Muscle and adipose tissue insulin resistance: malady without mechanism?

Insulin resistance is a major risk factor for numerous diseases, including type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of “common” insulin resistance. Despite considerable effort, the mechanisms that contribute to common insulin resistance are not resolved. There is universal agreement that extracellular perturbations, such as nutrient excess, hyperinsulinemia, glucocorticoids, or inflammation, trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells. Here, we present evidence that the impairment in insulin action is independent of proximal elements of the insulin signaling pathway and is likely specific to the glucoregulatory branch of insulin signaling. We propose that many intracellular stress pathways act in concert to increase mitochondrial reactive oxygen species to trigger insulin resistance. We speculate that this may be a physiological pathway to conserve glucose during specific states, such as fasting, and that, in the presence of chronic nutrient excess, this pathway ultimately leads to disease. This review highlights key points in this pathway that require further research effort. Insulin resistance is a major risk factor for numerous diseases, including type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of “common” insulin resistance. Despite considerable effort, the mechanisms that contribute to common insulin resistance are not resolved. There is universal agreement that extracellular perturbations, such as nutrient excess, hyperinsulinemia, glucocorticoids, or inflammation, trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells. Here, we present evidence that the impairment in insulin action is independent of proximal elements of the insulin signaling pathway and is likely specific to the glucoregulatory branch of insulin signaling. We propose that many intracellular stress pathways act in concert to increase mitochondrial reactive oxygen species to trigger insulin resistance. We speculate that this may be a physiological pathway to conserve glucose during specific states, such as fasting, and that, in the presence of chronic nutrient excess, this pathway ultimately leads to disease. This review highlights key points in this pathway that require further research effort. Insulin resistance is a pathophysiological state where cells display reduced responsiveness to the glucose-lowering activity of insulin. While there are rare cases where mutations in genes associated with insulin signaling or lipodystrophy cause insulin resistance, for the most part, insulin resistance is associated with obesity and, thus, a state of positive energy balance. This form of insulin resistance is frequently associated with hyperinsulinemia, increased waist circumference or visceral adiposity, metabolic dyslipidemia with high triglycerides and low HDL, and hepatic steatosis, features collectively referred to as the metabolic syndrome. We refer to this as “common insulin resistance”. Here, both insulin-dependent glucose disposal and suppression of glucose output are impaired, albeit the relative degree of impairment in each process can vary between individuals (1Abdul-Ghani M.A. Tripathy D. DeFronzo R.A. Contributions of beta-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose.Diabetes Care. 2006; 29: 1130-1139Crossref PubMed Google Scholar, 2Meyer C. Pimenta W. Woerle H.J. Van Haeften T. Szoke E. Mitrakou A. Gerich J. Different mechanisms for impaired fasting glucose and impaired postprandial glucose tolerance in humans.Diabetes Care. 2006; 29: 1909-1914Crossref PubMed Scopus (192) Google Scholar, 3Chen D.L. Liess C. Poljak A. Xu A. Zhang J. Thoma C. Trenell M. Milner B. Jenkins A.B. Chisholm D.J. et al.Phenotypic characterization of insulin-resistant and insulin-sensitive obesity.J. Clin. Endocrinol. Metab. 2015; 100: 4082-4091Crossref PubMed Scopus (33) Google Scholar). In this review, we focus on the literature surrounding insulin resistance in muscle and adipose tissue, and specifically on insulin-stimulated glucose transport into myocytes and adipocytes within these tissues. Impaired insulin action in other tissues, most notably the liver (4Samuel V.T. Shulman G.I. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.J. Clin. Invest. 2016; 126: 12-22Crossref PubMed Scopus (469) Google Scholar, 5Petersen M.C. Shulman G.I. Roles of diacylglycerols and ceramides in hepatic insulin resistance.Trends Pharmacol. Sci. 2017; 38: 649-665Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar), brain (6Chen W. Balland E. Cowley M.A. Hypothalamic insulin resistance in obesity: effects on glucose homeostasis.Neuroendocrinology. 