Diabetes and dyslipidemia: characterizing lipoprotein metabolism

Abstract

Premature atherosclerosis in diabetes accounts for much of the decreased life span. New treatments have reduced this risk considerably. This review explores the relationship among the disturbances in glucose, lipid, and bile salt metabolic pathways that occur in diabetes. In particular, excess nutrient intake and starvation have major metabolic effects, which have allowed us new insights into the disturbance that occurs in diabetes. Metabolic regulators such as the forkhead transcription factors, the farnesyl X transcription factors, and the fibroblast growth factors have become important players in our understanding of the dysregulation of metabolism in diabetes and overnutrition. The disturbed regulation of lipoprotein metabolism in both the intestine and the liver has been more clearly defined over the past few years, and the atherogenicity of the triglyceride-rich lipoproteins, and - in tandem - low levels of high-density lipoproteins, is seen now as very important. New information on the apolipoproteins that control lipoprotein lipase activity has been obtained. This is an exciting time in the battle to defeat diabetic atherosclerosis.

Keywords: dyslipidemia; farnesyl X transcription factors; fibroblast growth factor; forkhead transcription factor O1; low-density lipoprotein; obesity; type 2 diabetes.

Figure 1

Lipoprotein cascade. Notes: In the circulation, VLDL is gradually delipidated, resulting in increasingly smaller lipoprotein particles, ie, IDL, LDL, and small dense LDL. The intestinally derived chylomicron, characterized by presence of apoB48, is delipidated to form the chylomicron remnant, which is taken up by the liver. Abbreviations: HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.

Figure 2

Metformin stimulates AMPK, which downregulates gluconeogenesis both directly and through downregulation of FoxO. Abbreviation: AMPK, adenosine monophosphate-activated protein kinase.

Figure 3

FGF 15/19 and FGF 21 have opposing effects on bile acid synthesis through their effect on Cyp7A1. Note: Glucagon, leptin, and insulin increase FGF 21, which increases adipose tissue UCP1. Cyp7A1 is also termed cholesterol 7a-hydroxylase. Abbreviation: FGF, fibroblast growth factor.

Figure 4

Effect of FoxO1 on adipocyte differentiation and mitochondrial function. Notes: FoxO is a regulator of glucose metabolism, lipid accumulation, and adipocyte differentiation. It also increases adipocyte browning and interacts with Tfeb to regulate UCPs 1, 2, and 3. Abbreviation: Tfeb, transcription factor EB.

Figure 5

Cholesterol absorption and chylomicron assembly and breakdown. Notes: Diacylglycerol is formed from free fatty acids under the influence of DGAT-1. Dietary cholesterol uptake from the intestine into the lymph is regulated by NPC1L1. ApoB48 is synthesized in the intestine. Triglyceride, cholesterol, and apoB48 are combined under the influence of MTP to form the chylomicron. In the circulation, the chylomicron is delipidated by LPL and cleared by the liver. Abbreviations: DGAT, diglyceride acyltransferase; LPL, lipoprotein lipase.