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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 (31 August 2024) | Viewed by 9548

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Dr. Alessandra Puddu

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Guest Editor

Department of Internal Medicine and Medical Specialties, University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy
Interests: diabetes; retinopathy; VEGF-A; IGF-1; advanced glycation end-products
Special Issues, Collections and Topics in MDPI journals

Dr. Davide Maggi

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Guest Editor

Department of Internal Medicine and Medical Specialties, University of Genova, 16132 Genova, Italy
Interests: the role of caveoles in the insulin and IGF1 signal; new technologies in the treatment of diabetes mellitus; role of bariatric surgery in the regulation of metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetes is a metabolic disease characterized by hyperglycemia. This chronic disorder raises the risk of microvascular as well as neurological disorders and contributes to the pathophysiology of diabetes complications. Type II diabetes accounts for 85–90% of all diabetic patients. There are a range of reasons as to why diabetes can occur: insulin resistance and β cell dysfunction are the main causative abnormalities; however, several mutations in the genes important for glucose homeostasis and β cell development have been related to the progress of hyperglycemia. In addition, environmental factors may influence the incidence of hyperglycemia. Although several studies have aimed to elucidate the molecular mechanisms underlying the development of diabetes and its complications, their precise pathophysiology is not completely understood. This Special Issue aims to collect the latest research on different biological processes and molecular mechanisms that cause diabetes, with a special emphasis on 1. insulin deficiency and insulin resistance, 2. impaired signaling pathways involved in glucose metabolism, 3. glucose transport and defects in transport activity, 4. post-translational modifications of the proteins involved in metabolism, 5. genetic defects associated with diabetes, 6. oxidative stress, and 7. pharmacological agents regulating glucose metabolism.

Dr. Alessandra Puddu
Dr. Davide Maggi
Guest Editors

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Keywords

diabetes
insulin
glucose metabolism
oxidative stress

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Published Papers (10 papers)

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Research

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16 pages, 4165 KiB

Open AccessArticle

A Fresh Look at Islet Isolation from Rabbit Pancreases

by Ekaterina Vasilchikova, Polina Ermakova, Alexandra Bogomolova, Alena Kashirina, Liya Lugovaya, Julia Tselousova, Nasip Naraliev, Denis Kuchin, Elena Zagaynova, Vladimir Zagainov and Alexandra Kashina

Int. J. Mol. Sci. 2024, 25(19), 10669; https://doi.org/10.3390/ijms251910669 - 3 Oct 2024

Abstract

Islet transplantation represents a promising therapeutic approach for diabetes management, yet the isolation and evaluation of pancreatic islets remain challenging. This study focuses on the isolation of islets from rabbit pancreases, followed by a comprehensive assessment of their viability and functionality. We developed a novel method for isolating islet cells from the pancreas of adult rabbits. We successfully isolated viable islets, which were subsequently evaluated through a combination of viability assays, an insulin enzyme-linked immunosorbent assay (ELISA), and fluorescence lifetime imaging microscopy (FLIM). The viability assays indicated a high percentage of intact islets post-isolation, while the insulin ELISA demonstrated robust insulin secretion in response to glucose stimulation. FLIM provided insights into the metabolic state of the islets, revealing distinct fluorescence lifetime signatures correlating with functional viability. Our findings underscore the potential of rabbit islets as a model for studying islet biology and diabetes therapy, highlighting the efficacy of combining traditional assays with advanced imaging techniques for comprehensive functional assessments. This research contributes to the optimization of islet isolation protocols and enhances our understanding of islet functional activity dynamics in preclinical settings. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

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11 pages, 871 KiB

Open AccessArticle

Phenome-Wide Association Study of Latent Autoimmune Diabetes from a Southern Mexican Population Implicates rs7305229 with Plasmatic Anti-Glutamic Acid Decarboxylase Autoantibody (GADA) Levels

by Germán Alberto Nolasco-Rosales, José Jaime Martínez-Magaña, Isela Esther Juárez-Rojop, Ester Rodríguez-Sánchez, David Ruiz-Ramos, Jorge Ameth Villatoro-Velázquez, Marycarmen Bustos-Gamiño, Maria Elena Medina-Mora, Carlos Alfonso Tovilla-Zárate, Juan Daniel Cruz-Castillo, Humberto Nicolini and Alma Delia Genis-Mendoza

Int. J. Mol. Sci. 2024, 25(18), 10154; https://doi.org/10.3390/ijms251810154 - 21 Sep 2024

