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The Insulin Signaling Network in Health and Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 39151

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Prof. Ángela M. Valverde

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Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
Interests: insulin signaling; insulin resistance; type 2 diabetes mellitus; obesity; non-alcoholic fatty liver disease; inflammation; ER stress; autophagy

Special Issue Information

Dear Colleagues,

The insulin signaling pathway regulates cell growth and metabolic homeostasis. These fundamental biological processes are mediated by the insulin receptor, a member of the tyrosine kinase family of transmembrane receptors that binds insulin and IGFs. From the seminal discovery of the enzymatic tyrosine kinase activity of the insulin receptor in the 1980s, a complex network of intracellular cascades that rapidly connects the signals emerging from the cell membrane upon ligand binding to different intracellular compartments and the nucleus has been identified. Further, tissue-specific effects of insulin receptor-mediated signaling have unraveled a plethora of insulin actions in non-classical insulin-sensitive cells. Under physiological conditions, insulin signaling tightly controls processes as frequent as fasting–feeding cycles. However, negative modulation of critical components of the insulin/IGFs system leads to defects in development in many tissues as well as metabolic dysfunctions, among other abnormalities. Despite recent advances in the field, further knowledge on the molecular aspects of insulin signaling is required to better understand cellular physiology and the molecular basis of metabolic diseases. This Special Issue of Cells aims to present an Open Access collection of original research and review articles addressing the expanding field of insulin signaling in health and disease. Suggested potential topics include new players in insulin signaling; insulin signaling in non-classical insulin action tissues; modulation of insulin signaling by stress signals and inflammation; insulin signaling and mitochondrial dysfunction; the molecular basis of insulin resistance; and transcriptional control by insulin signaling.

Prof. Ángela M. Valverde
Guest Editor

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Keywords

signal transduction
insulin resistance
type 2 diabetes mellitus
obesity
cardiovascular disease
diabetic complications

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Published Papers (9 papers)

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Research

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13 pages, 1931 KiB

Open AccessArticle

Decreased Expression of Sam68 Is Associated with Insulin Resistance in Granulosa Cells from PCOS Patients

by Teresa Vilariño-García, Pilar Guadix, Mónica Dorado-Silva, Pascual Sánchez-Martín, Antonio Pérez-Pérez and Víctor Sánchez-Margalet

Cells 2022, 11(18), 2821; https://doi.org/10.3390/cells11182821 - 9 Sep 2022

Cited by 6 | Viewed by 2180

Abstract

Background and objective: Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, which leads to subfertility. PCOS is the most frequent metabolic disorder in women and the major cause of infertility. Susceptibility to developing PCOS is determined by a complex interaction between environmental and genetic factors. Although different mechanisms have been proposed to explain PCOS manifestations, defects in insulin actions or in the insulin signaling pathways are central in the pathogenesis of the syndrome. However, the mechanisms (molecular players and signaling pathways) underlying its primary origin still remain an unsolved issue. Current research is increasingly focusing on the discovery of novel biomarkers to further elucidate the complex pathophysiology of PCOS. Sam68, an RNA-binding protein, is recruited to insulin signaling, mediating different insulin actions. We aimed to investigate the role of Sam68 in insulin signaling and the possible implications of Sam68 in the insulin resistance in PCOS. Materials and methods: Granulosa cells were taken from women with PCOS (n = 25) and healthy donors (n = 25) and, within the age range of 20 to 42 years, from GINEMED, Assisted Reproduction Centre, Seville, Spain. The Sam68 expression level was analyzed both by qPCR and immunoblot. Statistical significance was assessed by one-way ANOVA, followed by a post-hoc test. A p value of < 0.05 was considered statistically significant. Results: We found that insulin stimulation increases the phosphorylation and expression level of Sam68 in granulosa cells from normal donors. The downregulation of Sam68 expression resulted in a lower activation of both the MAPK and the PI3K pathways in response to insulin. Moreover, the granulosa cells from the women with PCOS presented a lower expression of Sam68, as well as insulin receptor and insulin receptor substrate-1 (IRS-1). In these cells, the overexpression of Sam68 resulted in an increased activation of both the MAPK and the PI3K pathways in response to insulin. Conclusions: These results suggest the participation of Sam68 in insulin receptor signaling, mediating the insulin effect in granulosa cells, and they suggest the possible role of Sam68 in the insulin resistance of PCOS. Full article

(This article belongs to the Special Issue The Insulin Signaling Network in Health and Disease)

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17 pages, 2577 KiB

Open AccessArticle

Enhanced Wild-Type MET Receptor Levels in Mouse Hepatocytes Attenuates Insulin-Mediated Signaling

by Patricia Rada, Fabienne Lamballe, Elena Carceller-López, Ana B. Hitos, Celia Sequera, Flavio Maina and Ángela M. Valverde

