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Metabolites
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Insulin Signaling in Metabolic Homeostasis and Disease
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Insulin Signaling in Metabolic Homeostasis and Disease

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Cell Metabolism".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 15483

Special Issue Editors

Dr. Sameer Mohammad

E-Mail Website
Guest Editor
King Abdullah International Medical Research Center, Riyadh 11481, Saudi Arabia
Interests: insulin resistance; metabolic disorders; adipose tissue biology
Dr. Belén Picatoste Botija

E-Mail Website
Guest Editor
Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain
Interests: Insulin resistance; metabolic disease; adipose tissue biology; cardiovascular pathology

Special Issue Information

Dear Colleagues,

Insulin is a peptide hormone secreted by pancreatic β-cells that functions as a key regulator of metabolic homeostasis and fine-tunes the metabolism of carbohydrates, lipids, and proteins.

The discovery of insulin was a watershed moment in medicine, transforming both the treatment and prognosis of diabetes mellitus. Type 2 diabetes mellitus is a complex disease caused by impaired insulin action mainly in skeletal muscle, liver, and adipose tissue (insulin resistance) and reduced insulin secretion from pancreatic β-cell results. Understanding the mechanism of insulin resistance in peripheral tissue and defective insulin secretion from pancreatic β-cells is key to developing therapeutic drugs that can restore insulin secretion, reverse insulin resistance, and ameliorate metabolic abnormities associated with the disease. We welcome contributions from researchers in the form of original studies or review articles that address the rapidly growing field of insulin signaling in metabolic health and disease. The topics that will be covered in this Special Issue include but are not limited to diverse signaling mechanisms of insulin, novel players that modulate insulin signaling, insulin and GPCR signaling crosstalk, insulin signaling and mitochondrial dysfunction, molecular mechanism of insulin resistance, and effects of insulin resistance in other related pathologies, such as cardiovascular disease.

Dr. Sameer Mohammad
Dr. Belén Picatoste Botija
Guest Editors

Manuscript Submission Information

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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 signaling
  • insulin resistance
  • type 2 diabetes
  • obesity and metabolic syndrome

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Published Papers (7 papers)

