Emerging phenotype: Maturity-onset diabetes of the young type 5 (MODY-5) - mechanisms, clinical spectrum, and unmet needs

Abstract

Type 5 Diabetes or MODY-5 has recently emerged as a rare yet distinct phenotype among pediatric diabetes disorders, characterized predominantly by mutations in critical genes such as HNF1B and PPARG. Unlike more common diabetes types, this atypical form demonstrates extensive multisystem involvement, presenting clinically through diverse manifestations including renal cysts, pancreatic hypoplasia, growth disturbances, and neurological complications. Genetic analyses underscore its significant heterogeneity, illustrating a complex interplay among genetic mutations, epigenetic modifications, and environmental triggers that collectively shape its distinct pathogenesis. Molecular disruptions prominently include alterations in NF-κB signaling pathways, increased oxidative stress, mitochondrial dysfunction, and heightened profibrotic TGF-β activity, leading to early and severe multisystem complications. Despite these insights, clinical misclassification remains frequent, largely because diagnostic tools continue to prioritize conventional parameters such as HbA1c and fasting glucose rather than molecular diagnostics. Moreover, the absence of validated biomarkers specific to Type 5 Diabetes further impedes timely and precise diagnosis, underscoring critical gaps in current clinical practice. Addressing these diagnostic and therapeutic gaps necessitates expanded genetic screening, enhanced clinician education, and the establishment of subtype-specific clinical guidelines. This review proposes a structured framework to drive future diagnostic and therapeutic advancements, ultimately facilitating personalized management and improved outcomes for affected pediatric populations.

Keywords: Clinical management; Epigenetics; HNF1B; Molecular diagnostics; Monogenic diabetes; PPARG; Pediatric diabetes; Precision medicine; Type 5 diabetes.

Fig. 1

Molecular Pathways Implicated in Type 5 Diabetes Progression. A detailed depiction of disrupted molecular pathways, including NF-κB activation, oxidative stress, mitochondrial dysfunction, and TGF-β-mediated fibrosis contributing to the early-onset systemic complications. Created with BioRender.com Premium License by Fahrul Nurkolis (https://app.biorender.com, accessed on 05 March 2025)

Fig. 2

Proposed Mechanistic Model of Type 5 Diabetes Development. A schematic model illustrating the interplay between genetic mutations (e.g., HNF1B, PPARG), epigenetic modifications (DNA methylation, histone changes), and environmental triggers (e.g., diet, infections) leading to multisystemic manifestations in Type 5 Diabetes among children. Created with BioRender.com Premium License by Fahrul Nurkolis (https://app.biorender.com, accessed on 05 March 2025)

Fig. 3

Comparative Pathophysiology of Pediatric Diabetes Subtypes. A comparative diagram contrasting the major pathophysiological mechanisms among Type 1, Type 2, and Type 5 Diabetes (MODY-5), highlighting autoimmune, insulin resistance, and genetic-multisystem involvement, respectively. infections) leading to multisystemic manifestations in Type 5 Diabetes among children. Created with BioRender.com Premium License by Fahrul Nurkolis (https://app.biorender.com, accessed on 05 March 2025)

Fig. 4

Clinical Spectrum of Type 5 Diabetes (MODY-5) by Age of Onset. A visual summary displaying the variable age at onset of Type 5 Diabetes and its associated systemic complications such as renal anomalies, pancreatic dysplasia, and neurological deficits. infections) leading to multisystemic manifestations in Type 5 Diabetes among children. Created with BioRender.com Premium License by Fahrul Nurkolis (https://app.biorender.com, accessed on 05 March 2025)

Fig. 5

Diagnostic Challenges and Misclassification Pathways. Flowchart outlining the typical diagnostic misclassification pathway of pediatric Type 5 Diabetes, emphasizing where conventional methods fail and where molecular diagnostics could intervene. Created with BioRender.com Premium License by Fahrul Nurkolis (https://app.biorender.com, accessed on 05 March 2025)

Fig. 6

Future Directions for Research and Clinical Management. Proposed roadmap for advancing Type 5 Diabetes care, including biomarker discovery, genetic screening integration, multi-omic research, and individualized treatment frameworks. Created with BioRender.com Premium License by Fahrul Nurkolis (https://app.biorender.com, accessed on 05 March 2025)