RARE DISEASE
Neonatal diabetes mellitus
Neonatal diabetes mellitus
Neonatal diabetes mellitus
Synonyms: Congenital diabetes mellitus, Diabetes of infancy, Monogenic diabetes of infancy, NDM
Synonyms: Congenital diabetes mellitus, Diabetes of infancy, Monogenic diabetes of infancy, NDM
Synonyms: Congenital diabetes mellitus, Diabetes of infancy, Monogenic diabetes of infancy, NDM
Drug discovery
3
drugs
With orphan designations
Overview
Neonatal diabetes mellitus (NDM) is a rare monogenic disorder (1 in 90,000-260,000 births) characterized by insulin deficiency onset before 6 months of age. It manifests as transient (TNDM) or permanent (PNDM) forms, driven by genetic mutations in genes like KCNJ11, ABCC8, INS, or 6q24 imprinting defects. Diagnosis requires genetic testing, as 50% of PNDM cases involve KATP channel mutations responsive to sulfonylureas instead of insulin [1][6][19].
Burden
Associated with intrauterine growth restriction (70% of cases) and macroglossia/umbilical hernias in TNDM [1][4]
14–50% relapse risk in TNDM; lifelong diabetes management required for PNDM [4][12][15]
Economic burden stems from costly insulin regimens, genetic testing, and neurodevelopmental support needs [2][7][19]
Therapies
Insulin: Primary therapy for most cases, often via pumps for precise dosing in infants [3][6][13]
Sulfonylureas: First-line for KCNJ11/ABCC8 mutations (40% of PNDM), improving glycemic and neurodevelopmental outcomes [6][11][17]
Multidisciplinary care: Includes genetic counseling, nutritional support, and monitoring for comorbidities (e.g., neurodevelopmental disorders) [3][8][19]
Categories: rare endocrine diseases, rare genetic diseases
Research Papers
389 drug discovery papers about Neonatal diabetes mellitus, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
389 drug discovery papers about Neonatal diabetes mellitus, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-12 | Neonatal Diabetes Mellitus in a Resource-Limited Setting: Clinical Spectrum, Genetic Heterogeneity, Impact of Malnutrition, and Outcomes with Simplified Basal Insulin Therapy.
To characterize genetic heterogeneity, clinical spectrum, and management outcomes of neonatal diabetes mellitus (NDM) in a tertiary care center in a resource-limited region, with emphasis on emerging genetic etiologies and simplified insulin regimens. Observational case series with systematic prospective data collection at defined intervals. Seven consecutive infants with insulin-dependent hyperglycemia diagnosed within 6 months of life were enrolled and followed from presentation through 3-month outpatient follow-up. Clinical features, biochemical parameters, genetic testing results, and treatment responses were documented daily during hospitalization and at scheduled follow-up visits. Time to glycemic control (defined as blood glucose 100-180 mg/dL for ≥24 hours on stable therapy) and prognostic factors were analyzed. Three of 7 cases (42.9%) had identified genetic mutations: two GCK mutations and one homozygous NARS2 variant (c.583T>C; p.Phe195Leu; VUS). Four cases (57.1%) remained genetically unsolved; three of these initially received glibenclamide following a provisional ARMS PCR report suggestive of ABCC8 variant, which was subsequently reclassified as benign on whole exome sequencing, prompting discontinuation of sulfonylurea therapy. GCK and NARS2-mutated cases required insulin-only therapy. A novel NARS2 case with severe intrauterine growth restriction (birth weight 1.5 kg) and marked hyperglycemia (640 mg/dL) achieved glycemic control in 7 days using simplified NPH (Neutral Protamine Hagedorn) insulin monotherapy without mealtime boluses, enabling exclusive breastfeeding. Severe malnutrition combined with metabolic acidosis was the strongest independent predictor of delayed control (40 days versus 5-7 days). All cases achieved glycemic control. Genetic testing provides essential precision-medicine guidance for NDM management despite a 42.9% diagnostic yield limited by current gene panels. This series expands the NARS2-associated NDM phenotypic spectrum and demonstrates that simplified basal-only NPH insulin regimens achieve excellent outcomes in IUGR neonates while enabling exclusive breastfeeding. Pragmatic strategies optimized for resource-limited settings enable equitable, high-quality NDM care.
2026-03-31 | Five-year follow-up of incretin-based therapy in a patient with KCNJ11-related permanent neonatal diabetes: Achieving insulin discontinuation and sulfonylurea reduction.
Permanent neonatal diabetes mellitus (PNDM) is commonly caused by pathogenic variants in KCNJ11 that impair insulin secretion through ATP-sensitive potassium (KATP) channel dysfunction. Sulfonylureas (SUs) can stimulate insulin secretion and enable insulin discontinuation, but insulin withdrawal may remain difficult even under high-dose SU, especially when therapy is initiated later in life. We describe a woman with KCNJ11-related PNDM who achieved insulin discontinuation after adding sitagliptin, followed by further improvement with semaglutide during a five-year follow-up. HbA1c remained between 6.1% and 6.5% on semaglutide 0.25 mg/week, with a 60% reduction in glibenclamide and preserved endogenous insulin secretion. A transient HbA1c rise after semaglutide interruption, followed by improvement upon resumption, confirmed its reversible effect. No episodes of severe hypoglycemia or gastrointestinal adverse events occurred. This case suggests that combining insulin secretagogues targeting both KATP-dependent (triggering: SU) and KATP-independent (amplifying: incretin-based therapy) pathways may provide additive or synergistic benefits in PNDM.
2026-02-26 | Implementation of a Hybrid Closed-Loop Automated Insulin Delivery System in a 29-Day Infant With Neonatal Diabetes.
Neonatal diabetes mellitus (NDM) often requires insulin treatment to maintain adequate glycemic control and support growth and development. Conventional insulin treatment regimens are particularly challenging in NDM due to young age, developmentally appropriate feeding variation, and heightened insulin sensitivity leading to very small insulin dosing. We present this case as-to our knowledge-the earliest implementation of a hybrid closed-loop (HCLS) automated insulin delivery system in an NDM patient. HCLS with U10 significantly improved glycemic control compared to conventional insulin delivery with minimization of hypoglycemia. The adaptive capabilities of HCLS allowed for developmentally appropriate, ad libitum feeding without carbohydrate quantification, resulting in a meaningful quality of life improvement. This case adds to evidence supporting safe and effective use of diabetes technology in very young children. It demonstrates that the benefits seen in older populations can be achieved in neonatal patients and supports expanding clinical use of HCLS systems in this setting.
2025-11-06 | Additive Effects of Dorzagliatin and Glucagon-Like Peptide 1 Receptor Agonism in a Novel Mouse Model of GCK-MODY and in Obese db/db Mice.
Glucokinase (GK) catalyzes the key regulatory step in glucose-stimulated insulin secretion (GSIS). Correspondingly, hetero- and homozygous mutations in human GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes mellitus, respectively. To explore the possible utility of GK activators (GKAs) and of glucagon-like peptide 1 (GLP-1) receptor agonists in these diseases, we have developed a novel hypomorphic Gck allele in mice encoding an aberrantly spliced mRNA. In islets from homozygous knock-in (GckKI/KI) mice, GK immunoreactivity was reduced by >85%, and GSIS eliminated. Homozygous GckKI/KI mice displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c ∼108 mmol/mol), ketosis, and nephropathy. Heterozygous GckKI/+ mice were glucose intolerant (HbA1c ∼37 mmol/mol). Abnormal glucose-stimulated Ca2+ dynamics in GckKI/+ islets were completely reversed by the GKA dorzagliatin, which was largely inactive in homozygous GckKI/KI mouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male GckKI/+ mice, an action potentiated by dorzagliatin. Sex-dependent additive effects of these agents were also observed on insulin secretion in vitro. Similar additive effects of the drugs were observed in obese hyperglycemic db/db mice. Combined treatment with GKA and incretin mimetics may thus be useful in GCK-MODY and in more common forms of type 2 diabetes. Glucokinase (GK) deficiency can drive maturity-onset diabetes of the young (GCK-MODY) in heterozygotes and permanent neonatal diabetes in homozygotes. We describe a hypomorphic Gck allele that results in aberrant splicing in islets and liver lowering GK activity by ∼85%. Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of glucagon-like receptor-1 receptor activation sex dependently in heterozygous Gck mice and in obese hyperglycemic db/db mice. Combined use of these drugs may be useful in some forms of GCK-MODY and in obesity-related type 2 diabetes.