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Research

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17 pages, 2076 KiB  
Article
Sucralose Targets the Insulin Signaling Pathway in the SH-SY5Y Neuroblastoma Cell Line
by Marina Čović, Milorad Zjalić, Lovro Mihajlović, Marianna Pap, Jasenka Wagner, Dario Mandić, Željko Debeljak and Marija Heffer
Metabolites 2023, 13(7), 817; https://doi.org/10.3390/metabo13070817 - 4 Jul 2023
Cited by 1 | Viewed by 2159
Abstract
Sucralose is widely used as a non-nutritive sweetener (NNS). However, in order to justify its use as a non-nutritive food additive, sucralose would have to be metabolically neutral. The aim of this study was to examine whether sucralose altered the insulin signaling pathway [...] Read more.
Sucralose is widely used as a non-nutritive sweetener (NNS). However, in order to justify its use as a non-nutritive food additive, sucralose would have to be metabolically neutral. The aim of this study was to examine whether sucralose altered the insulin signaling pathway in an in vitro cell model of Parkinson’s disease (PD)—the dopaminergic differentiated cell line SH-SY5Y. Cells were exposed to sucralose alone and in combination with either insulin or levodopa. Activation of the insulin signaling pathway was assessed by quantifying protein kinase B (AKT) and glycogen synthase kinase 3 (GSK3), as well as the phosphorylated forms of insulin-like growth factor 1 receptor (IGF1-R). Metabolic effects were assayed using MALDI-TOF MS analysis. In the cell viability test, 2 mM sucralose had a negative effect, and levodopa in all combinations had a positive effect. Sucralose treatment alone suppressed GSK3 and IGF1-R phosphorylation in a dose-dependent manner. This treatment also altered the metabolism of fatty acids and amino acids, especially when combined with insulin and levodopa. Suppression of the insulin signaling pathway and sucralose-induced changes in the metabolic profile could underlie a diet-acquired insulin resistance, previously associated with neurodegeneration, or may be an altered response to insulin or levodopa medical therapy. Full article
(This article belongs to the Special Issue Insulin Signaling in Metabolic Homeostasis and Disease)
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13 pages, 2178 KiB  
Article
The Selective LAT1 Inhibitor JPH203 Enhances Mitochondrial Metabolism and Content in Insulin-Sensitive and Insulin-Resistant C2C12 Myotubes
by Caroline N. Rivera, Carly E. Smith, Lillian V. Draper, Gabriela E. Ochoa, Rachel M. Watne, Andrew J. Wommack and Roger A. Vaughan
Metabolites 2023, 13(6), 766; https://doi.org/10.3390/metabo13060766 - 19 Jun 2023
Cited by 2 | Viewed by 1942
Abstract
Population data have shown an association between higher circulating branched-chain amino acids (BCAA) and the severity of insulin resistance in people with diabetes. While several studies have assessed BCAA metabolism as a potential target for regulation, less attention has been paid to the [...] Read more.
Population data have shown an association between higher circulating branched-chain amino acids (BCAA) and the severity of insulin resistance in people with diabetes. While several studies have assessed BCAA metabolism as a potential target for regulation, less attention has been paid to the role of L-type amino acid transporter 1 (LAT1), the primary transporter of BCAA in skeletal muscle. The aim of this study was to assess the impact of JPH203 (JPH), a LAT1 inhibitor, on myotube metabolism in both insulin-sensitive and insulin-resistant myotubes. C2C12 myotubes were treated with or without 1 μM or 2 μM JPH for 24 h with or without insulin resistance. Western blot and qRT-PCR were used to assess protein content and gene expression, respectively. Mitochondrial and glycolytic metabolism were measured via Seahorse Assay, and fluorescent staining was used to measure mitochondrial content. BCAA media content was quantified using liquid chromatography–mass spectrometry. JPH at 1 μM (but not 2 μM) increased mitochondrial metabolism and content without inducing changes in mRNA expression of transcripts associated with mitochondrial biogenesis or mitochondrial dynamics. Along with increased mitochondrial function, 1μM treatment also reduced extracellular leucine and valine. JPH at 2 μM reduced pAkt signaling and increased extracellular accumulation of isoleucine without inducing changes in BCAA metabolic genes. Collectively, JPH may increase mitochondrial function independent of the mitochondrial biogenic transcription pathway; however, high doses may reduce insulin signaling. Full article
(This article belongs to the Special Issue Insulin Signaling in Metabolic Homeostasis and Disease)
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21 pages, 3132 KiB  
Article
Hepatic Insulin Resistance Model in the Male Wistar Rat Using Exogenous Insulin Glargine Administration
by Victor Enrique Sarmiento-Ortega, Diana Moroni-González, Alfonso Diaz, Miguel Ángel García-González, Eduardo Brambila and Samuel Treviño
Metabolites 2023, 13(4), 572; https://doi.org/10.3390/metabo13040572 - 18 Apr 2023
Viewed by 2045
Abstract
Metabolic diseases are a worldwide health problem. Insulin resistance (IR) is their distinctive hallmark. For their study, animal models that provide reliable information are necessary, permitting the analysis of the cluster of abnormalities that conform to it, its progression, and time-dependent molecular modifications. [...] Read more.
