In the recent article by Simonen et al. (1) demonstrating increased cholesterol synthesis in obese patients with diabetes, the authors did not consider a possible mechanism suggested by the “succinate hypothesis,” which is elegantly summarized by Fahien and MacDonald (2) in a separate article. Fahien and MacDonald showed that succinate esters are potent insulin secretagogues (almost as potent as glucose) through generation of succinyl-CoA (S-CoA). This seemed to be specific to S-CoA, since other citric acid cycle (CAC) molecules (malate, α-ketoglutarate, fumarate, and citrate) did not promote insulin release. S-CoA stimulates the enzyme succinyl-CoA-acetoacetate transferase (reaction 3, Fig. 1 ) to increase the production of aceto-acetyl-CoA, which can be utilized to form hydromethylglutaryl (HMG)-CoA, and mevalonate-biosynthetic precursors of cholesterol. In fact, the authors postulate that insulin release is triggered by production of mevalonate.
If this same pathway occurs in the liver, then the increased glucose of diabetes would be metabolized to pyruvate that can then enter the mitochondria. Conversion to acetyl-CoA and oxaloacetate by pyruvate dehydrogenase and pyruvate carboxylase would lead to increased production of acetyl-CoA and succinate that could result in increased production of HMG-CoA, mevalonate, and, presumably, cholesterol (Fig. 1).
Several authors have shown that cholesterol absorption is decreased and that cholesterol biosynthesis is increased in diabetes (3). The increased cholesterol synthesis is reduced by insulin (4). Since either metabolic alteration could be primary, and the other follow pari passu, it would be important to identify the initiating event in the hyperglycemic state. The succinate hypothesis would then suggest that the increased synthesis of cholesterol is primary. The data in the article by Simonen et al., which show a tighter correlation between glucose levels and increased cholesterol synthesis than with decreased cholesterol absorption, also support the primary role of synthesis.
A simplified scheme for the interaction between succinate and HMG-CoA metabolism (modified from Fig. 1, ref. 2).
A simplified scheme for the interaction between succinate and HMG-CoA metabolism (modified from Fig. 1, ref. 2).
References
Address correspondence to Norman H. Ertel, MD, FACP, Chief, Medical Service, VA New Jersey Health Care System, 385 Tremont Ave., East Orange, NJ 07018. E-mail: [email protected].
