Resolving the Paradox of Hepatic Insulin Resistance

Santoleri, Dominic; Titchenell, Paul M.

doi:10.1016/j.jcmgh.2018.10.016

Cited by 343Liver Disease Diagnosis and TreatmentMetabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and Lipoproteins

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Resolving the Paradox of Hepatic Insulin Resistance

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Santoleri, Dominic, Titchenell, Paul M.·2019·Cellular and Molecular Gastroenterology and Hepatology

DOI 10.1016/j.jcmgh.2018.10.016PMC PMC6369222

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Abstract

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.

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Reduced phosphorylation of the PI3K/Akt pathway is a hallmark of insulin resistance in PCOS patients.
“Reduced phosphorylation of the PI3K/Akt pathway is a hallmark of IR in PCOS patients10–12.”
From Efficacy and safety of GLP-1 receptor agonists on weight management and metabolic parameters in PCOS women: a meta-analysis of randomized controlled trials (2025) · cites this paper as [11]
The ‘Hepatic Insulin Signaling and Lipid Metabolism’ section links impaired PI3K/Akt signaling to insulin resistance in mouse liver and describes Akt activation by phosphorylation. It does not establish reduced pathway phosphorylation as a hallmark of insulin resistance in PCOS patients; searches for ‘PCOS patients’ and ‘polycystic ovary syndrome’ found no such passage. Page numbers were unavailable in our copy. (LLM, conf=0.84)
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Hepatic insulin resistance results in increased gluconeogenesis, lipogenesis, and synthesis of very-low-density lipoproteins.
“hepatic insulin resistance, among other effects, has proved to result in increased gluconeogenesis, lipogenesis, and synthesis of very-low-density lipoproteins (VLDL) [22]”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [22]
The Abstract reports increased gluconeogenesis and lipogenesis in insulin-resistant people. The Hepatic Insulin Signaling and Lipid Metabolism section describes increased VLDL secretion in insulin-resistant conditions, but cautions that hyperinsulinemia, rather than insulin resistance itself, may stimulate it; it does not establish increased VLDL synthesis as a direct result. Page numbers were not provided in the copy. (LLM, conf=0.88)
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1 retracted

