proteins

2026-07-13 | HNF1B-related disease: developmental origins, molecular mechanisms, and multisystem clinical challenges.

Variants or deletions involving the HNF1B gene cause HNF1B-MODY. HNF1B-MODY represents a multisystem disorder extending far beyond its original classification as a monogenic form of diabetes. HNF1B's role in human development includes critical involvement in the organogenesis of the kidney, pancreas, liver, genitourinary tract, and nervous system. Approximately half of affected individuals carry large 17q12 deletions encompassing HNF1B and neighboring genes, correlating with broader syndromic features such as intellectual disability, autism spectrum traits, and psychiatric illness. The increasing availability of next-generation sequencing, coupled with copy number variant analysis, has improved diagnostic yield. Underdiagnosis remains common due to variable expressivity and phenotypic overlap with more prevalent disorders. Notable progress has been made in dissecting tissue-specific roles of HNF1B. Patient-derived iPSC models and single-cell transcriptomics offer new insights into early developmental pathways and transcriptional networks. These tools enable organoid-based studies and the potential discovery of therapeutics. Clinically, awareness of symptoms, such as renal cysts, persistent hypomagnesemia, pancreatic hypoplasia, and non-autoimmune diabetes, has led to the development of diagnostic scoring systems and multidisciplinary care algorithms. Although current treatment remains supportive, research into gene regulation, epigenetic modifiers, and pharmacologic rescue strategies is ongoing. HNF1B-related disease illustrates how pleiotropic gene dysfunction can present with diverse organ involvement. Integrating genomics, developmental biology, and targeted surveillance may help improve early diagnosis and patient outcomes.

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2026-06-22 | Identification and functional characterization of a novel mutation in the NEUROD1 gene in a Chinese family with maturity-onset diabetes of the young.

Few families with maturity-onset diabetes of the young (MODY) caused by neurogenic differentiation factor 1 (NEUROD1) mutations have been identified. The aim of this study is to identify the affected gene in a Chinese family with MODY using whole exome sequencing (WES) and explore the potential pathogenicity of the identified mutation. WES was performed in patients with clinically suspected MODY, and candidate variants were verified with Sanger sequencing for family co-segregation. Structure-function alterations in the newly identified mutant protein were analyzed using three-dimensional modeling and dual luciferase reporter gene assays to assess pathogenicity. A novel heterozygous missense mutation, Y297D (c.889T > G, p.Tyr297Asp), in the NEUROD1 gene (NM_002500.5) was identified in a MODY proband and his affected relatives. Y297D mutation disrupted a C-H conjugated interaction and introduced a new hydrogen bond, altering the protein's local structure. These alterations reduced transcriptional activity in the transactivation domain of the Y297D mutant compared with that of the wild-type protein (P < .05). A novel NEUROD1 mutation has been identified in Chinese MODY, and the abnormal conformation of NEUROD1-Y297D reduced insulin transcription activity, impairing pancreatic β-cell function in patients with MODY6. Glucagon-like peptide-1 receptor agonist (GLP-1RAs) may be a precision hypoglycemic strategy to consider in diabetic patients with NEUROD1 mutations.

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2026-04-23 | When type 1 diabetes isn't the answer: A case series of siblings with misdiagnosed diabetes mellitus later confirmed as maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is an uncommon, monogenic form of diabetes that is often misdiagnosed as type 1 or type 2 diabetes, leading to unnecessary insulin therapy and missed opportunities for targeted management. We describe two siblings initially diagnosed with type 1 diabetes during adolescence and treated with insulin for several years. Two siblings, ages 16 and 19, have a family history of diabetes and were diagnosed with type 1 diabetes when they were young. Both twins maintained substantial endogenous insulin secretion and exhibited negative or low-titer diabetic autoantibodies in spite of long-term insulin therapy. Both patients were successfully switched from insulin to contemporary treatments, particularly GLP-1 receptor agonists, after a clinical reevaluation revealed suspicion of MODY. This led to better glycemic control without hypoglycemia. When young patients with atypical diabetes presentations have retained β-cell function, negative antibodies, and a strong family history, clinicians should keep a high index of suspicion for MODY.

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2026-04-06 | A Case of Oral Semaglutide for Treatment of Hepatocyte Nuclear Factor 4A Maturity-Onset Diabetes of the Young.

