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Review
. 2025 Jan 20:15:1497298.
doi: 10.3389/fendo.2024.1497298. eCollection 2024.

Current views on etiology, diagnosis, epidemiology and gene therapy of maturity onset diabetes in the young

Lilya U Dzhemileva  1 , Elena N Zakharova  1 , Anna O Goncharenko  1 , Maria V Vorontsova  1 , S A Rumyantsev  1 , Natalia G Mokrysheva  1 , Marina Y Loguinova  1 , Vladimir P Chekhonin  1
Affiliations
Review

Current views on etiology, diagnosis, epidemiology and gene therapy of maturity onset diabetes in the young

Lilya U Dzhemileva et al. Front Endocrinol (Lausanne). .

Abstract

MODY, or maturity-onset diabetes of the young, is a group of monogenic diseases characterized by autosomal dominant inheritance of a non-insulin-dependent form of diabetes that classically manifests in adolescence or in young adults under 25 years of age. MODY is a rare cause of diabetes, accounting for 1% of all cases, and is often misdiagnosed as type 1 or type 2 diabetes. It is of great importance to accurately diagnose MODY, as this allows for the most appropriate treatment of patients and facilitates early diagnosis for them and their families. This disease has a high degree of phenotypic and genetic polymorphism. The most prevalent forms of the disease are attributed to mutations in three genes: GCK (MODY 2) and (HNF)1A/4A (MODY 3 and MODY 1). The remaining MODY subtypes, which are less prevalent, have been identified by next generation sequencing (NGS) in the last decade. Mutations in the GCK gene result in asymptomatic, stable fasting hyperglycemia, which does not require specific treatment. Mutations in the HNF1A and HNF4A genes result in pancreatic β-cell dysfunction, which in turn causes hyperglycemia. This often leads to diabetic angiopathy. The most commonly prescribed drugs for the treatment of hyperglycemia are sulfonylurea derivatives. Nevertheless, with advancing age, some patients may require insulin therapy due to the development of resistance to sulfonylurea drugs. The strategy of gene therapy for monogenic forms of MODY is still an experimental approach, and it is unlikely to be widely used in the clinic due to the peculiarities of MODY structure and the high genetic polymorphism and clinical variability even within the same form of the disease. Furthermore, there is a lack of clear gene-phenotypic correlations, and there is quite satisfactory curability in the majority of patients. This review presents the main clinical and genetic characteristics and mutation spectrum of common and rarer forms of MODY, with a detailed analysis of the field of application of AVV vectors in the correction of hyperglycemia and insulin resistance.

Keywords: AAV-vectors; European and Asian populations; autosomal dominant inheritance; diabetes monogenic forms; gene therapy; maturity-onset diabetes of the young (MODY).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The involvement of specific genes in glucose homeostasis and the normal functioning of organs that regulate carbohydrate and lipid metabolism can result in damage that may manifest in various forms of MODY ( Supplementary Table S1 ).
Figure 2
Figure 2
Signalling pathways in pancreatic and peripancreatic cells whose abnormalities cause diabetes of the young at maturity (MODY). 1. The influx of glucose to the β-cell through GLUT-2 facilitates the transition of glucose to glucose-6-phosphate by GCK enzyme. This results in increased ATP production in mitochondria after the entry of G6P to the Krebs cycle. The subsequent closure of ATP-sensitive potassium channels and opening of voltage-gated calcium channels permit the release of insulin from the β cell. 2. The regulation of gene expression within the nucleus is depicted by the arrows. These indicate that a specific gene is regulated by the corresponding transcription factor (TF) in mature beta cells. Additionally, the arrows illustrate that a given protein has a binding site for the corresponding TF and/or is regulated by it at some point during pancreatic development. 3. The synthesis of insulin occurs within the cytosol, where preproinsulin is produced. Subsequently, the signal peptide is cleaved by endopeptidases within the endoplasmic reticulum (ER) during the processing of preproinsulin. The final stages of proinsulin processing occur in the Golgi apparatus, including the formation of the final vesicle, the release of C-peptide from insulin within the Golgi apparatus and within the vesicles, and exocytosis. 4. The illustration depicts the binding sites of the insulin promoter to MODY-related transcription factors. The mutations in question are those that occur in the promoter region of the INS gene, which prevent transcription factors from binding to cis-elements. Another category of mutation is that which occurs in the start codon, which abolishes translation. Finally, changes in the non-translated regions of mRNA have been observed, which increase the sensitivity of the molecule to RNA degradation. MODY-related transcription factors (PDX1, NEUROD1, HNF1a, HNF4a, HNF1b, and RFX6) play a pivotal role in pancreatic development, B-cell identification, and mature B-cell function. 5. Adiponectin (Ad) binding to the extracellular COOH terminus of adiponectin receptor 1 (AdipoR1) recruits APPL1 to the intracellular NH2 terminus of AdipoR1 and activation of AMPK, p38 MAPK, and Rab5. Binding of adiponectin to AdipoR1 stimulates glucose transporter 4 (GLUT4) translocation and glucose uptake through phosphorylated AMPK, phosphorylated p38 MAPK, and Rab5. 6. Serine phosphorylation of insulin receptor substrate (IRS) proteins has been demonstrated to enhance tyrosine phosphorylation and insulin signalling, thereby activating Akt and facilitating glucose uptake. 7.The binding of adiponectin to its receptor results in the activation of AMPK, which, in turn, activates tuberous sclerosis complex 2 (TSC2). Upon activation, TSC2, in conjunction with TSC1, inhibits the activity of Ras homology enriched in brain (Rheb), thereby suppressing the activity of mammalian target of rapamycin (mTOR) and S6 kinase (S6K). The inhibition of S6K by adiponectin enhances the ability of insulin to stimulate IRS-1 tyrosine phosphorylation, which in turn leads to Akt phosphorylation and subsequent activation of the insulin signalling pathway (, –99).
Figure 3
Figure 3
Frequencies of different forms of MODY diabetes in different European populations (, , –106).
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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the Ministry of Science and Higher Education of the Russian Federation (agreement No. 075-15-2022-310 from 20 April 2022).

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