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Molecular Advances on Insulin Resistance and Metabolic Dysfunction

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 17750

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Special Issue Editors

Prof. Dr. Melania Manco

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Guest Editor

Unit of Endocrinology, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy
Interests: obesity; insulin resistance and secretion; type 2 diabetes
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Amalia Gastaldelli

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Guest Editor

Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
Interests: insulin resistance; hepatology; diabetes; hypertension; metabolic syndrome; glucose metabolism; fatty liver; metabolism; nutrition
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Worldwide, the obesity epidemic has resulted in a surge of metabolic abnormalities and diseases stemming from the condition of insulin resistance that accompanies the obesity status. Insulin resistance represents an impaired biological response to insulin stimulation of target tissues, primarily liver, muscle, and adipose tissue. It is recognized as the root for hypertension, dyslipidemia, non alcholic fatty liver disease, policistic ovary syndome, atherosclerosis, and adverse cardiac remodeling/heart failure. Alterations in glucose and lipid metabolism, insulin secretion and action are among the most important mechanisms that explain the onset of these diseases.

Several modifiable and non-modifiable factors are implicated. Among modifiable risk factors sedentarity and unhealthy diets rich in saturated fat are the most important. However, it is becoming clear that during the last century the production and release of chemicals in the environment has increased and this per se has an effect on health. These chemicals once inhaled or ingested (since they are present in water and in the food chain) may act as endocrine disruptors (EDC) thus increasing the development of metabolic diseases and related comorbidities.

We invite investigators to contribute either original research articles or review articles focusing on the variety of molecular mechanisms that either contribute to the worsening of insulin resistance in obese patients, or that, triggered by insulin resistance, cause the onset and progression of comorbidities associated with obesity.

Prof. Dr. Melania Manco
Prof. Dr. Amalia Gastaldelli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

dysregulated fatty acid and/or branched chain amino acids
metabolism
metabolic inflexibility
tissue lipid accumulation, lipotoxicity and lipid mediated cell signaling
insulin resistance reversal
cancer development
low-grade inflammation and/or altered expression, synthesis and degradation and bioavailability of IGF binding proteins
environmental chemicals
mechanisms of T3D
microbiota and antimicrobials modulation
endocrine disruptors
altered immune system homeostasis

Published Papers (9 papers)

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Research

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38 pages, 4564 KiB

Open AccessArticle

Transfer of Proteins from Cultured Human Adipose to Blood Cells and Induction of Anabolic Phenotype Are Controlled by Serum, Insulin and Sulfonylurea Drugs

by Günter A. Müller and Timo D. Müller

Int. J. Mol. Sci. 2023, 24(5), 4825; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054825 - 02 Mar 2023

Cited by 3 | Viewed by 1410

Abstract

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are anchored at the outer leaflet of eukaryotic plasma membranes (PMs) only by carboxy-terminal covalently coupled GPI. GPI-APs are known to be released from the surface of donor cells in response to insulin and antidiabetic sulfonylureas (SUs) by lipolytic cleavage of the GPI or upon metabolic derangement as full-length GPI-APs with the complete GPI attached. Full-length GPI-APs become removed from extracellular compartments by binding to serum proteins, such as GPI-specific phospholipase D (GPLD1), or insertion into the PMs of acceptor cells. Here, the interplay between the lipolytic release and intercellular transfer of GPI-APs and its potential functional impact was studied using transwell co-culture with human adipocytes as insulin-/SU-responsive donor cells and GPI-deficient erythroleukemia as acceptor cells (ELCs). Measurement of the transfer as the expression of full-length GPI-APs at the ELC PMs by their microfluidic chip-based sensing with GPI-binding α-toxin and GPI-APs antibodies and of the ELC anabolic state as glycogen synthesis upon incubation with insulin, SUs and serum yielded the following results: (i) Loss of GPI-APs from the PM upon termination of their transfer and decline of glycogen synthesis in ELCs, as well as prolongation of the PM expression of transferred GPI-APs upon inhibition of their endocytosis and upregulated glycogen synthesis follow similar time courses. (ii) Insulin and SUs inhibit both GPI-AP transfer and glycogen synthesis upregulation in a concentration-dependent fashion, with the efficacies of the SUs increasing with their blood glucose-lowering activity. (iii) Serum from rats eliminates insulin- and SU-inhibition of both GPI-APs’ transfer and glycogen synthesis in a volume-dependent fashion, with the potency increasing with their metabolic derangement. (iv) In rat serum, full-length GPI-APs bind to proteins, among them (inhibited) GPLD1, with the efficacy increasing with the metabolic derangement. (v) GPI-APs are displaced from serum proteins by synthetic phosphoinositolglycans and then transferred to ELCs with accompanying stimulation of glycogen synthesis, each with efficacies increasing with their structural similarity to the GPI glycan core. Thus, both insulin and SUs either block or foster transfer when serum proteins are depleted of or loaded with full-length GPI-APs, respectively, i.e., in the normal or metabolically deranged state. The transfer of the anabolic state from somatic to blood cells over long distance and its “indirect” complex control by insulin, SUs and serum proteins support the (patho)physiological relevance of the intercellular transfer of GPI-APs. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction)

