Mechanisms for Insulin Resistance: Common Threads and Missing Links
2012; Cell Press; Volume: 148; Issue: 5 Linguagem: Inglês
10.1016/j.cell.2012.02.017
ISSN1097-4172
AutoresVarman T. Samuel, Gerald I. Shulman,
Tópico(s)Pancreatic function and diabetes
ResumoInsulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, these cellular changes may converge to promote the accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, a common final pathway leading to impaired insulin signaling and insulin resistance. Insulin resistance is a complex metabolic disorder that defies explanation by a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway, and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, these cellular changes may converge to promote the accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, a common final pathway leading to impaired insulin signaling and insulin resistance. All metazoans are heterotrophic; they need to eat. This defining characteristic poses a central challenge. Nutrient sources are often scarce, and caloric demands constantly change. Animals solved this problem by developing integrated mechanisms to promote anabolism when calorie supply exceeds demands but readily become catabolic when demands cannot be met with consumption. The secretion and action of insulin (and related molecules in lower phyla) provided one solution to this central problem. Following nutrient consumption, insulin promotes carbohydrate uptake at key storage sites and prompts the conversion of carbohydrate and protein to lipids, a more efficient storage for calories. Although this ability to store dietary energy for later times has supported the development of animal life for nearly 600 million years, it has recently gone awry for humans. In a remarkably short time, we have altered an environment of caloric scarcity and high caloric demands into one with abundant caloric supply with very little caloric demands. Obesity is now endemic, and many societies are grappling with the rising prevalence of obesity-associated diseases, including metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and atherosclerotic heart disease. These diseases exact tremendous tolls on society through both the loss of health and quality of life but also on health system resources. Insulin resistance is sine quo non with the pathogenesis for many of these modern diseases. Thus, understanding the pathogenesis of insulin resistance has become increasingly important to guide the development of future therapies and inform health and economic policy. As stated above, insulin action essentially provides an integrated set of signals that allow us to balance nutrient availability and demands (Figure 1). There are diseases with impairments in insulin production, as in type 1 diabetes or in the monogenic maturity onset diabetes of the young (MODY) syndromes. These diseases are significant and can abruptly interrupt health, especially for children. In comparison, insulin resistance is insidious and affects a far greater number of people. By some estimates, within 40 years, one in every three Americans will have type 2 diabetes (Boyle et al., 2010Boyle J.P. Thompson T.J. Gregg E.W. Barker L.E. Williamson D.F. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence.Popul. Health Metr. 2010; 8: 29Crossref PubMed Scopus (252) Google Scholar). Here, we review several mechanisms proposed to explain the pathogenesis of insulin resistance—mainly, the development of insulin resistance from ectopic lipid accumulation, the development of “endoplasmic reticulum stress” and activation of the unfolded protein response, and the contribution of systemic inflammation. Though many additional mechanisms have been offered, these three represent different aspects of metabolic control that ultimately may converge on common pathways to regulate insulin action. The association between lipids and insulin resistance is widely accepted. Early studies by Randle and colleagues in rodent heart and diaphragm muscle suggested that fatty acids impaired insulin-mediated glucose uptake in muscle by inhibition of pyruvate dehydrogenase, leading to reductions in glucose oxidation and accumulation of glycolytic intermediates (Randle et al., 1963Randle P.J. Garland P.B. Hales C.N. Newsholme E.A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.Lancet. 