Viewed by 446

Abstract

Latent autoimmune diabetes in adults (LADA) is characterized by the presence of glutamate decarboxylase autoantibodies (GADA). LADA has intermediate features between type 1 diabetes and type 2 diabetes. In addition, genetic risk factors for both types of diabetes are present in LADA. Nonetheless, evidence about the genetics of LADA in non-European populations is scarce. This study aims to perform a genome-wide association study with a phenome-wide association study of LADA in a southeastern Mexican population. We included 59 patients diagnosed with LADA from a previous study and 3121 individuals without diabetes from the MxGDAR/ENCODAT database. We utilized the GENESIS package in R to perform the genome-wide association study (GWAS) of LADA and PLINK for the phenome-wide association study (PheWAS) of LADA features. Nine polymorphisms reach the nominal association level (1 × 10⁻⁵) in the GWAS. The PheWAS showed that rs7305229 is genome-wide and associated with serum GADA levels in our sample (p = 1.84 × 10⁻⁸). rs7305229 is located downstream of the FAIM2 gene; previous reports associate FAIM2 variants with childhood obesity, body mass index, body adiposity measures, lymphocyte CD8+ activity, and anti-thyroid peroxidase antibodies. Our findings reveal that rs7305229 affects the GADA levels in patients with LADA from southeastern Mexico. More studies are needed to determine if this risk genotype exists in other populations with LADA. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

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14 pages, 6818 KiB

Open AccessCommunication

UTRs and Ago-2/miR-335 Complex Restricts Amylin Translation in Insulinoma and Human Pancreatic β-Cells

by Zhanar Kudaibergenova, Satyabrata Pany, Elizabeth Placheril and Aleksandar M. Jeremic

Int. J. Mol. Sci. 2024, 25(17), 9614; https://doi.org/10.3390/ijms25179614 - 5 Sep 2024

Viewed by 426

Abstract

Amylin promoter and transcriptional factors are well-established, inducible factors in the production of the main amyloidogenic pancreatic hormone, human islet amyloid peptide (hIAPP) or amylin. However, posttranscriptional mechanisms driving hIAPP expression in pancreas remain enigmatic, and hence were explored here. The translational assay revealed that both 5′ and 3′ untranslated regions (UTRs) of hIAPP restricted expression of the luciferase constructs only in constructs driven by the hIAPP promoter. Bioinformatics analysis revealed several putative seed sequences for a dozen micro RNAs (miRNAs) in hIAPP’s 3′ UTR. miR-182, miR-335, and miR-495 were the most downregulated miRNAs in stressed human islets exposed to endoplasmic reticulum (ER) or metabolic stressors, thapsigargin (TG) or high glucose (HG). Correspondingly, miR-335 mimics alone or in combination with miR-495 and miR-182 mimics significantly and potently (>3-fold) reduced hIAPP protein expression in HG-treated cultured human islets. siRNA-mediated silencing of Ago2 but not Ago1 significantly stimulated hIAPP expression and secretion from transfected, HG-treated human islets. Conversely, ectopic expression of Ago2 in hIAPP-expressing RIN-m5F cell line driven by CMV promoter reduced hIAPP intracellular protein levels. Collectively, the results point to a novel and synergistic role for hIAPP promoter, 5/3′ UTRs and Ago-2/miR-335 complex in post-transcriptional regulation of hIAPP gene expression in normal and metabolically active β-cells. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

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15 pages, 1772 KiB

Open AccessArticle

Advancing Diabetes Research: A Novel Islet Isolation Method from Living Donors

by Eleonora Di Piazza, Laura Todi, Gianfranco Di Giuseppe, Laura Soldovieri, Gea Ciccarelli, Michela Brunetti, Giuseppe Quero, Sergio Alfieri, Vincenzo Tondolo, Alfredo Pontecorvi, Antonio Gasbarrini, Enrico Celestino Nista, Andrea Giaccari, Giovambattista Pani and Teresa Mezza

Int. J. Mol. Sci. 2024, 25(11), 5936; https://doi.org/10.3390/ijms25115936 - 29 May 2024

