Pathophysiology of Diabetic Dyslipidemia

Abstract

Accumulating clinical evidence has suggested serum triglyceride (TG) is a leading predictor of atherosclerotic cardiovascular disease, comparable to low-density lipoprotein (LDL)-cholesterol (C) in populations with type 2 diabetes, which exceeds the predictive power of hemoglobinA1c. Atherogenic dyslipidemia in diabetes consists of elevated serum concentrations of TG-rich lipoproteins (TRLs), a high prevalence of small dense low-density lipoprotein (LDL), and low concentrations of cholesterol-rich high-density lipoprotein (HDL)2-C. A central lipoprotein abnormality is an increase in large TG-rich very-low-density lipoprotein (VLDL)1, and other lipoprotein abnormalities are metabolically linked to increased TRLs. Insulin critically regulates serum VLDL concentrations by suppressing hepatic VLDL production and stimulating VLDL removal by activation of lipoprotein lipase. It is still debated whether hyperinsulinemia compensatory for insulin resistance is causally associated with the overproduction of VLDL. This review introduces experimental and clinical observations revealing that insulin resistance, but not hyperinsulinemia stimulates hepatic VLDL production. LDL and HDL consist of heterogeneous particles with different size and density. Cholesterol-depleted small dense LDL and cholesterol-rich HDL2 subspecies are particularly affected by insulin resistance and can be named "Metabolic LDL and HDL," respectively. We established the direct assays for quantifying small dense LDL-C and small dense HDL(HDL3)-C, respectively. Subtracting HDL3-C from HDL-C gives HDL2-C. I will explain clinical relevance of measurements of LDL and HDL subspecies determined by our assays. Diabetic kidney disease (DKD) substantially worsens plasma lipid profile thereby potentiated atherogenic risk. Finally, I briefly overview pathophysiology of dyslipidemia associated with DKD, which has not been so much taken up by other review articles.

Keywords: Diabetes; HDL subspecies; Insulin resistance; Small dense LDL; Triglyceride-rich lipoproteins.

Fig. 1.

Pathogenesis of insulin resistance on VLDL overproduction and its related changes in other lipoproteins. Hepatic VLDL1 production is stimulated by insulin resistance, which is a central lipoprotein abnormality in diabetic dyslipidemia. The major sources of triglyceride (TG) in the liver are 1) free fatty acid (FFA) derived from adipose, 2) fatty acids derived from remnants of TRL (VLDL and chylomicron), and 3) de Novo Lipogenesis (DNL). Newly synthesized TG suppress intracellular apoB degradation. Insulin resistance is associated with reduced inhibition of hormone-sensitive lipase in adipose tissue, thereby augmented portal flux of FFA. TG synthesis from FFA or FFA per se strongly inhibit apoB degradation in the liver, thereby stimulates VLDL production. Hepatic uptake of TG-rich lipoprotein (TRL) remnants and DNL supply TG in the liver, but the contribution of these two factors to suppress apoB degradation are minor. Insulin resistance suppresses phosphoinositide (PI) 3-kinase mediated apoB degradation and enhances the action of microsomal triglyceride transfer protein (MTP), a rate-limiting factor of VLDL assembly. In the insulin-resistant state, VLDL1 production is preferentially increased without affecting VLDL2 production. Overproduction of VLDL1 is metabolically associated with preponderance of small dense LDL and reduced large cholesterol-rich HDL2.

Fig. 2.

Overproduction of TG-rich lipoproteins creates small dense LDL. Production of VLDL and chylomicrons (TG-rich lipoproteins (TRLs)) is stimulated in individuals with type 2 diabetes. The long residence time of TRLs in circulation promotes excessive transfer of TG to LDL and a concomitant transfer of cholesteryl esters (CE) to TRLs via the action of cholesteryl ester transfer protein (CETP). Hepatic TG lipase-mediated hydrolysis of core TG produces cholesterol-poor LDL particles (small dense LDL).

Fig. 3.

Relationship between LDL-C and small dense LDL-C concentrations in healthy controls, patients with type 2 diabetes without coronary heart diseases (CAD), and patients with CAD including diabetes. SdLDL-C levels corresponding to LDL-C levels are higher in patients with diabetes or CAD than in healthy controls. This figure is made based on our original data published in reference (80).