Is Hyperglycemia the Culprit in Diabetes-accelerated Atherosclerosis?
Final Report Abstract
Cardiovascular disease (CVD) is a complication of patients with diabetes and the metabolic syndrome. What factors contribute to this increase in cardiovascular risks in diabetes and metabolic syndrome? Hypertrigylcerdemia – which itself is a marker of increased cardiovascular disease - is a hallmark of diabetes. The mechanism for hypertriglyceridemia in diabetes is not fully explored. The first aim of this project was to study the mechanism for hypertriglyceridemia in diabetic mice. First I investigated whether insulin deficient diabetic mice had triglyceride changes that resemble those in diabetic humans. Streptozotocin (STZ)–induced insulin deficiency increased plasma triglyceride levels in mice. Contrary to the mouse models with impaired hepatic insulin receptor signalling, insulin deficiency did not reduce hepatic triglyceride secretion and de novo lipogenesis-related gene expression. Diabetic mice had a marked decrease in postprandial TG clearance, which was associated with decreased lipoprotein lipase (LpL) and PPARα mRNA levels in peripheral tissues and decreased LpL activity in skeletal muscle, heart and brown adipose tissue. Diabetic heterozygous LpL knockout mice had markedly elevated fasting plasma triglyceride levels and prolonged postprandial TG clearance. Therefore, insulin deficiency causes hypertriglyceridemia by decreasing peripheral lipolysis and not by an increase in hepatic TG production and secretion. This has potential implications for the treatment of diabetic dyslipidemia; targeting TG lipolysis & clearance appears a more reasonable target that targeting hepatic TG production. In a second project I developed a mouse model to study how the metabolic syndrome, the most common precursor of T2DM, or insulin-deficiency, the hallmark of T1DM, affects atherosclerosis regression. Atherosclerosis regression is impaired in people with diabetes but the reasons for that are not fully understood. A mouse model is much needed to understand why diabetes is detrimental to atherosclerosis regression and to identify possible therapeutic targets. Introduction of a helper-dependent adenovirus that expresses the LDL receptor led to a dramatic reduction in circulating atherogenic lipoproteins. In my studies, regression altered lesional macrophage number and the residual cells were of a less inflammatory phenotype. Moreover, regression led to greater lesional collagen, an indicator of repair and a more stable appearing lesion. These changes of atherosclerosis regression were less pronounced in hyperglycemic, insulin-deficient mice. In contrast, I did not detect differences in atherosclerosis regression in a mouse model of incipient metabolic syndrome with mild glucose intolerance. Despite the marked reduction in plasma cholesterol that is possible using high dose statins and other drugs, diabetes exerts significant vascular toxicity. In T2DM and the metabolic syndrome, factors other than hyperglycemia, including changes in the inflammatory milieu associated with obesity, are likely to prevent normal atherosclerosis regression, and the versatile approach afforded by HDAd-LDLR treatment will make possible insightful investigations of these and other dysmetabolic settings.
Publications
- Abstract 19022: Endothelial cell specific cd36 deletion reduces uptake of fatty acids by the heart. Circulation. 2014;130:A19022
Willecke F, Son N-H, Fang X, Drosatos K, Pietka T, Abumrad NA, Goldberg IJ
- Effects of high fat feeding and diabetes on regression of atherosclerosis induced by low-density lipoprotein receptor gene therapy in ldl receptor-deficient mice. PloS one 2015 10(6): e0128996
Willecke F, Chujun Y, Oka K, Chan L, Hu Y, Barnhart S, Bornfeldt KE, Goldberg IJ and Fisher EA
(See online at https://doi.org/10.1371/journal.pone.0128996) - Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocininduced diabetic mice. Arterioscler Thromb Vasc Biol. 2015;35:102-110
Willecke F, Scerbo D, Nagareddy P, Obunike JC, Barrett TJ, Abdillahi ML, Trent CM, Huggins LA, Fisher EA, Drosatos K, Goldberg IJ
(See online at https://doi.org/10.1161/ATVBAHA.114.304615)
