Resolving the Paradox of Hepatic Insulin Resistance

Insulin resistance is associated with numerous metabolic disorders, such as obesity and type II diabetes, that currently plague our society. Although insulin normally promotes anabolic metabolism in the liver by increasing glucose consumption and lipid synthesis, insulin-resistant individuals fail to inhibit hepatic glucose production and paradoxically have increased liver lipid synthesis, leading to hyperglycemia and hypertriglyceridemia. Here, we detail the intrahepatic and extrahepatic pathways mediating insulin's control of glucose and lipid metabolism. We propose that the interplay between both of these pathways controls insulin signaling and that mis-regulation between the 2 results in the paradoxic effects seen in the insulin-resistant liver instead of the commonly proposed deficiencies in particular branches of only the direct hepatic pathway. Insulin resistance is associated with numerous metabolic disorders, such as obesity and type II diabetes, that currently plague our society. Although insulin normally promotes anabolic metabolism in the liver by increasing glucose consumption and lipid synthesis, insulin-resistant individuals fail to inhibit hepatic glucose production and paradoxically have increased liver lipid synthesis, leading to hyperglycemia and hypertriglyceridemia. Here, we detail the intrahepatic and extrahepatic pathways mediating insulin's control of glucose and lipid metabolism. We propose that the interplay between both of these pathways controls insulin signaling and that mis-regulation between the 2 results in the paradoxic effects seen in the insulin-resistant liver instead of the commonly proposed deficiencies in particular branches of only the direct hepatic pathway. SummaryThis review describes the signaling pathways involved in the regulation of liver metabolism by insulin. In addition, it explores the molecular mechanisms underlying hepatic insulin resistance, highlighting the contribution of intrahepatic and extrahepatic pathways. This review describes the signaling pathways involved in the regulation of liver metabolism by insulin. In addition, it explores the molecular mechanisms underlying hepatic insulin resistance, highlighting the contribution of intrahepatic and extrahepatic pathways. Metabolic disorders such as obesity and type II diabetes mellitus (T2DM) have reached epidemic proportions and continue to be a leading cause of death worldwide.1Zimmet P. Alberti K.G.M.M. Shaw J. Global and societal implications of the diabetes epidemic.Nature. 2001; 414: 782-787Crossref PubMed Scopus (4547) Google Scholar The liver plays a central role in the systemic regulation of glucose and lipid metabolism and aberrant hepatic insulin action is thought to be a primary driver of insulin resistance, in which higher circulating insulin levels are necessary to adequately control blood glucose levels. During a normal physiologic fasting period, a high glucagon-to-insulin ratio decreases the rate of glucose consumption and shifts the liver to glucose production, first by consuming its stores of glycogen (glycogenolysis) and then from glucogenic precursors in a synthetic pathway (gluconeogenesis).2Ramnanan C.J. Edgerton D.S. Kraft G. Cherrington A.D. Physiologic action of glucagon on liver glucose metabolism.Diabetes Obes Metab. 2011; 13: 118-125Crossref PubMed Scopus (187) Google Scholar In the postprandial state, decreasing glucagon and increasing insulin levels signal the liver to increase glucose consumption, stop glucose production, and store excess nutrients in the form of glycogen and lipids.3Lin H.V. Accili D. Hormonal regulation of hepatic glucose production in health and disease.Cell Metab. 2011; 14: 9-19Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar In pathologic states, such as obesity and T2DM, insulin fails to appropriately regulate hepatic metabolism, leading to excess production of glucose despite accelerated rates of lipid synthesis, a condition now commonly referred to as selective hepatic insulin resistance.4Brown M.S. Goldstein J.L. Selective versus total insulin resistance: a pathogenic paradox.Cell Metab. 2008; 7: 95-96Abstract Full Text Full Text PDF PubMed Scopus (668) Google Scholar As a consequence, insulin-resistant disorders such as obesity and T2DM are closely linked to nonalcoholic fatty liver disease (NAFLD), a disorder that can lead to liver dysfunction and progress to deadly nonalcoholic steatohepatitis.5James O.F.W. Day C.P. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance.J Hepatol. 1998; 29: 495-501Abstract Full Text PDF PubMed Scopus (354) Google Scholar Increased rates of glucose production and lipogenesis are well documented in insulin-resistant human beings. Patients with NAFLD almost universally show hyperinsulinemia.6Sanyal A.J. Campbell-Sargent C. Mirshahi F. Rizzo W.B. Contos M.J. Sterling R.K. Luketic V.A. Shiffman M.L. Clore J.N. 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Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease.Gastroenterology. 2014; 146: 726-735Abstract Full Text Full Text PDF PubMed Scopus (580) Google Scholar In addition to increased lipid synthesis, insulin-resistant individuals have increased rates of hepatic glucose production (HGP).9Roden M. Stingl H. Chandramouli V. Schumann W.C. Hofer A. Landau B.R. Nowotny P. Waldhäusl W. Shulman G.I. Effects of free fatty acid elevation on and gluconeogenesis in humans.Endocrinol Metab. 2000; 49: 701-707Google Scholar Indeed, there is a significant correlation between rates of gluconeogenesis and the extent of liver fat in NAFLD patients.10Sunny 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 (411) Google Scholar Therefore, during the progression of insulin resistance, insulin fails to suppress HGP yet continues to drive excess lipid synthesis, leading to the sequela of NAFLD, hyperglycemia, and hypertriglyceridemia. Experiments in both mice and human beings have shown the essential role for hepatic insulin action in the regulation of glucose production and lipogenesis. Liver insulin resistant knockout mice (LIRKO) mice fail to inhibit glucose production and cannot induce de novo lipogenesis.11Biddinger S.B. Hernandez-Ono A. Rask-Madsen C. Haas J.T. Alemán J.O. Suzuki R. Scapa E.F. Agarwal C. Carey M.C. Stephanopoulos G. Cohen D.E. King G.L. Ginsberg H.N.N. Kahn C.R. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis.Cell Metab. 2008; 7: 125-134Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, 12Haas J.T. Miao J. Chanda D. Wang Y. Zhao E. Haas M.E. Hirschey M. Vaitheesvaran B. Farese Jr., R.V. Kurland I.J. Graham M. Crooke R. Foufelle F. Biddinger S.B. Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression.Cell Metab. 2012; 15: 873-884Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 13Semple R.K. Sleigh A. Murgatroyd P.R. Adams C.A. Bluck L. Jackson S. Vottero A. Kanabar D. Charlton-Menys V. Durrington P. Soos M.A. Carpenter T.A. Lomas D.J. Cochran E.K. Gorden P. O'Rahilly S. Savage D.B. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis.J Clin Invest. 2009; 119: 315-322PubMed Google Scholar, 14Michael M.D. Kulkarni R.N. Postic C. Previs S.F. 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The clinical findings corroborate the concept that the liver is the key driver of insulin's whole-body action on glucose and lipid homeostasis.13Semple R.K. Sleigh A. Murgatroyd P.R. Adams C.A. Bluck L. Jackson S. Vottero A. Kanabar D. Charlton-Menys V. Durrington P. Soos M.A. Carpenter T.A. Lomas D.J. Cochran E.K. Gorden P. O'Rahilly S. Savage D.B. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis.J Clin Invest. 2009; 119: 315-322PubMed Google Scholar Further supporting this statement, fat-specific deletion of the insulin receptor results in lipodystrophy along with insulin resistance and hyperglycemia.15Softic S. Boucher J. Solheim M.H. Fujisaka S. Haering M.F. Homan E.P. Winnay J. Perez-Atayde A.R. Kahn C.R. Lipodystrophy due to adipose tissue-specific insulin receptor knockout results in progressive NAFLD.Diabetes. 2016; 65: 2187-2200Crossref PubMed Scopus (72) Google Scholar However, these mice are not protected from NAFLD, and eventually develop nonalcoholic steatohepatitis, unlike the LIRKO mice and human beings with insulin-receptor mutations. Experiments using congenital mouse models can pose some issues because off-target effects of genetic manipulation can develop over time and obscure results. For example, LIRKO mice are typically smaller than wild-type mice, possibly because of defects in the insulin-like growth factor axis, and eventually the observed effects, such as hyperglycemia, disappear as a result of liver failure.14Michael M.D. Kulkarni R.N. Postic C. Previs S.F. Shulman G.I. Magnuson M.A. Kahn C.R. