Killing Two Birds With One Stone, Maybe

Abstract

Connections between glucose and lipid metabolism have long been recognized. It is well known that impaired glucose metabolism, particularly in diabetes mellitus, influences plasma levels of both apoB- and apoAI-containing lipoproteins and induces an abnormal lipid phenotype known as atherogenic dyslipidemia.1 This is characterized by high triglycerides, low high-density lipoprotein (HDL), and elevated low-density lipoprotein (LDL) particle concentration attributable to a preponderance of smaller-sized LDL. These effects are seen as secondary to the insulin-resistant state and caused by its interference with the lipid homeostatic mechanisms, including increased secretion of apoB-containing lipoproteins and reduced lipolysis of triglyceride-rich particles. However, a direct influence of primary abnormalities in lipid metabolism on glucose homeostatic mechanisms is not commonly recognized, with the exception of subjects with extreme hypertriglyceridemia caused by lipoprotein lipase deficiency, where diabetes mellitus may develop during periods of uncontrolled dyslipidemia, and control of glucose levels is achieved by adjustment of triglycerides.2 Although lipotoxicity is known to harm many tissues and cells, the presence of common dyslipidemia is not considered as a risk factor for changes in insulin sensitivity by liver, muscle, or adipose tissue, or in insulin production by the pancreatic beta cell. Article, see p 167 In the past few years, this general concept has been challenged with the recognition that membrane cholesterol levels regulate insulin exocytosis from beta cells. In particular, the absence of the main cellular cholesterol transporter, ABCA1, drastically reduces insulin output.3,4 Because ABCA1 controls the first step in the extracellular process known as reverse cholesterol transport, mediated by the circulating HDL particle, this suggests that natural or drug-induced changes in HDL metabolism or composition may influence the ability of beta cells to respond to physiological stimuli, including glucose. Hence, it is possible that in some instances diabetes mellitus development may be accelerated …