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“SCAP is required for activation of all isoforms of SREBP and its deletion significantly reduces cholesterol and fatty acid synthesis in the liver.(45) In addition, eliminating SCAP specifically in hepatocytes reduces lipid accumulation in the liver and is sufficient to prevent hepatic steatosis in ob/ob mice and sucro…”
Background
Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production
Titchenell, P. M., Quinn, W. J., Lu, M., Chu, Q., Lu, W., Li, C., Chen, H., Monks, B. R., Chen, J., Rabinowitz, J. D., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.022 · Cited by 298 · cited 10×
“by regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Figure 1), and its inhibition improves glycemia in insulin-resistant and diabetic mice.(3,32,74) Hepatic deletion of FoxO1 in mice results in significant decreases in glycogenolysis and gluconeogenesis.”
BackgroundResultInfluential
Role of hepatic STAT3 in brain-insulin action on hepatic glucose production
Inoue, H., Ogawa, W., Asakawa, A., Okamoto, Y., Nishizawa, A., Matsumoto, M., Teshigawara, K., Matsuki, Y., Watanabe, E., Hiramatsu, R., et al. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.009 · Cited by 294
Physiologic action of glucagon on liver glucose metabolism
Ramnanan, C. J., Edgerton, D. S., Kraft, G., & Cherrington, A. D. (2011) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01454.x · Cited by 293 · cited 1×
“During a normal physiologic fasting period, a high glucagonto-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).(2) In the postprandi…”
Background
Akt2 Is Required for Hepatic Lipid Accumulation in Models of Insulin Resistance
Leavens, K. F., Easton, R., Shulman, G. I., Previs, S. F., & Birnbaum, M. J. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.10.004 · Cited by 289 · cited 1×
“Mice lacking hepatic Akt2, the most abundant hepatic isoform, have decreased lipid accumulation, and decreased de novo lipogenesis in the liver of ob/ob mice or mice subjected to a high-fat diet.(30) However, despite its abundance, liver-specific deletion of Akt2 only results in mild insulin resistance owing to residu…”
Background
Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKCλ/ζ
Taniguchi, C. M., Kondo, T., Sajan, M. P., Luo, J., Bronson, R. T., Asano, T., Farese, R. V., Cantley, L. C., & Kahn, C. R. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.04.005 · Cited by 288
Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans
Roden, M., Stingl, H., Chandramouli, V, Schumann, W. C., Hofer, A., Landau, B. R., Nowotny, P., Waldhäusl, W., & Shulman, G. I. (2000) · Diabetes · doi:10.2337/diabetes.49.5.701 · Cited by 288
Free Fatty Acid as a Link in the Regulation of Hepatic Glucose Output by Peripheral Insulin
Rebrin, K., Steil, G. M., Getty‐Kaushik, L., & Bergman, R. N. (1995) · Diabetes · doi:10.2337/diab.44.9.1038 · Cited by 270
Hormone and glucose signalling in POMC and AgRP neurons
Belgardt, B., Okamura, T., & Brüning, J. C. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.179192 · Cited by 257 · cited 1×
“Insulin can act on neurons in the hypothalamus, particularly agouti-related peptide– and proopiomelanocortin-expressing neurons.(78) Knockout of the insulin receptor in agouti-related peptide–expressing neu-”
Background
The role of FOXO in the regulation of metabolism
Gross, D. N., Wan, M., & Birnbaum, M. J. (2009) · Current Diabetes Reports · doi:10.1007/s11892-009-0034-5 · Cited by 244
Interplay between ChREBP and SREBP-1c coordinates postprandial glycolysis and lipogenesis in livers of mice
Linden, A. G., Li, S., Choi, H. Y., Fang, F., Fukasawa, M., Uyeda, K., Hammer, R. E., Horton, J. D., Engelking, L. J., & Liang, G. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m081836 · Cited by 243 · cited 1×
“Moreover, overexpressing ChREBP was not sufficient to regain any significant lipogenic gene induction in mice lacking SREBP after SCAP deletion, showing that SREBP is required for the induction of lipogenic expression.(52) The interplay between ChREBP and SREBP1c in regulating lipogenic gene expression helps ensure th…”
Background
Metabolic Syndrome: Focus on Dyslipidemia
Ginsberg, H. N., Zhang, Y., & Hernández‐Ono, A. (2006) · Obesity · doi:10.1038/oby.2006.281 · Cited by 228
Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice
Altomonte, J., Richter, A. M., Harbaran, S., Suriawinata, J., Nakae, J., Thung, S. N., Meseck, M. L., Accili, D., & Dong, H. H. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00156.2003 · Cited by 228 · cited 1×
“by regulating expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (Figure 1), and its inhibition improves glycemia in insulin-resistant and diabetic mice.(3,32,74) Hepatic deletion of FoxO1 in mice results in significant decreases in glycogenolysis and gluconeogenesis.”
Background
Hepatic Insulin Signaling Is Required for Obesity-Dependent Expression of SREBP-1c mRNA but Not for Feeding-Dependent Expression
Haas, J. T., Miao, J., Chanda, D., Wang, Y., Zhao, E., Haas, M. E., Hirschey, M. D., Vaitheesvaran, B., Farese, R. V., Kurland, I. J., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.05.002 · Cited by 215 · cited 1×
“In addition, LIRKO mice fail to accumulate lipids and do not develop fatty liver, even when fed a high-fat diet, despite increased blood glucose and insulin levels.(12) These”
Background
Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling
Langlet, F., Haeusler, R. A., Lindén, D., Ericson, E., Norris, T., Johansson, A., Cook, J. R., Aizawa, K. S., Wang, L., Buettner, C., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.045 · Cited by 201
Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient ( ob/ob ) mice
Iizuka, K., Miller, B., & Uyeda, K. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00027.2006 · Cited by 195
Insulin's direct effects on the liver dominate the control of hepatic glucose production
Edgerton, D. S. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27073 · Cited by 194 · cited 10×
“However, other work has shown that insulin’s direct action on the liver dominates.32,72 Differences in experimental clamp conditions could underlie these contrasting results on the role of FFAs in the control of HGP.”
BackgroundInfluential
Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors
Haeusler, R. A., Hartil, K., Vaitheesvaran, B., Arrieta‐Cruz, I., Knight, C. M., Cook, J. R., Kammoun, H. L., Febbraio, M. A., Juárez, R. G., Kurland, I. J., et al. (2014) · Nature Communications · doi:10.1038/ncomms6190 · Cited by 192 · cited 1×
“Conversely, deletion of all FoxO isoforms from the liver activates lipogenic gene expression and induces de novo lipogenesis correlating with hepatic steatosis.(62) Because FoxO1 is thought to be a transcriptional activator, the specific mechanisms governing its inhibition of lipogenesis is unclear.”
Background
A growing role for mTOR in promoting anabolic metabolism
Howell, J. J., Ricoult, S. J. H., Ben‐Sahra, I., & Manning, B. D. (2013) · Biochemical Society Transactions · doi:10.1042/bst20130041 · Cited by 185
The Role of Fatty Acids in Mediating the Effects of Peripheral Insulin on Hepatic Glucose Production in the Conscious Dog
Sindelar, D., Chu, C. A., Rohlie, M., Neal, D., Swift, L., & Cherrington, A. (1997) · Diabetes · doi:10.2337/diab.46.2.187 · Cited by 179
Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver
Dentin, R., Tomás‐Cobos, L., Foufelle, F., Leopold, J. A., Girard, J. R., Postic, C., & Ferré, P. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2011.07.019 · Cited by 177
Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo
Titchenell, P. M., Chu, Q., Monks, B. R., & Birnbaum, M. J. (2015) · Nature Communications · doi:10.1038/ncomms8078 · Cited by 169 · cited 2×
“These mice also fail to promote hepatic lipogenesis in response to a high carbohydrate meal.(16) 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…”
BackgroundSelf-citation
Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver
Miyake, K., Ogawa, W., Matsumoto, M., Nakamura, T., Sakaue, H., & Kasuga, M. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15880 · Cited by 156
FoxO1 Inhibits Sterol Regulatory Element-binding Protein-1c (SREBP-1c) Gene Expression via Transcription Factors Sp1 and SREBP-1c
Deng, X., Zhang, W., O‐Sullivan, I., Williams, J. B., Dong, Q., Park, E. A., Raghow, R., Unterman, T. G., & Elam, M. B. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.347211 · Cited by 150 · cited 2×
“However, recent studies have argued that FoxO1 directly represses the transcription of SREBP1c.63 In addition, FoxO1 has been implicated in regulating the expression of glucokinase (Gck) through a repression mechanism mediated by Sin3a and Sin3b62,64,65 (Figure 1).”
Background
Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity
Kubota, N., Kubota, T., Kajiwara, E., Iwamura, T., Kumagai, H., Watanabe, T., Inoue, M., Takamoto, I., Sasako, T., Kumagai, K., et al. (2016) · Nature Communications · doi:10.1038/ncomms12977 · Cited by 143 · cited 1×
“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.(19,20) PIP3 initiates recruitment of Akt (named as such when it was discovered to be the oncogene responsible for thymoma in Ak mice, a…”
Background
Postprandial Hepatic Lipid Metabolism Requires Signaling through Akt2 Independent of the Transcription Factors FoxA2, FoxO1, and SREBP1c
Wan, M., Leavens, K. F., Saleh, D., Easton, R., Guertin, D. A., Peterson, T. R., Kaestner, K. H., Sabatini, D. M., & Birnbaum, M. J. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.09.001 · Cited by 140 · cited 1×