2025-10-13 | Diabetic Ketoacidosis as the Presentation of Immune Dysregulation, Polyendocrinopathy, Enteropathy, and X-Linked Syndrome: A Case Report.
Neonatal diabetes mellitus (NDM) is a rare and often misdiagnosed collection of disorders typically presenting in the first 6 months of life, characterized by insulin deficiency and hyperglycemia. This case study discusses a neonate initially suspected of having sepsis due to nonspecific symptoms such as vomiting, increased work of breathing, and grunting. Upon further investigation, the child was diagnosed with neonatal diabetic ketoacidosis (DKA) and treated accordingly. Genetic testing and subsequent management revealed that the infant was hemizygous for a FOXP3 missense variant, leading to a diagnosis of IPEX syndrome, an X-linked autoimmune disorder with a poor prognosis. This case highlights the importance of considering NDM in differential diagnoses, especially when symptoms mimic other neonatal illnesses such as sepsis, and emphasizes the need for prompt recognition and management to prevent complications. In addition, this article outlines the management strategies for IPEX syndrome, including insulin therapy, immune suppression, and the potential for hematopoietic stem cell transplantation.
gene therapies
2025-06-01 | Precision Diagnostics for Monogenic Diabetes in Children
Monogenic diabetes, caused by a single-gene defect, accounts for roughly 1–5% of pediatric diabetes cases. Although relatively uncommon, correct identification of these subtypes is critical, as accurate classification can markedly influence both treatment and prognosis. However, distinguishing monogenic forms from type 1 (T1D) or type 2 diabetes (T2D) remains challenging due to overlapping features, such as early onset and variable insulin requirements. Many children with monogenic diabetes are misdiagnosed and, consequently, may not receive optimal therapy. Advances in sequencing technologies, combined with growing knowledge of the underlying genetic causes, now enable earlier, more precise diagnoses and offer opportunities to tailor therapy—often avoiding insulin in favor of targeted interventions. In this review, we summarize key categories of monogenic diabetes, including maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM), and syndromic forms and outline current recommended diagnostic workflows and genetic testing strategies. Ultimately, we aim to provide clinicians with a clear, actionable framework for recognizing and managing these significant but often underrecognized forms of pediatric diabetes.
2025-04-11 | The genetics of low and high birthweight and their relationship with cardiometabolic disease.
Low birthweight infants are at increased risk not only of mortality, but also of type 2 diabetes mellitus and CVD in later life. At the opposite end of the spectrum, high birthweight infants have increased risk of birth complications, such as shoulder dystocia, neonatal hypoglycaemia and obesity, and similarly increased risk of type 2 diabetes mellitus and CVD. However, previous genome-wide association studies (GWAS) of birthweight in the UK Biobank have primarily focused on individuals within the 'normal' range and have excluded individuals with high and low birthweight (<2.5 kg or >4.5 kg). The aim of this study was to investigate genetic variation associated within the tail ends of the birthweight distribution, to: (1) see whether the genetic factors operating in these regions were different from those that explained variation in birthweight within the normal range; (2) explore the genetic correlation between extremes of birthweight and cardiometabolic disease; and (3) investigate whether analysing the full distribution of birthweight values, including the extremes, improved the ability to detect genuine loci in GWAS. We performed case-control GWAS analysis of low (<2.5 kg) and high (>4.5 kg) birthweight in the UK Biobank using REGENIE software (Nlow=20,947; Nhigh=12,715; Ncontrols=207,506) and conducted three continuous GWAS of birthweight, one including the full range of birthweights, one involving a truncated GWAS including only individuals with birthweights between 2.5 and 4.5 kg and a third GWAS that winsorised birthweight values <2.5 kg and >4.5 kg. Additionally, we performed bivariate linkage disequilibrium (LD) score regression to estimate the genetic correlation between low/normal/high birthweight and cardiometabolic traits. Bivariate LD score regression analyses suggested that high birthweight had a mostly similar genetic aetiology to birthweight within the normal range (genetic correlation coefficient [rG]=0.91, 95% CI 0.83, 0.99), whereas there was more evidence for a separate set of genes underlying low birthweight (rG=-0.74, 95% CI 0.66, 0.82). Low birthweight was also significantly positively genetically correlated with most cardiometabolic traits and diseases we examined, whereas high birthweight was mostly positively genetically correlated with adiposity and anthropometric-related traits. The winsorisation strategy performed best in terms of locus detection, with the number of independent genome-wide significant associations (p<5×10-8) increasing from 120 genetic variants at 94 loci in the truncated GWAS to 270 genetic variants at 178 loci, including 27 variants at 25 loci that had not been identified in previous birthweight GWAS. This included a novel low-frequency missense variant in the ABCC8 gene, a gene known to be involved in congenital hyperinsulinism, neonatal diabetes mellitus and MODY, that was estimated to be responsible for a 170 g increase in birthweight amongst carriers. Our results underscore the importance of genetic factors in the genesis of the phenotypic correlation between birthweight and cardiometabolic traits and diseases.
2025-03-10 | Two cases of neonatal hyperglycemia caused by a homozygous COQ9 stop-gain variant.
Neonatal diabetes mellitus (NDM) is a monogenic condition diagnosed <6 months of age with >40 genetic causes. International guidelines recommend referral for genetic testing immediately after diagnosis since the genetic result guides clinical management. We used next-generation sequencing to identify a homozygous pathogenic variant, p.(Arg244*), in COQ9 in 2 individuals referred for NDM testing. Both had insulin-treated hyperglycemia, severe structural brain defects, dysmorphic features, and lactic acidosis. Recessive loss-of-function variants in COQ9 cause Coenzyme Q10 deficiency-5, a multi-system mitochondrial disease, with 7 cases reported. Neonatal hyperglycemia has not been reported in any of these cases but has been described for two other Coenzyme Q10 disorders caused by variants in COQ2 and COQ4. Our report shows that individuals with COQ9-related disease can present with neonatal hyperglycemia, expanding the clinical spectrum of this disorder. We recommend the inclusion of COQ9, as well as COQ2 and COQ4, to gene panels used for NDM testing.
2024-07-10 | Monogenic diabetes in children: An underdiagnosed and poorly managed clinical dilemma.
Monogenic diabetes, constituting 1%-2% of global diabetes cases, arises from single gene defects with distinctive inheritance patterns. Despite over 50 ass-ociated genetic disorders, accurate diagnoses and management of monogenic diabetes remain inadequate, underscoring insufficient clinician awareness. The disease spectrum encompasses maturity-onset diabetes of the young (MODY), characterized by distinct genetic mutations affecting insulin secretion, and neonatal diabetes mellitus (NDM) - a heterogeneous group of severe hyperglycemic disorders in infants. Mitochondrial diabetes, autoimmune monogenic diabetes, genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape. A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY. NDM diagnosis warrants immediate molecular genetic testing for infants under six months. Identifying these genetic defects presents a unique opportunity for precision medicine. Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes. Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes. The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.
2023-12-16 | Application of CRISPR-Cas9 technology in diabetes research.
