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Biomolecules
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100th Anniversary of Insulin: Insulin Receptor Signaling in Health and...
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100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 38354

Special Issue Editors

Prof. Dr. Myron R. Szewczuk

E-Mail Website
Guest Editor
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada
Interests: the role of glycosylation in receptor activation; TOLL-like; nerve growth factor Trk; EGFR and insulin receptors
Special Issues, Collections and Topics in MDPI journals
Dr. Fiona Haxho

E-Mail Website
Guest Editor
Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Interests: medicine; inflammation; insulin receptor signaling; glycosylation; NEU1 sialidase

Special Issue Information

Dear Colleagues,

Several signaling molecules have been identified as critical players in the regulation of insulin-induced IR activation. G protein-coupled receptors (GPCR) have recently been implicated in intracellular crosstalk pathways with IR. The integration of GPCR and receptor tyrosine kinase (RTK) signaling, including IR upon ligand stimulation, is eloquently reviewed. Other reports have also shown that IR can interact with Gαi subunits upon receptor activation. An upregulation of IR expression and its activation is significantly associated with higher downstream G protein signaling cascades. G protein stoichiometry can dictate biased agonism through distinct receptor-G protein partitioning. The expression levels of Gα subunits influence the biased profiling of β-agonists and antagonists in that they determine both their activity and efficacy by affecting different membrane distribution of receptor-G protein populations. In the naïve state, the level of Gα expression influences the partitioning of not only Gα but also the co-expressed receptor in different membrane domains. This intriguing concept could explain where GPCR activation mutations correlate with increased downstream IR signaling in the complete absence of insulin. Can this G-protein signaling platform preassociate with insulin receptors with non-nutrition artificial sweetners, gut microbiome metabolites, μ-opioid and cannabinoid CB GPCRs? The gaps in our knowledge regarding how these metabolite consumptions are implicated in host metabolism via GPCR receptors reinforce the importance of research needed to understand the mechanistic action of these drugs on the body as promising metabolic candidates.

Collectively, these findings uncover a unique mode of control for IR activation and present an innovative approach to targeting insulin signaling via GPCR complexes. The key players potentiating receptor GPCR biased signaling of IRβ receptors can advance our understanding of the current dogma(s) governing crosstalks between GPCR biased metabolites and cellular responses contributing to diabetes. This research has the potential to uncover (a) novel mechanism(s) of metabolite-induced metabolic changes, epigenetic reprogramming, insulin resistance and diabetes.

Original manuscripts and reviews dealing with any aspect of insulin receptor and related pathophysiology are welcome.

Dr. Myron R. Szewczuk
Dr. Fiona Haxho
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • insulin receptor
  • IR signaling
  • GPCR signaling
  • insulin resistance
  • diabetes
  • non-nutritional artificial sweeteners
  • gut microbiome metabolites
  • metabolic syndrome
  • glycosylation
  • cancer
  • aging
  • bombesin
  • bradykinin
  • angiotensin I
  • angiotensin II
  • neu1 sialidase
  • MMP9
  • NMBR receptors
  • G protein-coupled receptor
  • μ-opioid
  • cannabinoid

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Published Papers (7 papers)

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Editorial

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3 pages, 167 KiB  
Editorial
Insulin Receptor Signaling in Health and Disease
by Leili Baghaie, David A. Bunsick and Myron R. Szewczuk
Biomolecules 2023, 13(5), 807; https://doi.org/10.3390/biom13050807 - 9 May 2023
Cited by 2 | Viewed by 2006
Abstract
Since the discovery of insulin over 100 years ago, our understanding of the insulin signaling pathway has greatly expanded [...] Full article
(This article belongs to the Special Issue 100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease)

