The role of lipids in the pathogenesis and treatment of type 2 diabetes and associated co-morbidities

Abstract

In the past decade, the incidence of type 2 diabetes (T2D) has rapidly increased, along with the associated cardiovascular complications. Therefore, understanding the pathophysiology underlying T2D, the associated complications and the impact of therapeutics on the T2D development has critical importance for current and future therapeutics. The prevailing feature of T2D is hyperglycemia due to excessive hepatic glucose production, insulin resistance, and insufficient secretion of insulin by the pancreas. These contribute to increased fatty acid influx into the liver and muscle causing accumulation of lipid metabolites. These lipid metabolites cause dyslipidemia and non-alcoholic fatty liver disease, which ultimately contributes to the increased cardiovascular risk in T2D. Therefore, understanding the mechanisms of hepatic insulin resistance and the specific role of liver lipids is critical in selecting and designing the most effective therapeutics for T2D and the associated co-morbidities, including dyslipidemia and cardiovascular disease. Herein, we review the effects and molecular mechanisms of conventional anti-hyperglycemic and lipid-lowering drugs on glucose and lipid metabolism. [BMB Reports 2016; 49(3): 139-148].

Fig. 1.. A pathophysiological development of diabetes and associated co-morbidities. Concomitant with impaired insulin action on glucose metabolism and lipogenesis remains unaffected in the liver . Therefore, unsuppressed hepatic glucose production along with increased lipogenesis likely worsens the development of hepatic steatosis and dyslipidemia . This may partially explain why conventional anti-hyperglycemic agents have not shown benefits on the life-threatening macrovascular complications, including CVD atherosclerosis and coronary heart diseases. On the contrary, tissue lipid lowering diabetic drugs could have the potential to decrease both tissue and circulating lipid abnormalities, thereby partially linking diabetic dyslipidemia to increased CVD risk. HGP: hepatic glucose production, G6P: glucose-6-phosphate, DNL: de novo lipogenesis, DAG: diacylglycerol, TAG: triglyceride, VLDL: very low-density lipoprotein, MGAT: monoacylglycerol acyltransferase, DGAT: diglyceride acyltransferase.