Regulation of Plasma Triglycerides in Insulin Resistance and Diabetes

doi:10.1016/j.arcmed.2005.01.005

Archives of Medical Research

Volume 36, Issue 3, May–June 2005, Pages 232-240

https://doi.org/10.1016/j.arcmed.2005.01.005 Get rights and content

Increased plasma levels of triglycerides (TG) in very low density lipoproteins (VLDL) are not only common characteristics of the dyslipidemia associated with insulin resistance and type 2 diabetes mellitus (T2DM) but are the central pathophysiologic feature of the abnormal lipid profile. Overproduction of VLDL leads to increased plasma levels of TG which, via an exchange process mediated by cholesterol ester transfer protein (CETP), results in low levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I, and the generation of small, dense, cholesterol ester depleted low density lipoproteins (LDL). Increased assembly and secretion of VLDL by the liver results from the complex, post-transcriptional regulation of apolipoprotein B (apoB) metabolism in the liver. In the presence of low levels of hepatic TG and cholesterol, much of the constitutively synthesized apoB is degraded by both proteasomal and non-proteasomal pathways. When excess TG, and to a lesser extent, cholesterol, are present, and in the presence of active microsomal triglycerides transfer protein, apoB is targeted for secretion. The major sources of TG in the liver: uptake of fatty acids (FA) released by lipolysis of adipose tissue TG, uptake of TGFA in VLDL and chylomicrons remnants, and hepatic de novo lipogenesis (the synthesis of FA from glucose) are all abnormally increased in insulin resistance. Treatment of the dyslipidemia in insulin resistant individuals and patients with T2DM has been successful in reducing cardiovascular disease; LDL cholesterol, TG, and HDL cholesterol are all appropriate targets for therapy when diet, exercise, and weight loss do not achieve goals.

Introduction

Numerous prospective cohort studies have indicated that type 2 diabetes mellitus (T2DM) is associated with a three- to fourfold increase in risk for coronary artery disease (CHD) 1, 2. The increase in risk is particularly evident in both younger age groups and women. Females with T2DM appear to lose a great deal of the protection that characterizes non-diabetic females. Furthermore, patients with T2DM have a 50% greater in-hospital mortality, and a twofold increased rate of death within 2 years of surviving a myocardial infarction. Overall, CHD is the leading cause of death in individuals with T2DM.

Much of this increased disease is associated with the presence of well-characterized risk factors for CHD, including characteristic abnormalities of plasma lipids and lipoprotein concentrations 3, 4. This combination of abnormalities, elevated blood levels of triglycerides (TG), low levels of high density lipoprotein (HDL) cholesterol, and relatively normal levels of low density lipoprotein (LDL) cholesterol carried in small, dense, cholesterol-poor LDL particles, has been called the diabetic dyslipidemia. Significant evidence supports a key role for insulin resistance, which is a central pathophysiologic feature of T2DM in the development of the diabetic dyslipidemia (5). Indeed, insulin-resistant individuals who are not diabetic have lipid profiles that are nearly identical to those seen in the large majority of subjects with T2DM. In this review, we will focus on the role of insulin resistance in the regulation of plasma TG levels, as elevations in TG determine, to a significant degree, the levels of HDL cholesterol and the composition of LDL. Normal lipid and lipoprotein physiology will be reviewed briefly as a base from which we will examine the role of insulin resistance.

Section snippets

Lipoprotein Composition

Lipoproteins are macromolecular complexes carrying various lipids and proteins in plasma (6). Several major classes of lipoproteins have been defined by their physical-chemical characteristics, particularly by their flotation characteristics during ultracentrifugation. However, lipoprotein particles actually form a continuum, varying in composition, size, density and function (Table 1). The lipids are mainly free and esterified cholesterol, TG, and phospholipids. The hydrophobic TG and

Postprandial Chylomicron Metabolism

After ingestion of a meal, dietary fat (TG) and cholesterol are absorbed into the cells of the small intestine and are incorporated into the cores of nascent chylomicrons. Apo B48 is required for the assembly of chylomicrons. The newly formed chylomicrons are secreted into the lymphatic system and then enter the circulation via the superior vena cava. In the lymph and the blood, chylomicrons acquire apo CII, apo CIII, and apo E. In the capillary beds of adipose tissue and muscle, chylomicrons

Postprandial Chylomicron Metabolism: Effects of Insulin Resistance

Chylomicron and chylomicron-remnant metabolism can be altered significantly in insulin resistance and T2DM. Recent studies indicate that, like apo B100 (see below), the association of apo B48 with dietary lipids to form chylomicrons is dysregulated in the presence of insulin resistance; increased apo B48 secretion has been demonstrated in the insulin-resistant, sucrose-fed hamster (8). It is not clear if this happens in humans. However, increased postprandial hyperlipidemia is characteristic of