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15 pages, 1033 KiB

Open AccessArticle

Insights into Insulin Resistance and Calcification in the Myocardium in Type 2 Diabetes: A Coronary Artery Analysis

by Queralt Martín-Saladich, Rafael Simó, Santiago Aguadé-Bruix, Olga Simó-Servat, Carolina Aparicio-Gómez, Cristina Hernández, Clara Ramirez-Serra, María Nazarena Pizzi, Albert Roque, Miguel A. González Ballester and José Raul Herance

Int. J. Mol. Sci. 2023, 24(4), 3250; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043250 - 07 Feb 2023

Cited by 1 | Viewed by 1634

Abstract

Type 2 diabetes (T2D) is responsible for high incidence of cardiovascular (CV) complications leading to heart failure. Coronary artery region-specific metabolic and structural assessment could provide deeper insight into the extent of the disease and help prevent adverse cardiac events. Therefore, in this study, we aimed at investigating such myocardial dynamics for the first time in insulin-sensitive (mIS) and insulin-resistant (mIR) T2D patients. We targeted global and region-specific variations using insulin sensitivity (IS) and coronary artery calcifications (CACs) as CV risk factor in T2D patients. IS was computed using myocardial segmentation approaches at both baseline and after an hyperglycemic–insulinemic clamp (HEC) on [¹⁸F]FDG-PET images using the standardized uptake value (SUV) (ΔSUV = SUV_HEC − SUV_BASELINE) and calcifications using CT Calcium Scoring. Results suggest that some communicating pathways between response to insulin and calcification are present in the myocardium, whilst differences between coronary arteries were only observed in the mIS cohort. Risk indicators were mostly observed for mIR and highly calcified subjects, which supports previously stated findings that exhibit a distinguished exposure depending on the impairment of response to insulin, while projecting added potential complications due to arterial obstruction. Moreover, a pattern relating calcification and T2D phenotypes was observed suggesting the avoidance of insulin treatment in mIS but its endorsement in mIR subjects. The right coronary artery displayed more ΔSUV, whilst plaque was more present in the circumflex. However, differences between phenotypes, and therefore CV risk, were associated to left descending artery (LAD) translating into higher CACs regarding IR, which could explain why insulin treatment was effective for LAD at the expense of higher likelihood of plaque accumulation. Personalized approaches to assess T2D may lead to more efficient treatments and risk-prevention strategies. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction)

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17 pages, 3362 KiB

Open AccessArticle

p27^Kip1 Deficiency Impairs Brown Adipose Tissue Function Favouring Fat Accumulation in Mice

by Ignacio Colon-Mesa, Neira Sainz, Patricia Corrales, María Collantes, Philipp Kaldis, José Alfredo Martinez, Gema Medina-Gómez, María Jesús Moreno-Aliaga and Xavier Escoté

Int. J. Mol. Sci. 2023, 24(3), 2664; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032664 - 31 Jan 2023

