Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia‐associated insulin resistance

Cen, Haoning Howard; Hussein, Bahira; Botezelli, José Diego; Wang, Su; Zhang, Jiashuo Aaron; Noursadeghi, Nilou; Jessen, Niels; Rodrigues, Brian; Timmons, James A.; Johnson, James D.

doi:10.1096/fj.202100497rr

Cited by 25 publications

(15 citation statements)

References 96 publications

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“…These data are consistent with the concept that modest hyperinsulinemia can drive down Insr levels 40 and the idea that insulin is a trophic signal for liver. Together, these data demonstrate that specifically preventing autocrine insulin feedback can have systemic effects on insulin sensitivity, body mass, and the size of some tissues.…”

Section: Resultssupporting

confidence: 89%

Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance

et al. 2022

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Insulin receptor (Insr) protein is present at higher levels in pancreatic β-cells than in most other tissues, but the consequences of β-cell insulin resistance remain enigmatic. Here, we use an Ins1cre knock-in allele to delete Insr specifically in β-cells of both female and male mice. We compare experimental mice to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined β-cells reveals transcriptomic consequences of Insr loss, which differ between female and male mice. Action potential and calcium oscillation frequencies are increased in Insr knockout β-cells from female, but not male mice, whereas only male βInsrKO islets have reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female βInsrKO and βInsrHET mice exhibit elevated insulin release in ex vivo perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr does not alter β-cell area up to 9 months of age, nor does it impair hyperglycemia-induced proliferation. Based on our data, we adapt a mathematical model to include β-cell insulin resistance, which predicts that β-cell Insr knockout improves glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance is significantly improved in female βInsrKO and βInsrHET mice compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. We observe no improved glucose tolerance in older male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of β-cell specific insulin resistance. The propensity for hyperinsulinemia is associated with mildly reduced fasting glucose and increased body weight. We further validate our main in vivo findings using an Ins1-CreERT transgenic line and find that male mice have improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that β-cell insulin resistance in the form of reduced β-cell Insr contributes to hyperinsulinemia in the context of glucose stimulation, thereby improving glucose homeostasis in otherwise insulin sensitive sex, dietary and age contexts.

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Section: Resultssupporting

confidence: 89%

Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance

et al. 2022

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“…A decrease in IRS-1 can be triggered in vitro by KHK-C induced perturbation in autophagy flux. Conversely, hyperinsulinemia equally downregulates IR in both HFD and HFD+F groups (50). Also, a decrease in ApoB observed in HFD+F group may contribute to severe hepatic steatosis in these mice.…”

Section: Discussionmentioning

confidence: 99%

Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD

Park

Helsley

Fadhul

et al. 2023

Preprint

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Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform increases endoplasmic reticulum (ER) stress in a dose dependent fashion, so when fructose is coupled with a HFD intake it leads to unresolved ER stress. Conversely, a liver-specific knockdown of KHK in C57BL/6J male mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in genetically obesity ob/ob, db/db and lipodystrophic FIRKO male mice, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepatic Khk expression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.

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“…All cells in the body have insulin receptors and require insulin signaling for key functions, including nutrient uptake for storage and anabolism. While the roles of Insr in hepatocytes, myocytes, and adipocytes are well studied (Cen et al, 2022; Cherrington, 2005; Haeusler et al, 2018), the consequences of Insr loss in pancreatic acinar cells remain understudied. In this study, we specifically deleted the Insr gene from acinar cells using the Ptf1a CreER allele and showed that insulin insensitivity in acinar cells had no obvious effects on systemic glucose homeostasis or serum insulin levels regardless of the Kras gene status.…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation

Zhang

Xia

Chu

et al. 2022

Preprint

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The rising incidence of pancreatic cancer is largely driven by increased prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of obesity and T2D, and is associated with increased cancer incidence and mortality. Genetic reduction of insulin production suppresses formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, it remained unclear whether hyperinsulinemia exerts its tumorigenic effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment. Here, we tested whether diet-induced hyperinsulinemia contributes to pancreatic cancer directly through insulin receptor (Insr) signaling in KrasG12D-expressing pancreatic acinar cells. Loss of insulin receptors in wild-type or KrasG12D-expressing acinar cells did not significantly influence fasting glucose or insulin. Strikingly, mice lacking Insr in KrasG12D-expressing acinar cells and their progeny had a significant reduction in PanIN plus tumor area in males (2.7-fold) and females (5.3-fold) compared to control mice. Mechanistically, proteome analyses implicated a reduction in digestive enzymes among altered protein networks in mice protected from PanINs, and together with phospho-proteome analysis, linked the spliceosome, ribosome, and secretory pathway to insulin signaling in context of pancreatic cancer initiation. Collectively, these data demonstrate that insulin receptor signaling in acinar cells promotes PanIN initiation in the context of obesity.

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Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia‐associated insulin resistance

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 25 publications

References 96 publications

Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance

Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance

Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD

Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation

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