Metabolic diseases are a worldwide health problem. Insulin resistance (IR) is their distinctive hallmark. For their study, animal models that provide reliable information are necessary, permitting the analysis of the cluster of abnormalities that conform to it, its progression, and time-dependent molecular modifications. We aimed to develop an IR model by exogenous insulin administration. The effective dose of insulin glargine to generate hyperinsulinemia but without hypoglycemia was established. Then, two groups (control and insulin) of male Wistar rats of 100 g weight were formed. The selected dose (4 U/kg) was administered for 15, 30, 45, and 60 days. Zoometry, a glucose tolerance test, insulin response, IR, and the serum lipid profile were assessed. We evaluated insulin signaling, glycogenesis and lipogenesis, redox balance, and inflammation in the liver. Results showed an impairment of glucose tolerance, dyslipidemia, hyperinsulinemia, and peripheral and time-dependent selective IR. At the hepatic level, insulin signaling was impaired, resulting in reduced hepatic glycogen levels and triglyceride accumulation, an increase in the ROS level with MAPK-ERK1/2 response, and mild pro-oxidative microenvironmental sustained by MT, GSH, and GR activity. Hepatic IR coincides with additions in MAPK-p38, NF-κB, and zoometric changes. In conclusion, daily insulin glargine administration generated a progressive IR model. At the hepatic level, the IR was combined with oxidative conditions but without inflammation. Full article
(This article belongs to the Special Issue Insulin Signaling in Metabolic Homeostasis and Disease)
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10 pages, 274 KiB  
Article
Hypertriglyceridemic Waist Phenotype and Its Association with Metabolic Syndrome Components, among Greek Children with Excess Body Weight
by Eirini Dikaiakou, Fani Athanasouli, Anatoli Fotiadou, Maria Kafetzi, Stefanos Fakiolas, Stefanos Michalacos and Elpis Athina Vlachopapadopoulou
Metabolites 2023, 13(2), 230; https://doi.org/10.3390/metabo13020230 - 3 Feb 2023
Cited by 3 | Viewed by 1504
Abstract
The hypertriglyceridemic waist (HTGW) phenotype is characterized by abdominal obesity and elevated serum triglycerides. We aimed to assess the prevalence of the HTGW phenotype among children with overweight or obesity and its association with indices of insulin resistance (IR) and dyslipidemia. A total [...] Read more.
The hypertriglyceridemic waist (HTGW) phenotype is characterized by abdominal obesity and elevated serum triglycerides. We aimed to assess the prevalence of the HTGW phenotype among children with overweight or obesity and its association with indices of insulin resistance (IR) and dyslipidemia. A total of 145 children with mean age of 10.2 years (SD = 2.31 years), 97.2% of whom with obesity, were analyzed. The HTGW phenotype was defined as WC > 90th Centers for Disease Control and Prevention (CDC) percentile and triglyceride levels of ≥100 mg/dL and ≥130 mg/dL for children 0 to 9 or >10 years of age, respectively. In total, 77.9% of the children had a waist circumference above the 90th percentile and 22.8% had elevated triglycerides. The prevalence of the HTGW phenotype in this sample was 19.3%. Patients with the HTGW phenotype had significantly lower levels of High-Density Lipoprotein (p < 0.001) and were insulin-resistant, as evident by an increased mean Triglycerides Glucose Index 8.64 (SD = 0.24) vs. 7.92 (SD = 0.41) for those without the HTGW phenotype (p < 0.001), and increased prevalence (54.5%) of Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in ≥2.5 in patients with HTGW (p = 0.045). Children with the HTGW phenotype were more likely to have increased HOMA-IR [OR 7.9 95% CI (1.94, 32.1)]. The HTGW phenotype is a low-cost and easily available index that might help to identify children with increased cardiometabolic risk. Full article
(This article belongs to the Special Issue Insulin Signaling in Metabolic Homeostasis and Disease)
12 pages, 1014 KiB  
Article
Single Point Insulin Sensitivity Estimator (SPISE) As a Prognostic Marker for Emerging Dysglycemia in Children with Overweight or Obesity
by Robert Stein, Florian Koutny, Johannes Riedel, Natascha Dörr, Klara Meyer, Marco Colombo, Mandy Vogel, Christian Heinz Anderwald, Matthias Blüher, Wieland Kiess, Antje Körner and Daniel Weghuber
Metabolites 2023, 13(1), 100; https://doi.org/10.3390/metabo13010100 - 7 Jan 2023
Cited by 4 | Viewed by 2343
Abstract
The single point insulin sensitivity estimator (SPISE) is a recently developed fasting index for insulin sensitivity based on triglycerides, high density lipoprotein cholesterol, and body mass index. SPISE has been validated in juveniles and adults; still, its role during childhood remains unclear. To [...] Read more.
The single point insulin sensitivity estimator (SPISE) is a recently developed fasting index for insulin sensitivity based on triglycerides, high density lipoprotein cholesterol, and body mass index. SPISE has been validated in juveniles and adults; still, its role during childhood remains unclear. To evaluate the age- and sex-specific distribution of SPISE, its correlation with established fasting indexes and its application as a prognostic marker for future dysglycemia during childhood and adolescence were assessed. We performed linear modeling and correlation analyses on a cross-sectional cohort of 2107 children and adolescents (age 5 to 18.4 years) with overweight or obesity. Furthermore, survival analyses were conducted upon a longitudinal cohort of 591 children with overweight/obesity (1712 observations) with a maximum follow-up time of nearly 20 years, targeting prediabetes/dysglycemia as the end point. The SPISE index decreased significantly with age (−0.34 units per year, p < 0.001) among children and adolescents with overweight and obesity. Sex did not have an influence on SPISE. There was a modest correlation between SPISE and established fasting markers of insulin resistance (R = −0.49 for HOMA-IR, R = −0.55 for QUICKI-IR). SPISE is a better prognostic marker for future dysglycemia (hazard ratio (HR) 3.47, 95% confidence interval (CI) 1.60–7.51, p < 0.01) than HOMA-IR and QUICKI-IR (HR 2.44, 95% CI 1.24–4.81, p < 0.05). The SPISE index is a surrogate marker for insulin resistance predicting emerging dysglycemia in children with overweight or obesity, and could, therefore, be applied to pediatric cohorts that lack direct insulin assessment. Full article
(This article belongs to the Special Issue Insulin Signaling in Metabolic Homeostasis and Disease)
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Review

