Impaired fasting glucose: Pro-diabetic, "atheroprotective" and modified by metabolic syndrome

Abstract

Aim: To investigate whether impaired fasting glucose (IFG) confers cardiovascular risk.

Methods: A non-diabetic population-based sample representative of middle-aged and elderly Turks was studied at 8.5 years' follow-up for incident diabetes and coronary heart disease (CHD). Metabolic syndrome (MetS) was defined by ATP-III criteria modified for male abdominal obesity, and IFG and type 2 diabetes were identified by criteria of the American Diabetes Association. Stratification by presence of MetS was used. Outcomes were predicted providing estimates for hazard ratio (HR) obtained by use of Cox proportional hazards regression analysis in models that controlled for potential confounders.

Results: In 3181 adults (aged 52 ± 11.5 years at baseline), analysis stratified by MetS, gender and IFG status distinguished normoglycemic subjects by a "hypertriglyceridemic waist" phenotype consisting of significantly higher waist circumference, fasting triglyceride and lower high-density lipoprotein-cholesterol, regardless of gender and MetS. Additionally, lipoprotein (Lp) (a) tended to be lower in (especially female) participants with MetS. Multivariable linear regression in a subset of the sample demonstrated decreased Lp (a) levels to be associated with increased fasting glucose and insulin concentrations, again particularly in women. In Cox regression analysis, compared with normoglycemia, baseline IFG adjusted for major confounders significantly predicted incident diabetes at a 3-fold HR in men and only women with MetS. Cox models for developing CHD in 339 individuals, adjusted for conventional risk factors, revealed that IFG status protected against CHD risk [HR = 0.37 (95%CI: 0.14-0.998)] in subjects free of MetS, a protection that attenuated partly in male and fully in female participants with MetS.

Conclusion: IFG status in non-diabetic people without MetS displays reduced future CHD risk, yet is modulated by MetS, likely due to autoimmune activation linked to serum Lp (a).

Keywords: Autoimmune activation; Coronary disease risk; Diabetes, type 2; Impaired fasting glucose; Lipoprotein (a); Metabolic syndrome.

Figure 1

Schematic illustration. Schematic illustration of major pathways derived from the current study leading from normoglycemia (NG)/impaired fasting glucose (IFG) to metabolic syndrome (MetS), diabetes (DM) and coronary heart disease (CHD) in non-diabetic men and women. Abdominal obesity and components of atherogenic dyslipidemia, the core of MetS, added to excess lipoprotein (Lp) (a), dysfunction of apoA-I and high-density lipoprotein (HDL) particles, commonly associated with normoglycemia rather than IFG, are major primary determinants of cardiometabolic risk, especially in men. Women often exhibit the added factor of lower assayable Lp (a) due to immune complex formation (ImC) which may lead from IFG via impaired glucose tolerance (IGT) to new-onset and established diabetes or via MetS to diabetes and, in turn, to CHD, contributed by menopause and alterations in sex hormones.