Association between lipids and apolipoproteins on type 2 diabetes risk; moderating effects of gender and polymorphisms; the ATTICA study

https://doi.org/10.1016/j.numecd.2020.01.008Get rights and content

Highlights

  • ApoA1 levels, ApoB:LDL and TG:apoA1 ratios are associated with 10-year risk of T2DM in males only.

  • In males only a unit change in apoB: LDL cholesterol increased risk of type 2 diabetes by 303%.

  • In males only a unit change in triglycerides: apoA1 increased risk of type 2 diabetes by 85%.

  • HOMA-IR predicted the 10-year incidence of T2DM only in apoA1 75 GG carriers.

  • Physical activity may moderate the influence of HOMA-IR on T2DM incidence only in carriers of apoA1 75 GG.

Abstract

Background and aims

Type 2 diabetes mellitus (T2DM) is a condition defined by hyperglycaemia, but also often presents with dyslipidaemia and suppressed HDL cholesterol. Mendelian randomization studies have suggested a causal link between low HDL cholesterol and T2DM. However, influences of gender, polymorphisms and lifestyle, all known to influence HDL cholesterol, have not been fully explored in a prospective cohort.

Methods and results

In 2001–2002, a random sample of 1514 males (18–87 years old) and 1528 females (18–89 years old) were recruited in the ATTICA study. The 10-year follow-up (2011–2012) included 1485 participants. Lipids and lipoproteins levels, glucose and insulin levels were measured together with apolipoprotein A1 (apoA1) 75 G/A genotype, which is known to influence HDL-cholesterol. In total, 12.9% of the study sample developed T2DM within the 10-year follow-up period. In multivariable models, for each mg/dL increase in apoA1 levels in males, 10-year T2DM risk decreased 1.02%; while every unit increase in apoB/LDL-cholesterol ratio increased risk 4-fold. Finally, for every unit increase in triglycerides/apoA1 ratio, the risk increased 85%. HOMA-IR independently predicted T2DM 10-year incidence only for carriers of GG polymorphism (all, p < 0.05), but not in carriers of the GA polymorphism (all, p > 0.05).

Conclusion

ApoA1 was associated with decreased T2DM risk and TG/ApoA1 and apoB/LDL were associated with increased risk of T2DM, only in males. ApoA1 polymorphism, which is associated with lower HDL cholesterol, influenced the predictive effects of HOMA-IR on T2DM incidence, which appeared to be moderated by physical activity, suggesting potential scope for more targeted preventative strategies.

Introduction

Type 2 diabetes mellitus (T2DM) is a rapidly growing global health challenge [[1], [2], [3]]. Traditionally, management and prevention of T2DM have focused mainly on glycaemia [4,5], despite it often presenting with dyslipidaemia. It is plausible that after hyperinsulinaemia, dyslipidaemia typified by suppressed HDL cholesterol is the second most dominant feature of Metabolic Syndrome in T2DM [6]. Recently, a Mendelian randomisation study suggested a potential causal link between suppressed HDLc and T2DM risk [7]. Despite this emerging evidence, the use of lipid and lipoprotein biomarkers still mainly focuses upon predicting cardiovascular disease (CVD) risk [8,9] including in people with T2DM [10], with little consideration of these biomarkers when assessing T2DM risk [11].

The mechanisms of how apolipoproteins and HDLc influence insulin action, a key aspect of T2DM pathogenesis has recently been explored [12]. The relationship between low HDLc and development of T2DM has been previously described [13,14], with causality partially assessed [15] as plasma insulin increased and plasma glucose decreased following an infusion of HDLc (including apoA1) in individuals with T2DM. The role of HDLc at physiological levels is less clear and dependent on experimental conditions. However, it appears that HDLc is potentially protective of β-cells against stressors, including glucose and oxidised LDLc [16,17], whereas triglyceride-rich particles may be detrimental [18]. The protective effects of HDLc may be attributable to apoA1 [17]; whereas low levels of HDLc are a known risk factor [12].

