Maturity-onset diabetes of the young resulting from mutations of the NEUROD1 gene (NEUROD1-MODY) is a rare form of diabetes and has not been well studied. We aimed to estimate its prevalence in Chinese patients with early-onset type 2 diabetes mellitus (EOD) and summarize its clinical and genetic characteristics.

We performed next-generation sequencing in 679 patients with EOD to screen rare variants in NEUROD1 exons and evaluated the effects of variants using in vitro experiments. All the reported NEUROD1-MODY cases were reviewed. Patients carrying pathogenic or likely pathogenic variants were diagnosed with NEUROD1-MODY according to the American College of Medical Genetics and Genomics guidelines.

Four rare variants were identified in 679 patients with EOD, but only P197H decreased the transcriptional activity in in vitro functional assays to an extent comparable to the well-known mutation causing NEUROD1-MODY. Its frequency was pretty higher in the European population (0.024) than that in the East Asian population (0.00034) according to the gnomAD database. Twenty-eight previously reported patients could be confirmed as diagnosed. The patients in Asia had a lower body mass index and a higher rate of ketosis compared with Caucasians, and the mutations present in Asia often occurred in the transactivation domain. Neurological abnormalities were observed in 10.7% of the patients with NEUROD1-MODY.

NEUROD1-MODY in Chinese patients with EOD is not common (≤ 0.15%). The P197H might account for MODY in Chinese with a higher penetrance than Caucasian and needs further exploration. The possible differences of phenotypes exist between the two ethnic populations.

Monogenic diabetes often occurs as a result of single-gene mutations. The illness is minimally affected by environmental and behavioral factors, and it constitutes around one to five percent of all cases of diabetes.

Newborn diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) are the predominant causes of monogenic diabetes, accounting for a larger proportion of cases, while syndromic diabetes represents a smaller percentage. MODY, a group of inherited non-autoimmune diabetes mellitus disorders, is quite common. However, it remains frequently misdiagnosed despite increasing public awareness. The condition is characterized by insulin resistance, the development of diabetes at a young age (before 25 years), mild high blood sugar levels, inheritance in an autosomal dominant pattern, and the preservation of natural insulin production.

Currently, there are 14 distinct subtypes of MODY that have been identified. Each subtype possesses distinct characteristics in terms of their frequency, clinical symptoms, severity of diabetes, related complications, and response to medicinal interventions. Due to the clinical similarities, lack of awareness, and high expense of genetic testing, distinguishing between type I (T1D) and type II diabetes mellitus (T2D) can be challenging, resulting in misdiagnosis of this type of diabetes. As a consequence, a significant number of individuals are being deprived of adequate medical attention. Accurate diagnosis enables the utilization of novel therapeutic strategies and enhances the management of therapy in comparison to type II and type I diabetes.

This article offers a concise overview of the clinical subtypes and characteristics of monogenic diabetes. Furthermore, this article discusses the various subtypes of MODY, as well as the process of diagnosing, managing, and treating the condition. It also addresses the difficulties encountered in detecting and treating MODY.

This review highlights emerging evidence supporting the premise of precision diabetes care including but not limited to monogenic diabetes and discuss potential opportunities, challenges, and limitations for clinical adoption.

Driven by a single gene mutation, monogenic diabetes remains the best use-case for precision diabetes care. However, the increasing prevalence of diabetes among adolescents and young adults in an obesogenic environment makes triaging potential patients for genetic screening clinically challenging. High-dimensional molecular biomarkers (i.e., multiomics) can improve the risk prediction for incident type 2 diabetes (T2D), over and above a well established prediction model based on clinical variables alone. Machine learning approaches using clinical variable-based clustering methods have generated novel and reproducible T2D subgroups with distinct phenotypic and omics characteristics that are associated with differential long-term outcomes. This stratification-strategy may inform clinical decisions. However, on-going discussion and research will be needed to understand the clinical utility of sub-phenotyping T2D for precision care.