“Studies have shown that activation of mTORC1 is required for de novo lipogenesis, however, activation of mTORC1 alone is not sufficient to induce lipogenesis in the absence of hepatic insulin signaling.(32,37) This is consistent with the phenotype of mice lacking Tsc specifically in hepatocytes because liver-specific…”
Result
The direct and indirect effects of insulin on hepatic glucose production in vivo
Cherrington, A. D., Edgerton, D. S., & Sindelar, D. K. (1998) · Diabetologia · doi:10.1007/s001250051021 · Cited by 137
Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion
Edgerton, D. S., Kraft, G., Smith, M. S., Farmer, B., Williams, P. E., Coate, K. C., Printz, R. L., O’Brien, R. M., & Cherrington, A. D. (2017) · JCI Insight · doi:10.1172/jci.insight.91863 · Cited by 131
Lipodystrophy Due to Adipose Tissue–Specific Insulin Receptor Knockout Results in Progressive NAFLD
Softic, S., Boucher, J., Solheim, M. H., Fujisaka, S., Haering, M.-F., Homan, E. P., Winnay, J. N., Pérez‐Atayde, A. R., & Kahn, C. R. (2016) · Diabetes · doi:10.2337/db16-0213 · Cited by 128 · cited 1×
“Further supporting this statement, fat-specific deletion of the insulin receptor results in lipodystrophy along with insulin resistance and hyperglycemia.(15) However, these mice are not protected from NAFLD, and eventually develop nonalcoholic steatohepatitis, unlike the LIRKO mice and human beings with insulin-recep…”
Background
A Combination of HNF-4 and Foxo1 Is Required for Reciprocal Transcriptional Regulation of Glucokinase and Glucose-6-phosphatase Genes in Response to Fasting and Feeding
Hirota, K., Sakamaki, J.-I., Ishida, J., Shimamoto, Y., Nishihara, S., Kodama, N., Ohta, K., Yamamoto, M. P., Tanimoto, K., & Fukamizu, A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806179200 · Cited by 123
The Critical Role of AKT2 in Hepatic Steatosis Induced by PTEN Loss
He, L., Hou, X., Kanel, G. C., Zeng, N., Galicia, V. A., Wang, Y., Yang, J., Wu, H., Birnbaum, M. J., & Stiles, B. L. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.090931 · Cited by 108
Glucose-6-Phosphate–Mediated Activation of Liver Glycogen Synthase Plays a Key Role in Hepatic Glycogen Synthesis
von Wilamowitz-Moellendorff, A., Hunter, R. W., Garcı́a-Rocha, M., Kang, L., López‐Soldado, I., Lantier, L., Patel, K., Peggie, M. W., Martínez-Pons, C., Voß, M., et al. (2013) · Diabetes · doi:10.2337/db13-0880 · Cited by 106
Hyperinsulinemia and in vivo very-low-density lipoprotein-triglyceride kinetics
Steiner, G. A., Haynes, F. J., Yoshino, G., & Vranić, M. (1984) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1984.246.2.e187 · Cited by 102
Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice
Han, S., Liang, C.-P., Westerterp, M., Senokuchi, T., Welch, C. L., Wang, Q., Matsumoto, M., Accili, D., & Tall, A. R. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36523 · Cited by 97 · cited 1×
“In addition, disrupting insulin signaling in mouse livers by deleting Akt or the insulin receptor reduces VLDL secretion.(57) Downstream of Akt, inhibiting or activating mTORC1 in the liver leads to decreased or increased VLDL secretion, respectively, through the regulation of phosphatidylcholine synthesis, a crucial…”
Background
mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion
Quinn, W. J., Wan, M., Shewale, S. V., Gelfer, R., Rader, D. J., Birnbaum, M. J., & Titchenell, P. M. (2017) · Journal of Clinical Investigation · doi:10.1172/jci96036 · Cited by 97 · cited 1×
“Downstream of Akt, inhibiting or activating mTORC1 in the liver leads to decreased or increased VLDL secretion, respectively, through the regulation of phosphatidylcholine synthesis, a crucial part of VLDL synthesis and secretion.(58) As such, insulin regulation of VLDL-TAG secretion is complex and the coordinated con…”
Background
Indirect effect of insulin to suppress endogenous glucose production is dominant, even with hyperglucagonemia.
Mittelman, S. D., Fu, Y. Y., Rebrin, K., Steil, G. M., & Bergman, R. N. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119867 · Cited by 94
Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins
Zhang, W., Bu, S. Y., Mashek, M. T., O‐Sullivan, I., Sibai, Z., Khan, S. A., Ilkayeva, O., Newgard, C. B., Mashek, D. G., & Unterman, T. G. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.021 · Cited by 82 · cited 1×
“due to its three active serine residues being mutated to alanines, FoxoAAA, fail to initiate transcription of lipogenic genes after feeding, leading to a reduction in lipogenesis and triglyceride secretion.(60,61) Conversely, deletion of all FoxO isoforms from the liver activates lipogenic gene expression and induces…”
Background
A Noncanonical, GSK3-Independent Pathway Controls Postprandial Hepatic Glycogen Deposition
Wan, M., Leavens, K. F., Hunter, R. W., Koren, S., von Wilamowitz-Moellendorff, A., Lu, M., Satapati, S., Chu, Q., Sakamoto, K., Burgess, S. C., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.001 · Cited by 81
Effects of free fatty acids on hepatic glycogenolysis and gluconeogenesis in conscious dogs
Chu, C. A., Sherck, S. M., Igawa, K., Sindelar, D. K., Neal, D. W., Emshwiller, M., & Cherrington, A. D. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00136.2001 · Cited by 71 · cited 9×
“Increased gluconeogenic flux largely contributes to this effect on HGP.(94) Recent genetic studies from several groups have supported these classic physiology studies and assert that FFA action on the liver drives HGP in insulin-resistant livers or livers completely devoid of hepatic insulin signaling.”
BackgroundInfluential
Deletion of hepatic carbohydrate response element binding protein (ChREBP) impairs glucose homeostasis and hepatic insulin sensitivity in mice
Jois, T., Chen, W., HOWARD, V. G., Harvey, R. E., Youngs, K., Thalmann, C., Saha, P., Chan, L., Cowley, M. A., & Sleeman, M. W. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.07.006 · Cited by 66 · cited 1×
“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.(51) Hepatic deletion of ChREBP in mice following a hi…”
Background
ChREBP expression in the liver, adipose tissue and differentiated preadipocytes in human obesity
del Pozo, C. H., Vesperinas, G., Rubio, M. Á., Corripio‐Sánchez, R., García, A. J. T., Obregón, M.-J., & Calvo, R. M. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2011.07.016 · Cited by 65 · cited 1×
“Consistent with these mouse studies, obese human beings typically have higher ChREBP expression in the liver, which correlates with fatty liver.(50) Recently, studies deleting ChREBP specifically in mouse hepatocytes showed mild insulin resistance and protection from hepatic steatosis when challenged with a high-carbo…”
Background
Ablation of PI3K p110-α Prevents High-Fat Diet–Induced Liver Steatosis
Chattopadhyay, M., Selinger, E. S., Ballou, L. M., & Lin, R. Z. (2011) · Diabetes · doi:10.2337/db10-0869 · Cited by 53
Effects of small changes in glucagon on glucose production during a euglycemic, hyperinsulinemic clamp
Myers, S. R., Diamond, M. P., Adkins-Marshall, B. A., Williams, P. E., Stinsen, R., & Cherrington, A. D. (1991) · Metabolism · doi:10.1016/0026-0495(91)90194-2 · Cited by 46 · cited 1×
“Under euglycemic clamp conditions, increased insulin concentrations led to a reduction in glucagon secretion.(87) Moreover, human studies have indicated a close correlation of insulin action and decreased glucagon concentrations, implying some effect of insulin on glucagon secretion.”
Background
Inhibiting or antagonizing glucagon: making progress in diabetes care
Lefèbvre, P. J., Paquot, N., & Scheen, A. J. (2015) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12480 · Cited by 45 · cited 1×
“Because of hyperglucagonemia’s long association with diabetes, many commercial antidiabetic drugs target some part of the glucagon signaling mechanism with some success.(90) Despite this well-established effect on”
Background
Insulin action on the liver in vivo
Cherrington, A. D., Moore, M. C., Sindelar, D. K., & Edgerton, D. S. (2007) · Biochemical Society Transactions · doi:10.1042/bst0351171 · Cited by 43
Impaired Insulin Suppression of VLDL-Triglyceride Kinetics in Nonalcoholic Fatty Liver Disease
Poulsen, M. K., Nellemann, B., Stødkilde-Jørgensen, H., Pedersen, S. B., Grønbæk, H., & Nielsen, S. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3476 · Cited by 39 · cited 2×
“Enhanced secretion of VLDL-TAG is another hallmark of people with insulin-resistant conditions, such as obesity or NAFLD.53,54 In particular, a failure of insulin to facilitate degradation of apolipoprotein B, a major protein in VLDL synthesis, as well as increased levels of FFAs and increased lipogenesis in insulin-r…”
Background
Impaired Insulin Action Is Associated With Increased Glucagon Concentrations in Nondiabetic Humans
Sharma, A. R., Varghese, R. T., Shah, M., Man, C. D., Cobelli, C., Rizza, R. A., Bailey, K. R., & Vella, A. V. (2017) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01197 · Cited by 38 · cited 1×
“Moreover, human studies have indicated a close correlation of insulin action and decreased glucagon concentrations, implying some effect of insulin on glucagon secretion.(88) Genetic evidence also supports this correlation, indicating that deletion of the insulin receptor from a cells in mouse pancreas leads to enhanc…”
Background
The Effects of Fasting and Refeeding on Liver Glycogen Synthase and Phosphorylase in Obese and Lean Mice
Chen, C., Williams, P. F., Cooney, G. J., Caterson, I. D., & Turtle, J. R. (1992) · Hormone and Metabolic Research · doi:10.1055/s-2007-1003285 · Cited by 27

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Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis
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“However, insulin-resistant individuals do not respond to this signaling process, and paradoxically show an increase in both hepatic glucose production and insulin secretion, which can induce or aggravate hyperglycemia.(15) The factors that promote the emergence of insulin resistance include altered insulin signaling,…”
Background
The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review
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“In humans, high pre-training levels of SeP were predictive of decreased aerobic exercise capacity, measured as VO2 max [50], suggesting that FFAs released by VAT lipolysis during and after exercise are less efficiently utilized by SkM and are instead preferentially reincorporated into VAT via VLDL.”
BackgroundInfluential
Acetyl-CoA Carboxylases and Diseases
Wang, Y., Yu, W., Li, S., Guo, D., He, J., & Wang, Y. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.836058 · Cited by 230
“In mammals, the accumulation of lipid in tissues, such as muscle and liver, is closely related to insulin resistance that associates with a myriad of metabolic disorders (84, 85).”
Background
Pathophysiological mechanisms underlying MAFLD
Kuchay, M. S., Choudhary, N. S., & Mishra, S. K. (2020) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2020.09.026 · Cited by 188
Estrogens in adipose tissue physiology and obesity-related dysfunction
Kuryłowicz, A. (2023) · Biomedicines · doi:10.3390/biomedicines11030690 · Cited by 178
Type 2 Diabetes Mellitus: A Comprehensive Review of Pathophysiology, Comorbidities, and Emerging Therapies
Singh, A. P., Shadangi, S., Gupta, P. K., & Rana, S. (2025) · Comprehensive physiology · doi:10.1002/cph4.70003 · Cited by 194
“…where periportal and perivenous hepatocytes perform distinct functions, and any dysregulation of this compartmentalization contributes to the overall metabolic dysregulation observed in insulin-resistant states (da Silva Rosa et al. 2020; Santoleri and Titchenell 2019; Mastrototaro and Roden 2021).”
Glucocorticoid-Induced Fatty Liver Disease
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Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease
Fougerat, A., Montagner, A., Loiseau, N., Guillou, H., & Wahli, W. (2020) · Cells · doi:10.3390/cells9071638 · Cited by 151
Non-alcoholic Fatty Liver Disease as a Canonical Example of Metabolic Inflammatory-Based Liver Disease Showing a Sex-Specific Prevalence: Relevance of Estrogen Signaling
Torre, S. D. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.572490 · Cited by 121
“NAFLD is closely linked with peripheral insulin resistance and hepatic insulin resistance (28–30), a condition where insulin fails to suppress hepatic glucose production (HPG, which accounts for 90% of endogenous glucose production) but promotes lipid synthesis leading to hyperglycemia, hypertriglyceridemia and hepati…”
Background
Serum concentration of asprosin in new-onset type 2 diabetes
Naiemian, S., Naeemipour, M., Zarei, M., Najafi, M. L., Gohari, A., Behroozikhah, M. R., Heydari, H., & Miri, M. (2020) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-020-00564-w · Cited by 94
Pathophysiological underpinnings of metabolic dysfunction-associated steatotic liver disease
Kuchay, M. S., Choudhary, N. S., & Ramos‐Molina, B. (2025) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00951.2024 · Cited by 103
Prognostic effect of triglyceride glucose-related parameters on all-cause and cardiovascular mortality in the United States adults with metabolic dysfunction-associated steatotic liver disease
Yu, M., Wei, X., Wei, Z., Song, G., Zhao, X., & Lei, Y. (2024) · Cardiovascular Diabetology · doi:10.1186/s12933-024-02287-y · Cited by 92
“Meanwhile, IR could also enhance gluconeogenesis but decrease hepatic glycogenesis, which can increase glucose production and release [48, 49].”
Background
Insulin resistance and adipose tissue interactions as the cornerstone of metabolic (dysfunction)-associated fatty liver disease pathogenesis
Pal, S. C., & Méndez‐Sánchez, N. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i25.3999 · Cited by 98
Beyond the X Factor: Relevance of Sex Hormones in NAFLD Pathophysiology
Torre, S. D. (2021) · Cells · doi:10.3390/cells10092502 · Cited by 90
Excessive Gluconeogenesis Causes the Hepatic Insulin Resistance Paradox and Its Sequelae
Onyango, A. N. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e12294 · Cited by 80
Therapeutic Activity of Green Tea Epigallocatechin-3-Gallate on Metabolic Diseases and Non-Alcoholic Fatty Liver Diseases: The Current Updates
James, A., Wang, K., & Wang, Y. (2023) · Nutrients · doi:10.3390/nu15133022 · Cited by 88
Lifestyle and Environmental Factors Affecting Male Fertility, Individual Predisposition, Prevention, and Intervention
Tesařík, J. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062797 · Cited by 72
Hepatic insulin receptor: new views on the mechanisms of liver disease
Lee, W., Najjar, S. M., Kahn, C. R., & Hinds, T. D. (2023) · Metabolism · doi:10.1016/j.metabol.2023.155607 · Cited by 76
Silymarin is an ally against insulin resistance: A review
MacDonald-Ramos, K., Michán, L., Martínez‐Ibarra, A., & Cerbón, M. A. (2020) · Annals of Hepatology · doi:10.1016/j.aohep.2020.08.072 · Cited by 72
Futile lipid cycling: from biochemistry to physiology
Sharma, A. K., Khandelwal, R., & Wolfrum, C. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01003-0 · Cited by 64
Role of metabolic dysfunction and inflammation along the liver–brain axis in animal models with obesity-induced neurodegeneration
Asimakidou, E., Saipuljumri, E. N., Lo, C. H., & Zeng, J. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-01770 · Cited by 65
“The liver plays a pivotal role in the regulation of glucose metabolism and aberrant insulin signaling in the liver is thought to be a primary driver of systemic or peripheral insulin resistance (Santoleri and Titchenell, 2019).”
Background
Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice
Yeh, C., Shen, Z., Wang, T.-W., Kao, C., Teng, Y., Yeh, T., Lu, C.-K., & Tsai, T. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00838-7 · Cited by 61
Luteolin loaded on zinc oxide nanoparticles ameliorates non-alcoholic fatty liver disease associated with insulin resistance in diabetic rats via regulation of PI3K/AKT/FoxO1 pathway
Ahmed, E. S. A., Mohamed, H. E., & Farrag, M. A. (2022) · International Journal of Immunopathology and Pharmacology · doi:10.1177/03946320221137435 · Cited by 59
“Whereas dysregulation of the insulin signaling induces insulin resistance in which insulin lose its ability to control and regulate the hepatic metabolism of both glucose and lipid, leading to hyperglycemia (excessive glucose production) and hyperlipidemia (accelerated rates lipogenesis).(7) Based on the strong link b…”
BackgroundInfluential
α-Lactalbumin peptide Asp-Gln-Trp alleviates hepatic insulin resistance and modulates gut microbiota dysbiosis in high-fat diet-induced NAFLD mice
Chen, H., Sun, Y., Zhao, H., Qi, X., Cui, H., Li, Q., & Ma, Y. (2022) · Food & Function · doi:10.1039/d2fo01343f · Cited by 58
Asprosin-neutralizing antibodies as a treatment for metabolic syndrome
Mishra, I., Duerrschmid, C., Ku, Z., He, Y., Xie, W., Silva, E. S., Hoffman, J., Xin, W., Zhang, N., Xu, Y., et al. (2021) · eLife · doi:10.7554/elife.63784 · Cited by 61
Xanthosine, a purine glycoside mediates hepatic glucose homeostasis through inhibition of gluconeogenesis and activation of glycogenesis via regulating the AMPK/ FoxO1/AKT/GSK3β signaling cascade
Ahmed, S. A., Sarma, P., Barge, S., Swargiary, D., Gurumayum, S., & Borah, J. C. (2023) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2023.110347 · Cited by 57
Novel insights into non-alcoholic fatty liver disease and dementia: insulin resistance, hyperammonemia, gut dysbiosis, vascular impairment, and inflammation
Cheon, S. Y., & Song, J. (2022) · Cell & Bioscience · doi:10.1186/s13578-022-00836-0 · Cited by 58
“Insulin resistance and poor insulin sensitivity are hallmark features of T2DM and NAFLD [119].”
Background
The usefulness of metabolic score for insulin resistance for the prediction of incident non-alcoholic fatty liver disease in Korean adults
Lee, J., Park, K., Lee, H. S., Park, H.-K., Han, J. H., & Ahn, S. B. (2022) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2022.0099 · Cited by 54
RETRACTED ARTICLE: Association of cord blood asprosin concentration with atherogenic lipid profile and anthropometric indices
Hussein, H. K., Aubead, N. M., Kzar, H. H., Karim, Y. S., Amin, A. H., Al-Gazally, M. E., Ahmed, T. I., Jawad, M. A., Hammid, A. T., Jalil, A. T., et al. (2022) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-022-00844-7 · Cited by 53
Retracted
Glycyrrhizic Acid and Its Derivatives: Promising Candidates for the Management of Type 2 Diabetes Mellitus and Its Complications
Tan, D., Tseng, H. H. L., Zhong, Z., Wang, S., Vong, C. T., & Wang, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231910988 · Cited by 55
“On the other hand, the liver is responsible for glucose uptake and lipid synthesis and metabolism [78].”
Background
Structural Characterization and Hypoglycemic Function of Polysaccharides from Cordyceps cicadae
Wang, Y., Zeng, T., Li, H., Wang, Y., Wang, J., & Yuan, H. (2023) · Molecules · doi:10.3390/molecules28020526 · Cited by 50
“The hypoglycemic mechanism is mainly related to activation of PI3K by insulin receptor substrates (IRSs) and subsequent activation of Akt [20,21], which transmits signals to downstream pathways to control cell survival and glucose and lipid metabolism [22,23].”
Background
Role of Long Non-Coding RNAs and the Molecular Mechanisms Involved in Insulin Resistance
Tello‐Flores, V. A., Beltrán‐Anaya, F. O., Ramírez‐Vargas, M. A., Esteban-Casales, B. E., Navarro‐Tito, N., Alarcón‐Romero, L. D. C., Luciano-Villa, C. A., Ramı́rez, M., Moral-Hernández, Ó. D., & Flores‐Alfaro, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147256 · Cited by 50
“Non-alcoholic fatty liver disease, a consequence of the high production and accumulation of lipids in the liver, is considered a key factor in the development of IR and T2D [60].”
Background
Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2
Aji, G., Huang, Y., Ng, M. L., Wang, W., Lan, T., Li, M., Li, Y., Chen, Q., Li, R., Yan, S., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007856117 · Cited by 49
Curcumin anti-diabetic effect mainly correlates with its anti-apoptotic actions and PI3K/Akt signal pathway regulation in the liver
Xia, Z., Zhang, S., Chen, Y., Li, K., Chen, W., & Liu, Y. (2020) · Food and Chemical Toxicology · doi:10.1016/j.fct.2020.111803 · Cited by 52
Glucocorticosteroids and the Risk of NAFLD in Inflammatory Bowel Disease
Jarmakiewicz-Czaja, S., Sokal-Dembowska, A., Pardak, P., & Filip, R. (2022) · Canadian Journal of Gastroenterology and Hepatology · doi:10.1155/2022/4344905 · Cited by 48
“Moreover, insulin resistance of liver cells plays an important role in the pathogenesis of the disease [77], which is associated with increased lipid synthesis in the liver, thus leading to the development of hypertriglyceridemia and hyperglycemia [78].”
Background
Comparison of the diagnostic performance of twelve noninvasive scores of metabolic dysfunction-associated fatty liver disease
Zou, H., Ma, X., Zhang, F., & Xie, Y. (2023) · Lipids in Health and Disease · doi:10.1186/s12944-023-01902-3 · Cited by 49
“Regardless of the “double-hit” theory or “multiple-hit” theory, IR is a crucial component in the development of MAFLD [8, 47–51].”
Background
Diabetes and the associated complications: The role of antioxidants in diabetes therapy and care
Dilworth, L., Stennett, D., Facey, A., Omoruyi, F. O., Mohansingh, S., & Omoruyi, F. O. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117641 · Cited by 68
Hepatopathy Associated With Type 1 Diabetes: Distinguishing Non-alcoholic Fatty Liver Disease From Glycogenic Hepatopathy
Mertens, J., Block, C. E. M. D., Spinhoven, M. J., Driessen, A. L. C., Francque, S., & Kwanten, W. J. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.768576 · Cited by 48
Exposure to dim light at night alters daily rhythms of glucose and lipid metabolism in rats
Rumanova, V. S., Okuliarová, M., Foppen, E., Kalsbeek, A., & Zeman, M. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.973461 · Cited by 49
“Glycogen phosphorylase is the ratelimiting enzyme in glycogen catabolism (Agius, 2015) and FOXO1 promotes transcription of gluconeogenic genes (Santoleri and Titchenell, 2019).”
Background
Therapeutic effects of icariin and icariside II on diabetes mellitus and its complications
Jiang, W., Ding, K., Yue, R., & Lei, M. (2023) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2159317 · Cited by 44
“Instead, excess glucose in the liver fuels excess fat synthesis, leading to nonalcoholic fatty liver disease (NAFLD), hypertriglyceridemia, and hyperglycemia (Santoleri and Titchenell 2019).”
Background
DEHP and DBP, common phthalates, induce glucose metabolism disorders in rats via oxidative damage of PI3K/Akt/GLUT4 signaling
Li, L., Huang, L., Lei, R., Zhang, P., Yang, Y., Liu, H., & Zhang, Y. (2023) · Environmental Pollution · doi:10.1016/j.envpol.2023.122948 · Cited by 45
Proteostasis Decline and Redox Imbalance in Age-Related Diseases: The Therapeutic Potential of NRF2
Buttari, B., Tramutola, A., Rojo, A. I., Chondrogianni, N., Saha, S., Berry, A., Giona, L., Miranda, J. P., Profumo, E., Davinelli, S., et al. (2025) · Biomolecules · doi:10.3390/biom15010113 · Cited by 49
“The mechanisms by which T2D develops are not fully understood [271], nevertheless, regardless of the causative factors, the key driver of diabetic phenotypes including the development of IR and dyslipidemia is a propathogenic shift in cellular metabolism.”
Atherosclerosis and Insulin Resistance: Is There a Link Between Them?
Brie, A. D., Christodorescu, R., Popescu, R., Adam, O., Tîrziu, A., & Brie, D. M. (2025) · Biomedicines · doi:10.3390/biomedicines13061291 · Cited by 50
Intestine-liver crosstalk in Type 2 Diabetes and non-alcoholic fatty liver disease
Nawrot, M., Peschard, S., Lestavel, S., & Staels, B. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154844 · Cited by 46
NAFLD in type 1 diabetes: overrated or underappreciated?
Mertens, J., Gaal, L. F. V., Francque, S., & Block, C. E. M. D. (2021) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/20420188211055557 · Cited by 44
Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness
Gu, L., Zhu, Y., Watari, K., Lee, M., Liu, J., Perez, S., Thai, M., Mayfield, J. E., Zhang, B., Rocha, K. C. E., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.03.021 · Cited by 43
Reduction of Hepatic Steatosis, Oxidative Stress, Inflammation, Ballooning and Insulin Resistance After Therapy with Safranal in NAFLD Animal Model: A New Approach
Sabir, U., Irfan, H. M., Alamgeer, Ullah, A., Althobaiti, Y. S., & Asim, M. H. (2022) · Journal of Inflammation Research · doi:10.2147/jir.s354878 · Cited by 43
“HFDmay produce irregularities in blood lipids due to insulin resistance, viciously leading to lipotoxicity and steatosis.(13) The kinetic, qualitative, and quantitative alterations in all lipoprotein subtypes may be the root cause of blood lipid irregularities and fatty liver.”
BackgroundInfluential
Androgen‐induced insulin resistance is ameliorated by deletion of hepatic androgen receptor in females
Andrisse, S., Feng, M., Wang, Z., Awe, O., Yu, L., Zhang, H., Bi, S., Wang, H., Li, L., Joseph, S., et al. (2021) · The FASEB Journal · doi:10.1096/fj.202100961r · Cited by 46
Insulin‐dependent glucose consumption dynamics in 3D primary human liver cultures measured by a sensitive and specific glucose sensor with nanoliter input volume
Kemas, A. M., Youhanna, S. C., Shafagh, R. Z., & Lauschke, V. M. (2021) · The FASEB Journal · doi:10.1096/fj.202001989rr · Cited by 46
Triglyceride glucose (TyG) index and the progression of liver fibrosis: A cross-sectional study
Tutunchi, H., Naeini, F., Mobasseri, M., & Ostadrahimi, A. (2021) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2021.04.025 · Cited by 40
Towards Understanding the Direct and Indirect Actions of Growth Hormone in Controlling Hepatocyte Carbohydrate and Lipid Metabolism
Vazquez-Borrego, M. C., del Río-Moreno, M., & Kineman, R. D. (2021) · Cells · doi:10.3390/cells10102532 · Cited by 39
Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice
Correnti, J., Lin, C., Brettschneider, J., Kuriakose, A., Jeon, S., Scorletti, E., Oranu, A. C., McIver-Jenkins, D., Kaneza, I., Buyco, D. G., et al. (2020) · Journal of Lipid Research · doi:10.1194/jlr.ra119000446 · Cited by 38
“Specifically, ASAH  Etoh-Dox-fed mice were re - fractory to insulin’s inhibitory effects on hepatic glucose production (HGP), while ceramidase-overexpressing mice exhibited a 57% reduction in HGP in response to insulin (Fig.”
Melatonin alleviates insulin resistance through the PI3K/AKT signaling pathway in ovary granulosa cells of polycystic ovary syndrome
Guo, R., Zheng, H., Li, Q., Qiu, X., Zhang, J., & Cheng, Z. (2022) · Reproductive Biology · doi:10.1016/j.repbio.2021.100594 · Cited by 37
The Potential Role of C-Reactive Protein in Metabolic-Dysfunction-Associated Fatty Liver Disease and Aging
Ding, Z., Wei, Y., Peng, J., Wang, S., Chen, G., & Sun, J. (2023) · Biomedicines · doi:10.3390/biomedicines11102711 · Cited by 40
“Individuals with insulin resistance fail to suppress hepatic glucose production and instead increase hepatic lipid synthesis, leading to hyperglycemia and hypertriglyceridemia [83].”
Background
Macrophages and the development and progression of non-alcoholic fatty liver disease
Alabdulaali, B., Al‐Rashed, F., Al‐Onaizi, M., Kandari, A., Razafiarison, J., Tonui, D., Williams, M. R., Blériot, C., Ahmad, R., & Alzaïd, F. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1195699 · Cited by 37
“In pathological conditions of insulin resistance, insulin fails to regulate liver metabolism, resulting in excessive glucose production alongside increased lipid synthesis (30); consequently, NAFLD is associated with insulin-resistance (31).”
Background
Adipose tissue in cortisol excess: What Cushing’s syndrome can teach us?
Bavaresco, A., Mazzeo, P., Lazzara, M., & Barbot, M. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116137 · Cited by 41
Type 2 diabetes – unmet need, unresolved pathogenesis, mTORC1-centric paradigm
Bar‐Tana, J. (2020) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-020-09545-w · Cited by 37
S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma
Delangre, E., Oppliger, E., Berkcan, S., Gjorgjieva, M., de Sousa, M. C., & Foti, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911030 · Cited by 32
“Ectopic accumulation of intracellular fatty acids (FAs) also leads to increased synthesis of toxic lipid species such as ceramides [19] that further aggravate IR and lipotoxicity.”
Background
Tobacco-induced hyperglycemia promotes lung cancer progression via cancer cell-macrophage interaction through paracrine IGF2/IR/NPM1-driven PD-L1 expression
Jang, H.-J., Min, H.-Y., Kang, Y. P., Boo, H., Kim, J., Ahn, J. H., Oh, S. H., Jung, J. H., Park, C., Park, J.-S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49199-9 · Cited by 34
Cold stress-induced autophagy and apoptosis disorders are mainly mediated by AMPK/PPAR/PI3K/AKT/mTOR pathways
Wang, D., Tian, Y., Wang, Q., Zhang, Y., Ye, B., Zuo, Z., He, J., Pan, Z., Sun, D., Zou, J., et al. (2024) · Aquaculture · doi:10.1016/j.aquaculture.2024.740574 · Cited by 34
Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions
Mir, R., Jeelani, M., Alharthi, M. H., Rizvi, S. F., Sohail, S. K., Wani, J. I., Sabah, Z. U., BinAfif, W. F., Nandi, P. S., Alshahrani, A. M., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062770 · Cited by 43
“Insulin decreases glycogenic enzymes and activates glycolysis and fatty acid synthesis enzymes via Akt2, which is a downstream of insulin signaling [224,225].”
Influential
A high‐fat diet reverses metabolic disorders and premature aging by modulating insulin and IGF1 signaling in SIRT6 knockout mice
Li, Z., Xu, K., Guo, Y., Ping, L., Gao, Y., Qiu, Y., Ni, J., Liu, Q., & Wang, Z. (2020) · Aging Cell · doi:10.1111/acel.13104 · Cited by 32
DHT causes liver steatosis via transcriptional regulation of SCAP in normal weight female mice
Seidu, T. A., McWhorter, P., Myer, J., Alamgir, R., Eregha, N., Bogle, D., Lofton, T., ECELBARGER, C. A., & Andrisse, S. (2021) · Journal of Endocrinology · doi:10.1530/joe-21-0040 · Cited by 32
Role of Sphingosine Kinase in Type 2 Diabetes Mellitus
Qi, Y., Wang, W., Song, Z., Aji, G., Liu, X. T., & Xia, P. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.627076 · Cited by 32
“Hepatic insulin resistance is considered a key pathogenic onset of prediabetes (73).”
Background
Pathophysiological Mechanisms in Non-Alcoholic Fatty Liver Disease: From Drivers to Targets
Santos‐Laso, Á., Gutiérrez‐Larrañaga, M., Alonso‐Peña, M., Medina, J. M., Iruzubieta, P., Arias, M., López‐Hoyos, M., & Crespo, J. (2021) · Biomedicines · doi:10.3390/biomedicines10010046 · Cited by 34
“Postprandial glucose clearance is compromised by IR since both peripheral glucose uptake and insulin-mediated hepatic gluconeogenesis and glycogenolysis suppression fail, promoting DNL by two different molecular mechanisms [45,51].”
Background
Efficacy and safety of GLP-1 receptor agonists on weight management and metabolic parameters in PCOS women: a meta-analysis of randomized controlled trials
Lin, S., Deng, Y., Huang, J., Li, M., Sooranna, S. R., Qin, M., & Tan, B. (2025) · Scientific Reports · doi:10.1038/s41598-025-99622-4 · Cited by 35
Liver insulinization as a driver of triglyceride dysmetabolism
Cook, J. R., Hawkins, M. A., & Pajvani, U. B. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00843-6 · Cited by 33
Insulin Therapy for the Management of Diabetes Mellitus: A Narrative Review of Innovative Treatment Strategies
Nkonge, K. M., Nkonge, D. K., & Nkonge, T. N. (2023) · Diabetes Therapy · doi:10.1007/s13300-023-01468-4 · Cited by 36
“Insulin signaling in the liver is known to induce hepatic de novo lipogenesis by activating transcription factors and enzymes involved in fatty acid biosynthesis [78, 79].”
Background
Pea ‐derived peptides, VLP, LLP, VA, and LL, improve insulin resistance in HepG2 cells via activating IRS‐1/PI3K/AKT and blocking ROS‐mediated p38MAPK signaling
Zhu, Y., Zhang, H., Wei, Y., Cai, M., Gu, R., Wang, Y., Ma, Y., & Chen, L. (2020) · Journal of Food Biochemistry · doi:10.1111/jfbc.13454 · Cited by 29
Cullin neddylation inhibitor attenuates hyperglycemia by enhancing hepatic insulin signaling through insulin receptor substrate stabilization
Chen, C., Gu, L., Matye, D. J., Clayton, Y., Hasan, M. N., Wang, Y., Friedman, J. E., & Li, T. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2111737119 · Cited by 29
The Role of Insulin-like Peptide in Maintaining Hemolymph Glucose Homeostasis in the Pacific White Shrimp Litopenaeus vannamei
Su, M., Zhang, X., Yuan, J., Zhang, X., & Li, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063268 · Cited by 29
“Disruption of insulin secretion causes metabolic disorders, such as hyperglycemia or hypertriglyceridemia, suggesting the important role of insulin in regulating blood sugar homeostasis [3,4].”
Background
HOMA-IR is positively correlated with biological age and advanced aging in the US adult population
Yang, H., Gong, R., Liu, M., Deng, Y., Zheng, X., & Hu, T. (2023) · European journal of medical research · doi:10.1186/s40001-023-01448-1 · Cited by 33
“Previous studies had shown that IR contributes to the development and poor prognosis of some diseases, including diabetes [2], obesity [3], polycystic ovarian syndrome (PCOS) [4], hypertension [5], cardiovascular disease [6], kidney disease [6], Non-alcoholic fatty liver disease (NAFLD) [7],…”
Background
IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease
Friedline, R. H., Noh, H. L., Suk, S., Albusharif, M., Dağdeviren, S., Saengnipanthkul, S., Kim, B. K., Kim, A. M., Kim, L. H., TAUER, L. A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-49633-y · Cited by 31
Chinese Medicinal Herbs Targeting the Gut–Liver Axis and Adipose Tissue–Liver Axis for Non-Alcoholic Fatty Liver Disease Treatments: The Ancient Wisdom and Modern Science
Zhang, S., Wong, Y.-T., Tang, K.-Y., Kwan, H. Y., & Su, T. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.572729 · Cited by 28
“In addition, insulin resistance can be acquired viamultiple mechanisms, and may affect various steps in the insulin signaling cascade which finally suppresses important metabolic pathways causing overproduction of glucose, and ultimately result in liver cell damage and death, and hence accelerates NAFLD progression (2…”
Background
Heme oxygenase, biliverdin reductase, and bilirubin pathways regulate oxidative stress and insulin resistance: a focus on diabetes and therapeutics
Lee, W., Kipp, Z. A., Pauss, S. N., Martinez, G. J., Bates, E. A., Badmus, O. O., Stec, D. E., & Hinds, T. D. (2025) · Clinical Science · doi:10.1042/cs20242825 · Cited by 30
“Insulin-resistant hepatocytes also threaten whole-body health as they can increase fat accumulation, reduce insulin clearance, increase circulating insulin half-life [6], and stimulate gluconeogenesis [6].”
Sphingosine‐1‐phosphate in mitochondrial function and metabolic diseases
Duan, M., Gao, P., Chen, S., Novák, P., Yin, K., & Zhu, X. (2022) · Obesity Reviews · doi:10.1111/obr.13426 · Cited by 29
“hepatocytes to insulin, resulting in increased glucose production and decreased glucose processing.(159)”
Background
Exercise training-attenuated insulin resistance and liver injury in elderly pre-diabetic patients correlates with NLRP3 inflammasome
Zhang, T., Tian, J., Fan, J., Liu, X., & Wang, R. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1082050 · Cited by 28
“The liver plays a central role in the systemic regulation of glucose and lipid metabolism and aberrant hepatic function is thought to be a primary driver of insulin resistance (33).”
Background
Hepatic Phospholipid Remodeling Modulates Insulin Sensitivity and Systemic Metabolism
Tian, Y., Mehta, K., Jellinek, M. J., Sun, H., Lu, W., Shi, R., Ingram, K., Friedline, R. H., Kim, J. K., Kemper, J. K., et al. (2023) · Advanced Science · doi:10.1002/advs.202300416 · Cited by 26
m6A methylation-mediated PGC-1α contributes to ferroptosis via regulating GSTK1 in arsenic-induced hepatic insulin resistance
Zhang, J., Song, J., Liu, S., Zhang, Y., Qiu, T., Jiang, L., Bai, J., Yao, X., Wang, N., Yang, G., et al. (2023) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2023.167202 · Cited by 27
Physalis peruviana L. Pulp Prevents Liver Inflammation and Insulin Resistance in Skeletal Muscles of Diet-Induced Obese Mice
la Fuente, F. P.-D., Nocetti, D., Sacristán, C., Ruiz, P., Guerrero, J., Jorquera, G., Uribe-Oporto, E., Bucarey, J. L., Espinosa, A., & Puente-Diaz, L. (2020) · Nutrients · doi:10.3390/nu12030700 · Cited by 28
“IR in the liver is a paradoxical process, referred to as “selective hepatic insulin resistance,” in which both glucose production and lipid storage are increased, altering the normal function of the liver by the increase of gluconeogenesis and de novo lipogenesis [5].”
Background
Role of Chitinase 3-Like 1 Protein in the Pathogenesis of Hepatic Insulin Resistance in Nonalcoholic Fatty Liver Disease
Zhang, S., Sousa, A., Lin, M., Iwano, A., Jain, R., Ma, B., Lee, C. M., Park, J. W., Kamle, S., Carlson, R. I., et al. (2021) · Cells · doi:10.3390/cells10020201 · Cited by 25
Liposomal quercetin: A promising strategy to combat hepatic insulin resistance and inflammation in type 2 diabetes mellitus
Rocha, S., Corvo, M. L., Freitas, M., & Fernandes, E. G. R. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.124441 · Cited by 26
MicroRNAs Dependent G‐ELNs Based Intervention Improves Glucose and Fatty Acid Metabolism While Protecting Pancreatic β‐Cells in Type 2 Diabetic Mice
Bajaj, G., Choudhary, D., Singh, V., Priyadarshi, N., Garg, P., Mantri, S. S., Rishi, V., & Singhal, N. K. (2024) · Small · doi:10.1002/smll.202409501 · Cited by 24
Selenium-enriched Lactiplantibacillus plantarum alleviates alkalinity stress-induced selective hepatic insulin resistance in common carp
Che, X., Shang, X., Weixu, Xing, M., Wei, H., Li, W., Li, Z., Teng, X., & Geng, L. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.141204 · Cited by 24
Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic Research
Bajgar, A., Krejčová, G., & Doležal, T. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.629238 · Cited by 22
“…is Frontiers in Cell and Developmental Biology | www.frontiersin.org 13 February 2021 | Volume 9 | Article 629238 known to respond differently to a lack of insulin signaling from most tissues in the body, which is called the “liver insulin resistance paradox ” (Santoleri and Titchenell, 2019).”
Background
Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm
Cooper, I. D., Brookler, K. H., Kyriakidou, Y., Elliott, B., & Crofts, C. A. P. (2021) · Biomedicines · doi:10.3390/biomedicines9070800 · Cited by 24
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“Overweight individuals with insulin resistance are incapable of adequately suppressing hepatic glucose production, thereby resulting in hyperglycemia [51].”
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Bile acid signaling in MASLD: From pathogenesis to therapeutic applications
Simbrunner, B., Paternostro, R., Reiberger, T., & Trauner, M. (2025) · Hepatology · doi:10.1097/hep.0000000000001539 · Cited by 28
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“S7) [26]: (1) Promoting glycogen synthesis by activating the phosphorylation of GSK3; (2) Affecting key enzyme activities in glycolysis/gluconeogenesis; (3) Transporting GLUT2 to the outer membrane of hepatocytes to enhance its utilization; (4) Reducing cAMP levels by inducing the activation of PDE3B and then improvin…”
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“Alternatively, during the development of insulin resistance, insulin cannot inhibit the production of glucose in the liver but paradoxically accelerates the synthesis of lipids, leading to an increase in triglycerides and blood glucose [69].”
Background
Dietary iron overload enhances Western diet induced hepatic inflammation and alters lipid metabolism in rats sharing similarity with human DIOS
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“These results confirm the detrimental functions of fundamentally stimulated FoxO1 throughout extreme liver insulin resistance in hyperglycemia and the insulin receptor monolayers of the insulin signaling branch phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt)-FoxO1 underlying the hepatic insulin-controlled gl…”
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“Aberrant hepatic insulin action is hypothesized to primarily drive IR, given that higher circulating insulin levels are necessary to adequately control the blood glucose levels [68].”
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Downregulation of hepatic fat accumulation, inflammation and fibrosis by nerolidol in purpose built western-diet-induced multiple-hit pathogenesis of NASH animal model
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“Akt inhibits FoxO1, resulting in an inhibition of gluconeogenesis by suppressing the expression of the proteins glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase (Pck1) [51].”
Background
Aqueous extract of Artemisia capillaris improves non-alcoholic fatty liver and obesity in mice induced by high-fat diet
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“PI3K/AKT signaling pathway plays an important role in the development of NAFLD (Huang et al., 2018; Santoleri and Titchenell, 2019).”
Background
Adipose tissue-derived exosomes contribute to obesity-associated liver diseases in long-term high-fat diet-fed mice, but not in short-term
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“The activated PI3K subsequently induces protein kinase B (Akt) phosphorylation, which inhibits glycogen synthase kinase 3 and Forkhead box protein O1 and activates the mammalian target of rapamycin complex 1 to stimulate glycogen synthesis, gluconeogenesis, and lipid synthesis (21).”
Background