There are several known modifiers of cardiovascular risk including gender, genetic factors and lifestyle which appear to act via altering an individual's lipid profile [19], which may also influence the risk of developing T2DM. Males typically have lower HDLc compared to pre-menopausal females, leading to suggestions that CVD risk reduction strategies should be tailored accordingly [20]. Beyond gender, a number of polymorphisms have been identified in apolipoprotein genes. A key single nucleotide polymorphism in the apoA1 gene is apoA1-75 G/A, which is associated with a lower apoA1 and HDLc concentration for the GG genotype compared to the AA and a lesser extent GA [21]. The G allele has also been associated with increased myocardial infarction risk [22]. It is, therefore, logical to explore the potential moderating effects of this polymorphism in cohorts at risk of developing T2DM.

Although HDLc has been proposed to be linked causally with T2DM; the link with and apoA1 and T2DM is less well defined, especially with respect to modifying effects of gender, polymorphisms or lifestyle. Therefore, this study aimed to explore potential associations of lipids, apolipoproteins, gender and apoA1 polymorphisms, and risk of developing T2DM in a cohort of Greek healthy adults.

Section snippets

Baseline sampling procedure (2001–2002)

The ATTICA study is a large-scale, health and nutrition, prospective survey, which was carried out during 2001–2002, in the province of Attica, where Athens is a major metropolis. People with a history of CVD or other atherosclerotic diseases or having chronic viral infections or living in institutions were excluded from participation. Of the initially invited 4056 individuals and after excluding those with CVD (i.e., n = 117) or those having chronic viral infections (n = 107), 3042 finally

Results

The study sample consisted of 1485 individuals (51% females) with a mean age of 45 ± 13 years (p for gender difference>0.05). Of these, 12.9% (191) developed T2DM within the 10-year follow-up period, but no difference was detected between genders (p = 0.574). Mean BMI at baseline of the total sample was 26.3 ± 4.28 kg/m2, with males having significantly higher mean BMI than females (27.2 ± 3.6 vs 25.3 ± 4.7 respectively, p < 0.001). Details of participant characteristics are in Table 1.

T2DM

Discussion

This analysis investigated the influence of apolipoprotein and lipid biomarkers as predictive factors for developing T2DM during a 10-year follow-up, focusing on the potentially influencing effects of gender, apoA1 polymorphisms along with any interactions with insulin resistance (HOMA) and physical activity. This analysis has provided further evidence of how lipid profile and apolipoproteins influence the risk of developing T2DM in a Greek cohort followed up for 10 years. Additionally, this is

Conclusions

Markers of lipids and apolipoproteins were associated with risk of developing T2DM only in males in this Greek cohort. Additional apoA1 polymorphisms appear to influence the predictive effect of HOMA-IR on T2DM incidence and the potential moderating role of physical activity; suggesting the potential for more targeted and individualized approaches for diabetes prevention strategies based on taking into account the influencing effects of genetic factors, lipid and apolipoprotein levels.

Funding

This work was supported by the Hellenic Cardiology Society, the Hellenic Atherosclerosis Society, the Graduate Program in Applied Nutrition and Dietetics, Harokopio University and the Coca-Cola SA funded this study by research grants (KE252/ELKE/HUA). The ATTICA Study is funded by research grants from the Hellenic Society of Cardiology (grant – 1, 2002).

Declarations of interest

None.

Author contributions

D.D.M., D.B.P., E.N.G., N.M.D., and N.N. conceptualised and wrote the paper. C.C., D.T., and C.P. interpreted the results and critically revised the manuscript. All authors approved the final version of the manuscript. D.B.P. is the guarantor of this work, had full access to all data in the study, and takes responsibility for the accuracy and integrity of the data and manuscript.

Acknowledgements

The authors would like to thank the ATTICA study group: Yannis Skoumas, Natasa Katinioti, Lambros Papadimitriou, Constantina Masoura, Spiros Vellas, Yannis Lentzas, Manolis Kambaxis, Konstanitna Paliou, Vassiliki Metaxa, Agathi Ntzouvani, Dimitris Mpougatas, Nikolaos Skourlis, Christina Papanikolaou, Aikaterini Kalogeropoulou, Evangelia Pitaraki, Alexandros Laskaris, Mihail Hatzigeorgiou, Adela Zana, Athanasios Grekas, and Eleni Kokkou, for either assistance in the physical examination and

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