Association of the Mediterranean Diet With Onset of Diabetes in the Women's Health Study

Abstract

Importance: Higher Mediterranean diet (MED) intake has been associated with reduced risk of type 2 diabetes, but underlying biological mechanisms are unclear.

Objective: To characterize the relative contribution of conventional and novel biomarkers in MED-associated type 2 diabetes risk reduction in a US population.

Design, setting, and participants: This cohort study was conducted among 25 317 apparently healthy women. The participants with missing information regarding all traditional and novel metabolic biomarkers or those with baseline diabetes were excluded. Participants were invited for baseline assessment between September 1992 and May 1995. Data were collected from November 1992 to December 2017 and analyzed from December 2018 to December 2019.

Exposures: MED intake score (range, 0 to 9) was computed from self-reported dietary intake, representing adherence to Mediterranean diet intake.

Main outcomes and measures: Incident cases of type 2 diabetes, identified through annual questionnaires; reported cases were confirmed by either telephone interview or supplemental questionnaire. Proportion of reduced risk of type 2 diabetes explained by clinical risk factors and a panel of 40 biomarkers that represent different physiological pathways was estimated.

Results: The mean (SD) age of the 25 317 female participants was 52.9 (9.9) years, and they were followed up for a mean (SD) of 19.8 (5.8) years. Higher baseline MED intake (score ≥6 vs ≤3) was associated with as much as a 30% lower type 2 diabetes risk (age-adjusted and energy-adjusted hazard ratio, 0.70; 95% CI, 0.62-0.79; when regression models were additionally adjusted with body mass index [BMI]: hazard ratio, 0.85; 95% CI, 0.76-0.96). Biomarkers of insulin resistance made the largest contribution to lower risk (accounting for 65.5% of the MED-type 2 diabetes association), followed by BMI (55.5%), high-density lipoprotein measures (53.0%), and inflammation (52.5%), with lesser contributions from branched-chain amino acids (34.5%), very low-density lipoprotein measures (32.0%), low-density lipoprotein measures (31.0%), blood pressure (29.0%), and apolipoproteins (23.5%), and minimal contribution (≤2%) from hemoglobin A1c. In post hoc subgroup analyses, the inverse association of MED diet with type 2 diabetes was seen only among women who had BMI of at least 25 at baseline but not those who had BMI of less than 25 (eg, women with BMI <25, age- and energy-adjusted HR for MED score ≥6 vs ≤3, 1.01; 95% CI, 0.77-1.33; P for trend = .92; women with BMI ≥25: HR, 0.76; 95% CI, 0.67-0.87; P for trend < .001).

Conclusions and relevance: In this cohort study, higher MED intake scores were associated with a 30% relative risk reduction in type 2 diabetes during a 20-year period, which could be explained in large part by biomarkers of insulin resistance, BMI, lipoprotein metabolism, and inflammation.

Figure 1.. Cumulative Incidence of Type 2 Diabetes by Mediterranean Diet (MED) Intake Groups

Figure 2.. Proportion of Diabetes Risk Reduction for Mediterranean Diet Score of 6 or Greater

Proportion was calculated as: HR_basic model – HR_{adjusted model}) / (HR_{basic model} – 1) × 100%. The basic model included age, randomized treat assignment, energy intake, smoking, menopausal status, postmenopausal hormone use, and physical activity. Insulin resistance included lipoprotein insulin resistance; high density lipoprotein (HDL) measures included HDL cholesterol, HDL particle size and particle concentration, and apolipoprotein A1; inflammation included fibrinogen, high-sensitivity C-reactive protein, intracellular adhesion molecule 1, and glycoprotein acetylation; branched chain amino acids included valine, leucine, and isoleucine; very low density lipoprotein (VLDL) measures included triglycerides and triglyceride-rich lipoprotein subfraction particle concentration and particle size; LDL measures included LDL cholesterol, LDL particle size and particle concentration, apolipoprotein B100; blood pressure included systolic and diastolic blood pressure as well as hypertension; small molecule metabolites include citrate, alanine, creatinine, and homocysteine.