HDL subclasses and the common CETP TaqIB variant predict the incidence of microangiopatic complications in type 2 diabetic women: A 9 years follow-up study
Introduction
Diabetic kidney disease (DKD) and diabetic retinopathy (DR) are the most common microvascular complications of diabetes; hypertension and hyperglycemia play an important role in the progression of these two disorders [1], [2]. Hyperglycaemia and hypertension management is the gold standard of therapy to prevent microvascular complications, however, DKD and DR progress in many patients despite the achievement of the recommended targets for glycaemia and blood pressure [3]. Thus, after the correction of these major risk factors, due to the better prevention and therapeutic options today available, the spectrum of alterations associated with microangiopathy has enormously enlarged.
In particular diabetic dyslipidemia, i.e. high triglycerides (TG) and low HDL cholesterol (HDL-C) levels, has been related to both DKD and DR [4], [5], but to date there is no final agreement on considering these conditions as a relevant risk factor for microvascular complications.
Thus, several recent studies indicated an association of high TG/low HDL-C levels with the development of DKD [4], [5], whereas other Authors did not found an association [6], [7].
Diabetic dyslipidemia has been also associated with DR [5], [8], although other studies did not show any association [9], [10], or even demonstrate an association between higher HDL-C levels and DR [11]. Furthermore, other reports suggest that the impact of hypertriglyceridemia and low HDL-C levels may be different for DKD and RD, being high TG levels an independent risk factor for RD [12] and low-HDL-C significantly associated with DKD [10].
These controversial findings on the role of diabetic dyslipidemia on microvascular complications may depend upon several factors. First, diabetic dyslipidemia may have a gender-specific impact on DKD and DR. It has been demonstrated that diabetic dyslipidemia have no impact on DKD and RD in women with type 2 diabetes [6], [7] and lower HDL-C levels seem to be associated with the progression of DKD in men but not in women [6].
Also genetic background may play a role and genes implied in TG/HDL metabolism may modulate the effects of diabetic dyslipidemia traits on microvascular outcomes. More than 50% of circulating HDL-C is genetically determined and the common TaqIB variant in the gene coding for cholesteryl ester transfer protein (CETP), a key enzyme in reverse cholesterol transport (RCT), has been associated with lower CETP activity, higher HDL-C levels and with amore atheroprotective HDL subpopulations profile [13], [14], especially in diabetic women [15].
Finally, lipid modifications associated to diabetes are not limited to quantitative variations of TG/HDL-C but they comprise also more subtle modifications of lipid fractions. Thus, measuring HDL-C or TG levels may not be sufficient to let the association of diabetic dyslipidemia with DKD and/or DR emerge. HDL particles differ in size and composition and it has been demonstrated that type 2 diabetes determines a shift in the distribution of Apo-AI containing HDL particles, with a depletion in the large lipid-rich α-1, α-2, and a rise in pre-α 1 and enriched in the small, lipid-poor α-3 HDL subpopulations [15]. These modifications result in smaller and cholesterol poor HDL particles compared with those of non-diabetic subjects.
In order to better clarify these issues, here we report our findings on the effect of diabetic dyslipidaemia, the distribution of the HDL LpA-I and LpA-I:A-II subclasses and the common CETP TaqIB variant on the incidence or the progression of DKD and DR in a group of women with type 2 diabetes, after a ∼9 years of follow-up.
Section snippets
Study population
Clinical and laboratory data from 97 women with type 2 diabetes attending the Metabolic Disease Outpatient Clinic of Messina University Hospital, Italy, collected between 1st January 2002 and 31st January 2015 (mean follow-up: 8.84 ± 3.88 years) were analysed.
At baseline, exclusion criteria for all participants were: pregnancy, hormonal replacement therapy, oral contraceptive use or multivitamin supplementation, current treatment with β blockers, fibrates, statins, omega 3 fatty acids, niacin,
Baseline clinical characteristics of T2D women participating to the study
Baseline clinical characteristics of 97 diabetic women completing the follow-up evaluation are shown in Table 1. Study participants (mean age 57 years) were obese (mean BMI 32 kg/m2; mean waist circumference 100 cm), insulin-resistant (mean HOMA-IR values >7), with an acceptable metabolic control (mean HbA1c 7.43%, 57 mmol/mol; mean FBG 163 mg/dl) despite the relatively long duration of diabetes (7 years). A family history of cardiovascular disease was present in the 37% of participants; 61% were
Discussion
Our data show that baseline BMI, HbA1c, triglycerides, HDL-C levels and HDL subpopulations, and to a minor extent the common CETP TaqIB polymorphism, predict the occurrence of microvascular complications in women with type 2 diabetes followed-up for ∼9 years.
The pathophysiologic role of glucose control, as documented by HbA1c values, on the incidence of DKD and RD is undisputed, both in subjects with type 1 and type 2 diabetes [22], [23]. Blood pressure control is the other fundamental step in
Conclusions
In conclusions, our data demonstrate that in diabetic women, atherogenic dyslipidemia as well as subtle modifications in lipoprotein particles profile and to a minor extent the common CETP Taq1B polymorphism are associated with incidence and progression of microvascular disease. These results strengthen the rationale for focusing on dyslipidemia treatment to prevent microvascular disease.
Acknowledgments
All the Authors significantly contributed to the study and approved the final manuscript.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
The Authors declare they do not have any conflict of interest.
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