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Functional Studies and Deep Phenotyping in Monogenic Forms of Diabetes, Severe Insulin Resistance and Hypoglycemia

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: 20 September 2026 | Viewed by 3474

Special Issue Editor

Dr. Fabrizio Barbetti

E-Mail Website
Guest Editor
Monogenic Diabetes Clinic, Unit of Endocrinology and Diabetes, Bambino Gesù Children’s Hospital, IRCCS, 00133 Rome, Italy
Interests: monogenic forms of diabetes; severe insulin resistance; hyperinsulinemic hypoglycemia

Special Issue Information

Dear Colleagues,

Monogenic forms of diabetes (MD), severe insulin resistance (SIR), and hyperinsulinemic hypoglycemia (HH) represent a sizeable number of cases in neonates, children, and young adults with these conditions. With the advent of next generation sequencing, many genetic variants with uncertain significance are discovered in genetic labs every day. One of the tools used to ascertain the pathogenic role of a genetic variant in a given disease are functional studies. Due to the intrinsic nature of proteins involved in MD, SIR, and HH that span enzymes, transciption factors, hormones, receptors, ion channels, and transfer-RNAs, functional studies may consist of biochemical assays, cell biology experiments, in vitro assays of transcription factor activity, animal models like mouse knockouts, and studies in human induced pluripotent stem cells (iPSCs) or human embryonic stem cells (hECSs) manipulted by CRISPR. Occasionally, results from functional studies in different variants may explain how variants in the same gene but with different impacts on protein action can cause discrete clinical subgroups of MD, SIR, or HH. This in turn may prompt deep phenotyping of carriers of different variants in the same gene with subtle clinical differences. This Special Issue focuses on any type of functional study commonly applied to support (or exclude) the pathogenic role of a genetic defect in the aforementioned conditions.

Dr. Fabrizio Barbetti
Guest Editor

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Keywords

  • monogenic diabetes
  • neonatal diabetes mellitus
  • MODY
  • severe insulin resistance
  • insulin receptor
  • lipodystrophy
  • hyperinsulinemic hypoglycemia
  • ABCC8/KCNJ11 dominant forms of HH

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Published Papers (3 papers)

