Dzhemileva Lilya U, Zakharova Elena N, Goncharenko Anna O, Vorontsova Maria V, Rumyantsev S A, Mokrysheva Natalia G, Loguinova Marina Y, Chekhonin Vladimir P
Endocrinology Research Centre, Moscow, Russia.
Front Endocrinol (Lausanne). 2025 Jan 20;15:1497298. doi: 10.3389/fendo.2024.1497298. eCollection 2024.
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.
青少年发病的成年型糖尿病（MODY）是一组单基因疾病，其特征为非胰岛素依赖型糖尿病的常染色体显性遗传，典型表现于青春期或25岁以下的年轻成年人。MODY是糖尿病的罕见病因，占所有病例的1%，常被误诊为1型或2型糖尿病。准确诊断MODY非常重要，因为这能为患者提供最恰当的治疗，并有助于患者及其家人的早期诊断。这种疾病具有高度的表型和遗传多态性。该疾病最常见的形式归因于三个基因的突变：GCK（MODY 2）和（肝细胞核因子）1A/4A（MODY 3和MODY 1）。其余不太常见的MODY亚型在过去十年中通过下一代测序（NGS）得以确定。GCK基因突变导致无症状、稳定的空腹高血糖，无需特殊治疗。HNF1A和HNF4A基因突变导致胰腺β细胞功能障碍，进而引起高血糖。这通常会导致糖尿病性血管病。治疗高血糖最常用的药物是磺脲类衍生物。然而，随着年龄增长，一些患者可能因对磺脲类药物产生耐药性而需要胰岛素治疗。针对单基因形式的MODY的基因治疗策略仍是一种实验性方法，由于MODY结构的特殊性以及即使在同一种疾病形式中也存在的高遗传多态性和临床变异性，不太可能在临床上广泛应用。此外，缺乏明确的基因-表型相关性，且大多数患者的治愈率相当令人满意。本综述介绍了常见和罕见形式的MODY的主要临床和遗传特征及突变谱，并详细分析了腺相关病毒（AAV）载体在纠正高血糖和胰岛素抵抗方面的应用领域。
