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Molecular Advances on Insulin Resistance and Metabolic Dysfunction, 2nd Edition

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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 (20 May 2025) | Viewed by 9690

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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

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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

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Published Papers (5 papers)

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Research

11 pages, 577 KiB

Open AccessArticle

Circulating N-Acetylaspartate Levels Associate with Measures of Peripheral and Tissue-Specific Insulin Sensitivity

by Eleni Rebelos, Miikka-Juhani Honka, Aino Latva-Rasku, Johan Rajander, Paulina Salminen, Ioanna A. Anastasiou, Dimitris Kounatidis, Nikolaos Tentolouris, Beatrice Campi, Angela Dardano, Giuseppe Daniele, Alessandro Saba, Ele Ferrannini and Pirjo Nuutila

Int. J. Mol. Sci. 2025, 26(11), 5107; https://doi.org/10.3390/ijms26115107 - 26 May 2025

Abstract

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain. Quantifiable amounts of NAA are also present in the blood, but its role in the peripheral tissues is largely unknown. First, we determined the acute effects of insulin administration on NAA concentrations; second, we assessed whether circulating NAA levels associate with markers of central and peripheral insulin sensitivity. A total of 24 persons living with obesity and 19 healthy, lean controls, without neurological disorders, underwent a euglycemic hyperinsulinemic clamp combined with fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) imaging of the brain, abdomen, and femoral area. Plasma concentrations of NAA were measured at baseline and ~2 h into the clamp using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS-MS). Glucose uptake (GU) rates were analysed using a fractional uptake rate. Serum acetate levels were also assessed using nuclear magnetic resonance (NMR) metabolomics. From baseline to steady-state, insulin levels increased from a mean level of 66 to 447 pmol/L (p < 0.0001). Over this period, circulating NAA concentrations decreased by 5% (p = 0.01), similarly in both groups. The change in NAA was inversely related with the change in plasma acetate (r = −0.36, p = 0.048). Circulating NAA was associated with waist–hip ratio (rho = −0.54, p = 0.0002), steady-state free fatty acids (rho = −0.44, p = 0.003), and directly with HDL cholesterol (rho = 0.54, p = 0.0002), adiponectin (rho = 0.48, p = 0.003), and whole-body insulin sensitivity (rho = 0.34, p = 0.03). Circulating NAA was directly related with skeletal muscle (rho = 0.42, p = 0.01) and visceral adipose tissue GU (rho = 0.41, p = 0.02). Insulin administration leads to a small decrease in circulating NAA levels, and NAA associates consistently with markers of insulin sensitivity. While plasma NAA may be relevant to aspects of whole-body homeostasis, mechanistic insights are needed. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction, 2nd Edition)

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20 pages, 2630 KiB

Open AccessArticle

A Comparison of the Effects of Milk, Yogurt, and Cheese on Insulin Sensitivity, Hepatic Steatosis, and Gut Microbiota in Diet-Induced Obese Male Mice

by Emad Yuzbashian, Dineli N. Fernando, René L. Jacobs, Till-Robin Lesker, Till Strowig, Siegfried Ussar and Catherine B. Chan

Int. J. Mol. Sci. 2025, 26(11), 5026; https://doi.org/10.3390/ijms26115026 - 23 May 2025

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Abstract

The effects of low-fat dairy products on insulin resistance (IR), hepatic steatosis, and gut microbiota composition in high-fat diet (HFD)-fed obese mice were examined. C57BL/6 male mice (n = 16/group) were fed a high-fat diet (HFD, 45% fat) or HFD supplemented with either fat-free milk (MILK), fat-free yogurt (YOG), or reduced-fat (19% milk fat) cheddar cheese (CHE) at 10% of the total energy intake for 8 weeks. Body weight, fat mass, liver lipids, and metabolic enzymes were evaluated. Compared with HFD, MILK reduced homeostatic assessment of insulin resistance along with increased hepatic insulin signaling and decreased hepatic gluconeogenic enzymes. YOG and MILK decreased hepatic triacylglycerol content and lipid droplet size, while CHE had no effect. In the liver, MILK and YOG downregulated de novo lipogenesis enzymes. In MILK, fat oxidation capacity was elevated. Compared with HFD, liver lipidomic analysis in MILK and YOG revealed unique profiles of decreased proinflammatory lipid species, including ceramides. Dairy feeding elicited an increase in beneficial bacteria, such as Streptococcus in YOG and Anaero-tignum in MILK, as shown by 16S rRNA sequencing of gut microbiota. In conclusion, the ability of milk and yogurt to reduce hepatic steatosis in HFD mice may be explained, at least in part, by the regulation of the gut microbiome and liver lipidome. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction, 2nd Edition)

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13 pages, 3091 KiB

Open AccessArticle

Akt Signaling and Nitric Oxide Synthase as Possible Mediators of the Protective Effect of N-acetyl-L-cysteine in Prediabetes Induced by Sucrose

by María Cecilia Castro, Hernán Gonzalo Villagarcía, Luciana Di Sarli Gutiérrez, Luisa González Arbeláez, Guillermo Schinella, María Laura Massa and Flavio Francini

Int. J. Mol. Sci. 2024, 25(2), 1215; https://doi.org/10.3390/ijms25021215 - 19 Jan 2024