Viewed by 1738

Abstract

The aim of this work was to investigate the effect of the whole-body deletion of p27 on the activity of brown adipose tissue and the susceptibility to develop obesity and glucose homeostasis disturbances in mice, especially when subjected to a high fat diet. p27 knockout (p27^−/−) and wild type (WT) mice were fed a normal chow diet or a high fat diet (HFD) for 10-weeks. Body weight and composition were assessed. Insulin and glucose tolerance tests and indirect calorimetry assays were performed. Histological analysis of interscapular BAT (iBAT) was carried out, and expression of key genes/proteins involved in BAT function were characterized by qPCR and Western blot. iBAT activity was estimated by ¹⁸F-fluorodeoxyglucose (¹⁸FDG) uptake with microPET. p27^−/− mice were more prone to develop obesity and insulin resistance, exhibiting increased size of all fat depots. p27^−/− mice displayed a higher respiratory exchange ratio. iBAT presented larger adipocytes in p27^−/− HFD mice, accompanied by downregulation of both Glut1 and uncoupling protein 1 (UCP1) in parallel with defective insulin signalling. Moreover, p27^−/− HFD mice exhibited impaired response to cold exposure, characterized by a reduced iBAT ¹⁸FDG uptake and difficulty to maintain body temperature when exposed to cold compared to WT HFD mice, suggesting reduced thermogenic capacity. These data suggest that p27 could play a role in BAT activation and in the susceptibility to develop obesity and insulin resistance. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction)

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9 pages, 1120 KiB

Open AccessArticle

The Predictive Role of Extracellular NAPRT for the Detection of Advanced Fibrosis in Biopsy-Proven Non-Alcoholic Fatty Liver Disease

by Angelo Armandi, Giorgia Colombo, Chiara Rosso, Gian Paolo Caviglia, Antonella Olivero, Maria Lorena Abate, Marta Guariglia, Nuria Perez Diaz del Campo, Gabriele Castelnuovo, Davide Giuseppe Ribaldone, Giorgio Maria Saracco, Armando A. Genazzani and Elisabetta Bugianesi

Int. J. Mol. Sci. 2023, 24(2), 1172; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021172 - 07 Jan 2023

Cited by 3 | Viewed by 1601

Abstract

Intrahepatic oxidative stress is a key driver of inflammation and fibrogenesis in non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the role of extracellular Nicotinamide phosphoribosyltransferase (eNAMPT) and extracellular nicotinic acid phosphoribosyltransferase (eNAPRT) for the detection of advanced fibrosis. eNAMPT and eNAPRT were tested in 180 consecutive biopsy-proven NAFLD patients and compared with liver stiffness (LS) and the FIB-4 score. eNAMPT was similarly distributed across fibrosis stages, whereas eNAPRT was increased in patients with advanced fibrosis (p = 0.036) and was associated with advanced fibrosis (OR 1.08, p = 0.016). A multiple stepwise logistic regression model containing significant variables for advanced fibrosis (eNAPRT, type 2 diabetes, age, male sex, ALT) had an area under the curve (AUC) of 0.82 (Se 89.6%, Sp 67.3%, PPV 46.7%, NPV 93.8%) when compared to that of LS (0.79; Se 63.5%, Sp 86.2%, PPV 66.0%, NPV 84.8%) and to that of the FIB-4 score (0.73; Se 80.0%, Sp 56.8%, PPV 44.9%, NPV 86.6%). The use of eNAPRT in clinical practice might allow for the better characterization of NAFLD patients at higher risk of disease progression. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction)

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18 pages, 3170 KiB

Open AccessArticle

Aortic Fibrosis in Insulin-Sensitive Mice with Endothelial Cell-Specific Deletion of Ceacam1 Gene

by Raghd Abu Helal, Harrison T. Muturi, Abraham D. Lee, Wei Li, Hilda E. Ghadieh and Sonia M. Najjar

Int. J. Mol. Sci. 2022, 23(8), 4335; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084335 - 14 Apr 2022