Diabetes is a chronic disorder with rapidly increasing prevalence that is a major global issue of our current era. There are two major types of diabetes. Polygenic forms of diabetes include type 1 diabetes (T1D) and type 2 diabetes (T2D) and its monogenic forms are maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM). There are no permanent therapeutic approaches for diabetes and current therapies rely on regular administration of various drugs or insulin injection. Recently, gene editing strategies have offered new promise for treating genetic disorders. Targeted genome editing is a fast-growing technology, recruiting programmable nucleases to specifically modify target genomic sequences. These targeted nucleases generate double-strand breaks at target regions in the genome, which induce cellular repair pathways including non-homologous end joining (NHEJ) and homology-directed repair (HDR). Clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) is a novel gene-editing system, permitting precise genome modification. CRISPR/Cas9 has great potential for various applications in diabetic research such as gene screening, generation of diabetic animal models and treatment. In this article, gene-editing strategies are summarized with a focus on the CRISPR/Cas9 approach in diabetes research.
proteins
2026-08-18 | Inhibition Mechanism of Pancreatic KATP Channels by Centipede Toxin.
The pancreatic adenosine triphosphate (ATP)-sensitive potassium (KATP) channel acts as a crucial metabolic sensor, regulating insulin secretion to maintain whole-body energy homeostasis. Gain-of-function mutations in this channel lead to neonatal diabetes mellitus, a rare disorder in which certain mutants exhibit resistance to standard sulfonylurea therapy. Recent studies have identified a centipede toxin, SpTx1, as a potent inhibitor of both human pancreatic KATP channels and their gain-of-function mutants. This toxin stimulates insulin secretion, offering a promising therapeutic strategy for neonatal diabetes. However, the molecular mechanism by which SpTx1 inhibits the KATP channel has remained unclear. Here, we report the crystal structure of SpTx1 and the cryo-electron microscopy structure of the KATP channel in complex with SpTx1. The structure reveals that a single SpTx1 molecule binds to the extracellular surface of the Kir6.2 tetramer. Multiple interactions at the SpTx1-Kir6.2 interface underpin the high affinity and specificity of SpTx1 for human Kir6.2. We demonstrate that SpTx1 inhibits potassium currents by physically blocking the ion conduction pore. Furthermore, a structure-guided search identified another centipede toxin, Sm3a, as a novel KATP channel blocker. Together, these findings provide key insights into the inhibitory mechanism of centipede toxins against the human Kir6.2-containing KATP channel and establish a foundation for developing these toxins into potential therapeutics for KATP channel-related diseases.
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.
2024-11-27 | The Identification of a Novel Pathogenic Variant in the GATA6 Gene in a Child with Neonatal Diabetes.
GATA6 syndrome is a rare monogenic disorder caused by heterozygous variants in the gene GATA6, which controls the early embryonic differentiation of germ layers and the development of different organs. We present the results of the 7-year follow-up of a child with this syndrome as well as the following conditions: diabetes mellitus, exocrine pancreatic insufficiency, gallbladder atresia, and congenital heart disease (CHD). At birth, the patient was diagnosed with neonatal diabetes mellitus (NDM) associated with heart (mitral valve prolapse) and gastrointestinal abnormalities (gallbladder atresia). Diabetes remitted within weeks and relapsed at the age of 2. We identified a de novo variant of a 4-nucleotide deletion (c.1302+4_1302+7del), previously unreported in the literature, in the donor splicing site of exon 3 of the GATA6 gene in a heterozygous state. Screening for other possible components of GATA6 syndrome revealed exocrine pancreatic insufficiency, and pancreatic enzyme replacement therapy resulted in improved dyspeptic symptoms, and growth rates increased. In addition, the patient was diagnosed with autoimmune thyroiditis and progressive myopia.
2024-10-21 | Long-Term Effects of Incretin-Based Drugs on Glycemic Control in Permanent Neonatal Diabetes.
Permanent neonatal diabetes mellitus (PNDM) is a genetic disorder, characterized by a decrease in endogenous insulin secretion. Therefore, exogenous insulin supplementation plays a central role in controlling glycemia. Although adding a sulfonylurea can help to discontinue insulin, discontinuation is sometimes difficult when the sulfonylurea is administered at older ages. A 24-year-old woman with longstanding PNDM who had poor glycemic control using insulin (47 U/day) and high-dose glibenclamide (0.6 mg/kg/day), had successfully discontinued insulin after initiating the dipeptidyl peptidase-4 inhibitor sitagliptin (50 mg/day). Additionally, hemoglobin A1c levels decreased by 4.8%. Double dosing of sitagliptin and subsequent switching to the glucagon-like peptide-1 receptor agonist semaglutide (0.25 mg/week followed by 0.5 mg/week) further decreased hemoglobin A1c values, with graded improvements in endogenous insulin secretion. There were no episodes of hypoglycemia during which glibenclamide was titrated down from 0.6 to 0.4 mg/kg/day. Intra- and inter-day glucose variability as assessed by continuous glucose monitoring was also improved. In patients with PNDM, administration and dose escalation of incretin-based drugs, in addition to a high-dose sulfonylurea, could be a useful treatment strategy. This strategy may be helpful for discontinuing insulin, downtitrating sulfonylureas, and subsequent achievement of better glycemic control regarding long-term stability and short-term variability.
2024-10-01 | 12599 Early Remission Of Chromosome 6 Q 24-related Neonatal Diabetes Mellitus
Abstract Disclosure: R. Pratibha: None. K. Dummula: None. Introduction: Chromosome 6q24 imprinting abnormalities represent the predominant cause of transient neonatal diabetes mellitus (TNDM), accounting for over two-thirds of cases with an estimated prevalence of 1 in 400,000. While remission typically manifests by 3 months of age, herein we detail a case of Chromosome 6q24-related TNDM exhibiting remission by 1.5 months of age. We share our clinical experience in managing this case without hypoglycemia and using C-Peptide levels as a monitoring tool to track the resolution. Case: A female infant, born at 36 weeks via elective C-section due to fetal growth restriction and oligohydramnios, was closely monitored in the nursery for potential hypoglycemia. Contrary to the expectation, she displayed escalating hyperglycemia, necessitating insulin infusion within 25 hours of birth. Apgar scores were 7 and 9, and the birth weight was 2095 g (6th percentile). Maternal history included impaired glucose tolerance in a previous pregnancy with borderline glucose tolerance during this gestation. The newborn physical exam was unremarkable except for mild macroglossia. Despite initial blood glucose (BG) of 52 mg/dl, it rose to 257 mg/dL by 16 hours. Insulin drip was started at 24 hours due to BG of 304 mg/dL. The monogenic diabetes panel obtained on day of life (DOL) #2 was negative; no acidosis was observed. The C- Peptide was low at 0.2 ng/ml. Insulin infusion was continued until DOL # 20. A trial of glyburide commenced on DOL #9 while on Insulin drip, yielded minimal response, prompting a transition to short-acting insulin for correction of hyperglycemia (>250 mg/dL). C-peptide level during sulfonylurea (SU) trial remained low (0.5 ng/mL). The infant required 2 to 3 corrections per day with 0.05 units of Lispro Insulin, with the last dose administered at 44 days. She did not receive any long-acting Insulin. As of her last follow-up at the endocrine clinic at 57 days of age, the infant is thriving well and has normal blood glucose levels. The 6q24 Methylation-MLPA study showed duplication of 6q24 on the paternally inherited chromosome 6. Significantly, she never encountered hypoglycemia during her hospital stay. The C-peptide increased to 0.8 ng/ml at DOL#37 and had normalized to 1.3 ng/mL by DOL#57 indicating remission of TNDM. Conclusion: 6q24-related TNDM may often be characterized by features such as small for gestational age (SGA), macroglossia, umbilical hernia, cardiac and renal abnormalities. Early presentation of hyperglycemia with this phenotype must prompt its diagnostic evaluation. Early resolution by 1.5 months as seen in our case is uncommon. Uniquely, we used C-peptide as a tracking tool to guide resolution and manage insulin therapy. Presentation: 6/3/2024
cell therapies
2025-10-08 | Cyclophosphamide post-haploidentical stem cell transplantation experience in an infant with IPEX syndrome.