Precision diabetes care has extended from uncommon monogenic diabetes to T2D which will need more complex approaches like multiomics and machine-learning methods. The successful clinical translation will require cumulative evidence and close collaboration among the stake holders.

Maturity-onset diabetes of the young (MODY) represents 1% to 5% of patients with diabetes mellitus (DM), and numerous genes associated with MODY have been identified. While mutations of the insulin gene (INS) are known to cause permanent neonatal DM, rare disease-causing variants have also been found in MODY. These patients demonstrate variable clinical phenotypes-from milder forms requiring lifestyle or oral agent interventions to severe forms requiring lifelong insulin. We present a case of MODY arising from a novel disease-causing INS variant, in an adolescent with atypical features. He was obese with clinical evidence of insulin resistance, diagnosed with DM through opportunistic oral glucose tolerance testing. He developed symptomatic hyperglycemia with worsening glycemic trend, requiring treatment with high-dose insulin and metformin. After 2.5 years, his glycemic profile normalized following weight loss, and pharmacotherapy was discontinued. Targeted gene testing revealed a de novo novel missense variant in exon 2 of the INS gene (p.His29Tyr), confirmed using bidirectional Sanger sequencing. Insulin resistance in patients with MODY can worsen their clinical course and increase risks of long-term complications. Management of these patients should be individualized. This case highlights the utility of genetic testing in diagnosing uncommon and variable forms of MODY, particularly those with atypical features.

Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P) or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank (UKB470K) adults, suggesting 97% false positives. We used the phenomenon of purifying hyperselection, which acts to decrease the frequency of SCGD causal diplotypes, to reduce false positives. Training of gene-disease-inheritance mode-diplotype tetrads in 618,290 control and affected subjects identified 293 variants or haplotypes and seven genes with variable inheritance contributing higher positive diplotype counts than consistent with purifying hyperselection and with little or no evidence of SCGD causality. With these changes, 2.0% of UKB470K adults were positive. In contrast, gNBS was positive in 7.2% of 3,118 critically ill children with suspected SCGDs and 7.9% of 705 infant deaths. When compared with rapid diagnostic genome sequencing (RDGS), gNBS had 99.1% recall. In eight true-positive children, gNBS was projected to decrease time to diagnosis by a median of 121 days and avoid life-threatening disease presentations in four children, organ damage in six children, ∼$1.25 million in healthcare cost, and ten (1.4%) infant deaths. Federated training predicated on purifying hyperselection provides a general framework to attain high precision in population screening. Federated training across many biobanks and clinical trials can provide a privacy-preserving mechanism for qualification of gNBS in diverse genetic ancestries.

Gain-of-function (GOF) variants of KCNJ11 cause neonate diabetes and maturity-onset diabetes of the young (KCNJ11-MODY), while loss-of-function (LOF) variants lead to hyperinsulinemia hypoglycemia and subsequent diabetes. Given the limited research of KCNJ11-MODY, we aimed to analyse its phenotypic features and prevalence in Chinese patients with early-onset type 2 diabetes (EOD).

We performed next-generation sequencing on 679 Chinese EOD patients to screen for KCNJ11 exons variants. Bioinformatics prediction and the American College of Medical Genetics and Genomics guidelines was used to determine the pathogenicity and diagnosed KCNJ11-MODY. A literature review was conducted to investigate the phenotypic features of KCNJ11-MODY.

We identified six predicted deleterious rare variants in six EOD patients (0.88%). They were classified as uncertain significance (variant of uncertain significance [VUS]), but more common in this EOD cohort than a general Chinese population database, however, without significant difference (53/10,588, 0.50%) (p = .268). Among 80 previously reported patients with KCNJ11-MODY, 23.8% (19/80) carried 9 (32.1%) LOF variants, who had significantly older age at diagnosis, higher birthweight and higher fasting C-peptide compared to patients with GOF variants. Many patients carrying VUS were not correctly diagnosed.