Cited by 3 | Viewed by 2196

Abstract

(1) Background: Mice with global Ceacam1 deletion developed plaque-like aortic lesions even on C57BL/6J background in the presence of increased endothelial cell permeability and insulin resistance. Loss of endothelial Ceacam1 gene caused endothelial dysfunction and reduced vascular integrity without affecting systemic insulin sensitivity. Because endothelial cell injury precedes atherosclerosis, we herein investigated whether the loss of endothelial Ceacam1 initiates atheroma formation in the absence of insulin resistance. (2) Methods: Endothelial cell-specific Ceacam1 null mice on C57BL/6J.Ldlr^−/− background (Ldlr^−/−VECadCre+Cc1^fl/fl) were fed an atherogenic diet for 3–5 months before metabolic, histopathological, and en-face analysis of aortae were compared to their control littermates. Sirius Red stain was also performed on liver sections to analyze hepatic fibrosis. (3) Results: These mice displayed insulin sensitivity without significant fat deposition on aortic walls despite hypercholesterolemia. They also displayed increased inflammation and fibrosis. Deleting Ceacam1 in endothelial cells caused hyperactivation of VEGFR2/Shc/NF-κB pathway with resultant transcriptional induction of NF-κB targets. These include IL-6 that activates STAT3 inflammatory pathways, in addition to endothelin-1 and PDGF-B profibrogenic effectors. It also induced the association between SHP2 phosphatase and VEGFR2, downregulating the Akt/eNOS pathway and reducing nitric oxide production, a characteristic feature of endothelial dysfunction. Similarly, hepatic inflammation and fibrosis developed in Ldlr^−/−VECadCre+Cc1^fl/fl mice without an increase in hepatic steatosis. (4) Conclusions: Deleting endothelial cell Ceacam1 caused hepatic and aortic inflammation and fibrosis with increased endothelial dysfunction and oxidative stress in the presence of hypercholesterolemia. However, this did not progress into frank atheroma formation. Because these mice remained insulin sensitive, the study provides an in vivo demonstration that insulin resistance plays a critical role in the pathogenesis of frank atherosclerosis. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction)

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Review

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16 pages, 1677 KiB

Open AccessReview

The Effects of Viruses on Insulin Sensitivity and Blood–Brain Barrier Function

by Jacob Raber, Elizabeth M. Rhea and William A. Banks

Int. J. Mol. Sci. 2023, 24(3), 2377; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032377 - 25 Jan 2023

Viewed by 2506

Abstract

In this review manuscript, we discuss the effects of select common viruses on insulin sensitivity and blood–brain barrier (BBB) function and the potential overlapping and distinct mechanisms involved in these effects. More specifically, we discuss the effects of human immunodeficiency virus (HIV), herpes, hepatitis, influenza, respiratory syncytial virus (RSV), and SARS-CoV-2 viruses on insulin sensitivity and BBB function and the proposed underlying mechanisms. These viruses differ in their ability to be transported across the BBB, disrupt the BBB, and/or alter the function of the BBB. For RSV and SARS-CoV-2, diabetes increases the risk of infection with the virus, in addition to viral infection increasing the risk for development of diabetes. For HIV and hepatitis C and E, enhanced TNF-a levels play a role in the detrimental effects. The winter of 2022–2023 has been labeled as a tridemic as influenza, RSV, and COVID-19 are all of concern during this flu season. There is an ongoing discussion about whether combined viral exposures of influenza, RSV, and COVID-19 have additive, synergistic, or interference effects. Therefore, increased efforts are warranted to determine how combined viral exposures affect insulin sensitivity and BBB function. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction)

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9 pages, 1144 KiB

Open AccessReview

Understanding Carbohydrate Metabolism and Insulin Resistance in Acute Intermittent Porphyria

by Isabel Solares, Daniel Jericó, Karol M. Córdoba, Montserrat Morales-Conejo, Javier Ena, Rafael Enríquez de Salamanca and Antonio Fontanellas

Int. J. Mol. Sci. 2023, 24(1), 51; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24010051 - 20 Dec 2022

Cited by 4 | Viewed by 2410

Abstract

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction)

