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Insulin, Glucose Metabolism, and Obesity
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Insulin, Glucose Metabolism, and Obesity

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 November 2023) | Viewed by 23484

Special Issue Editor

Dr. Giovanna Muscogiuri

E-Mail Website
Guest Editor
Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
Interests: obesity; metabolic syndrome; diabetes; insulin resistance; nutrients; nutrition; metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Obesity is one of the leading problems of modern civilization, with a key role in glucose metabolism and the development of insulin resistance, leading to other metabolic disorders along with the consequent development of type 2 diabetes. In both conditions (obesity and insulin resistance), the key role is played by gene–environment interaction; accordingly, epigenetic changes in chromatin structures and gene function may be responsible for genetic susceptibility. Epigenetic markers are believed to explain the link between gene–lifestyle interactions and the pathogenesis of numerous metabolic disorders and have even been proposed as specific biomarkers of metabolic disorders and possible therapeutic targets. Indeed, abundant data implicate obesity in DNA hypermethylation at both global and site-specific levels, including genes regulating insulin sensitivity, such as ADIPOQ, LPL, or PPARγ. However, the exact mechanism by means of which obesity influences glucose metabolism via DNA methylation remains unclear.

This Special Issue is calling for both original articles and reviews providing to the readers of IJMS a comprehensive elucidation about epigenetic interaction between obesity and glucose metabolism, which is necessary for developing novel research approaches as well as therapeutic strategies.

Dr. Giovanna Muscogiuri
Guest Editor

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Keywords

  • obesity
  • glucose metabolism
  • insulin
  • insulin resistance
  • insulin sensitivity
  • epigenetic
  • gene
  • diet
  • nutrients

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Published Papers (5 papers)

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Research

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14 pages, 3484 KiB  
Article
Dictyostelium Differentiation-Inducing Factor 1 Promotes Glucose Uptake via Direct Inhibition of Mitochondrial Malate Dehydrogenase in Mouse 3T3-L1 Cells
by Yuzuru Kubohara, Yuko Fukunaga, Ayako Shigenaga and Haruhisa Kikuchi
Int. J. Mol. Sci. 2024, 25(3), 1889; https://doi.org/10.3390/ijms25031889 - 4 Feb 2024
Cited by 2 | Viewed by 1394
Abstract
Differentiation-inducing factor 1 (DIF-1), found in Dictyostelium discoideum, has antiproliferative and glucose-uptake-promoting activities in mammalian cells. DIF-1 is a potential lead for the development of antitumor and/or antiobesity/antidiabetes drugs, but the mechanisms underlying its actions have not been fully elucidated. In this [...] Read more.
Differentiation-inducing factor 1 (DIF-1), found in Dictyostelium discoideum, has antiproliferative and glucose-uptake-promoting activities in mammalian cells. DIF-1 is a potential lead for the development of antitumor and/or antiobesity/antidiabetes drugs, but the mechanisms underlying its actions have not been fully elucidated. In this study, we searched for target molecules of DIF-1 that mediate the actions of DIF-1 in mammalian cells by identifying DIF-1-binding proteins in human cervical cancer HeLa cells and mouse 3T3-L1 fibroblast cells using affinity chromatography and liquid chromatography–tandem mass spectrometry and found mitochondrial malate dehydrogenase (MDH2) to be a DIF-1-binding protein in both cell lines. Since DIF-1 has been shown to directly inhibit MDH2 activity, we compared the effects of DIF-1 and the MDH2 inhibitor LW6 on the growth of HeLa and 3T3-L1 cells and on glucose uptake in confluent 3T3-L1 cells in vitro. In both HeLa and 3T3-L1 cells, DIF-1 at 10–40 μM dose-dependently suppressed growth, whereas LW6 at 20 μM, but not at 2–10 μM, significantly suppressed growth in these cells. In confluent 3T3-L1 cells, DIF-1 at 10–40 μM significantly promoted glucose uptake, with the strongest effect at 20 μM DIF-1, whereas LW6 at 2–20 μM significantly promoted glucose uptake, with the strongest effect at 10 μM LW6. Western blot analyses showed that LW6 (10 μM) and DIF-1 (20 μM) phosphorylated and, thus, activated AMP kinase in 3T3-L1 cells. Our results suggest that MDH2 inhibition can suppress cell growth and promote glucose uptake in the cells, but appears to promote glucose uptake more strongly than it suppresses cell growth. Thus, DIF-1 may promote glucose uptake, at least in part, via direct inhibition of MDH2 and a subsequent activation of AMP kinase in 3T3-L1 cells. Full article
(This article belongs to the Special Issue Insulin, Glucose Metabolism, and Obesity)
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16 pages, 2526 KiB  
Article
Genetic Background of Metabolically Healthy and Unhealthy Obesity Phenotypes in Hungarian Adult Sample Population
by Peter Piko, Erand Llanaj, Karoly Nagy and Roza Adany
Int. J. Mol. Sci. 2023, 24(6), 5209; https://doi.org/10.3390/ijms24065209 - 8 Mar 2023
Cited by 2 | Viewed by 2468
Abstract
A specific phenotypic variant of obesity is metabolically healthy (MHO), which is characterized by normal blood pressure and lipid and glucose profiles, in contrast to the metabolically unhealthy variant (MUO). The genetic causes underlying the differences between these phenotypes are not yet clear. [...] Read more.
A specific phenotypic variant of obesity is metabolically healthy (MHO), which is characterized by normal blood pressure and lipid and glucose profiles, in contrast to the metabolically unhealthy variant (MUO). The genetic causes underlying the differences between these phenotypes are not yet clear. This study aims to explore the differences between MHO and MUO and the contribution of genetic factors (single nucleotide polymorphisms—SNPs) in 398 Hungarian adults (81 MHO and 317 MUO). For this investigation, an optimized genetic risk score (oGRS) was calculated using 67 SNPs (related to obesity and to lipid and glucose metabolism). Nineteen SNPs were identified whose combined effect was strongly associated with an increased risk of MUO (OR = 1.77, p < 0.001). Four of them (rs10838687 in MADD, rs693 in APOB, rs1111875 in HHEX, and rs2000813 in LIPG) significantly increased the risk of MUO (OR = 1.76, p < 0.001). Genetic risk groups based on oGRS were significantly associated with the risk of developing MUO at a younger age. We have identified a cluster of SNPs that contribute to the development of the metabolically unhealthy phenotype among Hungarian adults suffering from obesity. Our findings emphasize the significance of considering the combined effect(s) of multiple genes and SNPs in ascertaining cardiometabolic risk in obesity in future genetic screening programs. Full article
(This article belongs to the Special Issue Insulin, Glucose Metabolism, and Obesity)
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Graphical abstract

