Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice.

By I. Shimomura, M. Matsuda, R. Hammer, Y. Bashmakov, Michael S. Brown, J. Goldstein. Molecules and Cells, 2000

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Diet-induced insulin resistance in mice lacking adiponectin/ACRP30 (2002, methodology): “In overnight-fasted mice, insulin (1 U/g body weight) was injected through inferior vena cava, and the gastrocnemius muscle and liver were excised at 3 and 4 min after injectio”
Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. (2019, background): “Studies conducted in primary hepatocytes and in rodent models of obesity and diabetes support the notion of selective pathway-specific insulin resistance in the liver (31-34).”
Protein sensors for membrane sterols. (2006, neutral): “, 1999; Foufelle and Ferre, 2002), and glucagon blocks this effect (Shimomura et al., 2000).”
Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP‐1c (2010, background): “IRS-1 would transduce the activating effects of insulin on SREBP-1c and its target genes, glucokinase and lipogenic genes, whereas IRS-2 would be involved in the inhibitory effects of insulin on FoxO1 and thus hepatic glucose production [57,59–61].”
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. (2002, background): “The elevated nSREBP-1c increases lipogenic gene expression, enhances fatty acid synthesis, and accelerates triglyceride accumulation (31, 39).”
New drug targets for type 2 diabetes and the metabolic syndrome (2001, background): “A critical player in potentiating the promoting effect of hyperinsulinaemia on hepatic lipid accumulation is the anabolic transcription factor SREBP-1, which upregulates genes such as that for fatty-acid synthas”
High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. (2002, background): “In animal models, chronic hyperinsulinemia is found to predispose the liver to both relative resistance to insulin action on suppression of gluconeogenesis, characterized by failure to increase insulin receptor substrate-2 and an increase in lipogenesis due to upregulation of sterol regulatory eleme”
Selective versus total insulin resistance: a pathogenic paradox. (2008, background): “Despite insulin resistance in the FoxO1 pathway, insulin sensitivity is maintained in the SREBP-1c pathway (Shimomura et al., 2000).”
Critical nodes in signalling pathways: insights into insulin action (2006, background): “Regardless of the mechanism, decreased levels of IRS proteins, coupled with decreased levels of the IR itself, certainly contribute to the insulin resistance in diabetic states in both rodents and human”
Suppressor of Cytokine Signaling 1 (SOCS-1) and SOCS-3 Cause Insulin Resistance through Inhibition of Tyrosine Phosphorylation of Insulin Receptor Substrate Proteins by Discrete Mechanisms (2004, background): “Indeed, these reductions in IRS proteins appeared to be secondary to the chronic hyperinsulinemia that occurs in the insulin-resistant state and is known to downregulate IRS-1 protein and IRS-2 mRNA (18, 43), because these did not occur in cultured cells overexpressing SOCS-1 or SOCS-3 (Fig.”
Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis (2010, background): “, (4) measured phosphorylation of serine 473 in Akt.”
Trends in insulin resistance: insights into mechanisms and therapeutic strategy (2022, background): “For example, some mouse models of profound hepatic IR exhibit increased G6pc (glucose-6-phosphatase) expression suggesting increased FOXO1 activity.(110) Moreover, correct hepatocellular insulin action also carries suppression of hepatic glycogenolysis and stimulation of glycogenesis.”