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14 pages, 2722 KiB

Open AccessReview

On the Need to Distinguish between Insulin-Normal and Insulin-Resistant Patients in Testosterone Therapy

by Lello Zolla

Int. J. Mol. Sci. 2022, 23(21), 12730; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112730 - 22 Oct 2022

Cited by 2 | Viewed by 1455

Abstract

Male hypogonadism is a disorder characterized by low levels of the hormone testosterone and patients may also have insulin sensitivity (IS) or insulin resistance (IR), such that they show different clinical complications and different metabolic pathways. In this review, we compare metabonomic differences observed between these two groups before and after testosterone therapy (TRT) in order to obtain information on whether the two hormones testosterone and insulin are synergistic or antagonistic. IS hypogonadism uses glucose as the main biofuel, while IR activates gluconeogenesis by the degradation of branched-chain amino acids. The Krebs (TCA) cycle is active in IS but connected with glutaminolysis, while in IR the TCA cycle stops at citrate, which is used for lipogenesis. In both cases, the utilization of fatty acids for energy (β-oxidation) is hampered by lower amounts of acetylcarnitine, although it is favored by the absence of insulin in IR. Increased free fatty acids (FFAs) are free in the blood in IS, while they are partially incorporated in triglycerides in IR. Thus, upon TRT, the utilization of glucose is increased more in IS than in IR, revealing that in IR there is a switch from preferential glucose oxidation to lipid oxidation. However, in both cases, a high production of lactate and acetyl-CoA is the final result, with these levels being much higher in IR. Lactate is used in IS in the glucose–lactate cycle between the liver and muscle to produce energy, while in IR lactate and acetyl-CoA are biotransformed into ketone bodies, resulting in ketonuria. In conclusion, the restoration of testosterone values in hypogonadism gives better results in IS than in IR patients: in IS, TRT restores most of the metabolic pathways, while in IR TRT impairs insulin, and when insulin is inactive TRT activates an ancestral molecular mechanism to produce energy. This evidence supports the hypothesis that, over time, hypogonadism switches from IS to IR, and in the latter case most of the insulin-related metabolisms are not reactivated, at least within 60 days of TRT. However, testosterone therapy in both IS and IR might be of benefit given supplementation with metabolites that are not completely restored upon TRT, in order to help restore physiological metabolisms. This review underlines the importance of using a systems biology approach to shed light on the molecular mechanisms of related biochemical pathways involving insulin and testosterone. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction)

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11 pages, 1571 KiB

Open AccessReview

Diet-Induced Metabolic Dysfunction of Hypothalamic Nutrient Sensing in Rodents

by Isabel Arrieta-Cruz, Blanca Samara Torres-Ávila, Hilda Martínez-Coria, Héctor Eduardo López-Valdés and Roger Gutiérrez-Juárez

Int. J. Mol. Sci. 2022, 23(7), 3958; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073958 - 02 Apr 2022

Cited by 2 | Viewed by 1863

Abstract

A sedentary lifestyle and excessive nutrient intake resulting from the consumption of high-fat and calorie-rich diets are environmental factors contributing to the rapid growth of the current pandemic of type 2 diabetes mellitus (DM2). Fasting hyperglycemia, an established hallmark of DM2, is caused by excessive production of glucose by the liver, resulting in the inability of insulin to suppress endogenous glucose production. To prevent inappropriate elevations of circulating glucose resulting from changes in nutrient availability, mammals rely on complex mechanisms for continuously detecting these changes and to respond to them with metabolic adaptations designed to modulate glucose output. The mediobasal hypothalamus (MBH) is the key center where nutritional cues are detected and appropriate modulatory responses are integrated. However, certain environmental factors may have a negative impact on these adaptive responses. For example, consumption of a diet enriched in saturated fat in rodents resulted in the development of a metabolic defect that attenuated these nutrient sensing mechanisms, rendering the animals prone to developing hyperglycemia. Thus, high-fat feeding leads to a state of “metabolic disability” in which animals’ glucoregulatory responses fail. We postulate that the chronic faltering of the hypothalamic glucoregulatory mechanisms contributes to the development of metabolic disease. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction)

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