Non-Cholesterol Sterol Levels Predict Hyperglycemia and Conversion to Type 2 Diabetes in Finnish Men

Henna Cederberg,Markku Laakso,Helena Gylling,Johanna Kuusisto,Jussi Paananen,Jagadish Vangipurapu,Jussi Pihlajamäki,Teemu Kuulasmaa,Alena Stančáková,Ulf Smith,Tatu A Miettinen

doi:10.1371/journal.pone.0067406

Abstract

We investigated the levels of non-cholesterol sterols as predictors for the development of hyperglycemia (an increase in the glucose area under the curve in an oral glucose tolerance test) and incident type 2 diabetes in a 5-year follow-up study of a population-based cohort of Finnish men (METSIM Study, N = 1,050) having non-cholesterol sterols measured at baseline. Additionally we determined the association of 538,265 single nucleotide polymorphisms (SNP) with non-cholesterol sterol levels in a cross-sectional cohort of non-diabetic offspring of type 2 diabetes (the Kuopio cohort of the EUGENE2 Study, N = 273). We found that in a cross-sectional METSIM Study the levels of sterols indicating cholesterol absorption were reduced as a function of increasing fasting glucose levels, whereas the levels of sterols indicating cholesterol synthesis were increased as a function of increasing 2-hour glucose levels. A cholesterol synthesis marker desmosterol significantly predicted an increase, and two absorption markers (campesterol and avenasterol) a decrease in the risk of hyperglycemia and incident type 2 diabetes in a 5-year follow-up of the METSIM cohort, mainly attributable to insulin sensitivity. A SNP of ABCG8 was associated with fasting plasma glucose levels in a cross-sectional study but did not predict hyperglycemia or incident type 2 diabetes. In conclusion, the levels of some, but not all non-cholesterol sterols are markers of the worsening of hyperglycemia and type 2 diabetes.

Highlights

Type 2 diabetes is associated with atherogenic dyslipidemia [1] increasing the risk of cardiovascular mortality and morbidity [2]
Atherogenic dyslipidemia predicts the development of type 2 diabetes [1], and sterols associated with cholesterol synthesis and absorption could contribute to the risk of the development of hyperglycemia and type 2 diabetes
We demonstrated for the first time that non-cholesterol sterol levels predicted the worsening of hyperglycemia and the development of incident type 2 diabetes in a 5-year prospective follow-up of a Finnish population-based study including 1,050 men

Summary

Introduction

Type 2 diabetes is associated with atherogenic dyslipidemia [1] increasing the risk of cardiovascular mortality and morbidity [2]. Atherogenic dyslipidemia predicts the development of type 2 diabetes [1], and sterols associated with cholesterol synthesis and absorption could contribute to the risk of the development of hyperglycemia and type 2 diabetes. Single nucleotide polymorphisms (SNPs) in the sitosterolemia genes ABCG5 and ABCG8, encoding the ATP-binding cassette subfamily G member proteins, have been shown to regulate cholesterol absorption [11,12,13]. These transporters actively efflux plant sterols and, to a lesser extent cholesterol, back into the intestinal lumen. The impact of SNPs in ABCG5/8, and possible other, yet undiscovered SNPs on the association between non-cholesterol sterol levels and glucose metabolism is largely unknown

Methods

Results

Conclusion