin resistance (HOMA-IR) and β -cell function (HOMA-B) with diabetes risk.During a median follow-up period of 5.9 years, 1,584 diabetic patients were matched with 2,198control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. RESULTS— Baseline levels of fasting glucose, insulin, and HOMA-IR were each significantlyhigher among case compared with control subjects, while HOMA-B was lower (all P  values <0.0001). After adjustment for matching factors and diabetes risk factors, all four markers weresignificantly associated with diabetes risk; the estimated relative risks per SD increment were 3.54 Address correspondence and reprint requests to Prof. Simin Liu, Department of Epidemiology, UCLA School of Public Health, Box951772, 650 Charles E. Young Dr. South, Los Angeles, CA 90095. E-mail: siminliu@ucla.edu.Additional information for this article can be viewed in an online appendix at http://dx.doi.org/10.2337/dc07-0358.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.  NIH Public Access Author Manuscript  Diabetes Care . Author manuscript; available in PMC 2007 August 27. Published in final edited form as:  Diabetes Care . 2007 July ; 30(7): 1747–1752. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t    (95% CI 3.02–4.13) for fasting glucose, 2.25 (1.99–2.54) for fasting insulin, 3.40 (2.95–3.92) for HOMA-IR, and 0.57(0.51–0.63) for HOMA-B. While no statistically significant multiplicativeinteractions were observed between these markers and ethnicity, the associations of both HOMA-IR and HOMA-B with diabetes risk remained significant and robust in each ethnic group, includingwhites, blacks, Hispanics, and Asians/Pacific Islanders. When evaluated jointly, the relations of HOMA-IR and HOMA-B with diabetes risk appeared to be independent and additive. HOMA-IR was more strongly associated with an increased risk than were other markers after we excluded thosewith fasting glucose ≥ 126 mg/dl at baseline. CONCLUSIONS— High HOMA-IR and low HOMA-B were independently and consistentlyassociated with an increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women.These data suggest the value of HOMA indexes for diabetes risk in epidemiologic studies.Insulin resistance and progressive pancreatic β -cell dysfunction have been identified as the twofundamental features in the pathogenesis of type 2 diabetes. As a widely validated clinical and epidemiological tool for estimating insulin resistance and β -cell function, the homeostasismodel assessment (HOMA) is derived from a mathematical assessment of the balance betweenhepatic glucose output and insulin secretion from fasting levels of glucose and insulin (1,2).The HOMA model requires only a single measurement of insulin and glucose in the basal stateand is thus considered an alternative in large-scale epidemiologic studies to the sophisticated “gold standard” methods that usually require dynamic data via costly and invasive procedures.The HOMA of insulin resistance (HOMA-IR) index, the product of basal glucose and insulinlevels divided by 22.5 (1,2), is regarded as a simple, inexpensive, and reliable surrogatemeasure of insulin resistance, while the HOMA of β -cell function (HOMA-B) index, computed as the product of 20 and basal insulin levels divided by the value of basal glucose concentrationsminus 3.5, has been proposed to be a good measure of β -cell function (2).Previous cross-sectional studies have shown that both high HOMA-IR and low HOMA-B wereassociated with increased prevalences of impaired glucose tolerance (IGT) and type 2 diabetesin Japanese (3), Mexican-American (4), and non-Hispanic (4) white subjects. Several prospective studies have shown the role of either HOMA-IR or HOMA-B or both in predictingfuture risk of type 2 diabetes and/or IGT in diverse populations (5–10). However, whether therelation between HOMA indexes and risk of type 2 diabetes differs by ethnicity is unknown.Furthermore, the comparative importance of HOMA-IR and HOMA-B in relation to risk of type 2 diabetes has been less well studied. In addition, most studies have included both menand women (5–10) and lacked statistical power to detect meaningful results for women.We therefore prospectively examined whether HOMA-IR and HOMA-B were consistentlyassociated with diabetes risk among apparently healthy American women aged over 50 