Maturity-onset diabetes of the young (MODY) is a form of autosomal dominant monogenic diabetes. Sulfonylureas are the mainstay of therapy for hepatocyte nuclear factor 4A (HNF4A) MODY. Here, we present a patient with HNF4A MODY successfully treated with oral semaglutide. A 58-year-old woman with diabetes presented for evaluation. Body mass index was 23.3 kg/m2 without signs of insulin resistance. Hemoglobin A1c was 6.1% on glipizide 5 mg daily and metformin 500 mg twice daily with fasting hyperglycemia in the morning and episodes of hypoglycemia.To decrease the frequency of hypoglycemia, her regimen was changed to glimepiride 1 mg daily and metformin 500 mg twice daily. Genetic testing results revealed HNF4A MODY, c.335G>A (p.Arg112GIn). Metformin was stopped and she switched to oral semaglutide 3 mg daily, increased to 7 mg daily after 30 days, and glimepiride 1 mg daily. After 3 months, glimepiride was discontinued due to hypoglycemia. Nine months after starting semaglutide and on monotherapy with semaglutide 7 mg daily, hemoglobin A1c was 5.7%, and her continuous glucose monitor reported 98% time in range with no episodes of hypoglycemia. To our knowledge, this is the first case of HNF4A MODY to be treated with oral semaglutide alone. Oral glucagon-like peptide receptor-1 receptor agonists may be used to treat HNF4A MODY as an independent or adjunctive therapy to sulfonylureas. Both medications work via different mechanisms to bypass the malfunctioning pathway caused by the HNF4A MODY variant. Glucagon-like peptide 1 receptor agonists, including oral semaglutide, may be safe and efficacious treatments for patients with HNF4A MODY.

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2026-02-04 | RFX6 maturity-onset diabetes of the young: clinical considerations and novel use of tirzepatide.

RFX6 maturity-onset diabetes of the young (RFX6-MODY) is a relatively new MODY subtype, with limited guidance on management, particularly in pregnancy. We report the clinical features and management of two female patients with RFX6-MODY and their progression during and post-pregnancy. These patients were diagnosed with type 2 diabetes mellitus (DM) at ages 13 and 19 years, initially managed on dietary modification alone. They were subsequently diagnosed with RFX6-MODY during pregnancy following calculation of MODY probability. Both required insulin during pregnancy and delivered healthy babies at 38 weeks. Three months post-delivery, tirzepatide was started for one of our patients and she has shown significant glycaemic improvement and weight loss. To our knowledge, this is the first reported use of tirzepatide in RFX6-MODY. RFX6-MODY may present at a much earlier age than previously reported in the literature. Many patients with RFX6-MODY do not appear to require insulin at diagnosis. Tirzepatide may be a beneficial therapeutic option for managing patients with RFX6-MODY who have adequate β-cell function. Pregnancy management in patients with RFX6-MODY is similar to type 2 DM, although higher insulin doses may be required.

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small molecules

2026-08-06 | Glycemic and Renal Effects of SGLT2 Inhibitors in Monogenic Diabetes: A Real-World National Study.

Evidence regarding the efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in monogenic diabetes is limited. We evaluated real-world metabolic, renal, and safety outcomes of SGLT2i therapy in adults with monogenic diabetes. This multicenter retrospective study included adults with genetically confirmed monogenic diabetes treated with SGLT2i. Clinical and biological data were collected at baseline and after approximately 1 and 2 years. Longitudinal changes were analysed using linear mixed-effects models adjusted for baseline value, age, and sex and treatment intensification. Forty patients (mean age 48.6 ± 15.2 years) with MIDD (n = 16), HNF1B-MODY (n = 9), HNF1A/HNF4A-MODY (n = 11), or other MODY subtypes (ABCC8, INS, RFX6; n = 4) were followed for 23.9 ± 5.9 months. HbA1c remained stable overall but decreased significantly in patients with baseline HbA1c ≥ 8% (9.6% ± 1.3% to 7.6% ± 0.7%; p = 0.001). UACR declined significantly (-35.6% at 1 year and -43.5% at 2 years; p = 0.004), particularly in those with baseline CKD (trend). Genotype-specific trends suggested greater glycemic improvement in HNF1A/HNF4A-MODY and greater UACR reduction in MIDD. eGFR declined modestly over time. Non-serious adverse events occurred in 15% of patients, 7.5% discontinued treatment, and no ketoacidosis, acute kidney injury, or deaths were reported. In this nationwide cohort of patients with monogenic diabetes-the largest reported to date-SGLT2i therapy was associated with improved glycemic control in individuals with baseline HbA1c ≥ 8%, reduced albuminuria, and showed a favourable safety profile. These findings support SGLT2i as a potential therapeutic option that warrants confirmation in larger controlled studies.

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2026-07-28 | Insulin Injection Behaviors and Association with Glycemic Outcomes in Patients with Diabetes: A Real-World Survey in Spain.