Cited by 1 | Viewed by 1596

Abstract

The aim of this work was to evaluate possible mechanisms involved in the protective effect of N-acetyl-L-cysteine (NAC) on hepatic endocrine-metabolic, oxidative stress, and inflammatory changes in prediabetic rats. For that, normal male Wistar rats (60 days old) were fed for 21 days with 10% sucrose in their drinking water and 5 days of NAC administration (50 mg/kg, i.p.) and thereafter, we determined: serum glucose, insulin, transaminases, uric acid, and triglyceride levels; hepatic fructokinase and glucokinase activities, glycogen content, lipogenic gene expression; enzymatic and non-enzymatic oxidative stress, insulin signaling pathway, and inflammatory markers. Results showed that alterations evinced in sucrose-fed rats (hypertriglyceridemia, hyperinsulinemia, and high liver fructokinase activity together with increased liver lipogenic gene expression and oxidative stress and inflammatory markers) were prevented by NAC administration. P-endothelial nitric oxide synthase (P-eNOS)/eNOS and pAKT/AKT ratios, decreased by sucrose ingestion, were restored after NAC treatment. In conclusion, the results suggest that NAC administration improves glucose homeostasis, oxidative stress, and inflammation in prediabetic rats probably mediated by modulation of the AKT/NOS pathway. Administration of NAC may be an effective complementary strategy to alleviate or prevent oxidative stress and inflammatory responses observed in type 2 diabetes at early stages of its development (prediabetes). Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction, 2nd Edition)

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13 pages, 1308 KiB

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Insulin Clearance at the Pubertal Transition in Youth with Obesity and Steatosis Liver Disease

by Roberto Franceschi, Danilo Fintini, Lucilla Ravà, Michela Mariani, Alessia Aureli, Elena Inzaghi, Stefania Pedicelli, Annalisa Deodati, Carla Bizzarri, Marco Cappa, Stefano Cianfarani and Melania Manco

Int. J. Mol. Sci. 2023, 24(19), 14963; https://doi.org/10.3390/ijms241914963 - 6 Oct 2023

Cited by 1 | Viewed by 1204

Abstract

No data are available on insulin clearance (Cl_I) trends during the pubertal transition. The aim of this study was to investigate in 973 youths with obesity whether Cl_I in fasting and post-oral glucose challenge (OGTT) conditions varies at the pubertal transition in relation to the severity of obesity and the presence of steatosis liver disease (SLD). The severity of obesity was graded according to the Centers for Disease Control. SLD was graded as absent, mild and severe based on alanine amino transferase levels. Cl_I was defined as the molar ratio of fasting C-peptide to insulin and of the areas under the insulin to glucose curves during an OGTT. In total, 35% of participants were prepubertal, 72.6% had obesity class II, and 52.6% had mild SLD. Fasting Cl_I (nmol/pmol × 10⁻²) was significantly lower in pubertal [0.11 (0.08–0.14)] than in prepubertal individuals [0.12 (0.09–0.16)] and higher in class III [0.15 (0.11–0.16)] than in class I obesity [0.11 (0.09–0.14)]. OGTT Cl_I was higher in boys [0.08 (0.06–0.10)] than in girls [0.07 (0.06–0.09)]; in prepubertal [0.08 (0.06–0.11)] than in pubertal individuals [0.07 (0.05–0.09)]; in class III [0.14 (0.08–0.17)] than in class I obesity [0.07 (0.05–0.10)]; and in severe SLD [0.09 (0.04–0.14)] than in no steatosis [0.06 (0.04–0.17)]. It was lower in participants with prediabetes [0.06 (0.04–0.07)]. OGTT Cl_I was lower in youths with obesity at puberty along with insulin sensitivity and greater secretion. The findings suggest that the initial increase in Cl_I in youth with severe obesity and SLD is likely to compensate for hyperinsulinemia and its subsequent decrease at the onset of prediabetes and other metabolic abnormalities. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction, 2nd Edition)

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13 pages, 2113 KiB

Open AccessArticle

Fatty Liver Index (FLI) Identifies Not Only Individuals with Liver Steatosis but Also at High Cardiometabolic Risk

by Fabrizia Carli, Silvia Sabatini, Melania Gaggini, Anna Maria Sironi, Giorgio Bedogni and Amalia Gastaldelli

Int. J. Mol. Sci. 2023, 24(19), 14651; https://doi.org/10.3390/ijms241914651 - 27 Sep 2023

Cited by 13 | Viewed by 5959

Abstract

A fatty liver index (FLI) greater than sixty (FLI ≥ 60) is an established score for metabolic dysfunction-associated steatotic liver disease (MASLD), which carries a high risk for diabetes and cardiovascular disease, while a FLI ≤ 20 rules out the presence of steatosis. Thus, we investigated whether FLI was associated with cardiometabolic risk factors, i.e., visceral (VAT), subcutaneous (SC), epicardial (EPI), extrapericardial (PERI), and total cardiac (CARD-AT) adipose tissue, hepatic fat ((by magnetic resonance imaging, MRI, and spectroscopy, MRS), and insulin resistance (IR, HOMA-IR and OGIS-index), and components of metabolic syndrome. All individuals with FLI ≥ 60 had MASLD, while none with FLI ≤ 20 had steatosis (by MRS). Subjects with FLI ≥ 60 had a higher BMI and visceral and cardiac fat (VAT > 1.7 kg, CARD-AT > 0.2 kg). FLI was positively associated with increased cardiac and visceral fat and components of metabolic syndrome. FLI, VAT, and CARD-AT were all associated with IR, increased blood pressure, cholesterol, and reduced HDL. For FLI ≥ 60, the cut-off values for fat depots and laboratory measures were estimated. In conclusion, FLI ≥ 60 identified not only subjects with steatosis but also those with IR, abdominal and cardiac fat accumulation, increased blood pressure, and hyperlipidemia, i.e., those at higher risk of cardiometabolic diseases. Targeted reduction of FLI components would help reduce cardiometabolic risk. Full article

(This article belongs to the Special Issue Molecular Advances on Insulin Resistance and Metabolic Dysfunction, 2nd Edition)

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