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Abstract

Pancreatic islet isolation is critical for type 2 diabetes research. Although -omics approaches have shed light on islet molecular profiles, inconsistencies persist; on the other hand, functional studies are essential, but they require reliable and standardized isolation methods. Here, we propose a simplified protocol applied to very small-sized samples collected from partially pancreatectomized living donors. Islet isolation was performed by digesting tissue specimens collected during surgery within a collagenase P solution, followed by a Lympholyte density gradient separation; finally, functional assays and staining with dithizone were carried out. Isolated pancreatic islets exhibited functional responses to glucose and arginine stimulation mirroring donors’ metabolic profiles, with insulin secretion significantly decreasing in diabetic islets compared to non-diabetic islets; conversely, proinsulin secretion showed an increasing trend from non-diabetic to diabetic islets. This novel islet isolation method from living patients undergoing partial pancreatectomy offers a valuable opportunity for targeted study of islet physiology, with the primary advantage of being time-effective and successfully preserving islet viability and functionality. It enables the generation of islet preparations that closely reflect donors’ clinical profiles, simplifying the isolation process and eliminating the need for a Ricordi chamber. Thus, this method holds promises for advancing our understanding of diabetes and for new personalized pharmacological approaches. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

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15 pages, 2147 KiB

Open AccessArticle

Low-Density Neutrophils Contribute to Subclinical Inflammation in Patients with Type 2 Diabetes

by Benjamin L. Dumont, Paul-Eduard Neagoe, Elcha Charles, Louis Villeneuve, Jean-Claude Tardif, Agnès Räkel, Michel White and Martin G. Sirois

Int. J. Mol. Sci. 2024, 25(3), 1674; https://doi.org/10.3390/ijms25031674 - 30 Jan 2024

Cited by 1 | Viewed by 1500

Abstract

Type 2 diabetes (T2D) is characterized by low-grade inflammation. Low-density neutrophils (LDNs) represent normally less than 2% of total neutrophils but increase in multiple pathologies, releasing inflammatory cytokines and neutrophil extracellular traps (NETs). We assessed the count and role of high-density neutrophils (HDNs), LDNs, and NET-related activities in patients with T2D. HDNs and LDNs were purified by fluorescence-activated cell sorting (FACS) and counted by flow cytometry. Circulating inflammatory and NETs biomarkers were measured by ELISA (Enzyme Linked Immunosorbent Assay). NET formation was quantified by confocal microscopy. Neutrophil adhesion onto a human extracellular matrix (hECM) was assessed by optical microscopy. We recruited 22 healthy volunteers (HVs) and 18 patients with T2D. LDN counts in patients with diabetes were significantly higher (160%), along with circulating NETs biomarkers (citrullinated H3 histone (H3Cit), myeloperoxidase (MPO), and MPO-DNA (137%, 175%, and 69%, respectively) versus HV. Circulating interleukins (IL-6 and IL-8) and C-Reactive Protein (CRP) were significantly increased by 117%, 171%, and 79%, respectively, in patients compared to HVs. Isolated LDNs from patients expressed more H3Cit, MPO, and NETs, formed more NETs, and adhered more on hECM compared to LDNs from HVs. Patients with T2D present higher levels of circulating LDN- and NET-related biomarkers and associated pro-inflammatory activities. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

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Review

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17 pages, 326 KiB

Open AccessReview

MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants

by Iderina Hasballa and Davide Maggi

Int. J. Mol. Sci. 2024, 25(16), 8790; https://doi.org/10.3390/ijms25168790 - 13 Aug 2024

Viewed by 656

Abstract

Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype–phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype–phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

16 pages, 1340 KiB

Open AccessReview

Mechanisms and Physiological Roles of Polymorphisms in Gestational Diabetes Mellitus

by Sarocha Suthon and Watip Tangjittipokin

Int. J. Mol. Sci. 2024, 25(4), 2039; https://doi.org/10.3390/ijms25042039 - 7 Feb 2024

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Abstract

Gestational diabetes mellitus (GDM) is a significant pregnancy complication linked to perinatal complications and an elevated risk of future metabolic disorders for both mothers and their children. GDM is diagnosed when women without prior diabetes develop chronic hyperglycemia due to β-cell dysfunction during gestation. Global research focuses on the association between GDM and single nucleotide polymorphisms (SNPs) and aims to enhance our understanding of GDM’s pathogenesis, predict its risk, and guide patient management. This review offers a summary of various SNPs linked to a heightened risk of GDM and explores their biological mechanisms within the tissues implicated in the development of the condition. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

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14 pages, 1649 KiB

Open AccessReview

Molecular Mechanisms Linking Diabetes with Increased Risk of Thrombosis

by Lucy Batten, Thozhukat Sathyapalan and Timothy M. Palmer

Int. J. Mol. Sci. 2023, 24(24), 17465; https://doi.org/10.3390/ijms242417465 - 14 Dec 2023

Viewed by 2007

Abstract

This review will provide an overview of what is currently known about mechanisms linking poor glycaemic control with increased thrombotic risk. The leading causes of death in people with diabetes are strokes and cardiovascular disease. Significant morbidity is associated with an increased risk of thrombosis, resulting in myocardial infarction, ischaemic stroke, and peripheral vascular disease, along with the sequelae of these events, including loss of functional ability, heart failure, and amputations. While the increased platelet activity, pro-coagulability, and endothelial dysfunction directly impact this risk, the molecular mechanisms linking poor glycaemic control with increased thrombotic risk remain unclear. This review highlights the complex mechanisms underlying thrombosis prevalence in individuals with diabetes and hyperglycaemia. Post-translational modifications, such as O-GlcNAcylation, play a crucial role in controlling protein function in diabetes. However, the role of O-GlcNAcylation remains poorly understood due to its intricate regulation and the potential involvement of multiple variables. Further research is needed to determine the precise impact of O-GlcNAcylation on specific disease processes. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

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12 pages, 2364 KiB

Open AccessCase Report

A Korean Family Presenting with Renal Cysts and Maturity-Onset Diabetes of the Young Caused by a Novel In-Frame Deletion of HNF1B

by Ji Yoon Han, Jin Gwack, Tae Yun Kim and Joonhong Park

Int. J. Mol. Sci. 2024, 25(18), 9823; https://doi.org/10.3390/ijms25189823 - 11 Sep 2024

Viewed by 356

Abstract

Maturity-onset diabetes of the young (MODY; OMIM # 606391) comprises a cluster of inherited disorders within non-autoimmune diabetes mellitus (DM), typically emerging during adolescence or young adulthood. We report a novel in-frame deletion of HNF1B in a family with renal cysts and MODY, furthering our understanding of HNF1B-related phenotypes. We conducted sequential genetic testing to investigate the glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas observed in the proband. A comprehensive clinical exome sequencing approach using a Celemics G-Mendeliome Clinical Exome Sequencing Panel was employed. Considering the clinical manifestations observed in the proband, gene panel sequencing identified a heterozygous HNF1B variant, c.36_38delCCT/p.(Leu13del) (reference transcript ID: NM_000458.4), as the most likely cause of MODY in the proband. The patient’s clinical presentation was consistent with MODY caused by the HNF1B variant, showing signs of glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas. Sanger sequencing confirmed the same HNF1B variant and established the paternally inherited autosomal dominant status of the heterozygous variant in the patient, as well as in his father and sister. The presence of early-onset diabetes, renal cysts, a family history of the condition, and nephropathy appearing before or after the diagnosis of diabetes mellitus (DM) suggests a diagnosis of HNF1B-MODY5. Early diagnosis is crucial for preventing complications of DM, enabling family screening, providing pre-conceptional genetic counseling, and monitoring kidney function decline. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

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10 pages, 948 KiB

Open AccessBrief Report

Insulin-Activated Signaling Pathway and GLUT4 Membrane Translocation in hiPSC-Derived Cardiomyocytes

by Giulia Querio, Susanna Antoniotti, Renzo Levi, Bernd K. Fleischmann, Maria Pia Gallo and Daniela Malan

Int. J. Mol. Sci. 2024, 25(15), 8197; https://doi.org/10.3390/ijms25158197 - 27 Jul 2024

Viewed by 583

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a cell model now widely used to investigate pathophysiological features of cardiac tissue. Given the invaluable contribution hiPSC-CM could make for studies on cardio-metabolic disorders by defining a postnatal metabolic phenotype, our work herein focused on monitoring the insulin response in CM derived from the hiPSC line UKBi015-B. Western blot analysis on total cell lysates obtained from hiPSC-CM showed increased phosphorylation of both AKT and AS160 following insulin treatment, but failed to highlight any changes in the expression dynamics of the glucose transporter GLUT4. By contrast, the Western blot analysis of membrane fractions, rather than total lysates, revealed insulin-induced plasma membrane translocation of GLUT4, which is known to also occur in postnatal CM. Thus, these findings suggest that hiPSC-derived CMs exhibit an insulin response reminiscent to that of adult CMs regarding intracellular signaling and GLUT4 translocation to the plasma membrane, representing a suitable cellular model in the cardio-metabolic research field. Moreover, our studies also demonstrate the relevance of analyzing membrane fractions rather than total lysates in order to monitor GLUT4 dynamics in response to metabolic regulators in hiPSC-CMs. Full article

(This article belongs to the Special Issue Molecular Research on Diabetes)

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