Some rare variants of KCNJ11 might contribute to the development of Chinese EOD, although available evidence has not enough power to support them as cause of KCNJ11-MODY. The clinical features of LOF variants were different from GOF variants in KCNJ11-MODY patients. It is necessary to evaluate the pathogenicity of VUS through function experiments.

Maturity onset diabetes of the young is one of the commonest causes of monogenic diabetes and can easily be mistaken for type 1 diabetes. A diagnosis of maturity onset diabetes of the young can have direct implications for genetic counseling, family screening, and precision diabetes treatment. However, the cost of genetic testing and identifying individuals to test are the main challenges for diagnosis and management in sub-Saharan Africa. We report the very first documented case of HNF1A maturity onset diabetes of the young in the sub-Saharan African region.

A 20-year-old female Black African young adult diagnosed with type 1 diabetes aged 14 presented for routine out-patient diabetes consultation. She was on multiple daily insulin injections; total combined dose 0.79 IU/kg/day with an HbA1c of 7.7%. The rest of her laboratory examinations were normal. On extended laboratory analysis, she had good residual insulin secretion with post-meal plasma C-peptide levels at 1150 pmol/L. She tested negative for glutamic acid decarboxylase (GAD65), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8) islet autoantibodies. Targeted next-generation sequencing (t-NGS) for monogenic diabetes was performed using DNA extracted from a buccal sample. She was diagnosed with HNF1A maturity onset diabetes of the young, with the c.607C > T; p.(Arg203Cys) pathogenic variant, which has never been reported in sub-Saharan Africa. Her clinical practitioners provided genetic and therapeutic counseling. Within 10 months following the diagnosis of maturity onset diabetes of the young, she was successfully switched from multiple daily insulin injections to oral antidiabetic tablets (sulphonylurea) while maintaining stable glycemic control (HBA1c of 7.0%) and reducing hypoglycemia. She expressed a huge relief from the daily finger pricks for blood glucose monitoring.

This case reveals that HNF1A maturity onset diabetes of the young (and probably other causes of monogenic diabetes) can present in sub-Saharan Africa. A diagnosis of maturity onset diabetes of the young can have significant life-changing therapeutic implications.

Diabetes, a complex multisystem metabolic disorder characterized by hyperglycemia, leads to complications that reduce quality of life and increase mortality. Diabetes pathophysiology includes dysfunction of beta cells, adipose tissue, skeletal muscle, and liver. Type 1 diabetes (T1D) results from immune-mediated beta cell destruction. The more prevalent type 2 diabetes (T2D) is a heterogeneous disorder characterized by varying degrees of beta cell dysfunction in concert with insulin resistance. The strong association between obesity and T2D involves pathways regulated by the central nervous system governing food intake and energy expenditure, integrating inputs from peripheral organs and the environment. The risk of developing diabetes or its complications represents interactions between genetic susceptibility and environmental factors, including the availability of nutritious food and other social determinants of health. This perspective reviews recent advances in understanding the pathophysiology and treatment of diabetes and its complications, which could alter the course of this prevalent disorder.

Beta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes.

The search of PubMed, MEDLINE, and Embase for individual and group level data for glycemic outcomes using inclusion (English, original articles written after 1992) and exclusion (VUS, multiple diabetes types, absent/aggregated treatment effect measures) criteria. The risk of bias was assessed using NHLBI study-quality assessment tools. Data extracted from Covidence were summarized and presented as descriptive statistics in tables and text.

There are 146 studies included, with only six being experimental studies. For GCK-related hyperglycemia, the six studies (35 individuals) assessing therapy discontinuation show no HbA1c deterioration. A randomized trial (18 individuals per group) shows that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes. Cohort and case studies support SU's effectiveness in lowering HbA1c. Two cross-over trials (each with 15-16 individuals) suggest glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes is limited. Most reported patients with HNF1B-diabetes (N = 293) and MD (N = 233) are on insulin without treatment studies. Limited data support oral agents after relapse in 6q24-TND and for thiamine improving glycemic control and reducing/eliminating insulin requirement in SLC19A2-diabetes.

