Plasma metabolomic profiling of dietary patterns associated with glucose metabolism status: The Maastricht Study

Abstract

Background: Glucose metabolism has been reported to be affected by dietary patterns, while the underlying mechanisms involved remain unclear. This study aimed to investigate the potential mediation role of circulating metabolites in relation to dietary patterns for prediabetes and type 2 diabetes.

Methods: Data was derived from The Maastricht Study that comprised of 3441 participants (mean age of 60 years) with 28% type 2 diabetes patients by design. Dietary patterns were assessed using a validated food frequency questionnaire (FFQ), and the glucose metabolism status (GMS) was defined according to WHO guidelines. Both cross-sectional and prospective analyses were performed for the circulating metabolome to investigate their associations and mediations with responses to dietary patterns and GMS.

Results: Among 226 eligible metabolite measures obtained from targeted metabolomics, 14 were identified to be associated and mediated with three dietary patterns (i.e. Mediterranean Diet (MED), Dietary Approaches to Stop Hypertension Diet (DASH), and Dutch Healthy Diet (DHD)) and overall GMS. Of these, the mediation effects of 5 metabolite measures were consistent for all three dietary patterns and GMS. Based on a 7-year follow-up, a decreased risk for apolipoprotein A1 (APOA1) and docosahexaenoic acid (DHA) (RR 0.60, 95% CI 0.55, 0.65; RR 0.89, 95% CI 0.83, 0.97, respectively) but an increased risk for ratio of ω-6 to ω-3 fatty acids (RR 1.29, 95% CI 1.05, 1.43) of type 2 diabetes were observed from prediabetes, while APOA1 showed a decreased risk of type 2 diabetes from normal glucose metabolism (NGM; RR 0.82, 95% CI 0.75, 0.89).

Conclusions: In summary, this study suggests that adherence to a healthy dietary pattern (i.e. MED, DASH, or DHD) could affect the GMS through circulating metabolites, which provides novel insights into understanding the biological mechanisms of diet on glucose metabolism and leads to facilitating prevention strategy for type 2 diabetes.

Keywords: Cohort study; Dietary patterns; Glucose metabolism; Metabolomics; Molecular epidemiology.

Fig. 1

Overview of the study design. Fasting blood samples were obtained, and plasma were extracted to quantify the circulation metabolites based on NMR platform. Diet was assessed at baseline by a validated, self-administered FFQ developed based on the Dutch national FFQ tool, which was then calculated into dietary patterns, i.e. Mediterranean diet (MED), Dietary Approaches to Stop Hypertension (DASH) Diet, and Dutch Healthy Diet (DHD). Participants underwent a standardized 2-h 75-g oral glucose tolerance test (OGTT) after fasting overnight along with information about diabetes medication to determine the glucose metabolism status (GMS), which was defined based on the World Health Organization 2006 criteria as; normal glucose metabolism, NGM, fasting plasma glucose <6.1 mmol/L; prediabetes, fasting plasma glucose of 6.1–6.9 mmol/L and no hypoglycaemic medications; and type 2 diabetes, fasting plasma glucose ≥7.0 mmol/L or hypoglycaemic medications. For safety reasons, participants using insulin or with a fasting plasma glucose (FPG) value above 11.0 mmol/L (determined by finger prick) did not undergo the OGTT. For these individuals, the FPG value and diabetes medication information was used to determine GMS. The exclusion criteria for participants included in the further analysis were performed as follows: (1) 48 participants without measured metabolites; (2) 43 participants without information on glucose metabolism status; (3) 168 participants with implausible energy intakes (<800 or >4200 kcal/day for men, and <500 or >3500 kcal/day for women); (4) 69 participants of whom data on dietary assessment were incomplete for the calculation of dietary patterns; (5) 38 non-Caucasian participants. Abbreviations: NMR, magnetic resonance spectroscopy; FFQ, food frequency questionnaire; MED, Mediterranean diet; DASH, Dietary Approaches to Stop Hypertension; DHD, Dutch Healthy Diet; OGTT, oral glucose tolerance test; GMS, glucose metabolism status; NGM, normal glucose metabolism; FPG, fasting plasma glucose

Fig. 2

Metabolite measures associated and mediated between dietary patterns and glucose metabolism status. A Plasma metabolite measures associated with three dietary patterns and glucose metabolism status with their overlap. B Associations of metabolite measures with dietary patterns, glucose metabolism status, HOMA-IR and HbA1c. Red/green squares indicate positive associations, while blue/purple squares indicate negative associations. C Parallel coordinates chart showing the 14 significant mediated effects of plasma metabolite measures. The left panel shows the dietary patterns, the middle panel shows the plasma metabolite measures, and the right panel shows the pairs of glucose metabolism status. The curved lines across panels indicate the mediated effects, while the colours correspond to different associations (i.e. grey for positive/negative, and green for negative/positive). Abbreviations: MED, Mediterranean Diet; DASH, Dietary Approaches to Stop Hypertension diet; DHD, Dutch Healthy Diet; GMS, glucose metabolism status; NGM, normal glucose metabolism; T2D, type 2 diabetes; HOMA-IR, Homeostatic Model Assessment for Insulin Resistance; HbA1c, haemoglobin A1c; ldl_c_metab, total cholesterol in very small VLDL (mmol/l); apoa1_metab, apolipoprotein A-I (g/l); unsatdeg_metab, estimated degree of unsaturation; dha_metab, 22:6, docosahexaenoic acid (mmol/l); ω-3_metab, ω-3 fatty acids (mmol/l); ile_metab, isoleucine; l_ldl_c_ratio, total cholesterol to total lipids ratio in large LDL (%); m_ldl_c_ratio, total cholesterol to total lipids ratio in medium LDL (%); s_ldl_c_ratio, total cholesterol to total lipids ratio in small LDL (%); m_hdl_tg_ratio, triglycerides to total lipids ratio in medium HDL (%); dha_fa_ratio,ratio of 22:6 docosahexaenoic acid to total fatty acids (%); la_fa_ratio, ratio of 18:2 linoleic acid to total fatty acids; ω-3_fa_ratio, ratio of ω-3 fatty acids to total fatty acids (%); ω-6_fa_ratio, ratio of ω-6 fatty acids to total fatty acids (%); pufa_fa_ratio, ratio of polyunsaturated fatty acids to total fatty acids (%); ω-6_ω-3_ratio, ratio of ω-6 fatty acids to ω-3 fatty acids; pufa_mufa_ratio, ratio of PUFA to MUFA; metab, metabolite; PUFA, polyunsaturated fatty acids; MUFA, monounsaturated fatty acids; VLDL, very low–density lipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein