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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Figure 1 PI3K/Akt signaling in hepatocytes. Insulin binds to and activates the insulin receptor on the liver surface after a meal. After activation, the receptor recruits and activates IRS, which then activates PI3K. PI3K phosphorylates the signaling lipid molecule PIP2 into PIP3 in a process that is opposed by PTEN. PIP3 activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which phosphorylates Akt at Thr308. To fully activate Akt, mTORC2 also must phosphorylate it at Ser473. From Akt, different pathways for controlling glucose and lipid homeostasis branch out. Glycogen synthesis is induced through Akt inhibition of GSK3. In addition, Akt can promote glycogen synthesis in a manner independent of GSK3, such as activation of GYS2 by glucose-6-phosphate (G6P). Akt inhibition of TSC activates mTORC1, which in turn activates the lipogenic gene program through activation of SREBP1c and Gck, which phosphorylates glucose to G6P, which feeds into glycolysis and glycogen synthesis. In addition, G6P activates ChREBP, which activates lipogenesis along with SREBP1c. Akt inhibits FoxO1, resulting in an inhibition of gluconeogenesis by suppressing expressing of the proteins glucose-6-phosphatase (G6pc) and Pck1. Externally, FFAs can promote gluconeogenesis and contribute to insulin resistance by being taken up by the liver and converted to Acetyl-CoA, which activates pyruvate carboxylase.CC BY-NC-ND · PubMed Central

Figure 2 Indirect insulin effects on the liver. Insulin can block gluconeogenesis and glycogenolysis in the liver through several indirect pathways. Its secretion from the pancreatic β cells inhibits glucagon secretion in neighboring α cells. In the adipose tissue, insulin inhibits lipolysis, which reduces the levels of circulating FFAs, which promote glucose production. Finally, insulin signaling in the hypothalamus and central nervous system acts on Agrp neurons to signal through the hepatic vagus branch to inhibit HGP.CC BY-NC-ND · PubMed Central

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Influential
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“…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).”
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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].”
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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].”
Background
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

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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