Optimal glycemic control is essential to prevent complications in diabetes, and insulin administration practices play a key role. This study assessed insulin injection behaviors and related glycemic outcomes among individuals using multiple daily injections in Spain. A cross-sectional online survey was conducted via an independent patient platform (Canal Diabetes). Adults (18-65 years) with type 1, type 2, or other forms of diabetes (e.g., maturity-onset diabetes of the young (MODY) or secondary diabetes) requiring daily insulin injections were included. Demographic, clinical, and behavioral data were analyzed using SPSS Statistics, version 23 (IBM Corp., Armonk, NY, USA). Among 288 participants (mean age: 43.7 ± 14.7 years; 28.8% male, 71.2% female), 74.7% had type 1 diabetes. Most were white (95.8%) with a mean diabetes duration of 17.8 ± 14.5 years. While 83.3% injected prandial insulin before meals, only 71.2% did so at least 15 min before eating. Errors were frequent: 38.5% reported underdosing and 26.7% overdosing more than five times in the past month. Participants injecting before meals had significantly better outcomes than those injecting at other times, including higher rates of glycated hemoglobin (HbA1c) ≤ 7.5% (83.3% versus 62.5%, p = 0.001), greater time in range (TIR) (74.4% versus 66.3%, p = 0.032), and lower mean glucose (144 versus 159 mg/dL, p = 0.019). Smart pen users (41.2%) reported fewer mild-to-moderate hypoglycemic events (p = 0.021), though no differences were observed in HbA1c or TIR. Insulin injection practices in Spain reveal significant variability and opportunities for improvement. Promoting timely premeal insulin administration and leveraging technologies such as smart pens may improve glycemic outcomes. ClinicalTrials.gov identifier, NCT06421467.

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2026-07-19 | Genetic spectrum and treatment implications of maturity-onset diabetes of the young in the eastern Black Sea region of Türkiye: a combined adult and pediatric cohort of 296 patients with identification of rare and novel variants.

Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous group of monogenic diabetes subtypes that is frequently misdiagnosed as type 1 or type 2 diabetes, and accurate genetic diagnosis enables a precision-medicine treatment approach. Regional Turkish data are limited, and previous Turkish series have been pediatric only. We characterized the genetic spectrum and therapeutic consequences of next-generation sequencing (NGS)-based MODY testing in a combined adult-and-pediatric cohort from the eastern Black Sea region of Türkiye. We retrospectively analyzed 296 consecutive patients with clinically suspected MODY referred between January 2022 and June 2025. A targeted NGS panel covering 14 MODY genes was applied, variants were classified per 2015 ACMG/AMP criteria, and treatment changes attributable to the genetic diagnosis were extracted from medical records. Pathogenic or likely pathogenic (P/LP) variants were identified in 43 of 296 patients (14.5%); diagnostic yield rose to 26.0% with variants of uncertain significance included. GCK-MODY accounted for 72.1% of P/LP findings, with a recurrent frameshift c.1256del p.(Phe419SerfsTer12) across nine apparently unrelated families consistent with a regional founder allele. Rare subtypes included MODY4 (PDX1), MODY6 (NEUROD1), MODY8 (CEL), MODY10 (INS), MODY12 (ABCC8) and MODY13 (KCNJ11). The genetic diagnosis directly modified pharmacological therapy in 14 patients, including insulin discontinuation in three KATP-channel MODY and one INS-MODY case. NGS-based MODY testing yields actionable findings in approximately one in seven clinically selected patients in this region and supports inclusion of MODY testing in routine endocrinology practice.

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2026-06-15 | Personalized management of glucokinase-related monogenic diabetes (GCK-MODY) during pregnancy: a case report.

Management of glucokinase-related monogenic diabetes (GCK-MODY) during pregnancy can be challenging. We present the case report of a 33-year-old woman, diagnosed with diabetes since the age of 9. She had no micro or macrovascular complications, and HbA1c ranged between 6.5% and 6.8%, without pharmacological treatment. Family history revealed multiple relatives with the diagnosis of diabetes, including a maternal cousin with confirmed GCK-MODY. The patient underwent genetic testing that identified the variant NM_000162.5:c.829_830insCGG p.(Leu276_Val277insAla), heterozygous for the GCK gene, classified as of uncertain significance. During pregnancy, the couple chose not to undergo invasive fetal testing. Given the presumptive diagnosis of GCK-MODY and since fetal genotype was not determined, the pregnancy was managed under the assumption of a potentially unaffected fetus. During follow-up, combined with nutritional counseling and promotion of regular exercise, the patient required initiation of basal insulin therapy. Then, to optimize metabolic control, continuous glucose monitoring (CGM) was implemented, and insulin therapy was progressively intensified to a basal-bolus regimen, ultimately reaching eight daily bolus administrations of rapid-acting insulin. Adequate glycemic control and appropriate fetal growth were achieved, and she delivered a male newborn at 36 weeks and 2 days, with 2970g and APGAR score of 9 at 1, 5 and 10 minutes. Genetic testing of the mother and sister was requested during the patient's pregnancy, but the results became available only after delivery. These confirmed the presence of the same variant in both relatives, supporting the diagnosis of GCK-MODY. This case highlights the complexity of managing presumptive GCK-MODY during pregnancy, in the setting of a variant of uncertain significance and absent fetal genotyping. It emphasizes the importance of CGM-guided intensive insulin therapy and the need for a multidisciplinary and individualized approach based on shared decision-making.

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2026-06-15 | Treatment Options for Patients with Maturity-Onset Diabetes of the Young (MODY): A Systematic Review of Literature: 2026 Update.