IPEX syndrome is a rare hemizygous X-linked disorder with complex autoimmune reactions, characterized by immune dysregulation, polyendocrinopathy, and enteropathy. It has a poor prognosis and a high mortality risk without prompt therapy. Treatment options include pharmacological immunosuppression, nutritional and supportive care, and hematopoietic stem cell transplantation, the latter as the only curative option. We present the case of a male infant, the second child of a nonconsanguineous couple, with negative prenatal screening and intrauterine growth restriction detected at 27 weeks' gestation. He was diagnosed with neonatal diabetes mellitus and treated with insulin. He was re-hospitalized for secretory diarrhea and rotavirus infection. At that moment, he was diagnosed with failure to thrive and hypothyroidism. He acquired multiple severe infections, including Candida parapsilosis fungemia, an urinary infection caused by extended-spectrum β-lactamase-producing Escherichia coli, and Klebsiella pneumoniae bacteremia. Endoscopy biopsy revealed chronic duodenitis with the absence of goblet and Paneth cells, findings suggestive of autoimmune enteropathy. Genetic testing identified a mutation in the FOXP3 gene, confirming the diagnosis of IPEX syndrome. We performed a hematopoietic stem cell transplantation from an alternative haploidentical donor and administered a cyclophosphamide post-transplant regime. At 320 days posttransplant, the patient fully recovered his nutritional status and immunity. Haploidentical transplantation with a post-transplant cyclophosphamide regime can be a viable therapeutic option for patients with IPEX syndrome, lacking an HLA-identical donor, with promising outcomes based on the follow-up data.
2024-09-08 | Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis.
Glucokinase (GCK), a key enzyme in glucose metabolism, plays a central role in glucose sensing and insulin secretion in pancreatic β-cells, as well as glycogen synthesis in the liver. Mutations in the GCK gene have been associated with various monogenic diabetes (MD) disorders, including permanent neonatal diabetes mellitus (PNDM) and maturity-onset diabetes of the young (MODY), highlighting its importance in maintaining glucose homeostasis. Additionally, GCK gain-of-function mutations lead to a rare congenital form of hyperinsulinism known as hyperinsulinemic hypoglycemia (HH), characterized by increased enzymatic activity and increased glucose sensitivity in pancreatic β-cells. This review offers a comprehensive exploration of the critical role played by the GCK gene in diabetes development, shedding light on its expression patterns, regulatory mechanisms, and diverse forms of associated monogenic disorders. Structural and mechanistic insights into GCK's involvement in glucose metabolism are discussed, emphasizing its significance in insulin secretion and glycogen synthesis. Animal models have provided valuable insights into the physiological consequences of GCK mutations, although challenges remain in accurately recapitulating human disease phenotypes. In addition, the potential of human pluripotent stem cell (hPSC) technology in overcoming current model limitations is discussed, offering a promising avenue for studying GCK-related diseases at the molecular level. Ultimately, a deeper understanding of GCK's multifaceted role in glucose metabolism and its dysregulation in disease states holds implications for developing targeted therapeutic interventions for diabetes and related disorders.
2023-12-02 | Metadichol-Induced Differentiation of Pancreatic Ductal Cells (PANC-1) into Insulin-Producing Cells
Endocrine gene expression in PANC-1, a type of pancreatic cancer cell, has been studied in the context of their potential to be reprogrammed toward a normal, differentiated state. Alkaline phosphatase activity has also been shown in pluripotent stem cells to differentiate between feeder and parental cells in reprogramming experiments. Metadichol®-based cell programming holds promise as a versatile and potentially safer approach for manipulating cellular behavior without the use of viral vectors, gating, or CRISPR. Using qRT‒PCR the results show multifold increase in the gene expression of CA9, GCG, INS MAFA, NEUROD1, NGN3, NKX2-2, PAX6: PDX1, SLC2A2, FOXO1, and SIRT1. ALP levels increased and this activity is often used to distinguish stem cells from feeder cells as well as from parental cells in reprogramming experiments. Pluripotency was confirmed by the presence of islet-like structures on day eight. Metadichol exhibits anticancer activity with a CC50 value of 5.50 µg/ml compared to standard doxorubicin with a CC50 value of 10.28 µg/ml. At 100 ug/ml Metadichol is 82% cytotoxic.in a MTT assay Anti-tumor gene Klotho’s expression was increased 70fold on day eight. All the genes seen expressed regulate endocrine cell development in the pancreas and are involved in insulin and glucagon secretion. Gene network analysis is presented to show how Metadichol induced expression leads to a closed loop feedback network and biological process that would help in mitigating diabetes and other related disorders.
2023-09-13 | Metadichol induced differentiation of pancreatic ductal cells (PANC-1) into insulin-producing cells
Abstract Endocrine gene expression in PANC-1, a type of pancreatic cancer cell, has been studied in the context of their potential to be reprogrammed toward a normal, differentiated state. Alkaline phosphatase activity has also been shown in pluripotent stem cells to differentiate between feeder and parental cells in reprogramming experiments. Metadichol ® -based cell programming holds promise as a versatile and potentially safer approach for manipulating cellular behavior without the use of viral vectors, gating, or CRISPR. This study investigated the multifold increase in the gene expression of CA9 , GCG , INS MAFA , NEUROD1 , NGN3 , NKX2-2 , PAX6: PDX1 , SLC2A2 , FOXO1 , and SIRT1 using qRT‒PCR. These genes regulate endocrine cell development in the pancreas and are involved in insulin and glucagon secretion. Gene network analysis is presented to show how Metadichol-induced expression leads to a closed loop feedback network and biological process that would help in mitigating diabetes and other related disorders.
2021-01-05 | Recent progress in pancreatic islet cell therapy
Abstract Human pluripotent stem cells (PSCs), including human embryonic stem cells and induced pluripotent stem cells, are promising cell sources in regenerating pancreatic islets through in vitro directed differentiation. Recent progress in this research field has made it possible to generate glucose-responsive pancreatic islet cells from PSCs. Single-cell RNA sequencing techniques have been applied to analyze PSC-derived endocrine beta-cells, which are then compared with human islets. This has led to the identification of novel signaling pathways and molecules involved in lineage commitment during pancreatic differentiation and maturation processes. Single-cell transcriptomics are also used to construct a detailed map of in vivo endocrine differentiation of developing mouse embryos to study pancreatic islet development. Mimicking those occurring in vivo, it was reported that differentiating PSCs can generate similar islet cell structures, while metabolomics analysis highlighted key components involved in PSC-derived pancreatic islet cell function, providing information for the improvement of in vitro pancreatic maturation procedures. In addition, cell transplantation into diabetic animal models, together with the cell delivery system, is studied to ensure the therapeutic potentials of PSC-derived pancreatic islet cells. Combined with gene-editing technology, the engineered mutation-corrected PSC lines originated from diabetes patients could be differentiated into functional pancreatic islet cells, suggesting possible autologous cell therapy in the future. These PSC-derived pancreatic islet cells are a potential tool for studies of disease modeling and drug testing. Herein, we outlined the directed differentiation procedures of PSC-derived pancreatic islet cells, novel findings through transcriptome and metabolome studies, and recent progress in disease modeling.
other
2022-09-30 | Monogenic diabetes clinic (MDC): 3-year experience
Abstract Aim In the pediatric diabetes clinic, patients with type 1 diabetes mellitus (T1D) account for more than 90% of cases, while monogenic forms represent about 6%. Many monogenic diabetes subtypes may respond to therapies other than insulin and have chronic diabetes complication prognosis that is different from T1D. With the aim of providing a better diagnostic pipeline and a tailored care for patients with monogenic diabetes, we set up a monogenic diabetes clinic (MDC). Methods In the first 3 years of activity 97 patients with non-autoimmune forms of hyperglycemia were referred to MDC. Genetic testing was requested for 80 patients and 68 genetic reports were available for review. Results In 58 subjects hyperglycemia was discovered beyond 1 year of age (Group 1) and in 10 before 1 year of age (Group 2). Genetic variants considered causative of hyperglycemia were identified in 25 and 6 patients of Group 1 and 2, respectively, with a pick up rate of 43.1% (25/58) for Group 1 and 60% (6/10) for Group 2 (global pick-up rate: 45.5%; 31/68). When we considered probands of Group 1 with a parental history of hyperglycemia, 58.3% (21/36) had a positive genetic test for GCK or HNF1A genes, while pick-up rate was 18.1% (4/22) in patients with mute family history for diabetes. Specific treatments for each condition were administered in most cases. Conclusion We conclude that MDC may contribute to provide a better diabetes care in the pediatric setting.
small molecules
2026-06-12 | Neonatal Diabetes Mellitus in a Resource-Limited Setting: Clinical Spectrum, Genetic Heterogeneity, Impact of Malnutrition, and Outcomes with Simplified Basal Insulin Therapy.
