There is extensive evidence that cholesterol metabolism is abnormal in diabetes. Total plasma cholesterol is elevated, and more subtle indices of sterol homeostasis are also deranged.
Insulinization of the poorly controlled diabetic reduces fecal bile acid excretion. Fecal neutral sterol excretion increases compensatorily, at least when caloric intake is maintained during insulinization. Thus, net sterol balance is not changed by insulin treatment, again assuming the diet remains constant. Other workers have found decreased sterol synthesis after insulinization if calories are reduced. Using isotopically labeled squalene turnover as a reflection of cholesterol synthesis, insulin treatment increases the flux of squalene.
Pursuing diabetes' effect on cholesterol synthesis at a more basic level, we found that HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, is increased in small intestine, and decreased in liver by diabetes in rats eating ad libitum.
These changes in reductase activity are due to hyperphagia (increased caloric and/or cholesterol intake), not to insulin deficiency alone, since diabetic rats restricted to a normal food intake have normal reductase activity in liver and small intestine. It appears that increased input of dietary and newly synthesized cholesterol by the small intestine raises plasma cholesterol level and represses reductase activity in liver of chronically diabetic rats.
Experiments measuring the incorporation of tritiated water into cholesterol find that diabetes has a net suppressive effect on cholesterol synthesis, consistent with insulin's increasing squalene turnover, and consistent with the suppressed liver synthesis being quantitatively more significant than increased intestinal synthesis. When dietary cholesterol intake is included in the calculation, however, hyperphagia may tip the balance in favor of increased net cholesterol input (synthesis plus diet).
We hypothesize that diet plays a central role in the diabetic's cholesterol homeostasis. The hyperphagia of experimental diabetes increases net cholesterol intake and increased HMG-CoA reductase in a hypertrophic small intestine.