Ketoacidosis in diabetic subjects treated with inhibitors of Na(+)-glucose co-transporters type-2: New mechanisms?

Ketoacidosis with mild or absent hyperglycemia has been reported in diabetic patients (both type-1 and 2), treated with inhibitors of Na+-glucose co-transporters type-2 (SGLT-2).[1] SGLT-2 enhances sodium and glucose re-absorption against concentration gradient in the proximal renal tubule, whereas SGLT-2 inhibitors cause increased urinary glucose excretion, thus contributing to systemic glucose lowering. As explanations for ketoacidosis, some hypotheses have been forwarded. The glucose-lowering effect of SGLT-2 inhibitors may lead to the (inappropriate) reduction of insulin dosage, resulting in enhanced lipolysis and ketone body production. In addition, increased tubular reabsorption and decreased renal clearance of acetoacetate,[2] increased glucagon/insulin ratio, depletion of body energy and carbohydrate stores favoring lipolysis, lipid oxidation[3] and ketogenesis, gastroenteritis-induced dehydration, and, finally, a low carbohydrate diet[2] have been proposed. Indeed, it is well known that ketogenesis can be inhibited by glucose.[4] However, these hypotheses can be integrated by additional considerations involving the sites of both ketone body production and of the SGLT-2 inhibition effects. The ketone bodies acetoacetate and 3-hydroxybutyrate are mainly produced by the liver, but also by skeletal muscle, particularly in uncontrolled diabetes.[5] While in muscle, the ketogenic capacity is low when expressed per gram of tissue, it may become quantitatively important given the large muscle mass. Conversely, although SGLT-2 expression/activity has been predominantly located in the kidney, they have also been detected in liver and skeletal muscle in human tissues.[6] Therefore, I would propose the following integrative mechanism: Treatment with SGLT-2 inhibitors, by reducing glucose uptake (both oxidative and nonoxidative) in peripheral tissues,[3] possibly also in liver and muscle, may favor a switch from glucose to lipid utilization, resulting in increased ketogenesis in these tissues. The decrease of systemic glucose concentration is probably the major cause of reduced glucose utilization. However, a possible direct effect of SGLT-2 inhibitors on SGLT-2-mediated glucose uptake in tissues or organs other than the kidney cannot be excluded “a priori,” and might be specifically investigated.