To characterize genetic heterogeneity, clinical spectrum, and management outcomes of neonatal diabetes mellitus (NDM) in a tertiary care center in a resource-limited region, with emphasis on emerging genetic etiologies and simplified insulin regimens. Observational case series with systematic prospective data collection at defined intervals. Seven consecutive infants with insulin-dependent hyperglycemia diagnosed within 6 months of life were enrolled and followed from presentation through 3-month outpatient follow-up. Clinical features, biochemical parameters, genetic testing results, and treatment responses were documented daily during hospitalization and at scheduled follow-up visits. Time to glycemic control (defined as blood glucose 100-180 mg/dL for ≥24 hours on stable therapy) and prognostic factors were analyzed. Three of 7 cases (42.9%) had identified genetic mutations: two GCK mutations and one homozygous NARS2 variant (c.583T>C; p.Phe195Leu; VUS). Four cases (57.1%) remained genetically unsolved; three of these initially received glibenclamide following a provisional ARMS PCR report suggestive of ABCC8 variant, which was subsequently reclassified as benign on whole exome sequencing, prompting discontinuation of sulfonylurea therapy. GCK and NARS2-mutated cases required insulin-only therapy. A novel NARS2 case with severe intrauterine growth restriction (birth weight 1.5 kg) and marked hyperglycemia (640 mg/dL) achieved glycemic control in 7 days using simplified NPH (Neutral Protamine Hagedorn) insulin monotherapy without mealtime boluses, enabling exclusive breastfeeding. Severe malnutrition combined with metabolic acidosis was the strongest independent predictor of delayed control (40 days versus 5-7 days). All cases achieved glycemic control. Genetic testing provides essential precision-medicine guidance for NDM management despite a 42.9% diagnostic yield limited by current gene panels. This series expands the NARS2-associated NDM phenotypic spectrum and demonstrates that simplified basal-only NPH insulin regimens achieve excellent outcomes in IUGR neonates while enabling exclusive breastfeeding. Pragmatic strategies optimized for resource-limited settings enable equitable, high-quality NDM care.
2026-03-31 | Five-year follow-up of incretin-based therapy in a patient with KCNJ11-related permanent neonatal diabetes: Achieving insulin discontinuation and sulfonylurea reduction.
Permanent neonatal diabetes mellitus (PNDM) is commonly caused by pathogenic variants in KCNJ11 that impair insulin secretion through ATP-sensitive potassium (KATP) channel dysfunction. Sulfonylureas (SUs) can stimulate insulin secretion and enable insulin discontinuation, but insulin withdrawal may remain difficult even under high-dose SU, especially when therapy is initiated later in life. We describe a woman with KCNJ11-related PNDM who achieved insulin discontinuation after adding sitagliptin, followed by further improvement with semaglutide during a five-year follow-up. HbA1c remained between 6.1% and 6.5% on semaglutide 0.25 mg/week, with a 60% reduction in glibenclamide and preserved endogenous insulin secretion. A transient HbA1c rise after semaglutide interruption, followed by improvement upon resumption, confirmed its reversible effect. No episodes of severe hypoglycemia or gastrointestinal adverse events occurred. This case suggests that combining insulin secretagogues targeting both KATP-dependent (triggering: SU) and KATP-independent (amplifying: incretin-based therapy) pathways may provide additive or synergistic benefits in PNDM.
2026-02-26 | Implementation of a Hybrid Closed-Loop Automated Insulin Delivery System in a 29-Day Infant With Neonatal Diabetes.
Neonatal diabetes mellitus (NDM) often requires insulin treatment to maintain adequate glycemic control and support growth and development. Conventional insulin treatment regimens are particularly challenging in NDM due to young age, developmentally appropriate feeding variation, and heightened insulin sensitivity leading to very small insulin dosing. We present this case as-to our knowledge-the earliest implementation of a hybrid closed-loop (HCLS) automated insulin delivery system in an NDM patient. HCLS with U10 significantly improved glycemic control compared to conventional insulin delivery with minimization of hypoglycemia. The adaptive capabilities of HCLS allowed for developmentally appropriate, ad libitum feeding without carbohydrate quantification, resulting in a meaningful quality of life improvement. This case adds to evidence supporting safe and effective use of diabetes technology in very young children. It demonstrates that the benefits seen in older populations can be achieved in neonatal patients and supports expanding clinical use of HCLS systems in this setting.
2025-11-06 | Additive Effects of Dorzagliatin and Glucagon-Like Peptide 1 Receptor Agonism in a Novel Mouse Model of GCK-MODY and in Obese db/db Mice.
Glucokinase (GK) catalyzes the key regulatory step in glucose-stimulated insulin secretion (GSIS). Correspondingly, hetero- and homozygous mutations in human GCK cause maturity-onset diabetes of the young (GCK-MODY) and permanent neonatal diabetes mellitus, respectively. To explore the possible utility of GK activators (GKAs) and of glucagon-like peptide 1 (GLP-1) receptor agonists in these diseases, we have developed a novel hypomorphic Gck allele in mice encoding an aberrantly spliced mRNA. In islets from homozygous knock-in (GckKI/KI) mice, GK immunoreactivity was reduced by >85%, and GSIS eliminated. Homozygous GckKI/KI mice displayed frank diabetes (fasting blood glucose >18 mmol/L; HbA1c ∼108 mmol/mol), ketosis, and nephropathy. Heterozygous GckKI/+ mice were glucose intolerant (HbA1c ∼37 mmol/mol). Abnormal glucose-stimulated Ca2+ dynamics in GckKI/+ islets were completely reversed by the GKA dorzagliatin, which was largely inactive in homozygous GckKI/KI mouse islets. The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male GckKI/+ mice, an action potentiated by dorzagliatin. Sex-dependent additive effects of these agents were also observed on insulin secretion in vitro. Similar additive effects of the drugs were observed in obese hyperglycemic db/db mice. Combined treatment with GKA and incretin mimetics may thus be useful in GCK-MODY and in more common forms of type 2 diabetes. Glucokinase (GK) deficiency can drive maturity-onset diabetes of the young (GCK-MODY) in heterozygotes and permanent neonatal diabetes in homozygotes. We describe a hypomorphic Gck allele that results in aberrant splicing in islets and liver lowering GK activity by ∼85%. Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of glucagon-like receptor-1 receptor activation sex dependently in heterozygous Gck mice and in obese hyperglycemic db/db mice. Combined use of these drugs may be useful in some forms of GCK-MODY and in obesity-related type 2 diabetes.
2025-10-13 | Diabetic Ketoacidosis as the Presentation of Immune Dysregulation, Polyendocrinopathy, Enteropathy, and X-Linked Syndrome: A Case Report.
