Insulin Resistance and Lipid Disorders

Roberto Miccoli; Cristina Bianchi; Giuseppe Penno; Stefano Del Prato


Future Lipidology. 2008;3(6):651-664. 

In This Article

Metabolism of Triglyceride-rich Lipoproteins

Overproduction of VLDL, with increased secretion of TG and ApoB100, appears to be central in the etiology of increased plasma VLDL levels in patients with insulin resistance or T2DM.[23] The steps accounting for such alterations are illustrated in Figure 1.

Impairment of muscle glucose uptake and oxidation is a consequence of insulin resistance in muscle, while impairment of hepatic glucose production is a consequence of insulin resistance in liver - finally, resistance to insulin's suppressive action in adipose tissue is accounting for the increased lipolysis in the insulin-resistant individual. Insulin resistance at the level of the adipose tissue results in reduced glucose uptake and impaired generation of glycerol hampering intracellular nonesterified fatty acid (NEFA) re-esterification and increased lipolysis. This is further enhanced by ineffective inhibition of hormone-sensitive lipase activity. The excess of NEFA flux will then feed the liver, resulting in stimulation of TG synthesis and assembly and secretion of VLDL particles. Increase of NEFA and glucose flux to the liver have been proven to be of great relevance for hepatic VLDL production.[24]

ApoB degradation may be regulated in the endoplasmic reticulum (ER) by lipid availability, as oleic acid has a protective effect on ER degradation of ApoB by a pathway involving the proteasome in Hep G2 cells.[25] One prevalent hypothesis is that the translocation of the ApoB polypeptide across the ER membrane may be at least temporarily arrested as a result of the failure to efficiently assemble the nascent lipoprotein particle. If translation proceeds without coupling to translocation, the nascent polypeptide chain can loop out of the translocation channel into the cytosol, making it accessible to components of the proteasomal degradation machinery. Cytosolic chaperones, including the heat-shock proteins (Hsp)70 and Hsp90, have been suggested to play a role in ApoB degradation by facilitating delivery of the ApoB polypeptide to the proteasome.[26] Post-translational mechanisms can also contribute to ApoB100 degradation at the ER level. Microsomal TG protein (MTP), a heterodimeric lipid-transfer protein necessary for assembly of ApoB-containing lipoproteins, plays a major role in the translocation of ApoB-100. Insulin seems to be an important factor in the intracellular degradation of freshly translated ApoB-100,[27] or modulation of MTP gene expression.[28] A condition of insulin resistance may directly affect the above patterns since insulin regulation of ApoB involves the activation of phosphatidylinositol 3-kinase (PI3K).[29] Therefore, in an insulin-resistant state, imbalance between secretion and degradation in favor of the former, as a consequence of the inability to suppress ApoB-100 degradation, results in increased VLDL secretion.[30]

Insulin resistance is commonly associated with compensatory hyperinsulinemia, which also contributes to the pathogenesis of dyslipidemia. The acute effect of insulin on VLDL kinetics in humans in vivo has been evaluated in few studies by different modelling approaches. Acute hyperinsulinemia induces a decrease of VLDL-TG and VLDL-ApoB production, with a greater reduction in TG than in ApoB.[31] As a consequence, insulin not only reduces the number of particles to be secreted, but also induces a shift from VLDL1 to VLDL2, a much smaller particle.[32] In T2DM, plasma TG elevation is caused by increased production of VLDL1 but not VLDL2 particles.[33] Furthermore, the circulating time of VLDL, intermediate-density lipoprotein and LDL is increased, probably due to decreased hepatic uptake.[34] Insulin resistance might lead to reduced LDL receptors, limiting remnant removal.[21]

Postprandial hyperlipidemia is common in insulin-resistant individuals and this is almost certainly associated with hepatic uptake of remnants that contain more TG than remnants in normal people. Uptake of TG-rich lipoproteins stimulates VLDL assembly and secretion as the liver attempts to maintain homeostasis regarding its fatty acid and TG content: delivery of excess remnant TG will lead to increased VLDL secretion, a cycle that has been demonstrated in cultured liver cells[35] as well as in man.[36]