Cells 2022, 11(5), 793; https://doi.org/10.3390/cells11050793 - 24 Feb 2022

Cited by 3 | Viewed by 2821

Abstract

Compelling evidence points to the MET receptor tyrosine kinase as a key player during liver development and regeneration. Recently, a role of MET in the pathophysiology of insulin resistance and obesity is emerging. Herein, we aimed to determine whether MET regulates hepatic insulin sensitivity. To achieve this, mice in which the expression of wild-type MET in hepatocytes is slightly enhanced above endogenous levels (Alb-R26^Met mice) were analyzed to document glucose homeostasis, energy balance, and insulin signaling in hepatocytes. We found that Alb-R26^Met mice exhibited higher body weight and food intake when compared to R26^stopMet control mice. Metabolic analyses revealed that Alb-R26^Met mice presented age-related glucose and pyruvate intolerance in comparison to R26^stopMet controls. Additionally, in Alb-R26^Met mice, high MET levels decreased insulin-induced insulin receptor (IR) and AKT phosphorylation compared to control mice. These results were corroborated in vitro by analyzing IR and AKT phosphorylation in primary mouse hepatocytes from Alb-R26^Met and R26^stopMet mice upon insulin stimulation. Moreover, co-immunoprecipitation assays revealed MET-IR interaction under both basal and insulin stimulation conditions; this effect was enhanced in Alb-R26^Met hepatocytes. Altogether, our results indicate that enhanced MET levels alter hepatic glucose homeostasis, which can be an early event for subsequent liver pathologies. Full article

(This article belongs to the Special Issue The Insulin Signaling Network in Health and Disease)

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18 pages, 2987 KiB

Open AccessArticle

Insulin Sensitivity Is Retained in Mice with Endothelial Loss of Carcinoembryonic Antigen Cell Adhesion Molecule 1

by Harrison T. Muturi, Saja S. Khuder, Hilda E. Ghadieh, Emily L. Esakov, Hyelim Noh, Heejoon Kang, Marcia F. McInerney, Jason K. Kim, Abraham D. Lee and Sonia M. Najjar

Cells 2021, 10(8), 2093; https://doi.org/10.3390/cells10082093 - 14 Aug 2021

Cited by 6 | Viewed by 3394

Abstract

CEACAM1 regulates endothelial barrier integrity. Because insulin signaling in extrahepatic target tissues is regulated by insulin transport through the endothelium, we aimed at investigating the metabolic role of endothelial CEACAM1. To this end, we generated endothelial cell-specific Ceacam1 null mice (VECadCre+Cc1^fl/fl) and carried out their metabolic phenotyping and mechanistic analysis by comparison to littermate controls. Hyperinsulinemic-euglycemic clamp analysis showed intact insulin sensitivity in VECadCre+Cc1^fl/fl mice. This was associated with the absence of visceral obesity and lipolysis and normal levels of circulating non-esterified fatty acids, leptin, and adiponectin. Whereas the loss of endothelial Ceacam1 did not affect insulin-stimulated receptor phosphorylation, it reduced IRS-1/Akt/eNOS activation to lower nitric oxide production resulting from limited SHP2 sequestration. It also reduced Shc sequestration to activate NF-κB and increase the transcription of matrix metalloproteases, ultimately inducing plasma IL-6 and TNFα levels. Loss of endothelial Ceacam1 also induced the expression of the anti-inflammatory CEACAM1-4L variant in M2 macrophages in white adipose tissue. Together, this could cause endothelial barrier dysfunction and facilitate insulin transport, sustaining normal glucose homeostasis and retaining fat accumulation in adipocytes. The data assign a significant role for endothelial cell CEACAM1 in maintaining insulin sensitivity in peripheral extrahepatic target tissues. Full article

(This article belongs to the Special Issue The Insulin Signaling Network in Health and Disease)

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17 pages, 3396 KiB

Open AccessFeature PaperArticle

Increased Hypothalamic Anti-Inflammatory Mediators in Non-Diabetic Insulin Receptor Substrate 2-Deficient Mice

by María Vinaixa, Sandra Canelles, África González-Murillo, Vítor Ferreira, Diana Grajales, Santiago Guerra-Cantera, Ana Campillo-Calatayud, Manuel Ramírez-Orellana, Óscar Yanes, Laura M. Frago, Ángela M. Valverde and Vicente Barrios

Cells 2021, 10(8), 2085; https://doi.org/10.3390/cells10082085 - 13 Aug 2021

Cited by 1 | Viewed by 2956

Abstract

Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2^−/−) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2^−/− mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2^−/− mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2^−/− mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2^−/− mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2^−/− mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2^−/− mice. Conversely, D IRS2^−/− mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes. Full article

(This article belongs to the Special Issue The Insulin Signaling Network in Health and Disease)

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14 pages, 2621 KiB

Open AccessFeature PaperArticle

Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model

by Almudena Gómez-Hernández, Natalia de las Heras, Andrea R. López-Pastor, Gema García-Gómez, Jorge Infante-Menéndez, Paula González-López, Tamara González-Illanes, Vicente Lahera, Manuel Benito and Óscar Escribano

Cells 2021, 10(8), 2035; https://doi.org/10.3390/cells10082035 - 9 Aug 2021

Cited by 5 | Viewed by 2745

Abstract

Background: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. Methods: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. Results: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels’ imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. Conclusion: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice. Full article

