ReviewType 1 diabetes, metabolic syndrome and cardiovascular risk
Introduction
Traditionally, patients with type 1 diabetes mellitus (T1DM) suffered microangiopathic complications, especially nephropathy, which had a negative impact on prognosis and quality of life [1]. In 1993, the Diabetes Control and Complications Trial (DCCT) demonstrated that intensive glucose lowering therapy could reduce by 50% the incidence of microangiopathy [2]. The Epidemiology of Diabetes Interventions and Complications trial (EDIC), an extension study of the DCCT, with a mean follow-up of 17 years, revealed a 57% reduction in the relative risk of non-fatal myocardial infarction, stroke or cardiovascular death in the group that had initially received intensive insulin therapy [3]. Ever since, most therapeutic efforts in T1DM have focused on reducing glycated hemoglobin levels. However, a growing body of evidence underlines the frequent coexistence of metabolic syndrome components in patients with T1DM [4], [5], [6], [7], resulting in the so-called "double diabetes" [8] (Fig. 1). This fact, together with the decline in the incidence of microangiopathy, has led to cardiovascular disease now being the leading cause of death in T1DM patients over 30 years of age [9].
Although acceptance of the metabolic syndrome has been controversial in certain scientific forums [10], several studies have shown the classic phenotype of the metabolic syndrome to be associated with increased mortality, nearly 10 times higher in those meeting all components [11]. The prevalence of the metabolic syndrome in the general population ranges from 20% to 50% [5], [12] but it can reach almost 80% in type 2 diabetes patients (T2DM) [5]. In T1DM patients its prevalence varies between 8% and 40% depending on the study population and the diagnostic criteria (Table 1) [4], [5], [6], [7], [13], [14], [15], [16], [17], [18], [19], [20].
Since all these aspects must be taken into account for therapeutic management, we considered it appropriate to review the main factors associated with the metabolic syndrome in T1DM patients and its relationship with the development of chronic complications and mortality.
Section snippets
T1DM and insulin resistance
The metabolic syndrome can be considered a surrogate marker for insulin resistance. Therefore, quantification of insulin resistance in this group of patients seems particularly relevant. The reference method for its calculation is the hyperinsulinemic euglycemic clamp; however, being too invasive, time-consuming and expensive, this technique is limited to research purposes. Thus, various formulas for insulin resistance calculation have been devised for its use at population level, with the
Adiponectin and insulin resistance
Recent studies reported that adiponectin, a fat-derived protein, plays an important role in the regulation of insulin action, glucose and lipid metabolism. In this regard, plasma concentrations of adiponectin are reduced in human obesity and negatively correlated with insulin resistance [29]. Hypoadiponectinemia is independently associated with the metabolic syndrome and with T2DM prevalence and incidence [30].
Paradoxically, adiponectin levels are elevated in T1DM and associated with the
T1DM and obesity
Obesity is currently considered to be the great epidemic of the century, with a prevalence increasing steadily worldwide over the past 20 years. Besides the known association between obesity and type 2 diabetes, a recent meta-analysis showed the presence of obesity in childhood to be a predictor of subsequent T1DM [36].
As mentioned previously, the DCCT study demonstrated the benefits of tight glycemic control in reducing the incidence of microangiopathy. However, this intensive approach also
T1DM and atherogenic dyslipidemia
Atherogenic dyslipidemia, characterized by decreased concentrations of high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia and increased levels of small and dense low-density lipoprotein (LDL) particles, is common in patients with coronary heart disease, metabolic syndrome and type 2 diabetes, and is largely responsible for residual macrovascular and microvascular risk [46], [47].
One proposed mechanism contributing to low HDL cholesterol levels in diabetic dyslipidemia is reduced
T1DM and hypertension
Hypertension constitutes one of the most prevalent cardiovascular risk factors worldwide and particularly in patients with diabetes mellitus, both types 1 and 2 [54]. In the general population, an estimated rise of 20 mm Hg from 115 mm Hg in systolic blood pressure or 10 mm Hg over 75 mm Hg in diastolic blood pressure doubles the risk of cardiovascular events [54]. Strict blood pressure control significantly reduces morbidity and mortality in the general population and in patients with T2DM [53],
Therapeutic strategies
Given this scientific evidence, therapeutic strategies aimed at improving insulin resistance in patients with T1DM are mandatory. Among non-pharmacologic strategies, those promoting a healthy lifestyle in order to reduce overweight and obesity must be emphasized, thereby avoiding the insulin resistance vicious circle (Fig. 2).
In patients with T2DM, physical exercise improves glycated hemoglobin levels and body mass index regardless of diet and other components [64], [65]. In T1DM patients, two
Future research areas
Evidence suggests that common polymorphisms of the adiponectin gene are associated with microangiopathic complications in patients with T2DM [70]. However, few studies have been conducted in T1DM patients and the results were inconclusive [71]. Given the importance of the interaction of genetic and environmental factors in the clinical phenotype of the disease, better understanding of the genetic influence of adiponectin could explain the paradoxical results obtained in T1DM and T2DM.
Little
Conclusions
The presence of metabolic syndrome components in T1DM patients is frequent and is associated with an increased incidence of chronic complications and mortality. eGDR, a surrogate marker of the metabolic syndrome, is useful in T1DM patients as it correlates with the presence of complications and mortality. Thus, patients with T1DM and metabolic syndrome traits should be identified as early as possible and treated appropriately. In this respect, pharmacologic and non-pharmacologic strategies to
Conflict of interest
The authors have nothing to disclose.
Acknowledgments
We thank Miss Christine O’Hara for review of the English version of the manuscript.
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