Finally, de novo fatty acid synthesis (lipogenesis) in the liver accounts for another source of TGs for assembly and secretion with ApoB100. Although data in humans are limited, recent studies have demonstrated that lipogenesis can contribute to VLDL-TG - and de novo synthesis may be increased in individuals with obesity and insulin resistance.[37,38] This view is also supported by activation of transcription factors, such as the sterol response-element binding protein isoform-1 (SREBP1-c).[39] This protein is a member of the basic helix-loop-helix-leucine zipper family of transcription factors that act as dimers to activate genes involved in lipid metabolism.[40] Both insulin and liver X-receptor (LXR) induce SREBP-1c transcription.[39] The effect of insulin on SREBP-1c is of relevance since it is through this effect that hyperinsulinemia may contribute to de novo lipogenesis.[41] Recently, it has been reported that mice with total hepatic insulin resistance exhibit hyperglycemia without hypertriglyceridemia - a state paradoxically less severe than selective hepatic insulin resistance. Insulin cannot suppress gluconeogenesis and, thus, the liver continues to secrete glucose. Insulin also cannot activate SREBP-1c and so hepatic TGs and circulating VLDL are low. The net result is hyperinsulinemia and hyperglycemia without hypertriglyceridemia. In T2DM, selective insulin resistance has implications for therapy. It seems preferable to search agents that will improve insulin sensitivity in the pathway that leads to suppression of hepatic gluconeogenesis and enhanced peripheral glucose uptake. With such an agent, insulin levels should fall, hepatic SREBP-1c levels should decline and lipotoxicity should be averted.[42] Furthermore, LXR-mediated lipogenesis also seems to be caused by increased carbohydrate-responsive element binding protein (ChREBP) expression and activity. The transcription factor ChREBP promotes the hepatic conversion of excess carbohydrate to lipid.[43]

Although increased VLDL secretion is an important mechanism leading to dyslipidemia associated with insulin resistance, it is not the only one. Removal of these particles is also involved. A reduction in postheparin lipoprotein lipase (LPL) levels has been observed in T2DM and increased chylomicrons, as can be found in insulin-resistant subjects, may compete for VLDL removal from the circulation. Hepatic uptake of VLDL remnants can also be altered owing to reduced expression of LDL receptors limiting remnant removal.[5]

Metabolism of Postprandial Chylomicrons

After ingestion of a meal, dietary fat (i.e., TG) and cholesterol are absorbed in the cells of the small intestine and incorporated in the core of nascent chylomicrons. Similar to what happens for ApoB100 and VLDL assembly, the association of ApoB48 with dietary lipids to form chylomicrons is altered in the presence of insulin resistance. Increased ApoB48 secretion was found in an experimental animal model of insulin resistance,[44] whereas intestinal lipoprotein overproduction is ameliorated by an insulin sensitizer such as rosiglitazone.[45] Reduced clearance of postprandial TG may contribute to postprandial hyperlipidemia in insulin-resistant subjects.[23] Indeed, ApoCIII synthesis is increased under the circumstance of impaired insulin action, accounting for lower LPL action and, finally, reduced clearance of postprandial TG.[46]

Whether the same mechanisms are operative in man is still unclear, but postprandial hyperlipidemia is a feature of insulin-resistant subjects. In the study by Annuzzi et al., performed under condition of hyperinsulinemic clamp, no major difference was found in LPL activity in post-heparin plasma obtained 6 h after a meal ingestion in T2DM as compared with control subjects, suggesting that it is increased secretion that mainly accounts for postprandial hyperlipidemia in insulin-resistant conditions.[14] Recently, the first human data demonstrated that intestinal ApoB48-containing TG-rich lipoprotein production rate is increased in hyperinsulinemic insulin-resistant humans.[47]

High-density Lipoproteins

An inverse relationship between VLDL-TG and HDL has also been reported.[48] Delayed clearance of TG-rich lipoproteins leads to reduced HDL concentration by facilitation of cholesteryl-ester transfer protein (CETP)-mediated exchange between cholesterol esters (CE) in HDL and TG in VLDL. In the presence of insulin resistance, elevated CETP activity, an important determinant of HDL metabolism, results in enhanced CE transfer from HDL to TG-rich lipoproteins and in reciprocal TG transfer, producing TG-enriched HDL, together with CE-enriched VLDL and remnants.[49] HDL particles possessing a low CE:TG ratio are less stable than normal particles.[48] Furthermore, in T2DM patients, plasma activity of phospholipid-transfer protein (PLTP) and hepatic lipase (HL) are increased, contributing to low HDL-C and changes in subclass distribution.[50] Recent studies in a LIRKO mouse reported a major reduction in HDL-C levels, even in the absence of hypertriglyceridemia and CETP. Although the exact mechanism by which insulin resistance produces this effect remains to be determined, preliminary studies show that HDL clearance is normal in LIRKO mice. It appears that hepatic insulin resistance reduces HDL-C by either decreasing HDL production or promoting a shift of HDL-C to non-HDL lipoproteins.[51]