Neonatal diabetes mellitus (NDM) is a rare and often misdiagnosed collection of disorders typically presenting in the first 6 months of life, characterized by insulin deficiency and hyperglycemia. This case study discusses a neonate initially suspected of having sepsis due to nonspecific symptoms such as vomiting, increased work of breathing, and grunting. Upon further investigation, the child was diagnosed with neonatal diabetic ketoacidosis (DKA) and treated accordingly. Genetic testing and subsequent management revealed that the infant was hemizygous for a FOXP3 missense variant, leading to a diagnosis of IPEX syndrome, an X-linked autoimmune disorder with a poor prognosis. This case highlights the importance of considering NDM in differential diagnoses, especially when symptoms mimic other neonatal illnesses such as sepsis, and emphasizes the need for prompt recognition and management to prevent complications. In addition, this article outlines the management strategies for IPEX syndrome, including insulin therapy, immune suppression, and the potential for hematopoietic stem cell transplantation.
gene therapies
2025-06-01 | Precision Diagnostics for Monogenic Diabetes in Children
Monogenic diabetes, caused by a single-gene defect, accounts for roughly 1–5% of pediatric diabetes cases. Although relatively uncommon, correct identification of these subtypes is critical, as accurate classification can markedly influence both treatment and prognosis. However, distinguishing monogenic forms from type 1 (T1D) or type 2 diabetes (T2D) remains challenging due to overlapping features, such as early onset and variable insulin requirements. Many children with monogenic diabetes are misdiagnosed and, consequently, may not receive optimal therapy. Advances in sequencing technologies, combined with growing knowledge of the underlying genetic causes, now enable earlier, more precise diagnoses and offer opportunities to tailor therapy—often avoiding insulin in favor of targeted interventions. In this review, we summarize key categories of monogenic diabetes, including maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM), and syndromic forms and outline current recommended diagnostic workflows and genetic testing strategies. Ultimately, we aim to provide clinicians with a clear, actionable framework for recognizing and managing these significant but often underrecognized forms of pediatric diabetes.
2025-04-11 | The genetics of low and high birthweight and their relationship with cardiometabolic disease.
Low birthweight infants are at increased risk not only of mortality, but also of type 2 diabetes mellitus and CVD in later life. At the opposite end of the spectrum, high birthweight infants have increased risk of birth complications, such as shoulder dystocia, neonatal hypoglycaemia and obesity, and similarly increased risk of type 2 diabetes mellitus and CVD. However, previous genome-wide association studies (GWAS) of birthweight in the UK Biobank have primarily focused on individuals within the 'normal' range and have excluded individuals with high and low birthweight (<2.5 kg or >4.5 kg). The aim of this study was to investigate genetic variation associated within the tail ends of the birthweight distribution, to: (1) see whether the genetic factors operating in these regions were different from those that explained variation in birthweight within the normal range; (2) explore the genetic correlation between extremes of birthweight and cardiometabolic disease; and (3) investigate whether analysing the full distribution of birthweight values, including the extremes, improved the ability to detect genuine loci in GWAS. We performed case-control GWAS analysis of low (<2.5 kg) and high (>4.5 kg) birthweight in the UK Biobank using REGENIE software (Nlow=20,947; Nhigh=12,715; Ncontrols=207,506) and conducted three continuous GWAS of birthweight, one including the full range of birthweights, one involving a truncated GWAS including only individuals with birthweights between 2.5 and 4.5 kg and a third GWAS that winsorised birthweight values <2.5 kg and >4.5 kg. Additionally, we performed bivariate linkage disequilibrium (LD) score regression to estimate the genetic correlation between low/normal/high birthweight and cardiometabolic traits. Bivariate LD score regression analyses suggested that high birthweight had a mostly similar genetic aetiology to birthweight within the normal range (genetic correlation coefficient [rG]=0.91, 95% CI 0.83, 0.99), whereas there was more evidence for a separate set of genes underlying low birthweight (rG=-0.74, 95% CI 0.66, 0.82). Low birthweight was also significantly positively genetically correlated with most cardiometabolic traits and diseases we examined, whereas high birthweight was mostly positively genetically correlated with adiposity and anthropometric-related traits. The winsorisation strategy performed best in terms of locus detection, with the number of independent genome-wide significant associations (p<5×10-8) increasing from 120 genetic variants at 94 loci in the truncated GWAS to 270 genetic variants at 178 loci, including 27 variants at 25 loci that had not been identified in previous birthweight GWAS. This included a novel low-frequency missense variant in the ABCC8 gene, a gene known to be involved in congenital hyperinsulinism, neonatal diabetes mellitus and MODY, that was estimated to be responsible for a 170 g increase in birthweight amongst carriers. Our results underscore the importance of genetic factors in the genesis of the phenotypic correlation between birthweight and cardiometabolic traits and diseases.
2025-03-10 | Two cases of neonatal hyperglycemia caused by a homozygous COQ9 stop-gain variant.
Neonatal diabetes mellitus (NDM) is a monogenic condition diagnosed <6 months of age with >40 genetic causes. International guidelines recommend referral for genetic testing immediately after diagnosis since the genetic result guides clinical management. We used next-generation sequencing to identify a homozygous pathogenic variant, p.(Arg244*), in COQ9 in 2 individuals referred for NDM testing. Both had insulin-treated hyperglycemia, severe structural brain defects, dysmorphic features, and lactic acidosis. Recessive loss-of-function variants in COQ9 cause Coenzyme Q10 deficiency-5, a multi-system mitochondrial disease, with 7 cases reported. Neonatal hyperglycemia has not been reported in any of these cases but has been described for two other Coenzyme Q10 disorders caused by variants in COQ2 and COQ4. Our report shows that individuals with COQ9-related disease can present with neonatal hyperglycemia, expanding the clinical spectrum of this disorder. We recommend the inclusion of COQ9, as well as COQ2 and COQ4, to gene panels used for NDM testing.
2024-07-10 | Monogenic diabetes in children: An underdiagnosed and poorly managed clinical dilemma.
Monogenic diabetes, constituting 1%-2% of global diabetes cases, arises from single gene defects with distinctive inheritance patterns. Despite over 50 ass-ociated genetic disorders, accurate diagnoses and management of monogenic diabetes remain inadequate, underscoring insufficient clinician awareness. The disease spectrum encompasses maturity-onset diabetes of the young (MODY), characterized by distinct genetic mutations affecting insulin secretion, and neonatal diabetes mellitus (NDM) - a heterogeneous group of severe hyperglycemic disorders in infants. Mitochondrial diabetes, autoimmune monogenic diabetes, genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape. A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY. NDM diagnosis warrants immediate molecular genetic testing for infants under six months. Identifying these genetic defects presents a unique opportunity for precision medicine. Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes. Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes. The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.
2023-12-16 | Application of CRISPR-Cas9 technology in diabetes research.
Diabetes is a chronic disorder with rapidly increasing prevalence that is a major global issue of our current era. There are two major types of diabetes. Polygenic forms of diabetes include type 1 diabetes (T1D) and type 2 diabetes (T2D) and its monogenic forms are maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM). There are no permanent therapeutic approaches for diabetes and current therapies rely on regular administration of various drugs or insulin injection. Recently, gene editing strategies have offered new promise for treating genetic disorders. Targeted genome editing is a fast-growing technology, recruiting programmable nucleases to specifically modify target genomic sequences. These targeted nucleases generate double-strand breaks at target regions in the genome, which induce cellular repair pathways including non-homologous end joining (NHEJ) and homology-directed repair (HDR). Clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) is a novel gene-editing system, permitting precise genome modification. CRISPR/Cas9 has great potential for various applications in diabetic research such as gene screening, generation of diabetic animal models and treatment. In this article, gene-editing strategies are summarized with a focus on the CRISPR/Cas9 approach in diabetes research.
proteins
2026-08-18 | Inhibition Mechanism of Pancreatic KATP Channels by Centipede Toxin.