There is limited evidence, and with moderate or serious risk of bias, to guide monogenic diabetes treatment. Further evidence is needed to examine the optimum treatment in monogenic subtypes.

Maturity-onset diabetes of the young (MODY) is a spectrum of clinically heterogenous forms of monogenic diabetes mellitus characterized by autosomal dominant inheritance, onset at a young age, and absence of pancreatic islets autoimmunity. This rare form of hyperglycemia, with clinical features overlapping with type 1 and type 2 diabetes mellitus, has 14 subtypes with differences in prevalence and complications occurrence which tailor therapeutic approach. MODY phenotypes differ based on the gene involved, gene penetrance and expressivity. While MODY 2 rarely leads to diabetic complications and is easily managed with lifestyle interventions alone, more severe subtypes, such as MODY 1, 3, and 6, require an individualized treatment approach to maintain a patient's quality of life and prevention of complications. This review summarizes current evidence on the presentation, diagnosis, and management of MODY, an example of a genetic cause of hyperglycemia that calls for a precision medicine approach.

Metformin, insulin, and insulin secretagogues do not alter HbA1c levels in glucokinase maturity-onset diabetes of the young (GCK-MODY). However, the efficacy of the new hypoglycemic drugs on GCK-MODY remains unclear.

We describe a case of GCK-MODY with unchanged blood glucose under different therapies during an 8 years' follow-up. His HbA1c and biochemical indices under different hypoglycemic treatments were recorded.

Oral glucose-lowering drugs, including thiazolidinediones, dipeptidyl peptidase 4 inhibitor, α-glucosidase inhibitor, and sodium-glucose cotransporter 2 inhibitor that had not been evaluated previously, did not improve the HbA1c level in this patient. However, the glucokinase activator dorzagliatin effectively and safely lowered his HbA1c level.

Dorzagliatin was effective and safe in this patient with GCK-MODY, providing potential application prospects for precise treatment of GCK-MODY with dorzagliatin.

This report describes a case of maturity-onset diabetes of the young (MODY) type 3 (MODY3) complicated with type 5 (MODY5), including the patient's clinical features, diagnosis, and treatment, and reviews relevant literature. Using next-generation sequencing of MODY (types 1-14) gene exons and Sanger sequencing for verification, the patient and her mother were assessed. Based on the clinical phenotype and genetic test results, the patient was diagnosed as MODY3 combined with MODY5. Treatment included insulin and linagliptin, with monitoring of blood glucose changes. Clinicians should enhance their understanding of MODY clinical phenotypes. In adolescents with diabetes who have congenital pancreatic and renal developmental defects, elevated high-density lipoprotein cholesterol, no spontaneous ketosis, insulin secretion defects, negative pancreatic autoantibodies, no significant insulin resistance, and who are not obese, gene testing should be conducted to screen for MODY. Accurate diagnosis and personalized treatment can aid in achieving glycemic control, improving quality of life, and optimizing reproductive planning.