Increased activity of HL on TG-enriched HDL results in smaller HDL particles, which are cleared more rapidly from circulation. Furthermore, TG-enriched HDL are intrinsically more unstable in the circulation, with ApoA-I loosely bound. Dysfunctional LPL, or reduced LPL activity, contributes to lowering the level of HDL by reducing the availability of surface constituents of TG-rich lipoproteins that normally sequester to the plasma pool of nascent HDL particles.[48]

Compositional modification of the HDL lipid core and a conformational change of ApoA-I are a driving force of functional deficiency of HDL particles in T2DM and insulin-resistant subjects; this mechanism is particularly relevant for small atheroprotective HDL3 particles. Lower levels of circulating HDL2-C, which is the more potent antiatherogenic HDL subfraction,[52] are associated with fatty liver, even after adjustment for whole-body insulin resistance and circulating adiponectin.[53] Insulin may exert a direct effect on the production of ApoA-I[54] or hepatic secretion of nascent HDL.[55,56] Thus, in insulin-resistant states, there is a substantial decrease of HDL particles, especially larger HDL2 (compared with smaller HDL3), and HDL containing mostly ApoA-I (i.e., LpA-I particles). These particles are more effective than LpA-I:A-II particles in the reverse cholesterol process and, therefore, are considered more antiatherogenic. Impaired antioxidative activity with defective protection of endothelial cells from oxidized LDL (ox-LDL)-induced apoptosis of small, dense HDL is intimately related to concomitance of hyperTG, hyperinsulinemia and insulin resistance.[56,57]

Supraphysiological concentrations of insulin impair cellular HDL binding, as well as HDL-mediated cholesterol efflux from fibroblasts in vitro, suggesting that very high levels of insulin decrease the initial step of reverse cholesterol transport.[58] Furthermore, when J774 macrophages are incubated with unsaturated NEFA, cellular cholesterol efflux is decreased, owing to diminished expression of ATP-binding cassette transporter A1 (ABCA1).[59]

Low-density Lipoproteins

Under conditions of low or normal TG formation, VLDL particles are good substrates for LPL-producing LDL2 and LDL1 moieties. LDL1 and LDL2 comprise large-size LDL particles, the most avidly bound substrate of LDL receptors. In insulin-resistant subjects, TG formation increases, larger VLDL1 particles are produced and lipolysis by LPL is less efficient, leading to production of remnant particles that are further metabolized by LPL and HL to form LDL3a.[60,61,62] The latter are processed by CETP, shuttling TGs back to remnant particles, and by HL to form LDL3b. A final pathway is the one involving very large VLDL1 particles, which are metabolized by LPL to produce highly atherogenic remnant particles. These can be cleared directly or metabolized by LPL and HL to the smallest LDL4 particles. LDL1 and LDL2 are also known as phenotype A and LDL3 and LDL4 as phenotype B particles. The presence of phenotype B is a common feature of dyslipidemia associated with insulin resistance.[63] However, small dense LDL are present in insulin resistant patients, even when they show relatively normal TG, suggesting that other factors are involved. These factors comprise higher activity of HL with facilitated hydrolysis of TG in LDL, as well as increased exchange of CE and TG between LDL (or HDL) and VLDL in the presence of higher levels of circulating fatty acids. Furthermore, even in the presence of normal fasting TG levels, elevation of postprandial chylomicrons and VLDL occur in insulin resistant and T2DM patients, which may accelerate the formation of small and dense LDL particles.

Previous studies have demonstrated that the occurrence of small dense LDL may be genetically influenced.[64] Thus, a common polymorphism in the CEPT gene has been found to be associated with LDL particle size.[65] Furthermore, potential candidate genes that may provide a link between insulin resistance and dyslipidemia have been identified in HL and the fatty acid binding protein (FABP) gene 2.[66]

Finally, small LDL particles are more likely to undergo oxidative modification. Ox-LDL is less efficiently cleared from the circulation and can trigger inflammation and the atherogenic process. Predominance of small dense LDL has been associated with a three- to seven-fold increased risk for coronary artery disease.


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