17 pages, 2493 KiB  
Article
CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells
by Cho-Cho Aye, Dean E. Hammond, Sergio Rodriguez-Cuenca, Mary K. Doherty, Phillip D. Whitfield, Marie M. Phelan, Chenjing Yang, Rafael Perez-Perez, Xiaoxin Li, Angels Diaz-Ramos, Gopal Peddinti, Matej Oresic, Antonio Vidal-Puig, Antonio Zorzano, Cristina Ugalde and Silvia Mora
Int. J. Mol. Sci. 2023, 24(4), 3399; https://doi.org/10.3390/ijms24043399 - 8 Feb 2023
Cited by 2 | Viewed by 2409
Abstract
CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism [...] Read more.
CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle. Full article
(This article belongs to the Special Issue Insulin, Glucose Metabolism, and Obesity)
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17 pages, 5560 KiB  
Article
Aldehyde Dehydrogenase 2 Activator Augments the Beneficial Effects of Empagliflozin in Mice with Diabetes-Associated HFpEF
by Guodong Pan, Bipradas Roy, Shailendra Giri, David E. Lanfear, Rajarajan A. Thandavarayan, Ashrith Guha, Pablo A. Ortiz and Suresh Selvaraj Palaniyandi
Int. J. Mol. Sci. 2022, 23(18), 10439; https://doi.org/10.3390/ijms231810439 - 9 Sep 2022
Cited by 7 | Viewed by 2641
Abstract
To ameliorate diabetes mellitus-associated heart failure with preserved ejection fraction (HFpEF), we plan to lower diabetes-mediated oxidative stress-induced 4-hydroxy-2-nonenal (4HNE) accumulation by pharmacological agents that either decrease 4HNE generation or increase its detoxification.A cellular reactive carbonyl species (RCS), 4HNE, was significantly increased in [...] Read more.
To ameliorate diabetes mellitus-associated heart failure with preserved ejection fraction (HFpEF), we plan to lower diabetes-mediated oxidative stress-induced 4-hydroxy-2-nonenal (4HNE) accumulation by pharmacological agents that either decrease 4HNE generation or increase its detoxification.A cellular reactive carbonyl species (RCS), 4HNE, was significantly increased in diabetic hearts due to a diabetes-induced decrease in 4HNE detoxification by aldehyde dehydrogenase (ALDH) 2, a cardiac mitochondrial enzyme that metabolizes 4HNE. Therefore, hyperglycemia-induced 4HNE is critical for diabetes-mediated cardiotoxicity and we hypothesize that lowering 4HNE ameliorates diabetes-associated HFpEF. We fed a high-fat diet to ALDH2*2 mice, which have intrinsically low ALDH2 activity, to induce type-2 diabetes. After 4 months of diabetes, the mice exhibited features of HFpEF along with increased 4HNE adducts, and we treated them with vehicle, empagliflozin (EMP) (3 mg/kg/d) to reduce 4HNE and Alda-1 (10 mg/kg/d), and ALDH2 activator to enhance ALDH2 activity as well as a combination of EMP + Alda-1 (E + A), via subcutaneous osmotic pumps. After 2 months of treatments, cardiac function was assessed by conscious echocardiography before and after exercise stress. EMP + Alda-1 improved exercise tolerance, diastolic and systolic function, 4HNE detoxification and cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathways in ALDH2*2 mice with diabetes-associated HFpEF. This combination was even more effective than EMP alone. Our data indicate that ALDH2 activation along with the treatment of hypoglycemic agents may be a salient strategy to alleviate diabetes-associated HFpEF. Full article
(This article belongs to the Special Issue Insulin, Glucose Metabolism, and Obesity)
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Review

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37 pages, 4113 KiB  
Review
Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials
by Mihaela-Simona Popoviciu, Lorena Păduraru, Galal Yahya, Kamel Metwally and Simona Cavalu
Int. J. Mol. Sci. 2023, 24(13), 10449; https://doi.org/10.3390/ijms241310449 - 21 Jun 2023
Cited by 51 | Viewed by 13842
Abstract
Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and [...] Read more.
Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio–metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies. Full article
(This article belongs to the Special Issue Insulin, Glucose Metabolism, and Obesity)
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