Maturity-onset diabetes of the young (MODY) is a rare monogenic form of diabetes characterized by impaired insulin secretion and genetic and clinical heterogeneity. Accurate molecular diagnosis enables precision medicine by guiding gene-specific treatment, improving glycemic control, and avoiding unnecessary therapies. Since our previous systematic review in 2020, new studies have further clarified therapeutic strategies and emerging treatment options. This review updates the evidence on pharmacological management of MODY and its clinical implications. A systematic review was conducted following PRISMA 2020 recommendations. PubMed was searched for studies published between April 2020 and October 2025. Eligible studies included individuals with genetically confirmed MODY receiving pharmacological treatment, therapeutic switches, or adjunctive therapies. Data were extracted and synthesized qualitatively due to heterogeneity in study design and outcome reporting. Ninety-one studies were included. Strong evidence confirms sulfonylureas (SUs) as first-line therapy in Hepatocyte Nuclear Factor 1A (HNF1A)-, Hepatocyte Nuclear Factor 4A (HNF4A)-, ATP-binding cassette transporter sub-family C member 8 (ABCC8)-, and potassium inwardly rectifying channel subfamily J member 11 (KCNJ11)-MODY, frequently enabling improved glycemic control and transition from insulin. Glucokinase (GCK)-MODY remains managed without pharmacological treatment outside pregnancy, but dorzagliatin, a novel agent acting as a glucokinase activator, may further expand precision treatment approaches. Insulin remains the mainstay of treatment in Hepatocyte Nuclear Factor 1B (HNF1B)- and Insulin (INS)-MODY, although adjunctive therapies may provide benefits. While SUs are supported by consistent observational evidence, the role of incretin-based therapies and sodium-glucose co-transporter 2 inhibitors remains exploratory, largely based on small studies and case reports. A major limitation of the available evidence is the predominance of small, heterogeneous observational studies, which limits the strength and generalizability of therapeutic recommendations. Recent literature largely confirms existing genotype-guided treatment recommendations while suggesting expanded therapeutic options for selected MODY subtypes. Precision medicine based on molecular diagnosis remains essential for optimal management.

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gene therapies

2026-08-12 | CRISPR/Cas9-based repair of a heterozygous HNF1A mutation in patient-derived hiPSCs.

Human induced pluripotent stem cells (hiPSCs) represent a powerful platform for disease modeling, especially in monogenic diseases as they preserve the donor's genetic background while enabling directed differentiation into disease-relevant cell types. This makes them highly suitable for studying disease mechanisms in a patient-specific and physiologically relevant context. Although CRISPR/Cas9 is widely applied for genome editing, precise correction of pathogenic variants in hiPSCs remains challenging due to the lack of standardized CRISPR component selection and experimental design. Here, we describe an optimized CRISPR-based strategy for correcting a heterozygous HNF1A frameshift mutation (c.235_236insG; p.Glu79Glyfs*16) in HNF1A-MODY patient-derived hiPSCs. Using electroporation, we efficiently delivered CRISPR components, including a ribonucleoprotein complex of Cas9 and single-guide RNA, along with a single-stranded oligodeoxynucleotide repair template. Corrected hiPSC lines were validated for pluripotency, absence of exogenous reprogramming factors, and off-target effects. Additionally, we discuss key technical challenges encountered during the editing process and provide practical recommendations that may improve the generation of mutation-corrected hiPSC lines. These guidelines could serve as a useful reference for researchers employing CRISPR-based strategies for generation of reliable disease modelling tools.

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2026-06-05 | 2398-P: Identifying Clinical Discriminators of GCK-MODY in a Type 2 Diabetes–Dominant Population in Taiwan

Introduction and Objective: Young-onset type 2 diabetes (YOD) is increasingly prevalent, whereas glucokinase maturity-onset diabetes of the young (GCK-MODY)—a common MODY subtype across ethnicities—remains underrecognized. Because widespread genetic testing is impractical, overlapping clinical features often lead to misclassification and overtreatment. We aimed to identify clinical discriminators of GCK-MODY in a youth-onset, type 2 diabetes (T2DM)-predominant population to inform targeted genetic testing. Methods: This hospital-based observational study enrolled individuals with diabetes onset at ≤40 years and a family history of diabetes. Whole-exome sequencing (WES) focused on 27 MODY-related genes was performed, with variants classified per American College of Medical Genetics and Genomics criteria. Clinical and metabolic features were compared between patients without pathogenic/likely pathogenic variants and those with GCK-MODY. Results: WES was performed in 150 young individuals with diabetes (51.3% males). Pathogenic or likely pathogenic (P/LP) variants were identified in 21 participants (14%), most commonly GCK (n=10, 48% of variant-positive cases); the remaining variants involved other established MODY-related genes. Compared with young-onset diabetes patients without P/LP variants, individuals with GCK-MODY exhibited a distinct metabolic profile, including lower body mass index, waist circumference, triglycerides, and C-peptide levels. A model incorporating sex, waist circumference, triglycerides, and C-peptide demonstrated good discrimination for GCK-MODY (AUC = 0.842). Conclusion: Phenotype-driven identification of GCK-MODY using simple clinical and metabolic markers may improve the efficiency of genetic testing, reduce misclassification and overtreatment, and support precision management in youth-onset diabetes populations dominated by T2DM. Disclosure Y. Sheen: None. H. Tsai: None. H.P. Chen: None. J. Chen: None. Funding Taichung Veterans General Hospital and National Health Research Institutes, Taiwan

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2026-02-16 | Identification of maturity-onset diabetes of the young through targeted next-generation sequencing in Thai patients with atypical diabetes in real-world practice.