The pancreatic adenosine triphosphate (ATP)-sensitive potassium (KATP) channel acts as a crucial metabolic sensor, regulating insulin secretion to maintain whole-body energy homeostasis. Gain-of-function mutations in this channel lead to neonatal diabetes mellitus, a rare disorder in which certain mutants exhibit resistance to standard sulfonylurea therapy. Recent studies have identified a centipede toxin, SpTx1, as a potent inhibitor of both human pancreatic KATP channels and their gain-of-function mutants. This toxin stimulates insulin secretion, offering a promising therapeutic strategy for neonatal diabetes. However, the molecular mechanism by which SpTx1 inhibits the KATP channel has remained unclear. Here, we report the crystal structure of SpTx1 and the cryo-electron microscopy structure of the KATP channel in complex with SpTx1. The structure reveals that a single SpTx1 molecule binds to the extracellular surface of the Kir6.2 tetramer. Multiple interactions at the SpTx1-Kir6.2 interface underpin the high affinity and specificity of SpTx1 for human Kir6.2. We demonstrate that SpTx1 inhibits potassium currents by physically blocking the ion conduction pore. Furthermore, a structure-guided search identified another centipede toxin, Sm3a, as a novel KATP channel blocker. Together, these findings provide key insights into the inhibitory mechanism of centipede toxins against the human Kir6.2-containing KATP channel and establish a foundation for developing these toxins into potential therapeutics for KATP channel-related diseases.
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.
2024-11-27 | The Identification of a Novel Pathogenic Variant in the GATA6 Gene in a Child with Neonatal Diabetes.
GATA6 syndrome is a rare monogenic disorder caused by heterozygous variants in the gene GATA6, which controls the early embryonic differentiation of germ layers and the development of different organs. We present the results of the 7-year follow-up of a child with this syndrome as well as the following conditions: diabetes mellitus, exocrine pancreatic insufficiency, gallbladder atresia, and congenital heart disease (CHD). At birth, the patient was diagnosed with neonatal diabetes mellitus (NDM) associated with heart (mitral valve prolapse) and gastrointestinal abnormalities (gallbladder atresia). Diabetes remitted within weeks and relapsed at the age of 2. We identified a de novo variant of a 4-nucleotide deletion (c.1302+4_1302+7del), previously unreported in the literature, in the donor splicing site of exon 3 of the GATA6 gene in a heterozygous state. Screening for other possible components of GATA6 syndrome revealed exocrine pancreatic insufficiency, and pancreatic enzyme replacement therapy resulted in improved dyspeptic symptoms, and growth rates increased. In addition, the patient was diagnosed with autoimmune thyroiditis and progressive myopia.
2024-10-21 | Long-Term Effects of Incretin-Based Drugs on Glycemic Control in Permanent Neonatal Diabetes.
Permanent neonatal diabetes mellitus (PNDM) is a genetic disorder, characterized by a decrease in endogenous insulin secretion. Therefore, exogenous insulin supplementation plays a central role in controlling glycemia. Although adding a sulfonylurea can help to discontinue insulin, discontinuation is sometimes difficult when the sulfonylurea is administered at older ages. A 24-year-old woman with longstanding PNDM who had poor glycemic control using insulin (47 U/day) and high-dose glibenclamide (0.6 mg/kg/day), had successfully discontinued insulin after initiating the dipeptidyl peptidase-4 inhibitor sitagliptin (50 mg/day). Additionally, hemoglobin A1c levels decreased by 4.8%. Double dosing of sitagliptin and subsequent switching to the glucagon-like peptide-1 receptor agonist semaglutide (0.25 mg/week followed by 0.5 mg/week) further decreased hemoglobin A1c values, with graded improvements in endogenous insulin secretion. There were no episodes of hypoglycemia during which glibenclamide was titrated down from 0.6 to 0.4 mg/kg/day. Intra- and inter-day glucose variability as assessed by continuous glucose monitoring was also improved. In patients with PNDM, administration and dose escalation of incretin-based drugs, in addition to a high-dose sulfonylurea, could be a useful treatment strategy. This strategy may be helpful for discontinuing insulin, downtitrating sulfonylureas, and subsequent achievement of better glycemic control regarding long-term stability and short-term variability.
2024-10-01 | 12599 Early Remission Of Chromosome 6 Q 24-related Neonatal Diabetes Mellitus
Abstract Disclosure: R. Pratibha: None. K. Dummula: None. Introduction: Chromosome 6q24 imprinting abnormalities represent the predominant cause of transient neonatal diabetes mellitus (TNDM), accounting for over two-thirds of cases with an estimated prevalence of 1 in 400,000. While remission typically manifests by 3 months of age, herein we detail a case of Chromosome 6q24-related TNDM exhibiting remission by 1.5 months of age. We share our clinical experience in managing this case without hypoglycemia and using C-Peptide levels as a monitoring tool to track the resolution. Case: A female infant, born at 36 weeks via elective C-section due to fetal growth restriction and oligohydramnios, was closely monitored in the nursery for potential hypoglycemia. Contrary to the expectation, she displayed escalating hyperglycemia, necessitating insulin infusion within 25 hours of birth. Apgar scores were 7 and 9, and the birth weight was 2095 g (6th percentile). Maternal history included impaired glucose tolerance in a previous pregnancy with borderline glucose tolerance during this gestation. The newborn physical exam was unremarkable except for mild macroglossia. Despite initial blood glucose (BG) of 52 mg/dl, it rose to 257 mg/dL by 16 hours. Insulin drip was started at 24 hours due to BG of 304 mg/dL. The monogenic diabetes panel obtained on day of life (DOL) #2 was negative; no acidosis was observed. The C- Peptide was low at 0.2 ng/ml. Insulin infusion was continued until DOL # 20. A trial of glyburide commenced on DOL #9 while on Insulin drip, yielded minimal response, prompting a transition to short-acting insulin for correction of hyperglycemia (>250 mg/dL). C-peptide level during sulfonylurea (SU) trial remained low (0.5 ng/mL). The infant required 2 to 3 corrections per day with 0.05 units of Lispro Insulin, with the last dose administered at 44 days. She did not receive any long-acting Insulin. As of her last follow-up at the endocrine clinic at 57 days of age, the infant is thriving well and has normal blood glucose levels. The 6q24 Methylation-MLPA study showed duplication of 6q24 on the paternally inherited chromosome 6. Significantly, she never encountered hypoglycemia during her hospital stay. The C-peptide increased to 0.8 ng/ml at DOL#37 and had normalized to 1.3 ng/mL by DOL#57 indicating remission of TNDM. Conclusion: 6q24-related TNDM may often be characterized by features such as small for gestational age (SGA), macroglossia, umbilical hernia, cardiac and renal abnormalities. Early presentation of hyperglycemia with this phenotype must prompt its diagnostic evaluation. Early resolution by 1.5 months as seen in our case is uncommon. Uniquely, we used C-peptide as a tracking tool to guide resolution and manage insulin therapy. Presentation: 6/3/2024
cell therapies
2025-10-08 | Cyclophosphamide post-haploidentical stem cell transplantation experience in an infant with IPEX syndrome.
IPEX syndrome is a rare hemizygous X-linked disorder with complex autoimmune reactions, characterized by immune dysregulation, polyendocrinopathy, and enteropathy. It has a poor prognosis and a high mortality risk without prompt therapy. Treatment options include pharmacological immunosuppression, nutritional and supportive care, and hematopoietic stem cell transplantation, the latter as the only curative option. We present the case of a male infant, the second child of a nonconsanguineous couple, with negative prenatal screening and intrauterine growth restriction detected at 27 weeks' gestation. He was diagnosed with neonatal diabetes mellitus and treated with insulin. He was re-hospitalized for secretory diarrhea and rotavirus infection. At that moment, he was diagnosed with failure to thrive and hypothyroidism. He acquired multiple severe infections, including Candida parapsilosis fungemia, an urinary infection caused by extended-spectrum β-lactamase-producing Escherichia coli, and Klebsiella pneumoniae bacteremia. Endoscopy biopsy revealed chronic duodenitis with the absence of goblet and Paneth cells, findings suggestive of autoimmune enteropathy. Genetic testing identified a mutation in the FOXP3 gene, confirming the diagnosis of IPEX syndrome. We performed a hematopoietic stem cell transplantation from an alternative haploidentical donor and administered a cyclophosphamide post-transplant regime. At 320 days posttransplant, the patient fully recovered his nutritional status and immunity. Haploidentical transplantation with a post-transplant cyclophosphamide regime can be a viable therapeutic option for patients with IPEX syndrome, lacking an HLA-identical donor, with promising outcomes based on the follow-up data.
