Markedly increased cholesterol synthesis and low absorption of cholesterol in our obese patients with type 2 diabetes (1) prompted Dr. Ertel (2) to question whether the “succinate hypothesis” could explain the changes in cholesterol metabolism.
According to the succinate mechanism, summarized by Fahien and MacDonald (3), a basic requirement for insulin release would be the generation of mevalonic acid. This would be regulated by insulinotropic action of succinate and other nutrient secretagogues through several intracellular metabolic (cytosolic and mitochondrial) reactions in islet and apparently also hepatic cells. Intact pancreatic islets synthesize and metabolize mevalonate, the production of which results in the release of insulin from islet cells. Lovastatin and simvastatin, inhibitors of mevalonate production, can inhibit glucose-induced release of insulin from islets, which can be prevented by mevalonate (3). Accordingly, statin treatment, especially the use of long-term ones, should be associated with decreased insulin secretion and perhaps reduced development of diabetes. No exact insulin measurements have been performed during statin treatments, but in one study, the development of diabetes appeared to be reduced by statin (4).
Ertel (2) assumed, according to the succinate mechanism, that the metabolism of pyruvate is enhanced in hepatic mitochondria of diabetes, resulting in increased production of hydroxymethylglutaryl (HMG)-CoA, mevalonate, and cholesterol, apparently in the presence of obesity and excess insulin. It should be emphasized that this also might occur during normal conditions without diabetes or obesity. Namely, nondiabetic men with blood glucose in the highest tertile have higher cholesterol synthesis, lower cholesterol absorption, and a lower insulin sensitivity index (despite having higher insulin) than those with blood glucose levels in the lowest tertile (5). This indicates that cholesterol metabolism is changed proportionately to insulin resistance, reaching higher levels in overweight and obesity. Additional change in altered cholesterol metabolism is probably seen proportionately to insulin resistance also by diabetes, as demonstrated in the article by Simonen et al. (1). Since overweight conditions without and with diabetes increase hepatic synthesis of not only cholesterol, but also of triglycerides, the succinate mechanism could cover lipid and also fatty acid metabolism in a larger scale. However, the mechanism of reduced cholesterol absorption efficiency still remains open.
Address correspondence to Tatu A. Miettinen, Institute of Biomedicum Helsinki, C4 22, P.O. Box 700, 00029-HUS, Helsinki, Finland. E-mail: email@example.com.