Insulin Resistance and Lipid Disorders

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

Disclosures

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

In This Article

Dysregulation of Lipid Metabolism and Insulin Resistance

Whilst current definitions may still define insulin resistance in terms of insulin effects on glucose metabolism, the last decade has seen a shift from the traditional 'glucocentric' view of the syndrome associated with insulin resistance to an increasingly acknowledged 'lipocentric' viewpoint. The notion that lipids may act as signaling factors that regulate metabolic functions in target tissues was first suggested more than 40 years ago, when Randle et al. hypothesized that obesity-associated insulin resistance could be explained by substrate competition between increased circulating NEFA and glucose for oxidative metabolism in insulin-responsive cells. The importance of NEFA and lipid metabolism was also outlined by McGarry, who suggested that insulin resistance and concomitant hyperglycemia could be viewed in the context of underlying abnormalities of lipid metabolism.[67] More recently, glucose uptake, rather than intracellular glucose metabolism, has been implicated as a rate-limiting step for NEFA-induced insulin resistance.[68] In this model, NEFA and some of their metabolites, including acyl-CoA, ceramides and diacyglycerol, have been demonstrated to serve as signaling molecules that activate protein kinases such as PKC, JNK and IKK. These kinases can impair insulin signaling by increasing inhibitory serine phosphorylation of insulin receptor substrates (IRS), the key mediators of insulin signaling, and activating an inflammatory response.[68]

In such a lipocentric framework, the term lipotoxicity was introduced by Unger to describe the deleterious effect of TG accumulation in pancreatic β-cells, resulting in impaired glucose-stimulated insulin secretion and accelerated apoptosis.[69,70] The same concept (and definition) has been expanded to include the multiple effects of circulating lipids on insulin-sensitive tissue, specifically, the role of lipids in the generation and maintenance of insulin resistance.

Obviously, excess adipose tissue plays a central role in supplying excess NEFA into the circulation and, therefore, favoring the development of atherogenic dyslipidemia. We have previously demonstrated that overall NEFA flux in insulin resistant obese individuals is not solely the result of impaired insulin action at the adipocyte level, but also the result of expanded adipose tissue.[71] A significant inverse correlation has been repeatedly reported between adiposity (in particular visceral adiposity) and insulin sensitivity,[72] but a significant correlation has also been reported to link insulin action with ectopic fat deposition in muscle[73] and in liver.[74] Increased fat accumulation in the liver is a marker of hepatic insulin resistance and a close correlate of all components of the MS independent of obesity.[75] The latter may evolve in nonalcoholic steatohepatitis (NASH), a condition commonly occurring in overweight/obese individuals with T2DM, dyslipidemia and hyperinsulinemia.[76] Insulin resistance has been claimed to represent the common link between NASH and the accompanying dyslipidemia and hypertension.[77] Finally, it has been hypothesized that hepatic stearoyl-CoA desaturase 1 (SCD1), the rate-limiting enzyme in monounsaturated fatty acid synthesis necessary for assembly of VLDL particles, may be involved in the pathophysiology of fatty liver and insulin resistance in humans. High hepatic SCD1 activity index is associated with low liver fat content and high insulin sensitivity in obese subjects and it may protect from fat accumulation in the liver and insulin resistance in obesity.[32]

In keeping with the lipocentric approach is the appreciation of the role of 'metabolic' receptors for lipids,[78] such as the peroxisome proliferator-activated receptors (PPARs) and the LXRs, as well as the appreciation that disturbances in the central nervous system may be well implicated in MS.[79] Still, the wide involvement of insulin-sensitive tissues in the ectopic fat deposition raises the hypothesis that a common mechanism occurring in all involved tissues may favor lipid accumulation. Both functional[80] and genetic[81,82] studies point out the potential role of impaired mitochondrial function (Figure 2). Impaired activation of oxidative phosphorylation may result in acyl-CoA moieties that are made available for lipid synthesis and local deposition.[80] Increasing sedentary lifestyle, excess caloric intake and the associated relative increase of fat mass probably contribute to the development of insulin resistance with age.[68] However, it has been suggested that it is not the dysfunction of adipose tissue that accounts for such a defect, rather impaired mitochondrial function tends to develop. Furthermore, at the adipocyte level, the number and activity of mitochondria may set the threshold at which NEFA are released into the circulation.[83] Although some of the mitochondrial dysfunction may represent an acquired defect, reduction in oxidative phosphorylation is likely to be a genetic alteration. Recent data indicate that nuclear-encoded genes that regulate mitochondrial biogenesis, such as PPAR-γ coactivator 1α,[81,82] AMP kinase[84] and calmodulin IV kinase[85] may represent the genetic background for insulin resistance.