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Research

20 pages, 7402 KB  
Article
HNF1B-MODY in the Norwegian MODY Registry and the Norwegian Childhood Diabetes Registry: Clinical Insights and Prevalence Informed by Genetic and Functional Evaluation
by Aishwarya Pavithram, Bente B. Johansson, Erling Tjora, Pernille Svalastoga, Khadra A. Mohamed, Ingvild L. Koløen, Maren Toftdahl, Torild Skrivarhaug, Marc Vaudel, Lise Bjørkhaug, Kristin A. Maloney, Toni I. Pollin, Stefan Johansson, Christine Bellanné-Chantelot, Jørn V. Sagen, Janne Molnes and Pål R. Njølstad
Int. J. Mol. Sci. 2026, 27(11), 5067; https://doi.org/10.3390/ijms27115067 - 3 Jun 2026
Viewed by 221
Abstract
Interpreting HNF1B variants is challenging in clinical practice. We aimed to integrate functional, clinical, and family data to improve variant classification, describe clinical features of carriers and report registry-level prevalence of HNF1B alterations. Clinical, genetic, and family data were analyzed from the Norwegian [...] Read more.
Interpreting HNF1B variants is challenging in clinical practice. We aimed to integrate functional, clinical, and family data to improve variant classification, describe clinical features of carriers and report registry-level prevalence of HNF1B alterations. Clinical, genetic, and family data were analyzed from the Norwegian MODY Registry (NMR) and the Norwegian Childhood Diabetes Registry (NCDR). Clinical features of sequence variant and 17q12 deletion (17q12del) carriers were summarized, and variants were classified using ACMG-AMP-ClinGen criteria. Registry-level prevalence was reported with 95% confidence intervals. HNF1B sequence variants were functionally assessed, showing that lower transactivation (TA) was associated with higher clinical severity. Eleven variants demonstrated impaired functional activity, with TA inversely correlated with clinical burden (ρ = −0.701, p = 0.002). We identified 28 individuals with 17q12del (21 in NMR, seven in NCDR) and 15 individuals carrying 14 unique pathogenic/likely pathogenic (P/LP) sequence variants, all detected in the NMR. Overall, 36/486 probands (7.4%) with genetically confirmed monogenic diabetes in the NMR carried a P/LP HNF1B sequence variant or 17q12del. In the NCDR, ~0.2% carried 17q12del (7/3583; 3/7 GADA/IA-2A-positive). Functional data enabled reclassification of three variants. Since many pediatric 17q12del carriers in the NMR were referred for testing due to structural renal anomalies without diabetes, HNF1B screening should be considered in children with renal/extra-renal features, irrespective of diabetes or autoantibody status. Full article
(This article belongs to the Special Issue Functional Studies and Deep Phenotyping in Monogenic Forms of Diabetes, Severe Insulin Resistance and Hypoglycemia)
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15 pages, 3664 KB  
Article
Structural Communication Between C-Peptide and Insulin Within the Proinsulin Molecule
by Rubing Shao, Maroof Alam, Leena Haataja and Peter Arvan
Int. J. Mol. Sci. 2026, 27(1), 483; https://doi.org/10.3390/ijms27010483 - 2 Jan 2026
Viewed by 1285
Abstract
Despite years of study, the biological role of the human proinsulin connecting peptide (C-peptide) remains poorly understood. Nevertheless, the C-peptide exhibits subdomains including conserved residues that are thought to have co-evolved with the insulin moiety of proinsulin. Genome-wide association studies in humans suggest [...] Read more.
Despite years of study, the biological role of the human proinsulin connecting peptide (C-peptide) remains poorly understood. Nevertheless, the C-peptide exhibits subdomains including conserved residues that are thought to have co-evolved with the insulin moiety of proinsulin. Genome-wide association studies in humans suggest that alterations of glycemic control may exhibit a possible linkage with the presence of certain C-peptide variants other than frame-shifts, stop codons, alternative splice variants, or the addition of an extra unpaired Cys residue. Although the C-peptide is ultimately excised from insulin, here, we have bioengineered missense mutations in the amino-terminal portion of the C-peptide (especially involving or near preproinsulin residues Q62,V63) that we find impair proinsulin folding and trafficking efficiency and, in this way, impair insulin biogenesis. We show that proinsulin bearing a C-peptide missense variant can also physically interact with co-expressed wildtype proinsulin, affecting the trafficking behavior of both proinsulin proteins in a manner that is directly related to the relative expression ratio of the variant and wildtype gene products. We conclude that in addition to other possible functions, the amino-terminal portion of the C-peptide influences proinsulin folding and trafficking and, in this way, affects human insulin production. Full article
(This article belongs to the Special Issue Functional Studies and Deep Phenotyping in Monogenic Forms of Diabetes, Severe Insulin Resistance and Hypoglycemia)
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19 pages, 1928 KB  
Article
Functional Characterization of Glucokinase Variants to Aid Clinical Interpretation of Monogenic Diabetes
by Varsha Rajesh, Dora Evelyn Ibarra, Jing Yang, Haichen Zhang, Amy Barrett, Eleanor G. Kaplan, Amit Kumthekar, Fanny Sunden, Han Sun, Ananta Addala, Aaron Misakian, Lisa R. Letourneau-Freiberg, Colleen O. Jodarski, Kristin A. Maloney, Cécile Saint-Martin, Polly M. Fordyce, Toni I. Pollin and Anna L. Gloyn
Int. J. Mol. Sci. 2026, 27(1), 156; https://doi.org/10.3390/ijms27010156 - 23 Dec 2025
Viewed by 1409
Abstract
Precision medicine starts with a precision diagnosis. Yet up to 80% of cases of monogenic diabetes, a form of diabetes characterized by mutations in a single gene, are either overlooked or misdiagnosed. A genetic test for monogenic diabetes does not always lead to [...] Read more.
Precision medicine starts with a precision diagnosis. Yet up to 80% of cases of monogenic diabetes, a form of diabetes characterized by mutations in a single gene, are either overlooked or misdiagnosed. A genetic test for monogenic diabetes does not always lead to a precise diagnosis, as novel variants are often classified as variants of unknown significance. Variant interpretation requires collation of a framework of evidence, including population, computational, and segregation data, and can be assisted by functional analysis. The inclusion of functional data can be challenging, depending on the number of benign and pathogenic variants available for benchmarking assays. Glucokinase is the rate-limiting step for glucose metabolism in the pancreatic beta-cell and governs the threshold for glucose-stimulated insulin release. Loss-of-function alleles in the glucokinase (GCK) gene are a cause of stable fasting hyperglycemia from birth and/or diabetes. In this study, we functionally characterized 25 variants identified during diagnostic testing or in exome sequencing studies. We assessed their kinetic characteristics, stability, and interaction with pharmacological and physiological regulators. We integrated our functional data with existing data from the ClinGen Monogenic Diabetes Variant Curation Expert Review panel using a gene-specific framework to assist variant classification. We show how functional evidence can aid variant classification, thus enabling diagnostic certainty. Full article
(This article belongs to the Special Issue Functional Studies and Deep Phenotyping in Monogenic Forms of Diabetes, Severe Insulin Resistance and Hypoglycemia)
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