Does HDL Play a Causal Role in the Pathogenesis of Diabetes?

Several epidemiological studies have shown the association between low plasma concentrations of HDL-C and increased risks not only of CHD but also T2DM (Di et al. 2009; von Eckardstein et al. 2000).

We have seen that some of the metabolic perturbations (hyperglycemia, hypertriglyceridemia, etc.) associated with diabetes (and the metabolic syndrome) are mechanistically linked to decreased HDL cholesterol levels in blood. Traditionally, a reduced plasmatic level of HDL cholesterol has been interpreted to be the result of such metabolic perturbations, which are already present in the prediabetic state, and hence an innocent bystander of T2DM. However, several more recent studies suggest that HDLs help to maintain euglycemia via both insulin-dependent and insulin-independent pathways (Drew et al. 2012; von Eckardstein and Sibler 2011). The infusion of artificially reconstituted HDL (rHDL) was found to improve glycemia in patients with T2DM (Drew et al. 2009). In a post hoc analysis of data from diabetic participants in the ILLUMINATE trial, the addition of the CETP inhibitor torcetrapib to atorvastatin was found to increase HDL-C and to improve glycemic control (Barter et al. 2011). Several in vitro and animal experiments provided evidence that HDL improves the function and survival of beta cells as well as glucose-lowering metabolism in the muscle, liver, and adipose tissue (Drew et al. 2012; von Eckardstein and Sibler 2011; von Eckardstein and Widmann 2014). In mice, the absence of ApoA-I leads to hyperinsulinemia and hyperglycemia as well as altered responses to insulin tolerance tests. Vice versa, ApoA-I transgenic mice exhibit lower fasting glucose levels and improved glucose tolerance test compared with wild-type mice (Han et al. 2007; Lehti et al. 2013). These data point to a modulating role of HDLs in maintaining normal glucose homeostasis. Moreover, genetically increased HDL cholesterol and ApoA-I levels in mice prevented high-fat diet-induced glucose homeostasis impairment (Lehti et al. 2013). Although it remains to be determined whether this is related to differences in skeletal muscle insulin resistance, adipose tissue mass, or differences in beta cell function, these data obtained in mice indicate that ApoA-I plays a modulatory role in the regulation of glucose homeostasis. This notion is also supported by studies in humans displaying altered HDL metabolism due to polymorphisms in the ApoA-I and ABCA1 genes that have been associated with increased risk of diabetes and impaired glucose uptake (Morcillo et al. 2005; Villarreal-Molina et al. 2008). Heterozygotes for rare mutations in the ABCA1 gene that profoundly decrease HDL-C levels were found to be less glucose tolerant than their unaffected relatives (Vergeer et al. 2010). However, it should also be noted that larger population studies did not find any association between heterozygosity for ABCA1 mutations and risk of diabetes (Schou et al. 2012).

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