2017; 104: 364-381Crossref PubMed Scopus (27) Google Scholar, 7Vogt M.C. Bruning J.C. CNS insulin signaling in the control of energy homeostasis and glucose metabolism - from embryo to old age.Trends Endocrinol. Metab. 2013; 24: 76-84Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar) and vasculature (8Wasserman D.H. Wang T.J. Brown N.J. The vasculature in prediabetes.Circ. Res. 2018; 122: 1135-1150Crossref PubMed Scopus (32) Google Scholar), also play a key role in whole-body insulin resistance, and we direct readers to reviews that explore insulin resistance at these sites in detail. We will examine the evidence that common insulin resistance, in the context of muscle and adipose tissue, results from a defect in “proximal” insulin signaling, which we define for the purposes of this review as the signaling intermediates that lead to the activation of Akt. We argue that common insulin resistance arises as a consequence of intracellular stress, specifically oxidative stress, which selectively targets the glucose transport arm of the insulin signaling network, and we discuss the role that impaired glucose transport into muscle and adipose tissue may play in the progression of whole-body insulin resistance. Finally, we explore the concept that insulin resistance, or impaired glucose disposal into muscle and adipose tissue, may be a normal physiological state that, under certain conditions, acts to prioritize glucose use to specific tissues, such as the brain. This pathway may be co-opted in obesity leading to a pathological state of chronic insulin resistance. We recommend several other reviews that have focused on other aspects of insulin resistance that will not be discussed in this review. Most notably, Czech (9Czech M.P. Insulin action and resistance in obesity and type 2 diabetes.Nat. Med. 2017; 23: 804-814Crossref PubMed Scopus (321) Google Scholar) provided an elegant distillation of the complex relationship between hyperinsulinemia and insulin resistance, while others have presented evidence in support of a range of other factors as causes of insulin resistance, including diacylglycerols (DAGs) (10Samuel V.T. Petersen K.F. Shulman G.I. Lipid-induced insulin resistance: unravelling the mechanism.Lancet. 2010; 375: 2267-2277Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar), ceramides (11Chavez J.A. Summers S.A. A ceramide-centric view of insulin resistance.Cell Metab. 2012; 15: 585-594Abstract Full Text Full Text PDF PubMed Scopus (346) Google Scholar), and inflammation (12Saltiel A.R. Olefsky J.M. Inflammatory mechanisms linking obesity and metabolic disease.J. Clin. Invest. 2017; 127: 1-4Crossref PubMed Scopus (459) Google Scholar). In considering mechanisms that contribute to insulin resistance, it is necessary to summarize the signaling events that are triggered upon engagement of the insulin receptor (IR), as well as the downstream metabolic consequences of this for muscle, adipose tissue, and the whole body. Under fasting conditions, hepatic glucose output and release of fatty acids from triacylglycerol (TAG) stores in adipose tissue (lipolysis) provide substrates for oxidation and ATP production. In the fed state, increases in circulating amino acids, fatty acids, and glucose stimulate insulin secretion. Insulin suppresses hepatic glucose output and adipose tissue lipolysis, lowering blood glucose and fatty acid levels. It also increases hepatic lipid synthesis for subsequent storage in adipose tissue and stimulates glucose uptake into fat and muscle. The majority of glucose from a meal is deposited in muscle and liver with as little as 5% taken up by adipose tissue (13Ng J.M. Azuma K. Kelley C. Pencek R. Radikova Z. Laymon C. Price J. Goodpaster B.H. Kelley D.E. PET imaging reveals distinctive roles for different regional adipose tissue depots in systemic glucose metabolism in nonobese humans.Am. J. Physiol. Endocrinol. 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Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2.Cell Metab. 2013; 17: 1009-1020Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). This begins with activation of the IR, a tyrosine kinase that phosphorylates IR substrates (IRSs), such as IRS1/IRS2, on multiple tyrosine residues (Fig. 1A). These recruit proteins containing SH2 domains, including phosphoinositide 3-kinase (PI3K) and Grb2. This in turn activates the two major protein kinase signaling pathways found in most eukaryotic cells, those mediated by the Ser/Thr kinases, Akt and MAPK/ERK. In particular, Akt has been intensely studied in the context of metabolism, with its activation being both necessary and sufficient for insulin-stimulated glucose transport (17Ng Y. Ramm G. Lopez J.A. James D.E. Rapid activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3–L1 adipocytes.Cell Metab. 