Insulin and Atherosclerosis
My last post probably sounded really speculative when I suggested that whatever causes diabetes, should also be suspected to cause atherosclerosis. This raises the rather disconcerting possibility that insulin itself causes atherosclerosis or at least makes it worse. Insulin resistance and hyperinsulinemia characterize Type 2 diabetes so it’s certainly possible that chronically high insulin causes the high incidence of atherosclerosis in diabetics in addition to the other effects insulin may have on triglycerides, lipoproteins, or blood pressure. Since refined and easily digestible carbohydrates cause us to secrete insulin excessively then they might be responsible for causing or exacerbating atherosclerosis in non-diabetics.
This idea, along with the idea the insulin regulates blood pressure, is not new and has been neglected for decades. Science writer Gary Taubes noted that the fourteenth edition (2005) of Joslin’s Diabetes Mellitus contained a brief portion of this argument. Harvard diabetologist Edward Freener and Victor Dzau, the president of the Duke University Health System, wrote
“The effects of insulin on cardiovascular disease in diabetes and insulin resistance are related to both systematic metabolic abnormalities and the direct effects of insulin action on the vasculature.”
The second mention in the book was from two Harvard cardiologists and they acknowledge the association between insulin resistance, hyperinsulinemia, and heart disease. They suggest that if insulin resistance is not the problem, then “another possibility” is that insulin itself “has direct cardiovascular effects.” Ironically, the evidence came from the same type of experiment that began the cholesterol hypothesis a century ago. Rabbits develop plaques on their arteries when fed a high-cholesterol diet. However, diabetic rabbits (Type I – who cannot store fat) will not suffer this atherosclerotic fate no matter how cholesterol-rich their diet. Infuse insulin along with the cholesterol-laden diet and plaques and lesions will promptly blossom everywhere. This phenomenon was first reported in 1949 in rabbits, and then a few years later, in chickens by Jeremiah Stamler and his mentor Louis Katz, and later in dogs too. Insulin itself may be “one factor in the pathogenesis of the frequent, premature, severe atherosclerosis of diabetic persons” according to Stamler and his colleagues.
Robert Stout
In 1960, Robert Stout of Queen’s University in Belfast published a series of studies reporting that insulin enhances the transport of cholesterol and fats into the cells of the arterial wall and stimulates the synthesis of cholesterol and fat in the arterial lining. A primary role of insulin is to facilitate fat storage in the fat tissue so it was not surprising that it would have the same effect on the lining of blood vessels. In July 1969, Stout and British diabetologist John Vallance-Owen pre-empted Gerald Reaven’s Syndrome X hypothesis by suggesting that the “ingestion of large quantities of refined carbohydrate” leads first to hyperinsulinemia and insulin resistance and then to atherosclerosis and heart disease. In certain individuals, the insulin secretion after eating these carbohydrates would be “disproportionately large.”
“Carbohydrate is disposed of in three sites: Fat tissue, liver, and arterial wall. Obesity is produced. In the liver, triglyceride and cholesterol are synthesized and find their way into the circulation. Lipid synthesis is also stimulated in the arterial wall and is augmented by deposition of triglycerides and cholesterol which in a few decades would reach significant proportions.”
In 1975, Stout and University of Washington pathologist Russell Ross reported that insulin also stimulates the proliferation of the smooth muscle cells that line the interior of arteries, a necessary step in the thickening of artery walls characteristic of both atherosclerosis and hypertension. This hypothesis is the simplest explanation for the intimate association of diabetes and atherosclerosis; the excessive secretion of insulin accelerates atherosclerosis and perhaps other vascular complications. It also implies, as Stout suggested, that any dietary factor – refined carbohydrates in particular – that increases insulin secretion would increase heart disease risk. There were some who embraced the hypothesis but Reaven chose to ignore it. His hypothesis proposed that primarily insulin resistance through its influence on triglycerides caused heart disease. He considered hyperinsulinemia to be a secondary phenomenon. Stout considered hyperinsulinemia to be the primary cause of atherosclerosis.
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