yearsfrom the Women’s Health Initiative Observational Study (WHI-OS), an ethnically diversecohort of postmenopausal women including whites, blacks, Hispanics, and Asian/PacificIslanders. RESEARCH DESIGN AND METHODS The WHI-OS is an ongoing longitudinal study designed to examine the association betweenclinical, socioeconomic, behavioral, and dietary risk factors and subsequent incidence of healthoutcomes, including cardiovascular disease and diabetes. Details of the scientific rationale,eligibility, and other design aspects have been published elsewhere (11). Between September 1994 and December 1998, the WHI-OS enrolled a total of 93,676 women aged 50 to 79 yearsat 40 clinical centers throughout the U.S. At baseline, women completed screening and enrollment questionnaires, underwent a physical examination, and provided fasting blood samples (after an overnight fast for at least 12 h). WHI-OS participants were followed by Song et al.Page 2  Diabetes Care . Author manuscript; available in PMC 2007 August 27. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t    annually mailed, self-administered questionnaires and an additional clinical center visit at 3years after enrollment.The study has been reviewed and approved by human subjects review committees at each participating institution, and signed informed consent was obtained from all women enrolled.  Ascertainment of case and control subjects Among 82,069 (87.6%) postmenopausal women free of cardiovascular disease and diabetes at baseline, 1,584 women who had self-reported first-time use of hypoglycemic medication (oralagents or insulin) during a median follow-up of 5.9 years (mean 5.5 years) were chosen asincident case subjects and matched with 2,198 control subjects on age (±2.5 years), ethnicity(White/Caucasian, Black/African, Hispanic/Latino, and Asian/Pacific Islander), clinicalcenter, time of blood draw (±0.10 h), and length of follow-up. Of these, 968 case subjectsamong whites were matched with one control subject each, and 366, 152, and 98 case subjectsamong ethnic minority women were matched with two control subjects each for Black,Hispanic, and Asian/Pacific Islanders, respectively. The 1:2 matching ratio was used for minorities to strengthen the power in these smaller sample sizes of cases. Our study did notinclude American Indian or native Alaskan women because of their limited sample size. Biochemical measurement All biochemical assays were carried out by laboratory staff blinded to case/control status. Blood samples from case and their matched control subjects were handled identically, shipped in thesame batch, thawed, and assayed in random order in the same analytical run to reducesystematic bias and interassay variation. Glucose was measured enzymatically on the Hitachi911 analyzer using Roche Diagnostics regents (Indianapolis, IN). Insulin was measured by anultra-sensitive enzyme-linked immunosorbent assay from ALPCO Diagnostics (Windham, NH). The coefficients of variation were 1.7% for glucose and 5.8% for insulin. Statistical analysis HOMA-IR was computed as follows: fasting insulin ( μ IU/ml) × fasting glucose (mmol/ml)/22.5. HOMA-B was calculated using the following formula: 20 × fasting insulin ( μ IU/ml)/fasting glucose (mmol/ml) −  3.5. Basal fasting glucose, insulin, and two derived HOMAindexes were not normally distributed and were thus logarithmically transformed. Age-and ethnicity-adjusted Pearson’s partial correlation coefficients were calculated to evaluateassociations between these markers among control subjects. We performed a conditionallogistic regression model to estimate the odds ratio (OR) per each SD increment in each of markers (in log scale) because there was a significant linear relationship with diabetes risk for each of them. Since risk-set sampling was used for our matched case-control pairs, the ORsyield unbiased estimates of the relative risks (RRs). In the matched analyses, we adjusted for matching factors such as age, ethnicity, clinical center, and time of blood draw. In multivariateanalyses, we adjusted for BMI (modeled as a continuously distributed covariate), family historyof diabetes (yes or no), smoking (never, past, or current), alcohol intake (never, past, or current), physical activity (quintiles), and current postmenopausal hormone use (yes or no). A likelihood ratio test was used to test statistical significance of interactions by ethnicity.We also conducted subgroup analyses to examine potential interactions by levels of  prespecified factors including BMI (<25 and ≥ 25 kg/m 2 ), waist (<35 and ≥ 35 inches), hormoneuse (yes/no), physical activity (less than and more than/equal to the median), and family historyof diabetes (yes/no). A likelihood ratio test was performed to test significances. Song et al.Page 3  Diabetes Care . Author manuscript; available in PMC 2007 August 27. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t    To evaluate the joint relationship between HOMA-IR and HOMA-B, we divided the study population into four groups according to their median cut points in control subjects (HOMA-IR <1.44 and ≥ 1.44; HOMA-B <81.7 and ≥ 81.7) and estimated each subgroup-specific OR.To address the concern about undiagnosed diabetes at baseline, we conducted secondaryanalyses by excluding case and control subjects with a fasting glucose ≥ 126 mg/dl at baseline.We further excluded incident case subjects diagnosed during the 1st year of follow-up whowere more likely to have undiagnosed diabetes at baseline.All analyses were performed with the use of SAS software (version 9.1; SAS Institute, Cary, NC). All P  values were two tailed. RESULTS Overall, diabetes case subjects had a higher prevalence of traditional diabetes risk factors at baseline than control subjects (Table 1). As expected, women with diabetes had significantlyhigher levels of baseline fasting insulin, glucose, and HOMA-IR and lower HOMA-B thantheir matched control subjects (all P  values < 0.0001).Fasting insulin levels were almost completely correlated with HOMA-IR ( r   = 0.99) and highlycorrelated with HOMA-B ( r   = − 0.84). Fasting glucose was strongly associated with HOMA-IR ( r   = 0.51) and modestly associated with HOMA-B ( r   = − 0.17). The two HOMA indexeswere also correlated with each other ( r   = − 0.76). HOMA-IR was more strongly correlated withBMI and waist-to-hip ratio than was HOMA-B.After adjustment for matching factors, increasing levels of fasting glucose, insulin, and HOMA-IR were significantly associated with an increased risk of diabetes, while HOMA-Bwas significantly associated with a lower risk of diabetes (Table 2). Further adjustment for BMI, alcohol intake, physical activity, smoking, postmenopausal hormone use, and familyhistory of diabetes attenuated the positive associations of fasting glucose, insulin, and HOMA-IR but strengthened the inverse association of HOMA-B (model 1). When waist-to-hip ratiowas further adjusted, similar changes were observed (model 2).In the same multivariable models stratified by ethnicity (Table 2), fasting glucose, insulin, and HOMA-IR appeared to be strongly associated with diabetes risk in each of four ethnic groups,while HOMA-B retained significant associations with diabetes in whites, blacks, and Hispanicsin all models but not in Asian/Pacific Islanders because of small sample size. The RR estimatesfor fasting glucose also tended to be unstable, with a wide 95% CI in Asian/Pacific Islanders.However, the ethnic differences in these associations did not reach statistical significance whentested for a formal interaction.After we excluded 736 case and 26 control subjects with a fasting glucose ≥ 126 mg/dl at baseline (Table 2), fasting insulin and HOMA-IR remained significantly associated withdiabetes risk with stable estimates in all women and all ethnic groups, although the associationstrength was stronger for HOMA-IR than for insulin. Notably, due to decreased statistical power, the RR estimate variability became unusually large for fasting glucose, and the directionfor the association of HOMA-B and diabetes risk was even changed after additional controllingfor diabetes risk factors (Table 2).The positive associations with diabetes were evident for HOMA-IR and fasting insulin inwomen with a BMI ≥ 25 kg/m 2  (both P  values for interaction = 0.03). No significant effectmodifications were observed for other factors (Table 3). Song et al.Page 4  Diabetes Care . Author manuscript; available in PMC 2007 August 27. NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  NI  H-P A A  u t  h  or M an u s  c r i   p t  
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