2008; 7: 348-356Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Akt is recruited to the plasma membrane via binding of its PH domain to PI3K-produced phosphatidylinositol-3,4,5-phosphate (PIP3). It is activated by phosphorylation on Thr308 and Ser473 by PDK1 and mTORC2, respectively [reviewed in (18Manning B.D. Cantley L.C. AKT/PKB signaling: navigating downstream.Cell. 2007; 129: 1261-1274Abstract Full Text Full Text PDF PubMed Scopus (4086) Google Scholar)]. Consequently, these sites are routinely used as markers of Akt activation and subsequently as a measure of the cell's response to insulin. Beyond glucose transport, Akt has more than 100 substrates with a wide array of biological endpoints. These include regulating metabolism, protein synthesis (via mTORC1), transcription (e.g., via FOXO, SREBP1), and cellular proliferation. Here, we focus on the role of Akt in lipid and glucose metabolism. Insulin rapidly increases glucose transport through the regulated trafficking of the glucose transporter, GLUT4, from intracellular stores to the cell surface in muscle and adipose cells (19James D.E. Brown R. Navarro J. Pilch P.F. Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein.Nature. 1988; 333: 183-185Crossref PubMed Google Scholar, 20Stöckli J. Fazakerley D.J. James D.E. GLUT4 exocytosis.J. Cell Sci. 2011; 124: 4147-4159Crossref PubMed Scopus (170) Google Scholar) (Fig. 1A). This is mediated by the phosphorylation of proteins that regulate GLUT4 trafficking, such as TBC1D4/AS160 (21Sano H. Kane S. Sano E. Miinea C.P. Asara J.M. Lane W.S. Garner C.W. Lienhard G.E. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation.J. Biol. Chem. 2003; 278: 14599-14602Abstract Full Text Full Text PDF PubMed Scopus (672) Google Scholar). 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In addition to increasing glucose transport, insulin suppresses adipose tissue lipolysis (Fig. 1A). While this is one of the most important actions of insulin, our understanding of this process is relatively scant. The β-adrenergic receptor agonists activate lipolysis by increasing cAMP, leading to activation of protein kinase A (PKA) and phosphorylation of lipid droplet proteins to promote TAG hydrolysis (27Duncan R.E. Ahmadian M. Jaworski K. Sarkadi-Nagy E. Sul H.S. Regulation of lipolysis in adipocytes.Annu. Rev. Nutr. 2007; 27: 79-101Crossref PubMed Scopus (496) Google Scholar). Insulin is thought to inhibit this via Akt-dependent phosphorylation and activation of the phosphodiesterase, PDE3B, lowering cAMP levels and inhibiting PKA (28Kitamura T. Kitamura Y. Kuroda S. Hino Y. Ando M. Kotani K. Konishi H. Matsuzaki H. Kikkawa U. Ogawa W. et al.Insulin-induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine-threonine kinase Akt.Mol. Cell. 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The insulin-directed phosphorylation site on ATP-citrate lyase is identical with the site phosphorylated by the cAMP-dependent protein kinase in vitro.J. Biol. Chem. 1982; 257: 10681-10686Abstract Full Text PDF PubMed Google Scholar); and 2) formation of the TAG-glyceride backbone from glucose diverted from glycolysis (33Beale E.G. Hammer R.E. Antoine B. Forest C. Glyceroneogenesis comes of age.FASEB J. 2002; 16: 1695-1696Crossref PubMed Scopus (50) Google Scholar). As described below, this latter step represents a key convergence point in metabolic regulation whereby fat cell glucose metabolism may have a profound influence on adipocyte lipid storage independently of de novo lipogenesis. One of the arguments in favor of the view that insulin resistance is due to a proximal signaling defect is that monogenic mutations in proximal components of the insulin signaling pathway in humans, including IR, IRS1, PI3K, and Akt2, are associated with profound insulin resistance (34Melvin A. 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This is based on four arguments: 1) insulin resistance is observed in rodents and humans in the absence of decreased signal transduction; 2) most of the proximal insulin signaling components, like IR, IRS1, or Akt, operate at a threshold well below their maximum capacity such that modest changes in expression or impairments in function of these will have no significant impact on overall signaling (we define this concept as “spareness”); 3) circumventing the IR or IRS1 using alternate growth factors is not sufficient to block the defect observed in insulin resistance; and 4) insulin resistance in muscle and adipose tissue is quite selective for glucose transport. Decreased IR expression, tyrosine phosphorylation, and kinase activity have been observed in a variety of tissues from insulin-resistant animals (36Kadowaki T. Kasuga M. Akanuma Y. Ezaki O. Takaku F. Decreased autophosphorylation of the insulin receptor-kinase in streptozotocin-diabetic rats.J. Biol. 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