Figure 2.

(A) In skeletal muscle and liver intramyocellular LCCoA and DAG, owing to increased release of FA from adipose tissue and/or reduced mitochondrial β-oxidation, can inhibit insulin signaling through activation of PKC or serine/threonine kinase cascade. Fat accumulation increases ROS production and leads to inhibition of insulin signaling. In addition, decreased mitochondrial β-oxidation results in increased ROS generation. Mitochondrial dysfunction can increase intramyocellular lipids and insulin resistance. Excess accumulation of lipids can trigger stress of the ER. Cell-extrinsic modulators, such as endocrine and inflammatory mediators, contribute to FA-induced insulin resistance. Proinflammatory cytokines, via activation of their transduction pathways, are able to alter insulin signaling by inactivating insulin receptor substrates through serine/threonine phosphorylation (IKK, JNK and PKC-θ). (B) The proposed mechanisms of early β-cell failure include mitochondrial dysfunction, oxidative stress, ER stress, dysfunctional TG/FFA cycling and glucolipotoxicity. Elevated β-cell cholesterol concentrations may reduce insulin secretion by increasing dimerization of nNOS, which downregulates GK thus impairing glucose sensing. Furthermore, abnormal activity of cholesterol efflux by ABCA1 may impair insulin exocytosis.

ABCA1 = Adenosine triphosphate-binding cassette transporter A1; DAG = Diacylglycerol; ER = Endoplasmic reticulum; FA = Fatty acid; FFA = Free fatty acid; FAT/CD36 = Fatty acid transporter; GK = Glucokinase; GLUT-2 = Glucose transporter type 2; IKK = I-κ-kinase; JNK = c-Jun NH2-terminal kinase; LCCoA = Long-chain acyl-CoA; LDLR = LDL receptor; nNOS = Neural NO synthase; ROS = Reactive oxygen species; TG = Triglyceride.

As previously mentioned, the term lipotoxicity was initially employed to describe the toxic effect exerted by increased lipid availability on pancreatic islets. Of interest, lipid metabolic receptors are also likely to be implicated in the genesis of such a toxicity. Exposure to long-chain fatty acids increases PPAR-α expression and may play a role in sustaining β-cell secretory capacity.[86] However, in hyperglycemic states, PPAR-α mRNA may be suppressed and this event may be a component of glucotoxicity.[87] Although interesting, these findings may be limited to the murine model as PPAR-γ, but not PPAR-α receptors, are expressed in β-cells.[88] A major effect of PPAR-γ is played at the level of adipose tissues where they regulate fatty acid storage, cell differentiation, maturation and growth.[89] In the pancreatic islet, elevation of NEFA results in downregulation of PPAR-γ expression and impaired glucose-mediated insulin release. This effect can be almost completely prevented by concomitant incubation with a thiazolidinedione (TZD).[88]

In summary, disturbances in lipid storage and lipid mobilization are likely to be the main effects in T2DM and related conditions characterized by insulin resistance. According to this view, a spectrum of conditions, all characterized by insulin resistance and dyslipidemia, can be described spanning from massive obesity to visceral obesity to localized accumulation of adipose tissue as it occurs in lipodystrophy. The latter is, indeed, known to be associated with insulin resistance and characteristic atherogenic dyslipidemia.[90]

While elevated levels of TGs and low levels of HDL-C are a common feature of patients with insulin resistance, the potential role of cholesterol in lipotoxic disease of islets has only recently been explored (Figure 2). Recent evidence suggests that alterations of plasma and islet cholesterol levels may contribute to islet dysfunction and loss of insulin secretion. ABCA1, which regulates islet cholesterol efflux, is essential for normal β-cell function and absence of ABCA1 results in islet cholesterol overload and impaired insulin release.[91] Several genetic alterations of cholesterol metabolism are associated with T2DM. In vitro studies suggest that increasing islet cholesterol can induce β-cell death and impairment of insulin secretion, while reducing islet cholesterol enhances insulin secretion.[92]

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