1963; 1: 785-789Abstract PubMed Google Scholar). In rats, acute (<2 hr) lipid infusions decreased myocellular glucose utilization with the expected increases in intramyocellular glucose 6-phosphate (G-6-P) concentrations, as predicted by Randle's hypothesis (Jucker et al., 1997Jucker B.M. Rennings A.J.M. Cline G.W. Shulman G.I. 13C and 31P NMR studies on the effects of increased plasma free fatty acids on intramuscular glucose metabolism in the awake rat.J. Biol. Chem. 1997; 272: 10464-10473Crossref PubMed Scopus (62) Google Scholar). Although this may hold true for acute experimental challenges, it does not explain insulin resistance in chronic disease states, which can be attributed to reductions in both insulin-stimulated muscle glycogen synthesis and glucose oxidation (Shulman et al., 1990Shulman G.I. Rothman D.L. Jue T. Stein P. DeFronzo R.A. Shulman R.G. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy.N. Engl. J. Med. 1990; 322: 223-228Crossref PubMed Scopus (960) Google Scholar). Subsequent in vivo measurements of intramyocellular glucose and G-6-P concentrations in a variety of rodent and human experimental models have clearly demonstrated that lipid-induced insulin resistance in skeletal muscle can be attributed to impaired insulin signaling and decreased insulin-stimulated glucose transport, and not to decreased glycolysis, as Randle hypothesized (Cline et al., 1999Cline G.W. Petersen K.F. Krssak M. Shen J. Hundal R.S. Trajanoski Z. Inzucchi S. Dresner A. Rothman D.L. Shulman G.I. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes.N. Engl. J. Med. 1999; 341: 240-246Crossref PubMed Scopus (382) Google Scholar, Dresner et al., 1999Dresner A. Laurent D. Marcucci M. Griffin M.E. Dufour S. Cline G.W. Slezak L.A. Andersen D.K. Hundal R.S. Rothman D.L. et al.Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.J. Clin. Invest. 1999; 103: 253-259Crossref PubMed Google Scholar, Griffin et al., 1999Griffin M.E. Marcucci M.J. Cline G.W. Bell K. Barucci N. Lee D. Goodyear L.J. Kraegen E.W. White M.F. Shulman G.I. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.Diabetes. 1999; 48: 1270-1274Crossref PubMed Scopus (715) Google Scholar, Roden et al., 1996Roden M. Price T.B. Perseghin G. Petersen K.F. Rothman D.L. Cline G.W. Shulman G.I. Mechanism of free fatty acid-induced insulin resistance in humans.J. Clin. Invest. 1996; 97: 2859-2865Crossref PubMed Google Scholar). In parallel, molecular studies suggested that insulin resistance could be attributed to impaired GLUT4 translocation, largely due to defects in insulin signaling (Ciaraldi et al., 1995Ciaraldi T.P. Abrams L. Nikoulina S. Mudaliar S. Henry R.R. Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects.J. Clin. Invest. 1995; 96: 2820-2827Crossref PubMed Google Scholar, Garvey et al., 1998Garvey W.T. Maianu L. Zhu J.H. Brechtel-Hook G. Wallace P. Baron A.D. Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance.J. Clin. Invest. 1998; 101: 2377-2386Crossref PubMed Google Scholar) (Figure 1). Lipids are clearly associated with insulin resistance. But, is it the circulating plasma lipids or the lipids accumulating within insulin responsive tissues that are responsible? Studies in normal weight, nondiabetic adults found that intramyocellular triglyceride content is a far stronger predictor of muscle insulin resistance than circulating fatty acids (Krssak et al., 1999Krssak M. Falk Petersen K. Dresner A. DiPietro L. Vogel S.M. Rothman D.L. Roden M. Shulman G.I. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study.Diabetologia. 1999; 42: 113-116Crossref PubMed Scopus (710) Google Scholar), suggesting that intramyocellular lipids may cause muscle insulin resistance. This empiric observation has been tested experimentally in normal rats infused with Intralipid/heparin. Though plasma fatty acids are acutely increased, muscle insulin resistance did not develop until 3–4 hr into the lipid infusion, concordant with the accumulation of intramyocellular diacylglycerol (DAG) and impairment in insulin signaling and muscle glucose uptake. Of note, insulin resistance occurred independently of changes in muscle triglyceride content, thus dissociating muscle triglyceride concentrations from insulin resistance (Dresner et al., 1999Dresner A. Laurent D. Marcucci M. Griffin M.E. Dufour S. Cline G.W. Slezak L.A. Andersen D.K. Hundal R.S. Rothman D.L. et al.Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.J. Clin. Invest. 1999; 103: 253-259Crossref PubMed Google Scholar, Yu et al., 2002Yu C. Chen Y. Cline G.W. Zhang D. Zong H. Wang Y. Bergeron R. Kim J.K. Cushman S.W. Cooney G.J. et al.Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle.J. Biol. Chem. 2002; 277: 50230-50236Crossref PubMed Scopus (795) Google Scholar). Diacylglycerols are signaling intermediates that activate members of the protein kinase C (PKC) family. In these experiments, muscle lipid accumulation is associated with activation of the novel PKC (nPKC) isoform PKCθ, providing a potential link between lipid accumulation and alteration in intracellular signaling. This link between DAG-mediated activation of nPKCs and muscle insulin resistance has been replicated in human studies (Itani et al., 2002Itani S.I. Ruderman N.B. Schmieder F. Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha.Diabetes. 2002; 51: 2005-2011Crossref PubMed Google Scholar, Szendroedi et al., 2011Szendroedi J. Yoshimura T. Phielix E. Marcucci M. Zhang D. Baudot S. Fuehrer C. Herder C. Nowotny P. Shulman G. et al.The role of diacylglycerol concentrations in the development of lipid-mediated insulin resistance in human skeletal muscle.in: European Association for the Study of Diabetes. Portrugal, Lisbon2011Google Scholar). Though both of these studies have associated muscle diacylglycerol accumulation with nPKC activation, there are some differences. Lipids infused together with insulin over 6 hr result in activation of PKCδ (Itani et al., 2002Itani S.I. Ruderman N.B. Schmieder F. Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha.Diabetes. 2002; 51: 2005-2011Crossref PubMed Google Scholar). In contrast, PKCθ activation predominates when lipids were infused for 4 hr prior to insulin infusion (Szendroedi et al., 2011Szendroedi J. Yoshimura T. Phielix E. Marcucci M. Zhang D. Baudot S. Fuehrer C. Herder C. Nowotny P. Shulman G. et al.The role of diacylglycerol concentrations in the development of lipid-mediated insulin resistance in human skeletal muscle.in: European Association for the Study of Diabetes. Portrugal, Lisbon2011Google Scholar). Together, these studies support the paradigm that diacylglycerol accumulation in muscle can lead to muscle insulin resistance through activation of nPKCs (Figure 2). Ectopic lipid accumulation in the liver, termed nonalcoholic fatty liver disease (NAFLD), is now considered the most common chronic liver disease in the United States. By some estimates, 50% of Americans will have NAFLD by 2030 (Z.M. Younossi et al., 2011, EASL, conference). However, many individuals with NAFLD also have increased visceral adiposity, a marked expansion of the omental fat. Though visceral adipose tissue has been implicated as causing hepatic insulin resistance, several studies present compelling data to the contrary. Patients with severe lipodystrophy (Petersen et al., 2002Petersen K.F. Oral E.A. Dufour S. Befroy D. Ariyan C. Yu C. Cline G.W. DePaoli A.M. Taylor S.I. Gorden P. Shulman G.I. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy.J. Clin. Invest. 2002; 109: 1345-1350Crossref PubMed Google Scholar) and a mouse model of lipoatrophy (Kim et al., 2000Kim J.K. Gavrilova O. Chen Y. Reitman M.L. Shulman G.I. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice.J. Biol. Chem. 2000; 275: 8456-8460Crossref PubMed Scopus (262) Google Scholar) have no visceral fat but manifest severe hepatic insulin resistance associated with marked hepatic steatosis. In both, hepatic insulin resistance resolves when the hepatic steatosis is reversed, either with fat transplantation in mice (Kim et al., 2000Kim J.K. Gavrilova O. Chen Y. Reitman M.L. Shulman G.I. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice.J. Biol. Chem. 2000; 275: 8456-8460Crossref PubMed Scopus (262) Google Scholar) or recombinant leptin therapy in humans with lipodystrophy. Though recombinant leptin therapy works exquisitely well in patients with lipodystrophy, its application to a broader set of obese individuals has not yielded similar results. But enforced dietary caloric restriction can still rapidly reduce hepatic steatosis in obese patients (Lim et al., 2011Lim E.L. Hollingsworth K.G. Aribisala B.S. Chen M.J. Mathers J.C. Taylor R. Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.Diabetologia. 