2024-09-08 | Glucokinase (GCK) in diabetes: from molecular mechanisms to disease pathogenesis.
Glucokinase (GCK), a key enzyme in glucose metabolism, plays a central role in glucose sensing and insulin secretion in pancreatic β-cells, as well as glycogen synthesis in the liver. Mutations in the GCK gene have been associated with various monogenic diabetes (MD) disorders, including permanent neonatal diabetes mellitus (PNDM) and maturity-onset diabetes of the young (MODY), highlighting its importance in maintaining glucose homeostasis. Additionally, GCK gain-of-function mutations lead to a rare congenital form of hyperinsulinism known as hyperinsulinemic hypoglycemia (HH), characterized by increased enzymatic activity and increased glucose sensitivity in pancreatic β-cells. This review offers a comprehensive exploration of the critical role played by the GCK gene in diabetes development, shedding light on its expression patterns, regulatory mechanisms, and diverse forms of associated monogenic disorders. Structural and mechanistic insights into GCK's involvement in glucose metabolism are discussed, emphasizing its significance in insulin secretion and glycogen synthesis. Animal models have provided valuable insights into the physiological consequences of GCK mutations, although challenges remain in accurately recapitulating human disease phenotypes. In addition, the potential of human pluripotent stem cell (hPSC) technology in overcoming current model limitations is discussed, offering a promising avenue for studying GCK-related diseases at the molecular level. Ultimately, a deeper understanding of GCK's multifaceted role in glucose metabolism and its dysregulation in disease states holds implications for developing targeted therapeutic interventions for diabetes and related disorders.
2023-12-02 | Metadichol-Induced Differentiation of Pancreatic Ductal Cells (PANC-1) into Insulin-Producing Cells
Endocrine gene expression in PANC-1, a type of pancreatic cancer cell, has been studied in the context of their potential to be reprogrammed toward a normal, differentiated state. Alkaline phosphatase activity has also been shown in pluripotent stem cells to differentiate between feeder and parental cells in reprogramming experiments. Metadichol®-based cell programming holds promise as a versatile and potentially safer approach for manipulating cellular behavior without the use of viral vectors, gating, or CRISPR. Using qRT‒PCR the results show multifold increase in the gene expression of CA9, GCG, INS MAFA, NEUROD1, NGN3, NKX2-2, PAX6: PDX1, SLC2A2, FOXO1, and SIRT1. ALP levels increased and this activity is often used to distinguish stem cells from feeder cells as well as from parental cells in reprogramming experiments. Pluripotency was confirmed by the presence of islet-like structures on day eight. Metadichol exhibits anticancer activity with a CC50 value of 5.50 µg/ml compared to standard doxorubicin with a CC50 value of 10.28 µg/ml. At 100 ug/ml Metadichol is 82% cytotoxic.in a MTT assay Anti-tumor gene Klotho’s expression was increased 70fold on day eight. All the genes seen expressed regulate endocrine cell development in the pancreas and are involved in insulin and glucagon secretion. Gene network analysis is presented to show how Metadichol induced expression leads to a closed loop feedback network and biological process that would help in mitigating diabetes and other related disorders.
2023-09-13 | Metadichol induced differentiation of pancreatic ductal cells (PANC-1) into insulin-producing cells
Abstract Endocrine gene expression in PANC-1, a type of pancreatic cancer cell, has been studied in the context of their potential to be reprogrammed toward a normal, differentiated state. Alkaline phosphatase activity has also been shown in pluripotent stem cells to differentiate between feeder and parental cells in reprogramming experiments. Metadichol ® -based cell programming holds promise as a versatile and potentially safer approach for manipulating cellular behavior without the use of viral vectors, gating, or CRISPR. This study investigated the multifold increase in the gene expression of CA9 , GCG , INS MAFA , NEUROD1 , NGN3 , NKX2-2 , PAX6: PDX1 , SLC2A2 , FOXO1 , and SIRT1 using qRT‒PCR. These genes regulate endocrine cell development in the pancreas and are involved in insulin and glucagon secretion. Gene network analysis is presented to show how Metadichol-induced expression leads to a closed loop feedback network and biological process that would help in mitigating diabetes and other related disorders.
2021-01-05 | Recent progress in pancreatic islet cell therapy
Abstract Human pluripotent stem cells (PSCs), including human embryonic stem cells and induced pluripotent stem cells, are promising cell sources in regenerating pancreatic islets through in vitro directed differentiation. Recent progress in this research field has made it possible to generate glucose-responsive pancreatic islet cells from PSCs. Single-cell RNA sequencing techniques have been applied to analyze PSC-derived endocrine beta-cells, which are then compared with human islets. This has led to the identification of novel signaling pathways and molecules involved in lineage commitment during pancreatic differentiation and maturation processes. Single-cell transcriptomics are also used to construct a detailed map of in vivo endocrine differentiation of developing mouse embryos to study pancreatic islet development. Mimicking those occurring in vivo, it was reported that differentiating PSCs can generate similar islet cell structures, while metabolomics analysis highlighted key components involved in PSC-derived pancreatic islet cell function, providing information for the improvement of in vitro pancreatic maturation procedures. In addition, cell transplantation into diabetic animal models, together with the cell delivery system, is studied to ensure the therapeutic potentials of PSC-derived pancreatic islet cells. Combined with gene-editing technology, the engineered mutation-corrected PSC lines originated from diabetes patients could be differentiated into functional pancreatic islet cells, suggesting possible autologous cell therapy in the future. These PSC-derived pancreatic islet cells are a potential tool for studies of disease modeling and drug testing. Herein, we outlined the directed differentiation procedures of PSC-derived pancreatic islet cells, novel findings through transcriptome and metabolome studies, and recent progress in disease modeling.
other
2022-09-30 | Monogenic diabetes clinic (MDC): 3-year experience
Abstract Aim In the pediatric diabetes clinic, patients with type 1 diabetes mellitus (T1D) account for more than 90% of cases, while monogenic forms represent about 6%. Many monogenic diabetes subtypes may respond to therapies other than insulin and have chronic diabetes complication prognosis that is different from T1D. With the aim of providing a better diagnostic pipeline and a tailored care for patients with monogenic diabetes, we set up a monogenic diabetes clinic (MDC). Methods In the first 3 years of activity 97 patients with non-autoimmune forms of hyperglycemia were referred to MDC. Genetic testing was requested for 80 patients and 68 genetic reports were available for review. Results In 58 subjects hyperglycemia was discovered beyond 1 year of age (Group 1) and in 10 before 1 year of age (Group 2). Genetic variants considered causative of hyperglycemia were identified in 25 and 6 patients of Group 1 and 2, respectively, with a pick up rate of 43.1% (25/58) for Group 1 and 60% (6/10) for Group 2 (global pick-up rate: 45.5%; 31/68). When we considered probands of Group 1 with a parental history of hyperglycemia, 58.3% (21/36) had a positive genetic test for GCK or HNF1A genes, while pick-up rate was 18.1% (4/22) in patients with mute family history for diabetes. Specific treatments for each condition were administered in most cases. Conclusion We conclude that MDC may contribute to provide a better diabetes care in the pediatric setting.
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Drug Discovery Landscape
3 orphan drug designations for Neonatal diabetes mellitus, including 1 approved therapy.
3 orphan drug designations for Neonatal diabetes mellitus, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
recombinant human insulin | proteins | FDA | — | Hellene Solomon Wan, MD - Induvidual sponsor. |
glibentek (glibenclamide oral suspension) | small molecules | FDA | AMMTeK | |
Glibenclamide [AMGLIDIA] | small molecules | EMA | Approved | AMMTeK |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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