Unexplained reciprocal regulation of diabetes and lipoproteins.

Abstract

Type 2 diabetes is associated with a characteristic dyslipidemia that may exacerbate cardiovascular risk. The causes of, and the effects of new antihyperglycemia medications on, this dyslipidemia, are under investigation. In an unexpected reciprocal manner, lowering LDL-cholesterol with statins slightly increases the risk of diabetes. Here we review the latest findings. The inverse relationship between LDL-cholesterol and diabetes has now been confirmed by multiple lines of evidence. This includes clinical trials, genetic instruments using aggregate single nucleotide polymorphisms, as well as at least eight individual genes - HMGCR, NPC1L1, HNF4A, GCKR, APOE, PCKS9, TM6SF2, and PNPLA3 - support this inverse association. Genetic and pharmacologic evidence suggest that HDL-cholesterol may also be inversely associated with diabetes risk. Regarding the effects of diabetes on lipoproteins, new evidence suggests that insulin resistance but not diabetes per se may explain impaired secretion and clearance of VLDL-triglycerides. Weight loss, bariatric surgery, and incretin-based therapies all lower triglycerides, whereas SGLT2 inhibitors may slightly increase HDL-cholesterol and LDL-cholesterol. Diabetes and lipoproteins are highly interregulated. Further research is expected to uncover new mechanisms governing the metabolism of glucose, fat, and cholesterol. This topic has important implications for treating type 2 diabetes and cardiovascular disease.