Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs

Abstract

Aims/hypothesis Diabetes is associated with an increased risk of atherosclerotic cardiovascular disease, but whether there is a direct and independent role for impaired glucose control in atherogenesis remains uncertain. We investigated whether diabetes with poor glycaemic control would accelerate atherogenesis in a novel pig model of atherosclerosis, the D374Y-PCSK9 + transgenic minipig. Methods Nineteen minipigs were fed a cholesterol-enriched, high-fat diet; ten of these pigs were injected with streptozotocin to generate a model of diabetes. Restricted feeding was implemented to control the pigs' weight gain and cholesterol intake. After 49 weeks of high-fat feeding, the major arteries were harvested for a detailed analysis of the plaque burden and histological plaque type.Results Stable hyperglycaemia was achieved in the diabetic minipigs, while the plasma total and LDL-cholesterol and creatinine levels were unaffected. Diabetes failed to increase atherosclerosis in any of the vessels examined. The plaque burden in the aorta and right coronary artery was comparable between the groups, and was even reduced in the left anterior descending (LAD) coronary and iliofemoral arteries in the diabetic pigs compared with the controls. The distribution of plaque types and the collagen and macrophage contents were similar between the groups, except for a reduced infiltration of macrophages in the LAD arteries of the diabetic pigs. Conclusions/interpretation Poorly controlled diabetes with no alterations in plasma cholesterol or creatinine concentrations did not augment the plaque burden or promote the development of more advanced lesions in this large-animal model of humanlike atherosclerosis. This is consistent with clinical studies in patients with type 1 diabetes, indicating that hyperglycaemia per se is not an independent promoter of atherosclerotic disease, but that other diabetes-associated risk factors are important.

Serum insulin levels are associated with vulnerable plaque components in the carotid artery: the Rotterdam Study

“…Surprisingly, we found no effects of serum glucose levels in carotid plaque composition. In the context of glucose, our findings are in contrast with studies that link glucose levels below 7.0 mmol/L with an increased risk of vascular disease (28). However, a recent meta-analysis of 102 prospective studies that investigated the relationship between fasting glucose levels and risk of vascular diseases concluded that glucose concentrations were non-linear and modestly associated with the risk of vascular diseases among individuals without diabetes (21), meaning that glucose levels below and higher than 7.0 mmol/L were associated with increased risk for coronary heart disease and ischemic stroke (21).…”

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association

“…Although there are several hypotheses concerning why this occurs, the basis for the correlation between diabetes mellitus and increased atherosclerosis remains incompletely understood, especially whether hyperglycemia per se accelerates the development of atherosclerosis. 89,90 Several models of diabetes mellitus have been developed in mice, rabbits, pigs, and nonhuman primates, as reviewed in detail elsewhere. 91 The most common is the streptozotocin injection model, which mimics a type 1-like form of diabetes mellitus in animals.…”

Does Elevated Glucose Promote Atherosclerosis? Pros and Cons

“…A similar lack of hyperglycemia in promoting atherosclerosis have been shown in diabetic Ldlr −/− mice fed a high-fat diet 13 and in diabetic hypercholesterolemic minipigs. 14 Thus, hyperglycemia is not sufficient to promote atherosclerosis. This might be due to the fact that dyslipidemia is a much stronger driver of atherosclerosis than is diabetes per se , and that in hypercholesterolemic models, the effects of diabetes are masked, as has been demonstrated in diabetic hyperlipidemic mice.…”