In this prospective, nested, case-control study from a large-scale, multiethnic cohort of postmenopausal women, we confirm that both HOMA-IR and HOMA-B derived from basal levels of fasting insulin and glucose were consistently associated with diabetes risk. These associations were independent of BMI and waist-to-hip ratio as well as other conventional diabetes risk factors. No statistically significant multiplicative interactions by ethnicity were noted. When evaluated jointly, the associations of HOMA-IR and HOMA-B with diabetes risk tended to be independent and additive, with the highest RR of diabetes associated with high HOMA-IR and low HOMA-B.
The HOMA model is the most widely used surrogate measure for assessing insulin resistance and β-cell function in clinical and epidemiologic studies (2
). The HOMA model was initially proposed by Matthews et al. (1
) in 1985 and was considered a structural model of the underlying physiological basis for the feedback loop between the liver and the β-cell in fasting (2
). The simplified formulae were derived from a mathematical assessment of the balance between hepatic glucose output and insulin secretion from basal levels of both glucose and insulin (1
). The validity of HOMA-IR has been evaluated by comparison with the physiologic measures of insulin sensitivity by some “gold standard” methods in individuals with normal glucose tolerance (NGT), those with IGT, and diabetic patients. HOMA-IR has been shown to correlate well with insulin resistance index derived from the euglycemic clamp (NGT individuals: r
= 0.40–0.58 [12,13]; diabetic patients: r
= 0.57–0.73 [12,14,15]; and combined diabetic and nondiabetic individuals: r
= 0.56–0.82 [12,16]) and from directly measured insulin sensitivity, estimated using the minimal model from the frequently sampled intravenous glucose tolerance test (NGT individuals: r
= −0.49 to −0.70 [7,17–19]; IGT individuals: r
= −0.83 ; and nonobese diabetic patients: r
= 0.50 ). Overall, there were good correlations between HOMA-IR and insulin resistance assessed from those well-validated methods. In contrast, it remains controversial whether HOMA-B is an accurate reflection of pancreatic β-cell function. In both nondiabetic and diabetic individuals, HOMA-B has been shown to correlate moderately well with those sophisticated measures of insulin secretion using the hyperglycemic clamps (r
= 0.62–0.69) (1
), continuous infusion glucose model assessment (r
= 0.87) (1
), the acute insulin response (AIR) estimated from the intravenous glucose tolerance test (r
= 0.65) (21
), and the ratio of change in insulin to change in glucose over the first 30 min of an oral glucose tolerance test (r
= 0.38 in nondiabetic participants, r
= 0.64 in diabetic patients, and r
= 0.44 for the overall population) (4
The ability of the HOMA model to predict the development of type 2 diabetes has been evaluated in both cross-sectional and cohort studies. Previous cross-sectional studies have shown the relationships between HOMA-IR and HOMA-B and the prevalence of IGT and type 2 diabetes in Japanese (3
), Mexican-American (4
), and non-Hispanic white subjects (4
). HOMA-IR significantly predicted risk of incident IGT in 128 Japanese Americans with NGT with >10 years of follow-up (8
) and 10-year diabetes incidence in the Bruneck Study of 1,000 Italians (5
). In a recent study of combined prospective data involving a total of 3,574 participants including non-Hispanic white, African-American, Hispanic American, and Mexican subjects with 5–8 years of follow-up, HOMA-IR displayed a more consistent ability to predict type 2 diabetes compared with other insulin resistance indexes (7
). In line with these findings, our study has confirmed that HOMA-IR was a robust surrogate compared with fasting glucose, insulin, or HOMA-B in each of four ethnic groups of American women with different diabetes risk factor profiles. Of note, our secondary analyses showed limited utility of HOMA-B, most likely because its independent association with diabetes risk seemed to be very sensitive to statistical power loss and specification of multivariable model.
A few prospective studies have also evaluated the role of both HOMA-IR and HOMA-B in predicting future risk of type 2 diabetes and/or IGT (6
). Increased HOMA-IR and decreased HOMA-B have been shown to significantly predict type 2 diabetes among 1,449 Mexicans during a 3.5-year follow-up (6
), 644 Chinese followed for 4.5 years (9
), and 81 healthy first-degree relatives of African-American patients with type 2 diabetes followed for 6 years (10
). With similar findings, our large prospective data further showed the independent and additive associations of HOMA-IR and HOMA-B with diabetes risk, indicating the importance of assessing both insulin resistance and β-cell function in relation to diabetes risk.
The strengths of our multiethnic study include its prospective study design, large sample size, and detailed measures of variables. Nonetheless, several limitations of the present study merit consideration. First, bias from the inclusion of undiagnosed diabetes may be a concern. However, when the analyses were restricted to all case and control subjects with a fasting glucose <126 mg/dl at baseline, the findings were not appreciably altered. We also had similar results after further excluding all the case subjects occurring in the first follow-up year who were likely to have undiagnosed diabetes. These results suggest that bias due to undiagnosed diabetes was unlikely to be substantial. Also, we cannot exclude the possibility of residual confounding by incompletely measured or unmeasured physiologic covariates; it seems unlikely that more complete statistical adjustment would fully eliminate the observed associations or the consistency of our findings across diverse populations.
In summary, our prospective data showed that the basal levels of HOMA indexes, especially HOMA-IR, were independently and consistently associated with diabetes risk in a multiethnic cohort of U.S. postmenopausal women. These prospective associations appeared to be robust across diverse ethnic groups. Our findings suggest the utility of the HOMA indexes for assessing insulin resistance and β-cell function in identifying individuals who are at high risk and who may benefit from interventions for diabetes prevention.