2011; 54: 2506-2514Crossref PubMed Scopus (154) Google Scholar, Petersen et al., 2005Petersen K.F. Dufour S. Befroy D. Lehrke M. Hendler R.E. Shulman G.I. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes.Diabetes. 2005; 54: 603-608Crossref PubMed Scopus (384) Google Scholar). Subjects with poorly controlled T2D who were placed on a hypocaloric diet for up to 12 weeks experienced a marked and rapid decrease in liver fat content (∼85%), associated specifically with a normalization in hepatic insulin sensitivity and reductions in fasting hyperglycemia and hepatic glucose production without changes in intramyocellular lipid or insulin-mediated whole-body glucose disposal (Petersen et al., 2005Petersen K.F. Dufour S. Befroy D. Lehrke M. Hendler R.E. Shulman G.I. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes.Diabetes. 2005; 54: 603-608Crossref PubMed Scopus (384) Google Scholar). Consistent with these observations, Fabbrini et al. demonstrate that hepatic insulin resistance is primarily related to intrahepatic lipid content, not visceral fat mass (Fabbrini et al., 2009Fabbrini E. Magkos F. Mohammed B.S. Pietka T. Abumrad N.A. Patterson B.W. Okunade A. Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity.Proc. Natl. Acad. Sci. USA. 2009; 106: 15430-15435Crossref PubMed Scopus (310) Google Scholar). And, they find that surgical removal of visceral adipose tissue did not alter glucose homeostasis or insulin sensitivity (Fabbrini et al., 2010Fabbrini E. Tamboli R.A. Magkos F. Marks-Shulman P.A. Eckhauser A.W. Richards W.O. Klein S. Abumrad N.N. Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults.Gastroenterology. 2010; 139: 448-455Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Taken together, these studies demonstrate that ectopic lipid accumulation of lipid within the liver can specifically cause hepatic insulin resistance. Genetic rodent models that alter expression of lipid transport proteins provide evidence for the role of ectopic lipid accumulation in the pathogenesis of insulin resistance. Lipoprotein lipase (LpL) is a key enzyme that hydrolyzes circulating triglyceride, permitting tissue uptake through specific fatty acid transport proteins (FATPs) together with CD36. Muscle-specific overexpression of lipoprotein lipase (LpL) promotes muscle lipid uptake and muscle insulin resistance (Kim et al., 2001Kim J.K. Fillmore J.J. Chen Y. Yu C. Moore I.K. Pypaert M. Lutz E.P. Kako Y. Velez-Carrasco W. Goldberg I.J. et al.Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance.Proc. Natl. Acad. Sci. USA. 2001; 98: 7522-7527Crossref PubMed Scopus (425) Google Scholar). In contrast, deletion of LpL (Wang et al., 2009Wang H. Knaub L.A. Jensen D.R. Young Jung D. Hong E.G. Ko H.J. Coates A.M. Goldberg I.J. de la Houssaye B.A. Janssen R.C. et al.Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues.Diabetes. 2009; 58: 116-124Crossref PubMed Scopus (32) Google Scholar) or of other proteins involved in fat transport, such as CD36 (Goudriaan et al., 2003Goudriaan J.R. Dahlmans V.E.H. Teusink B. Ouwens D.M. Febbraio M. Maassen J.A. Romijn J.A. Havekes L.M. Voshol P.J. CD36 deficiency increases insulin sensitivity in muscle, but induces insulin resistance in the liver in mice.J. 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Velez-Carrasco W. Goldberg I.J. et al.Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance.Proc. Natl. Acad. Sci. USA. 2001; 98: 7522-7527Crossref PubMed Scopus (425) Google Scholar, Merkel et al., 1998Merkel M. Weinstock P.H. Chajek-Shaul T. Radner H. Yin B. Breslow J.L. Goldberg I.J. Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia.J. Clin. Invest. 1998; 102: 893-901Crossref PubMed Google Scholar). Adenoviral-mediated overexpression of hepatic CD36 causes NAFLD, even in regular chow-fed mice (Koonen et al., 2007Koonen D.P. Jacobs R.L. Febbraio M. Young M.E. Soltys C.L. Ong H. Vance D.E. Dyck J.R. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity.Diabetes. 2007; 56: 2863-2871Crossref PubMed Scopus (111) Google Scholar). Loss of hepatic fatty acid transport, specifically through deletion of FATP2 (Falcon et al., 2010Falcon A. Doege H. Fluitt A. Tsang B. Watson N. Kay M.A. Stahl A. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase.Am. J. Physiol. Endocrinol. Metab. 2010; 299: E384-E393Crossref PubMed Scopus (35) Google Scholar) or FATP5 (Doege et al., 2008Doege H. Grimm D. Falcon A. Tsang B. Storm T.A. Xu H. Ortegon A.M. Kazantzis M. Kay M.A. Stahl A. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia.J. Biol. Chem. 2008; 283: 22186-22192Crossref PubMed Scopus (37) Google Scholar), protects against the development of hepatic steatosis and glucose intolerance (Figure 3). The liver also actively exports lipids. The importance of this balance between hepatic lipid uptake and export is demonstrated in mice that overexpress human apolipoprotein CIII (ApoC3). ApoC3 can inhibit LpL activity and limit peripheral fat uptake, thereby promoting postprandial hyperlipidemia. Though transgenic mice that overexpress ApoC3 (ApoC3 tg) have marked hypertriglyceridemia, hepatic lipid content in regular chow-fed mice is not different than wild-type mice fed the same diet (Lee et al., 2011bLee H.Y. Birkenfeld A.L. Jornayvaz F.R. Jurczak M.J. Kanda S. Popov V. Frederick D.W. Zhang D. Guigni B. Bharadwaj K.G. et al.Apolipoprotein CIII overexpressing mice are predisposed to diet-induced hepatic steatosis and hepatic insulin resistance.Hepatology. 2011; 54: 1650-1660Crossref PubMed Scopus (28) Google Scholar). However, when placed on a high-fat diet, ApoC3 tg mice develop hepatic steatosis with diacylglycerol accumulation, PKCε activation, and hepatic insulin resistance (Lee et al., 2011bLee H.Y. Birkenfeld A.L. Jornayvaz F.R. Jurczak M.J. Kanda S. Popov V. Frederick D.W. Zhang D. Guigni B. Bharadwaj K.G. et al.Apolipoprotein CIII overexpressing mice are predisposed to diet-induced hepatic steatosis and hepatic insulin resistance.Hepatology. 2011; 54: 1650-1660Crossref PubMed Scopus (28) Google Scholar). The development of hepatic steatosis could be attributed to a mismatch between hepatic lipid uptake and lipid export in the high fat-fed mice; hepatic lipid uptake is increased under both conditions, but export, via ApoB100 containing VLDL particles, is decreased in the hyperinsulinemic fat-fed mice due to suppression of ApoB100 expression. This has relevance to human disease. Lean individuals (body mass index < 25 kg/m2) who carry polymorphisms in the insulin response element of the ApoC3 gene (rs2854116 and rs2854117) have increased fasting plasma ApoC3 concentrations and fasting hypertriglyceridemia (Petersen et al., 2010Petersen K.F. Dufour S. Hariri A. Nelson-Williams C. Foo J.N. Zhang X.-M. Dziura J. Lifton R.P. Shulman G.I. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease.N. Engl. J. Med. 2010; 362: 1082-1089Crossref PubMed Scopus (165) Google Scholar). This is associated with a decrease in plasma lipid clearance after both an oral and intravenous lipid challenge and an increase in hepatic steatosis. Thus, as with the ApoC3 tg mice, when individuals carrying polymorphisms in ApoC3 exist in “toxic environments” (Novak and Brownell, 2011Novak N.L. Brownell K.D. Taxation as prevention and as a treatment for obesity: the case of sugar-sweetened beverages.Curr. Pharm. Des. 2011; 17: 1218-1222Crossref PubMed Google Scholar), they are prone to NAFLD and hepatic insulin resistance. Importantly, this subtle gene-environment relationship is not evident in obese subjects who already have a high prevalence of NAFLD (Kozlitina et al., 2011Kozlitina J. Boerwinkle E. Cohen J.C. Hobbs H.H. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance.Hepatology. 2011; 53: 467-474Crossref PubMed Scopus (48) Google Scholar). Thus, ectopic lipid accumulation in liver either from increased delivery or decreased export can lead to hepatic insulin resistance. Though genetic defects in hepatic mitochondrial fatty acid oxidation (e.g., mice lacking long-chain acyl-CoA dehydrogenase [LCAD]) can also be a predisposing condition to hepatic steatosis and hepatic insulin resistance (Zhang et al., 2007Zhang D. Liu Z.-X. Choi C.S. Tian L. Kibbey R. Dong J. Cline G.W. Wood P.A. Shulman G.I. Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance.Proc. Natl. Acad. Sci. USA. 2007; 104: 17075-17080Crossref PubMed Scopus (106) Google Scholar), studies in patients with NAFLD are few and differ in their conclusions, with some studies reporting reduced (Cortez-Pinto et al., 1999Cortez-Pinto H. Chatham J. Chacko V.P. Arnold C. Rashid A. Diehl A.M. Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study.JAMA. 1999; 282: 1659-1664Crossref PubMed Scopus (254) Google Scholar, Schmid et al., 2011Schmid A.I. Szendroedi J. Chmelik M. Krssák M. Moser E. Roden M. Liver ATP synthesis is lower and relates to insulin sensitivity in patients with type 2 diabetes.Diabetes Care. 2011; 34: 448-453Crossref PubMed Scopus (39) Google Scholar) and others reporting increased hepatic mitochondrial metabolism (Sunny et al., 2011Sunny N.E. Parks E.J. Browning J.D. Burgess S.C. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease.Cell Metab. 2011; 14: 804-810Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). Lipids, as signaling intermediates, encompass a vast range of molecules with distinct functions. Though circulating lipids (e.g., endotoxins and prostaglandins) were the earliest recognized lipid signals, intracellular lipid intermediates (such as diacylglycerols, ceramides, and PIP3) also mediate intracellular signaling. The local production of these lipid metabolites has been thought to provide some degree of signaling localization. That is, signaling events and therefore cellular actions can be directed to specific regions within the cell in response to the generation of a key lipid intermediate. So, what is the pathological lipid moiety that triggers insulin resistance? Upon cellular entry, fatty acids are rapidly esterified with coenzyme A to fatty acyl-CoAs. These are successively transferred to a glycerol backbone to form mono-, di-, and triacylglycerols. They can also esterify with sphingosine to form ceramides. Some of these lipid intermediates (e.g., diacylglycerol and ceramides) are also known to function as second messengers in key signaling pathways. These lipid intermediates comprise a lineup of metabolic suspects implicated in the pathogenesis insulin resistance. These associations can be directly tested using genetic mouse models that modulate the expression of the enzymes involved in lipid metabolism. Mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase (mtGPAT) catalyzes the formation of lysophosphatidic acid from fatty acyl CoA and glycerol 3-phosphate (Figure 3). When mtGPAT-deficient (mtGPAT1−/−) mice are placed on a high-fat diet, they accumulate hepatic fatty acyl-CoA, but not hepatic diacylglycerol and triglyceride (Neschen et al., 2005Neschen S. Morino K. Hammond L.E. Zhang D. Liu Z.X. Romanelli A.J. Cline G.W. Pongratz R.L. Zhang X.M. Choi C.S. et al.Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice.Cell Metab. 2005; 2: 55-65Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). Despite the 2-fold increase in fatty acyl-CoA, mtGPAT1-deficient mice are protected from diet-induced hepatic insulin resistance. Though hepatic mtGPAT overexpression does not decrease fatty acyl-Coa, it still leads to hepatic insulin resistance that is associated with increased lysophosphatidic acid, DAG, and TAG (Nagle et al., 2007Nagle C.A. An J. Shiota M. Torres T.P. Cline G.W. Liu Z.X. Wang S. Catlin R.L. Shulman G.I. Newgard C.B. Coleman R.A. Hepatic overexpression of glycerol-sn-3-phosphate acyltransferase 1 in rats causes insulin resistance.J. Biol. Chem. 2007; 282: 14807-14815Crossref PubMed Scopus (64) Google Scholar). Together, these studies suggest that fatty acyl CoAs do not cause insulin resistance. Several lines of evidence support a role for ceramides in the pathogenesis of insulin resistance. Ceramides are primarily membrane lipids, a precursor in the formation of sphingomyelin. However, increases in hepatic and muscle ceramide content, along with diacylglycerols, have been associated with insulin resistance in obese Zucker (fa/fa rats, homozygous for a truncated, nonfunctional leptin receptor) (Turinsky et al., 1990Turinsky J. O'Sullivan D.M. Bayly B.P. 1,2-Diacylglycerol and ceramide levels in insulin-resistant tissues of the rat in vivo.J. Biol. Chem. 1990; 265: 16880-16885Abstract Full Text PDF PubMed Google Scholar). Treating fat-fed mice with myriocin, an inhibitor of serine palmitoyl transferase 1, specifically attenuates the increase in muscle ceramide content in fat-fed mice without any change in long-chain acyl-CoAs, diacylglycerols, or triglyceride and improves glucose tolerance. The role of ceramides as a mediator of insulin resistance may be limited to saturated fats. Myriocin prevents acute skeletal muscle insulin resistance following infusion of palmitate, but not oleate (Holland et al., 2007Holland W.L. Brozinick J.T. Wang L
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