(This article belongs to the Special Issue The Insulin Signaling Network in Health and Disease)

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15 pages, 2750 KiB

Open AccessArticle

Cerebral Insulin Bolus Revokes the Changes in Hepatic Lipid Metabolism Induced by Chronic Central Leptin Infusion

by Vicente Barrios, Elena López-Villar, Laura M. Frago, Sandra Canelles, Francisca Díaz-González, Emma Burgos-Ramos, Gema Frühbeck, Julie A. Chowen and Jesús Argente

Cells 2021, 10(3), 581; https://doi.org/10.3390/cells10030581 - 6 Mar 2021

Cited by 3 | Viewed by 2351

Abstract

Central actions of leptin and insulin on hepatic lipid metabolism can be opposing and the mechanism underlying this phenomenon remains unclear. Both hormones can modulate the central somatostatinergic system that has an inhibitory effect on growth hormone (GH) expression, which plays an important role in hepatic metabolism. Using a model of chronic central leptin infusion, we evaluated whether an increase in central leptin bioavailability modifies the serum lipid pattern through changes in hepatic lipid metabolism in male rats in response to an increase in central insulin and the possible involvement of the GH axis in these effects. We found a rise in serum GH in leptin plus insulin-treated rats, due to an increase in pituitary GH mRNA levels associated with lower hypothalamic somatostatin and pituitary somatostatin receptor-2 mRNA levels. An augment in hepatic lipolysis and a reduction in serum levels of non-esterified fatty acids (NEFA) and triglycerides were found in leptin-treated rats. These rats experienced a rise in lipogenic-related factors and normalization of serum levels of NEFA and triglycerides after insulin treatment. These results suggest that an increase in insulin in leptin-treated rats can act on the hepatic lipid metabolism through activation of the GH axis. Full article

(This article belongs to the Special Issue The Insulin Signaling Network in Health and Disease)

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Review

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13 pages, 496 KiB

Open AccessReview

Organ Crosstalk and the Modulation of Insulin Signaling

by Alejandra Romero and Juergen Eckel

Cells 2021, 10(8), 2082; https://doi.org/10.3390/cells10082082 - 13 Aug 2021

Cited by 25 | Viewed by 5106

Abstract

A highly complex network of organ communication plays a key role in regulating metabolic homeostasis, specifically due to the modulation of the insulin signaling machinery. As a paradigm, the role of adipose tissue in organ crosstalk has been extensively investigated, but tissues such as muscles and the liver are equally important players in this scenario. Perturbation of organ crosstalk is a hallmark of insulin resistance, emphasizing the importance of crosstalk molecules in the modulation of insulin signaling, potentially leading to defects in insulin action. Classically secreted proteins are major crosstalk molecules and are able to affect insulin signaling in both directions. In this review, we aim to focus on some crosstalk mediators with an impact on the early steps of insulin signaling. In addition, we also summarize the current knowledge on the role of extracellular vesicles in relation to insulin signaling, a more recently discovered additional component of organ crosstalk. Finally, an attempt will be made to identify inter-connections between these two pathways of organ crosstalk and the potential impact on the insulin signaling network. Full article

(This article belongs to the Special Issue The Insulin Signaling Network in Health and Disease)

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22 pages, 2564 KiB

Open AccessReview

Dietary Flavonoids and Insulin Signaling in Diabetes and Obesity

by María Ángeles Martín and Sonia Ramos

Cells 2021, 10(6), 1474; https://doi.org/10.3390/cells10061474 - 11 Jun 2021

Cited by 50 | Viewed by 5311

Abstract

Type 2 diabetes (T2D) and obesity are relevant worldwide chronic diseases. A common complication in both pathologies is the dysregulation of the insulin-signaling pathway that is crucial to maintain an accurate glucose homeostasis. Flavonoids are naturally occurring phenolic compounds abundant in fruits, vegetables and seeds. Rising evidence supports a role for the flavonoids against T2D and obesity, and at present, these compounds are considered as important potential chemopreventive agents. This review summarizes in vitro and in vivo studies providing data related to the effects of flavonoids and flavonoid-rich foods on the modulation of the insulin route during T2D and obesity. Notably, few human studies have evaluated the regulatory effect of these phenolic compounds at molecular level on the insulin pathway. In this context, it is also important to note that the mechanism of action for the flavonoids is not fully characterized and that a proper dosage to obtain a beneficial effect on health has not been defined yet. Further investigations will contribute to solve all these critical challenges and will enable the use of flavonoids to prevent, delay or support the treatment of T2D and obesity. Full article

(This article belongs to the Special Issue The Insulin Signaling Network in Health and Disease)

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42 pages, 2441 KiB

Open AccessReview

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

by Jesús Burillo, Patricia Marqués, Beatriz Jiménez, Carlos González-Blanco, Manuel Benito and Carlos Guillén

Cells 2021, 10(5), 1236; https://doi.org/10.3390/cells10051236 - 18 May 2021

Cited by 101 | Viewed by 10987

Abstract

Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction. Full article

(This article belongs to the Special Issue The Insulin Signaling Network in Health and Disease)

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