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.Mol Cell. 2000; 6: 87-97Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar In these instances, inducible genetic knockouts hold some benefit because one can observe the direct effects of the knockout before the off-target effects begin to manifest. In this case, inducible knockout of the insulin receptor reciprocates the glucose intolerance and hyperinsulinemia of the LIRKO mice without the off-target metabolic effects. These mice also fail to promote hepatic lipogenesis in response to a high carbohydrate meal.16Titchenell P.M. Chu Q. Monks B.R. Birnbaum M.J. Hepatic insulin signaling is dispensible for suppression of glucose output by insulin in vivo.Nat Commun. 2015; 6: 7078Crossref PubMed Scopus (105) Google Scholar Resolving what specific factors mediate insulin action on the liver to generate these paradoxical effects has become a major focus in obesity and T2DM studies and has provided many insights into the molecular mechanisms of insulin action and hepatic metabolism. Here, we discuss these pathways in depth and suggest an integrated model to deconvolute the paradox of hepatic insulin action that integrates the direct effects of insulin action on the liver with many extrahepatic pathways from peripheral metabolic organs. Strong evidence has indicated that the phosphoinositide-3-phosphate kinase (PI3K)/Akt pathway is the key signaling pathway that mediates the effects of insulin on anabolic metabolism in all organisms.17Taniguchi C.M. Emanuelli B. Kahn C.R. Critical nodes in signalling pathways: insights into insulin action.Nat Rev Mol Cell Biol. 2006; 7: 85-96Crossref PubMed Scopus (2081) Google Scholar When insulin binds to the insulin receptor (IR), it recruits and activates PI3K through insulin-receptor substrates (IRS), generating phosphatidylinositol (3,4,5)-trisphosphate (PIP3). IRS proteins link the PI3K pathway to the insulin receptor by binding to phosphotyrosine residues on the insulin receptor.18Gual P. Le Marchand-Brustel Y. Tanti J.F. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.Biochimie. 2005; 87: 99-109Crossref PubMed Scopus (671) Google Scholar Knockout of multiple insulin-receptor substrates prevents activation of the pathway in response to insulin, leading to insulin resistance and hyperglycemia, but not hepatic steatosis.19Dong X.C. Copps K.D. Guo S. Li Y. Kollipara R. DePinho R.A. White M.F. 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In addition to SREBP1c, carbohydrate response element binding protein (ChREBP) is a well-studied, glucose-responsive transcription factor that may play a role in controlling hepatic lipid metabolism. Glucose-6-phosphate is the key activator of ChREBP, facilitating its migration to the nucleus46Dentin R. Tomas-Cobos L. Foufelle F. Leopold J. Girard J. Postic C. Ferré P. Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver.J Hepatol. 2012; 56: 199-209Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar (Figure 1). Because insulin signaling enhances glucose uptake in the liver, ChREBP becomes activated. As a transcription factor, ChREBP activates similar lipogenic genes to SREBP1c, although its roles in insulin sensitivity remain controversial. Normal mice with ChREBP deleted globally show decreased lipogenesis as well as mild insulin resistance.47Iizuka K. Bruick R.K. Liang G. Horton J.D. 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The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans.J Clin Invest. 2012; 122: 2176-2194Crossref PubMed Scopus (279) Google Scholar Consistent with these mouse studies, obese human beings typically have higher ChREBP expression in the liver, which correlates with fatty liver.50Hurtado Del Pozo C. Vesperinas-García G. Rubio M.Á. Corripio-Sánchez R. Torres-García A.J. Obregon M.J. Calvo R.M. ChREBP expression in the liver, adipose tissue and differentiated preadipocytes in human obesity.Biochim Biophys Acta. 2011; 1811: 1194-1200Crossref PubMed Scopus (52) Google Scholar Recently, studies deleting ChREBP specifically in mouse hepatocytes showed mild insulin resistance and protection from hepatic steatosis when challenged with a high-carbohydrate diet, but had no effect on lipogenesis and lipogenic gene expression under normal chow.51Jois T. Chen W. Howard V. Harvey R. Youngs K. Thalmann C. Saha P. Chan L. Cowley