Research

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19 pages, 2576 KiB  
Article
Dietary Soy Prevents Alcohol-Mediated Neurocognitive Dysfunction and Associated Impairments in Brain Insulin Pathway Signaling in an Adolescent Rat Model
by Ming Tong, Jason L. Ziplow, Princess Mark and Suzanne M. de la Monte
Biomolecules 2022, 12(5), 676; https://doi.org/10.3390/biom12050676 - 8 May 2022
Cited by 10 | Viewed by 2962
Abstract
Background: Alcohol-related brain degeneration is linked to cognitive-motor deficits and impaired signaling through insulin/insulin-like growth factor type 1 (IGF-1)-Akt pathways that regulate cell survival, plasticity, metabolism, and homeostasis. In addition, ethanol inhibits Aspartyl-asparaginyl-β-hydroxylase (ASPH), a downstream target of insulin/IGF-1-Akt signaling and an activator [...] Read more.
Background: Alcohol-related brain degeneration is linked to cognitive-motor deficits and impaired signaling through insulin/insulin-like growth factor type 1 (IGF-1)-Akt pathways that regulate cell survival, plasticity, metabolism, and homeostasis. In addition, ethanol inhibits Aspartyl-asparaginyl-β-hydroxylase (ASPH), a downstream target of insulin/IGF-1-Akt signaling and an activator of Notch networks. Previous studies have suggested that early treatment with insulin sensitizers or dietary soy could reduce or prevent the long-term adverse effects of chronic ethanol feeding. Objective: The goal of this study was to assess the effects of substituting soy isolate for casein to prevent or reduce ethanol’s adverse effects on brain structure and function. Methods: Young adolescent male and female Long Evans were used in a 4-way model as follows: Control + Casein; Ethanol + Casein; Control + Soy; Ethanol + Soy; Control = 0% ethanol; Ethanol = 26% ethanol (caloric). Rats were fed isocaloric diets from 4 to 11 weeks of age. During the final experimental week, the Morris Water maze test was used to assess spatial learning (4 consecutive days), after which the brains were harvested to measure the temporal lobe expression of the total phospho-Akt pathway and downstream target proteins using multiplex bead-based enzyme-linked immunosorbent assays (ELISAs) and duplex ELISAs. Results: Ethanol inhibited spatial learning and reduced brain weight, insulin signaling through Akt, and the expression of ASPH when standard casein was provided as the protein source. The substitution of soy isolate for casein largely abrogated the adverse effects of chronic ethanol feeding. In contrast, Notch signaling protein expression was minimally altered by ethanol or soy isolate. Conclusions: These novel findings suggest that the insulin sensitizer properties of soy isolate may prevent some of the adverse effects that chronic ethanol exposure has on neurobehavioral function and insulin-regulated metabolic pathways in adolescent brains. Full article
(This article belongs to the Special Issue 100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease)
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10 pages, 1334 KiB  
Article
Clinical Role of Serum miR107 in Type 2 Diabetes and Related Risk Factors
by Diana Šimonienė, Darius Stukas, Albertas Daukša and Džilda Veličkienė
Biomolecules 2022, 12(4), 558; https://doi.org/10.3390/biom12040558 - 8 Apr 2022
Cited by 9 | Viewed by 2039
Abstract
Background: As the diagnostic and treatment options for diabetes improve, more attention nowadays is being paid to the exact identification of the etiopathological mechanism of type 2 diabetes (T2DM). Insulin resistance (IR) is a pathogenetic background for T2DM. Several studies demonstrate that miRNAs [...] Read more.
Background: As the diagnostic and treatment options for diabetes improve, more attention nowadays is being paid to the exact identification of the etiopathological mechanism of type 2 diabetes (T2DM). Insulin resistance (IR) is a pathogenetic background for T2DM. Several studies demonstrate that miRNAs play an important role in systemic inflammation and thus in T2DM pathogenesis. Overexpression of miR-107 may cause an imbalance of glucose homeostasis, obesity, and dyslipidemia, by regulating insulin sensitivity through the insulin signaling pathway. Methods: 53 patients with T2DM and 54 nondiabetic patients were involved in the study. This study aimed to examine whether miR-107 expression in the serum of patients with diabetes was different from the control group (non-diabetic) and whether miR-107 expression correlated with lipid levels, BMI, and other factors, and finally, with insulin resistance in general. Results: miR-107 expression was higher in the T2DM group than in the control group (1.33 versus 0.63 (p = 0.016). In general, miR-107 expression was directly and positively associated with BMI (r = 0.3, p = 0.01), age (r = 0.3, p = 0.004), and male gender (p = 0.006). Moreover, miR-107 was related to dyslipidemia: Patients with higher miR-107 levels had lower HDL levels (in the control group: r = −0.262, p = 0.022 vs. diabetic group: r = −0.315, p = 0.007). Finally, the overexpression of miR-107 was associated with higher HOMA-IR in the diabetic group (r = 0.373, p = 0.035). Conclusion: MiR-107 expression is higher among diabetic patients than that of nondiabetic control subjects. Higher miR-107 levels are also related to dyslipidemia (lower HDL levels)—in the general cohort and non-diabetic subjects. Moreover, higher miR-107 expression is related to insulin resistance in the diabetic group. In general, higher miR-107 expression levels are related to a higher BMI, older age, and the male gender. Full article
(This article belongs to the Special Issue 100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease)
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21 pages, 5533 KiB  
Article
Reduction in the Dietary VA Status Prevents Type 2 Diabetes and Obesity in Zucker Diabetic Fatty Rats
by Tiannan Wang, Xia Tang, Xinge Hu, Jing Wang and Guoxun Chen
Biomolecules 2022, 12(4), 528; https://doi.org/10.3390/biom12040528 - 31 Mar 2022
Cited by 7 | Viewed by 2527
Abstract
We hypothesized that the vitamin A (VA) status regulates type 2 diabetes (T2D) development in Zucker diabetic fatty (ZDF) rats. Zucker Lean and ZDF rats at weaning were fed a VA deficient with basal fat (VAD-BF, no VA and 22.1% fat energy), VA [...] Read more.
We hypothesized that the vitamin A (VA) status regulates type 2 diabetes (T2D) development in Zucker diabetic fatty (ZDF) rats. Zucker Lean and ZDF rats at weaning were fed a VA deficient with basal fat (VAD-BF, no VA and 22.1% fat energy), VA marginal with BF (VAM-BF, 0.35 mg retinyl palmitate (RP)/kg), VA sufficient with BF (VAS-BF, 4.0 mg RP/kg), VAD with high fat (VAD-HF, 60% fat energy), VAM-HF or VAS-HF diet for 8 weeks, including an oral glucose tolerance test (OGTT) at week 7.5. The hepatic mRNA and proteins levels were determined using real-time PCR and Western blot, respectively. The VAD-BF/HF and VAM-BF/HF diets prevented peripheral hyperglycemia and attenuated obesity in ZDF rats, which occurred in the presence of the VAS-BF/HF diets. This lowered VA status reduced venous blood hyperglycemia, hyperinsulinemia and hyperlipidemia, and improved OGTT and homeostasis model assessment for insulin resistance results in ZDF rats. The expression levels of key hepatic genes for glucose and fat metabolism were regulated by VA status and dietary fat contents. An interaction between VA and HF condition was also observed. We conclude that the reduction in the dietary VA status in both BF and HF conditions prevents T2D and obesity in ZDF rats. Full article
(This article belongs to the Special Issue 100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease)
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Review