Maturity-onset diabetes of the young (MODY) is often misdiagnosed as either autoimmune type 1 diabetes (T1D) or polygenic type 2 diabetes (T2D), resulting in missed diagnosis and inappropriate treatment. Differentiating MODY from T2D is challenging in Asians with low body mass index (BMI) and strong family history. The clinical impact of genetic testing in a real-world case series of Thai patients with atypical diabetes is not well defined. In this study, we aim to evaluate the diagnostic yield and clinical implications of targeted gene panel testing at a specialized diabetes outpatient clinic in Bangkok. We performed next-generation sequencing analysis of 33 monogenic diabetes genes in Thai patients recruited in 2019-2025 who had atypical features of diabetes including age-at-diagnosis≤ 40 years, BMI ≤25 kg/m2, random plasma C-peptide levels ≥ 0.1 ng/mL after at least three years of clinically-diagnosed T1D, syndromic features such as organ abnormalities or non-classical T1D or T2D presentations. Of the 33 probands with atypical diabetes (age-at-diagnosis 34.4 ± 14.4 years, BMI 23.7 ± 3.3 kg/m2, insulin-treated 39.3%), genetic testing identified a pathogenic or likely pathogenic variant in 4 (12.1%) probands. Variants in GCK were the most frequent (n=2, 50.0%), followed by HNF1A (n=1, 25.0%), and HNF1B (n=1, 25.0%). Genetic diagnoses led to targeted therapies and identification of MODY cases among family members. The latter often have concomitant obesity-driven insulin resistance contributing to hyperglycemia. Genetic testing for monogenic diabetes in a real-world setting identified disease-causing variant in 12.1% of young Thai patients with atypical diabetes. Despite this low yield, accurate genetic diagnoses improved clinical management in both probands and family members. These findings underscore the potential contribution of a strong polygenic background or yet unidentified MODY-X genes among Thai patients. Establishing a register of family-based cohorts documenting the molecular diagnosis of atypical diabetes will advance diagnosis and treatment.

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2025-12-21 | Multifaceted functions of transcription regulatory factor X6 (RFX6): from pancreatic development to cancer progression.

Regulatory factor X6 (RFX6) is defined as the sixth member of the RFX family based on its highly conserved and specific wing-helix DNA-binding domain. Its expression in adults is predominantly localized to pancreatic islets, small intestine, and colon. Extensive research has demonstrated that RFX6 regulates cellular processes, such as pancreatic development, differentiation of islet progenitor cells, and insulin secretion, through the modulation of specific miRNAs (such as miR145 and miR195) and mRNAs (such as Pdx1, Neurod1, GCK, and Abcc8). Hence, mutations and deletions in RFX6 have been linked to the onset of various types of diabetes, including type 2 diabetes, Maturity-onset diabetes of the young, neonatal diabetes mellitus, especially Mitchell-Riley Syndrome (MRS). Specifically, homozygous mutations in RFX6 impede the proper differentiation of pancreatic progenitor cells, leading to inhibition of pancreatic head-tail development and endocrine cell formation, thereby contributing to the pathogenesis of MRS. Furthermore, examination of RFX6 target genes reveals a potential association with tumor development, indicating that RFX6 may play a role in cancer progression. Dysregulated expression or mutations of the RFX6 gene in prostate cancer, hepatocellular carcinoma, gastric cancer, melanoma, and other tumors have garnered significant interest, with studies showing that such alterations affect tumor cell proliferation, migration, and invasion, and are correlated with an unfavorable clinical prognosis in patients carrying RFX6 mutations. This review delves into the various functions of RFX6, emphasizing its crucial regulatory roles in pancreatic development, tumorigenesis, and progression. In addition, recent advancements in MRS therapy are outlined, underscoring the importance of RFX6-targeted therapy in MRS and cancer.

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2025-11-25 | MODY Is Prevalent in Later-Onset Diabetes and Has Potential for Targeted Therapy but Is Challenging to Identify.