VLDL Metabolism

VLDLs are initially assembled in the endoplasmic reticulum of hepatocytes. During and after synthesis of apo B100, the protein required for VLDL assembly, phospholipids, TG, and both free and esterified cholesterol are added in the ER and possibly the Golgi. VLDL TG derives from the combination of glycerol with 3 FA that have either been taken up from plasma or synthesized in the liver. VLDL cholesterol is either synthesized in the liver from acetate or delivered to the liver by lipoproteins,

VLDL Metabolism: Effects of Insulin Resistance

Overproduction of VLDL, with increased secretion of both triglyceride and apo B100, seems to be the central and most important etiology of increased plasma VLDL levels in patients with insulin resistance or T2DM (5). As noted above, the series of steps whereby apo B100 assembles with lipids and VLDL is secreted is regulated posttranscriptionally. Recent studies in cell culture, rodents, and humans have provided significant insights regarding the mechanisms whereby insulin resistance can drive

VLDL Catabolism in Insulin Resistance

As described earlier in the section on chylomicron metabolism, modest reductions in postheparin LPL levels have been reported (3) in some T2DM, and this may contribute significantly to elevated TG levels, particularly in severely hyperglycemic patients. Additionally, as described above, VLDL and chylomicrons can compete for the same LPL-mediated pathway for TG removal from the circulation. Also described earlier in this review, hepatic uptake of VLDL remnants is a complex process involving

Role of Insulin Resistance in the Generation of Small Dense LDL

In people with insulin resistance and T2DM, regulation of plasma levels of LDL, like that of its precursor VLDL, is complex. In the presence of hypertriglyceridemia, dense, cholesteryl ester-depleted, triglyceride-enriched LDL are present. Thus, individuals with T2DM and mild to moderate hypertriglyceridemia may have the Pattern B profile of LDL described by Austin and Krauss (43). The basis for small dense LDL in insulin resistance is derived in large part from the action of cholesteryl ester

Role of Insulin Resistance in the Generation of Low Levels of HDL Cholesterol

HDL cholesterol and apo AI levels are characteristically reduced in insulin-resistant people. Much of this derives, as in the case of small dense LDL, from the action of CETP-mediated transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins (chylomicrons and VLDL). A consistent finding is the inverse relationship between plasma insulin (or C-peptide) concentrations, which are measures of insulin resistance and HDL cholesterol levels. Fractional catabolism of apo AI is increased

Weight Loss

Although a discussion of the various dietary approaches to the treatment of insulin resistance and T2DM remains controversial and is beyond the scope of this review, there is universal agreement that weight reduction is an essential part of dietary therapy in individuals with insulin resistance dyslipidemia. Several groups have shown that when weight reduction is achieved and maintained in T2DM patients, there is a sustained decrease in triglyceride levels. Studies with weight loss in diabetic

Summary

People with insulin resistance have a characteristic dyslipidemia that has, as its central feature, overproduction of VLDL and hypertriglyceridemia. Regulation of the hepatic assembly and secretion of apo B-lipoproteins has been investigated extensively for the past several decades and much is known about how lipid substrates and insulin signaling regulate the formation and secretion of VLDL. New information about the molecules involved in both lipogenesis and the synthesis, degradation, and

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Review articleRegulation of Plasma Triglycerides in Insulin Resistance and Diabetes

Introduction

Section snippets

Lipoprotein Composition

Postprandial Chylomicron Metabolism

Postprandial Chylomicron Metabolism: Effects of Insulin Resistance

VLDL Metabolism

VLDL Metabolism: Effects of Insulin Resistance

VLDL Catabolism in Insulin Resistance

Role of Insulin Resistance in the Generation of Small Dense LDL

Role of Insulin Resistance in the Generation of Low Levels of HDL Cholesterol

Weight Loss

Summary

Am J Kidney Dis

J Lipid Res

J Biol Chem

J Lipid Res

J Lipid Res

J Biol Chem

Biochim Biophys Acta

Trends Cardiovasc Med

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Diabetes Metab

Am J Clin Nutr

Mol Cell

Biochim Biophys Acta

J Biol Chem

J Biol Chem

Endocrinol Metab Clin North Am

Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarctions

N Engl J Med

Lipoprotein physiology in nondiabetic and diabetic states: relationship to atherogenesis

Diabetes Care

Diabetic dyslipidaemia: from basic research to clinical practice

Diabetologia

Insulin resistance and cardiovascular disease

J Clin Invest

Lipoprotein physiology. Chapter 1

Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man

J Clin Invest

Review article
Regulation of Plasma Triglycerides in Insulin Resistance and Diabetes