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23 pages, 1711 KiB  
Review
Actions and Consequences of Insulin in the Striatum
by Jyoti C. Patel, Kenneth D. Carr and Margaret E. Rice
Biomolecules 2023, 13(3), 518; https://doi.org/10.3390/biom13030518 - 11 Mar 2023
Cited by 7 | Viewed by 3084
Abstract
Insulin crosses the blood–brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which [...] Read more.
Insulin crosses the blood–brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which shows abundant expression of insulin receptors (InsRs) throughout. These receptors are found on interneurons and striatal projections neurons, as well as on glial cells and dopamine axons. A striking functional consequence of insulin elevation in the striatum is promoting an increase in stimulated dopamine release. This boosting of dopamine release involves InsRs on cholinergic interneurons, and requires activation of nicotinic acetylcholine receptors on dopamine axons. Opposing this dopamine-enhancing effect, insulin also increases dopamine uptake through the action of insulin at InsRs on dopamine axons. Insulin acts on other striatal cells as well, including striatal projection neurons and astrocytes that also influence dopaminergic transmission and striatal function. Linking these cellular findings to behavior, striatal insulin signaling is required for the development of flavor–nutrient learning, implicating insulin as a reward signal in the brain. In this review, we discuss these and other actions of insulin in the striatum, including how they are influenced by diet and other physiological states. Full article
(This article belongs to the Special Issue 100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease)
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16 pages, 926 KiB  
Review
Insulin Receptors and Insulin Action in the Heart: The Effects of Left Ventricular Assist Devices
by Konstantina Pantazi, Eleni Karlafti, Alexandra Bekiaridou, Matthaios Didagelos, Antonios Ziakas and Triantafyllos Didangelos
Biomolecules 2022, 12(4), 578; https://doi.org/10.3390/biom12040578 - 14 Apr 2022
Cited by 7 | Viewed by 2816
Abstract
This year, 2022, marks the 100th anniversary of the isolation of human insulin and its administration to patients suffering from diabetes mellitus (DM). Insulin exerts many effects on the human body, including the cardiac tissue. The pathways implicated include the PKB/Akt signaling pathway, [...] Read more.
This year, 2022, marks the 100th anniversary of the isolation of human insulin and its administration to patients suffering from diabetes mellitus (DM). Insulin exerts many effects on the human body, including the cardiac tissue. The pathways implicated include the PKB/Akt signaling pathway, the Janus kinase, and the mitogen-activated protein kinase pathway and lead to normal cardiac growth, vascular smooth muscle regulation, and cardiac contractility. This review aims to summarize the existing knowledge and provide new insights on insulin pathways of cardiac tissue, along with the role of left ventricular assist devices on insulin regulation and cardiac function. Full article
(This article belongs to the Special Issue 100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease)
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17 pages, 1769 KiB  
Review
Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives
by Mariyam Khalid, Georg Petroianu and Abdu Adem
Biomolecules 2022, 12(4), 542; https://doi.org/10.3390/biom12040542 - 4 Apr 2022
Cited by 270 | Viewed by 19923
Abstract
Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end [...] Read more.
Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end products (AGEs), which play a central role in the pathophysiology of diabetic complications. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-β, JNK, and NF-κB, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications. In this review, we will summarize the exogenous and endogenous sources of AGEs, their role in metabolic dysfunction, and current understandings of AGEs/RAGE signaling cascade. The focus of this review is to recapitulate the role of the AGEs/RAGE axis in the pathogenesis of type 2 diabetes mellitus and its associated complications. Furthermore, we present an overview of future perspectives to offer new therapeutic interventions to intervene with the AGEs/RAGE signaling pathway and to slow down the progression of diabetes-related complications. Full article
(This article belongs to the Special Issue 100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease)
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