Unraveling the Regulation of Hepatic Metabolism by Insulin
Titchenell, P. M., Lazar, M. A., & Birnbaum, M. J. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.03.003 · Cited by 457
Insulin signaling to hepatic lipid metabolism in health and disease
Leavens, K. F., & Birnbaum, M. J. (2011) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2011.562481 · Cited by 169
Insulin Regulation of Hepatic Lipid Homeostasis
Uehara, K., Santoleri, D., Whitlock, A. E. G., & Titchenell, P. M. (2023) · Comprehensive Physiology · doi:10.1002/cphy.c220015 · Cited by 49
Insulin resistance in the liver: Deficiency or excess of insulin?
Bazotte, R. B., Silva, L. G., & Schiavon, F. P. M. (2014) · Cell Cycle · doi:10.4161/15384101.2014.947750 · Cited by 64
Pathway-selective Insulin Resistance and Metabolic Disease: The Importance of Nutrient Flux
Otero, Y. F., Stafford, J. M., & McGuinness, O. P. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.r114.576355 · Cited by 97

Authors: Santoleri, D., & Titchenell, P. M.
Affiliations: University of Pennsylvania (US)
Corresponding author: Titchenell, Paul M.
ORCID: Santoleri, Dominic
Titchenell, Paul M.
Venue: Cellular and Molecular Gastroenterology and Hepatology
Publisher: Elsevier BV
Published: 2019
Volume: 7
Issue: 2
Pages: 447-456
ISSN: 2352-345X (ISSN-L)
DOI: 10.1016/j.jcmgh.2018.10.016
PMC: PMC6369222
OpenAlex: W2899043265
Cited by: 336
References: 102
Citations by year: 2026: 35 · 2025: 57 · 2024: 61 · 2023: 63 · 2022: 51 · 2021: 40 · 2020: 24 · 2019: 5
FWCI: 2.57
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health (K01 DK111715, P30 DK19525)
Topics: Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: hepatic insulin resistance, insulin signaling, hepatic glucose production, hepatic lipid synthesis, hypertriglyceridemia, hyperglycemia, type 2 diabetes, obesity, glucose metabolism, lipid metabolism
MeSH terms: Animals, Humans, Insulin, Insulin Resistance, Liver, Models, Biological, Signal Transduction, Lipid Metabolism

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Resolving the Paradox of Hepatic Insulin Resistance

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