The nature of large vessel disease in diabetes mellitus

Abstract

Reprint requests: Thomas Ledet, MD, Research Laboratory for Biochemical Pathology, Aarhus Kommunehospital, DK-8000, Aarhus C, Denmark. The problem of cardiovascular disease and diabetes mellitus can be subdivided into one distinct zone where large-scale research work has provided a number of well documented pieces of information from epidemiologic and clinical studies, and another, large and indeterminate grey region of unasked questions and unposed problems, which is inhabited by borderline problems between diabetes and cardiovascular research. The epidemiologist has told us that heart disease occurs 3-5 times more frequently among diabetic patients. At present, it is not possible to explain this very high frequency as a consequence of the usual risk factors in atherosclerosis, such as increased serum LDL.’ Likewise, various experimental investigations have not been able to provide an explanation through analyses of non-enzymatic glycosylated lipoproteins.* In our laboratory, the study of large vessel disease in diabetes mellitus is guided by a hypothesis that postulates the existence of a diabetic macroangiopathy which develops independent of the usual atherosclerotic risk factors, but is a result of diabetic intermediary metabolism and endocrinopathy.3s4 Since deposition of a strong PAS-positive substance in the wall of the smaller blood vessels is a characteristic feature of diabetic microangiopathy, we decided to investigate the extent of this PAS-positive substance in the larger coronary arteries from a group of NIDDM patients.5 The data obtained from the diabetic patients were compared with the results from a group of age and gender matched nondiabetic subjects. An area of the tunica media was selected, based on the presence or absence of atherosclerotic plaques in the tunica intima. Using a traditional point counting procedure, we estimated the area occupied by the PAS-positive material in the tunica media. It appeared that a significantly larger area was occupied by the PAS-positive substance in the coronary arteries from diabetic individuals than was the case in nondiabetics. Moreover, it appeared that the size of the PAS-positive area was completely independent of the presence of atherosclerotic plaques (Figure 1). The same pattern was observed when the amount of collagen was evaluated using a histologic staining technique and the same point counting. In other histologic sections taken from the same samples of the coronary arteries, the area occupied by acid mucopolysaccharides (glycosaminoglycans) was evaluated by identification with alcian blue, again with the point counting procedure. It could be shown that the area containing acid mucopolysaccharides was substantially reduced in coronary arteries from diabetic patients, independent of the presence of atherosclerotic plaques. The basement membrane in the tunica media is a PAS-positive structure surrounding individual arterial smooth muscle cells.6s7 Since the basement membrane is abnormal in many organs in diabetic patients, we have focused on the elaboration of that structure in a tissue culture system of rabbit aortic smooth muscle cells. Using normolipemic fasting serum from a group with IDDM and a group with NIDDM, we have evaluated the elaboration of basement membrane, and found that sera from the diabetic patients significantly enhanced the accumulation of basement membrane material compared with sera from normolipemic nondiabetic individuals of the same age and gender (Figure 2).* In the same culture system, we tested the effect of hyperlipemic serum obtained from rabbits fed a high cholesterol diet for more than 6 weeks, but found no influence on basement membrane accumulation.