Maturity-onset diabetes of the young (MODY) can present after the age of 40 years, but its prevalence and clinical characteristics, and the utility of simple clinical features for selecting cases in this age group, remain poorly defined. We analyzed whole-exome and clinical data from 51,619 individuals with diabetes diagnosed after age 40 years from one U.K. and one U.S. cohort. The prevalence of MODY due to a pathogenic variant in the 10 most common MODY genes was 1 in 191 (0.52%) in the U.K. cohort and 1 in 633 (0.16%) in the U.S. cohort. For subtypes with treatment implications (i.e., GCK, HNF1A, HNF4A, ABCC8, KCNJ11), prevalence was 1 in 234 and 1 in 935 in the U.K. and U.S. cohorts, respectively. GCK-MODY was most common, followed by HNF4A and the lower-penetrance RFX6-MODY. Clinical features of MODY largely overlapped with non-MODY diabetes either treated with insulin from diagnosis or not. Only BMI, HbA1c and HDL values were statistically different between patients with MODY and those with non-MODY diabetes in both cohorts (P < 0.0018 for all). Applying strict clinical criteria (i.e., BMI <25, noninsulin treated, and parent with diabetes) only increased the MODY diagnosis to 2.64% and 0.87% in the respective cohorts but missed >86% of cases. MODY is prevalent in later-onset diabetes and has potential for targeted therapy but is challenging to identify. Maturity-onset diabetes of the young (MODY) can present later in life, and diagnosis can enable precision treatment. However, individuals with later-onset diabetes are rarely tested. How common is MODY in people diagnosed with diabetes after age 40 years? Can they be identified clinically? MODY affects 1 in 191-633 individuals with diabetes onset after 40 years, but clinical features alone cannot reliably identify them. MODY is relatively common in later-onset diabetes but difficult to detect clinically, limiting routine genetic testing in this group.

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cell therapies

2025-07-16 | Global perspectives on monogenic forms of diabetes.

Monogenic forms of diabetes represent an uncommon but very heterogeneous subset of the disease, with variable associated clinical features and key differences in treatment options. In this review, we discuss how advances in precision medicine and genomic sequencing have enhanced our understanding of the aetiology and clinical variability of monogenic diabetes. We highlight current global challenges, including the over-representation of individuals of European genetic ancestry in research studies, which complicates diagnosis in non-European populations, and national disparities in genetic testing strategies, which influence diagnostic accuracy. Additionally, we address issues in variant interpretation stemming from the increased understanding of variable penetrance in monogenic diabetes and the need to expand current reference datasets to exclude common genetic variation. Finally, we explore future directions, including the potential benefits of ongoing genetic studies for under-represented populations, the benefits and potential pitfalls of newborn screening programmes, and the potential of stem cell-derived islet transplantation and glucagon-like peptide- 1 receptor agonists as treatments for some forms of monogenic diabetes.

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2024-12-23 | Investigating the pathogenicity of the recessive HNF1A p.A251T variant in monogenic diabetes using iPSC-derived beta-like cells.

Monogenic diabetes, formerly called Maturity-Onset Diabetes of the Young (MODY), involves single-gene mutations, typically with dominant inheritance, and has been associated with variants in 14 genes. Among these, HNF1A mutations are the most common, and their diagnosis allows the use of alternative therapies, including sulfonylureas. In an earlier study, we described a variant displaying recessive transmission, p.A251T (Misra, S et al, Diabetes Care, 2020). Initial functional studies revealed only a modest impact on protein function. We extend these earlier in vitro studies to demonstrate that beta-like cells derived from pluripotent stem cells from variant carriers show impaired differentiation into insulin-positive cells, whereas differentiation into alpha cells is significantly enhanced. Additionally, mutant cells showed impaired glucose-stimulated insulin secretion but partially preserved responsiveness to treatment with sulfonylureas. Our study provides proof of principle for the utility of using patient-derived stem cells as a platform to assess the pathogenicity of HNF1A variants, and to explore potential treatment strategies.

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2024-12-05 | Generation of iPSC line ERCi004-A from human dermal fibroblasts of a patient with maturity-onset diabetes of the young type 3 caused by a heterozygous mutation in the HNF1A gene

Abstract Maturity-onset diabetes of the young type 3 (MODY3) disorder is characterized by an autosomal dominant type of inheritance and highly heterogeneous clinical phenotype influenced by type and position of mutation in the HNF1A gene. We reprogrammed dermal fibroblasts derived from a patient with MODY3 carrying a heterozygous mutation in the site encoding the transactivation domain of the HNF1A protein (c. 864delGinsCC, p.Gly292ArgfsTer25) into iPSCs using transfection with self-replicating RNA vector. Obtained iPSCs (ERCi004-A line) proliferate in dense monolayer cell colonies, have a normal karyotype (46,XX), express pluripotency markers (OCT4, SOX2, TRA-1-60). The functional pluripotency of iPSCs was confirmed by their ability to form embryoid bodies and differentiate into the three germ layers (ecto-, endo-, and mesoderm). Sanger sequencing of iPSCs confirmed the presence of pathogenic heterozygous mutation in the HNF1A gene. This cell line could be useful to modeling of MODY3 pathology to improve understanding of the mechanism of the transactivation domain mutation, as well as a potential source for autologous cell-based therapy.

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2021-09-27 | Generation of β Cells from iPSC of a MODY8 Patient with a Novel Mutation in the Carboxyl Ester Lipase (CEL) Gene.