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14 pages, 1856 KiB  
Review
Neuroendocrine Effects on the Risk of Metabolic Syndrome in Children
by Giovanna Scorrano, Saverio La Bella, Sara Matricardi, Francesco Chiarelli and Cosimo Giannini
Metabolites 2023, 13(7), 810; https://doi.org/10.3390/metabo13070810 - 29 Jun 2023
Cited by 1 | Viewed by 1773
Abstract
The endocrine and nervous systems reciprocally interact to manage physiological individual functions and homeostasis. The nervous system modulates hormone release through the hypothalamus, the main cerebrally specialized structure of the neuroendocrine system. The hypothalamus is involved in various metabolic processes, administering hormone and [...] Read more.
The endocrine and nervous systems reciprocally interact to manage physiological individual functions and homeostasis. The nervous system modulates hormone release through the hypothalamus, the main cerebrally specialized structure of the neuroendocrine system. The hypothalamus is involved in various metabolic processes, administering hormone and neuropeptide release at different levels. This complex activity is affected by the neurons of various cerebral areas, environmental factors, peripheral organs, and mediators through feedback mechanisms. Therefore, neuroendocrine pathways play a key role in metabolic homeostasis control, and their abnormalities are associated with the development of metabolic syndrome (MetS) in children. The impaired functioning of the genes, hormones, and neuropeptides of various neuroendocrine pathways involved in several metabolic processes is related to an increased risk of dyslipidaemia, visceral obesity, insulin resistance, type 2 diabetes mellitus, and hypertension. This review examines the neuroendocrine effects on the risk of MetS in children, identifying and underlying several conditions associated with neuroendocrine pathway disruption. Neuroendocrine systems should be considered in the complex pathophysiology of MetS, and, when genetic or epigenetic mutations in “hot” pathways occur, they could be studied for new potential target therapies in severe and drug-resistant paediatric forms of MetS. Full article
(This article belongs to the Special Issue Insulin Signaling in Metabolic Homeostasis and Disease)
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17 pages, 791 KiB  
Review
Metabolic-Associated Fatty Liver Disease and Insulin Resistance: A Review of Complex Interlinks
by Thomas M. Barber, Stefan Kabisch, Andreas F. H. Pfeiffer and Martin O. Weickert
Metabolites 2023, 13(6), 757; https://doi.org/10.3390/metabo13060757 - 15 Jun 2023
Cited by 3 | Viewed by 2452
Abstract
Metabolic-associated fatty liver disease (MAFLD) has now surpassed alcohol excess as the most common cause of chronic liver disease globally, affecting one in four people. Given its prevalence, MAFLD is an important cause of cirrhosis, even though only a small proportion of patients [...] Read more.
Metabolic-associated fatty liver disease (MAFLD) has now surpassed alcohol excess as the most common cause of chronic liver disease globally, affecting one in four people. Given its prevalence, MAFLD is an important cause of cirrhosis, even though only a small proportion of patients with MAFLD ultimately progress to cirrhosis. MAFLD suffers as a clinical entity due to its insidious and often asymptomatic onset, lack of an accurate and reliable non-invasive diagnostic test, and lack of a bespoke therapy that has been designed and approved for use specifically in MAFLD. MAFLD sits at a crossroads between the gut and the periphery. The development of MAFLD (including activation of the inflammatory cascade) is influenced by gut-related factors that include the gut microbiota and intactness of the gut mucosal wall. The gut microbiota may interact directly with the liver parenchyma (through translocation via the portal vein), or indirectly through the release of metabolic metabolites that include secondary bile acids, trimethylamine, and short-chain fatty acids (such as propionate and acetate). In turn, the liver mediates the metabolic status of peripheral tissues (including insulin sensitivity) through a complex interplay of hepatokines, liver-secreted metabolites, and liver-derived micro RNAs. As such, the liver plays a key central role in influencing overall metabolic status. In this concise review, we provide an overview of the complex mechanisms whereby MAFLD influences the development of insulin resistance within the periphery, and gut-related factors impact on the development of MAFLD. We also discuss lifestyle strategies for optimising metabolic liver health. Full article
(This article belongs to the Special Issue Insulin Signaling in Metabolic Homeostasis and Disease)
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