Maturity-onset diabetes of the young (MODY) 8 is a rare form of monogenic diabetes characterized by a mutation in CEL (carboxyl ester lipase) gene, which leads to exocrine pancreas dysfunction, followed by β cell failure. Induced pluripotent stem cells can differentiate into functional β cells. Thus, β cells from MODY8 patients can be generated in vitro and used for disease modelling and cell replacement therapy. A genetic study was performed in a patient suspected of monogenic diabetes. A novel heterozygous pathogenic variant in CEL (c.1818delC) was identified in the proband, allowing diagnosis of MODY8. Three MODY8-iPSC (induced pluripotent stem cell) clones were reprogrammed from skin fibroblasts of the patient, and their pluripotency and genomic stability confirmed. All 3 MODY8-iPSC differentiated into β cells following developmental stages. MODY8-iPSC-derived β cells were able to secrete insulin upon glucose dynamic perifusion. The CEL gene was not expressed in iPSCs nor during any steps of endocrine differentiation. iPSC lines from a MODY8 patient with a novel pathogenic variant in the CEL gene were generated; they are capable of differentiation into endocrine cells, and β cell function is preserved in mutated cells. These results set the basis for in vitro modelling of the disease and potentially for autologous β cell replacement.

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2018-01-30 | Monogenic diabetes: Implementation of translational genomic research towards precision medicine.

Various forms of early onset non-autoimmune diabetes are recognized as monogenic diseases, each subtype being caused by a single highly penetrant gene defect at the individual level. Monogenic diabetes (MD) is clinically and genetically heterogeneous, including maturity onset diabetes of the young and infancy-onset and neonatal diabetes mellitus, which are characterized by functional defects of insulin-producing pancreatic β-cells and hyperglycemia early in life. Depending on the genetic cause, MD differs in the age at diabetes onset, the severity of hyperglycemia, long-term diabetic complications, and extrapancreatic manifestations. In this review we discuss the many challenges of molecular genetic diagnosis of MD in the face of a substantial genetic heterogeneity, as well as the clinical benefit and cost-effectiveness of an early genetic diagnosis, as demonstrated by simulation models based on lifetime complications and treatment costs. We also discuss striking examples of proof-of-concept of genomic medicine, which have enabled marked improvement in patient care and long-term clinical management. Recent advances in genome editing and pluripotent stem cell reprogramming technologies provide new opportunities for in vitro diabetes modeling and the discovery of novel drug targets and cell-based diabetes therapies. A review of these future directions makes the case for exciting translational research to further our understanding of the pathophysiology of early onset diabetes.

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other

2021-12-13 | The dual role of RFX6 in directing β cell development and insulin production.

RFX6 transcription factor is believed to play a central role in directing cell development of insulin-producing pancreatic islet. RFX6 homozygous mutations cause syndromic neonatal diabetes with hypoplastic pancreas. However, RFX6 heterozygous mutations cause maturity-onset diabetes of the young (MODY) with normal pancreas development. Here, we show that RFX6 may control islet cell development and insulin production in different manners. The rfx6 knockout zebrafish generated by CRISPR/Cas9 exhibited an overt diabetes phenotype. Pancreatic islet failed to form compact structures in the knockout fish. While endocrine pancreatic islet non-β-cells were absent, insulin-producing β-cells were present in the knockout fish. Although insulin mRNA level was normal in the β-cells of the knockout fish, insulin protein level was decreased. High-throughput RNA sequencing (RNAseq) showed that differentially expressed genes were enriched in the translation term in islet β-cells from the knockout fish. Chromatin immunoprecipitation sequencing (ChIPseq) of normally developed islet β-cells from mice demonstrated that rfx6 interacted with translation initiation factors and controlled insulin translation. Our data indicate that Rfx6 may act as a transcription factor regulating the transcription of genes involved in mRNA translation, which may represent a new mechanism and treatment strategy for diseases.

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2020-03-01 | <p>Loss of HNF1α Function Contributes to Hepatocyte Proliferation and Abnormal Cholesterol Metabolism via Downregulating miR-122: A Novel Mechanism of MODY3</p>

Mutations in hepatocyte nuclear factor 1α (HNF1α) are the cause of maturity-onset diabetes of the young type 3 (MODY3) and involved in the development of hepatocellular adenoma and abnormal lipid metabolism. Previously, we have found that the serum microRNA (miR)-122 levels in MODY3 patients were lower than those in type 2 diabetes mellitus and healthy controls. This study aimed to investigate the mechanism of decreased miR-122 levels in patients with MODY3 and whether low levels of miR-122 mediate tumorigenesis and abnormal lipid metabolism associated with HNF1α deficiency in human hepatocytes.The expression of miR-122 was examined by real-time PCR. Dual-luciferase reporter assay was performed to confirm the transcriptional regulation of miR-122 by HNF1α. HepG2 cells were transfected with siRNA or miRNA mimic to downregulate or upregulate the expression of HNF1α or miR-122, respectively. CCK-8 and colony formation assay were used to determine cell proliferation. Lipid accumulation was examined by Oil Red O staining and intracellular triglyceride and cholesterol quantification assays.HNF1α regulated the expression of miR-122 by directly binding to its promoter. Knockdown of HNF1α in HepG2 cells reduced the expression of miR-122, increased proliferation and promoted intracellular cholesterol accumulation. Overexpression of miR-122 partially rescued the phenotypes associated with HNF1α deficiency in human hepatocytes. Mechanistically, HNF1α modulated cholesterol homeostasis via miR-122-dependent activation of sterol regulatory element-binding protein-2 (SREBP-2) and regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). Moreover, circulating miR-122 levels were associated with serum cholesterol levels.Loss of HNF1α function led to hepatocyte proliferation and abnormal cholesterol metabolism by downregulating miR-122. Our findings revealed a novel mechanism that low levels of miR-122 mediate tumorigenesis and abnormal lipid metabolism associated with MODY3. MiR-122 may be a potential therapeutic target for the treatment of MODY3.

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2017-07-19 | MicroRNAs as stress regulators in pancreatic beta cells and diabetes

MicroRNAs have emerged as important regulatory non-coding RNAs that tune cellular responses to physiological perturbations and disease conditions. An increasing body of literature underlines the important roles of miRNA function in pancreatic β-cells in response to metabolic, genetic and inflammatory stress. Lessons from genetic loss- and gain-of-function studies have implicated several highly expressed and evolutionary conserved miRNAs in stress signal modulation, resolution and buffering, thereby forming stabilizing miRNA networks that preserve β-cell differentiation, function, proliferation and cell survival. This review will summarize our current knowledge of how biologically relevant miRNAs regulate stress responses in pancreatic β-cells, discuss the challenges and opportunities associated with using secreted miRNAs as biomarkers and forecast how mechanistic knowledge of miRNA function can be exploited in developing miRNA-based therapeutics. miRNAs play important roles in the function, differentiation, proliferation, and survival of pancreatic β-cells. Many miRNA families that are regulated by metabolic, genetic, and inflammatory stressors have been found to coordinate the adaptive responses of β-cells in vivo in conditions such as obesity and diabetes.

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2010-11-01 | Loss of Nix in Pdx1-deficient mice prevents apoptotic and necrotic β cell death and diabetes

Mutations in pancreatic duodenal homeobox (PDX1) are linked to human type 2 diabetes and maturity-onset diabetes of the young type 4. Consistent with this, Pdx1-haploinsufficient mice develop diabetes. Both apoptosis and necrosis of β cells are mechanistically implicated in diabetes in these mice, but a molecular link between Pdx1 and these 2 forms of cell death has not been defined. In this study, we introduced an shRNA into mouse insulinoma MIN6 cells to deplete Pdx1 and found that expression of proapoptotic genes, including NIP3-like protein X (Nix), was increased. Forced Nix expression in MIN6 and pancreatic islet β cells induced programmed cell death by simultaneously activating apoptotic and mitochondrial permeability transition–dependent necrotic pathways. Preventing Nix upregulation during Pdx1 suppression abrogated apoptotic and necrotic β cell death in vitro. In Pdx1-haploinsufficient mice, Nix ablation normalized pancreatic islet architecture, β cell mass, and insulin secretion and eliminated reactive hyperglycemia after glucose challenge. These results establish Nix as a critical mediator of β cell apoptosis and programmed necrosis in Pdx1-deficient diabetes.

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2007-12-13 | Mutations of HNF-1β inhibit epithelial morphogenesis through dysregulation of SOCS-3

Hepatocyte nuclear factor-1β (HNF-1β) is a Pit-1, Oct-1/2, Unc-86 (POU) homeodomain-containing transcription factor expressed in the kidney, liver, pancreas, and other epithelial organs. Mutations of HNF-1β cause maturity-onset diabetes of the young, type 5 (MODY5), which is characterized by early-onset diabetes mellitus and congenital malformations of the kidney, pancreas, and genital tract. Knockout of HNF-1β in the mouse kidney results in cyst formation. However, the signaling pathways and transcriptional programs controlled by HNF-1β are poorly understood. Using genome-wide chromatin immunoprecipitation and DNA microarray (ChIP-chip) and microarray analysis of mRNA expression, we identified SOCS3 (suppressor of cytokine signaling-3) as a previously unrecognized target gene of HNF-1β in the kidney. HNF-1β binds to the SOCS3 promoter and represses SOCS3 transcription. The expression of SOCS3 is increased in HNF-1β knockout mice and in renal epithelial cells expressing dominant-negative mutant HNF-1β. Increased levels of SOCS-3 inhibit HGF-induced tubulogenesis by decreasing phosphorylation of Erk and STAT-3. Conversely, knockdown of SOCS-3 in renal epithelial cells expressing dominant-negative mutant HNF-1β rescues the defect in HGF-induced tubulogenesis by restoring phosphorylation of Erk and STAT-3. Thus, HNF-1β regulates tubulogenesis by controlling the levels of SOCS-3 expression. Manipulating the levels of SOCS-3 may be a useful therapeutic approach for human diseases induced by HNF-1β mutations.

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