Women with maturity-onset diabetes of the young (MODY) need tailored antenatal care and monitoring of their offspring. Each MODY subtype has different implications for glycaemic targets, treatment choices and neonatal management. Hyperglycaemia of MODY is often first diagnosed in adolescence or early adulthood and therefore is clinically relevant to pregnant women. MODY remains an under-recognised and undiagnosed condition. Pregnancy represents an opportune time to make a genetic diagnosis of MODY and provide precision treatment. This review describes the nuance of antenatal care in women with MODY and the implications for pregnancies affected by a positive paternal genotype. Mutations in hepatic nuclear factor 1-alpha (HNF1A) and 4-alpha (HNF4A) genes are associated with progressive β-cell dysfunction resulting in early onset diabetes. Patients are largely managed with sulphonylureas outside of pregnancy. Macrosomia and persistent neonatal hypoglycaemia are reported in 54% and 15% of HNF4A genotype positive offspring respectively with a median increase in birthweight of 790 g. Close observation of foetal growth in utero allows optimal timing of delivery to minimise peri- and postpartum materno-foetal complications. Glucokinase (GCK)-MODY causes mild fasting hyperglycaemia which does not require treatment outside of pregnancy. Birthweight of offspring of maternal carriers is dependent on foetal genotype; heterozygous mutation carriers are usually normal weight while genotype negative offspring are large for gestational age (600 g heavier). Affected offspring of paternal carriers may be small for gestational age (500 g lighter). Serial growth scans with measurement of the abdominal circumference indirectly differentiate foetal genotype. Measurement of cell free foetal DNA in maternal blood from the late first trimester is superior to traditionally used ultrasound to distinguish foetal genotype. Cost and accessibility may limit its use.

Clinical prediction models can help identify high-risk patients and facilitate timely interventions. However, developing such models for rare diseases presents challenges due to the scarcity of affected patients for developing and calibrating models. Methods that pool information from multiple sources can help with these challenges.

We compared three approaches for developing clinical prediction models for population screening based on an example of discriminating a rare form of diabetes (Maturity-Onset Diabetes of the Young - MODY) in insulin-treated patients from the more common Type 1 diabetes (T1D). Two datasets were used: a case-control dataset (278 T1D, 177 MODY) and a population-representative dataset (1418 patients, 96 MODY tested with biomarker testing, 7 MODY positive). To build a population-level prediction model, we compared three methods for recalibrating models developed in case-control data. These were prevalence adjustment ("offset"), shrinkage recalibration in the population-level dataset ("recalibration"), and a refitting of the model to the population-level dataset ("re-estimation"). We then developed a Bayesian hierarchical mixture model combining shrinkage recalibration with additional informative biomarker information only available in the population-representative dataset. We developed a method for dealing with missing biomarker and outcome information using prior information from the literature and other data sources to ensure the clinical validity of predictions for certain biomarker combinations.

The offset, re-estimation, and recalibration methods showed good calibration in the population-representative dataset. The offset and recalibration methods displayed the lowest predictive uncertainty due to borrowing information from the fitted case-control model. We demonstrate the potential of a mixture model for incorporating informative biomarkers, which significantly enhanced the model's predictive accuracy, reduced uncertainty, and showed higher stability in all ranges of predictive outcome probabilities.

We have compared several approaches that could be used to develop prediction models for rare diseases. Our findings highlight the recalibration mixture model as the optimal strategy if a population-level dataset is available. This approach offers the flexibility to incorporate additional predictors and informed prior probabilities, contributing to enhanced prediction accuracy for rare diseases. It also allows predictions without these additional tests, providing additional information on whether a patient should undergo further biomarker testing before genetic testing.

Monogenic diabetes is characterized as a group of diseases caused by rare variants in single genes. Like for other rare diseases, multiple genes have been linked to monogenic diabetes with different measures of pathogenicity, but the information on the genes and variants is not unified among different resources, making it challenging to process them informatically. We have developed an automated pipeline for collecting and harmonizing data on genetic variants linked to monogenic diabetes. Furthermore, we have translated variant genetic sequences into protein sequences accounting for all protein isoforms and their variants. This allows researchers to consolidate information on variant genes and proteins linked to monogenic diabetes and facilitates their study using proteomics or structural biology. Our open and flexible implementation using Jupyter notebooks enables tailoring and modifying the pipeline and its application to other rare diseases.

Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A)-MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes.

We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped HNF1A variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers' phenotype and treatment response to sulfonylurea.

In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing, revealing 19 with HNF1A variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic.

Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of evidence. We demonstrate here that combining clinical phenotyping with functional protein studies provides a powerful tool to obtain a precise diagnosis of HNF1A-MODY.

Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients.

We searched PubMed and Embase for publications that used 'simple subclassification' approaches using simple categorisation of clinical characteristics, or 'complex subclassification' approaches which used machine learning or 'omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches.

Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes.

Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.

Beta-cell monogenic forms of diabetes are the area of diabetes care with the strongest support for precision medicine. We reviewed treatment of hyperglycemia in GCK-related hyperglycemia, HNF1A-HNF4A- and HNF1B-diabetes, Mitochondrial diabetes (MD) due to m.3243A>G variant, 6q24-transient neonatal diabetes (TND) and SLC19A2-diabetes.

Systematic reviews with data from PubMed, MEDLINE and Embase were performed for the different subtypes. Individual and group level data was extracted for glycemic outcomes in individuals with genetically confirmed monogenic diabetes.

147 studies met inclusion criteria with only six experimental studies and the rest being single case reports or cohort studies. Most studies had moderate or serious risk of bias.For GCK-related hyperglycemia, six studies (N=35) showed no deterioration in HbA1c on discontinuing glucose lowering therapy. A randomized trial (n=18 per group) showed that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes, and cohort and case studies supported SU effectiveness in lowering HbA1c. Two crossover trials (n=15 and n=16) suggested glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes was limited. While some patients with HNF1B-diabetes (n=301) and MD (n=250) were treated with oral agents, most were on insulin. There was some support for the use of oral agents after relapse in 6q24-TND, and for thiamine improving glycemic control and reducing insulin requirement in SLC19A2-diabetes (less than half achieved insulin-independency).

There is limited evidence to guide the treatment in monogenic diabetes with most studies being non-randomized and small. The data supports: no treatment in GCK-related hyperglycemia; SU for HNF1A-diabetes. Further evidence is needed to examine the optimum treatment in monogenic subtypes.

Heterozygous pathogenic variants in HNF4A gene cause maturity-onset diabetes of the young type 1 (MODY1). The mutation carriers for MODY1 have been reported to be relatively rare, in contrast to the most frequently reported forms of MODY2 and MODY3.

Whole exome sequencing (WES) and Sanger sequencing were performed for genetic analysis of MODY pedigrees. Tertiary structures of the mutated proteins were predicted using PyMOL software.

Three heterozygous missense mutations in the HNF4A gene, I159T, W179C, and D260N, were identified in the probands of three unrelated MODY families using WES, one of which (W179C) was novel. Cascade genetic screening revealed that the mutations co-segregated with hyperglycemic phenotypes in their families. The molecular diagnosis of MODY1 has partly transformed its management in clinical practice and improved glycemic control. The proband in family A successfully converted to sulfonylureas and achieved good glycemic control. Proband B responded well to metformin combined with diet therapy because of his higher body mass index (BMI). The proband in family C, with paternal-derived mutations, had markedly defective pancreatic β-cell function due to the superposition effect of T2DM susceptibility genes from the maternal grandfather, and he is currently treated with insulin. In silico analysis using PyMOL showed that the I159T and D260N mutations altered polar interactions with the surrounding residues, and W179C resulted in a smaller side chain.

We identified three heterozygous missense mutations of HNF4A from Chinese MODY families. Structural alterations in these mutations may lead to defects in protein function, further contributing to the hyperglycemic phenotype of mutation carriers.

Functionally disruptive variants in the glucokinase gene (GCK) cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry GCK variants. We aimed to investigate whether carriers of rare GCK variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with GCK-diabetes.

Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of GCK participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with GCK-diabetes took part in a three-month treatment withdrawal.

Carriers of pathogenic and likely pathogenic variants had lower median fasting glucose and C-peptide levels compared to carriers of variants of uncertain significance and benign variants (median fasting glucose: 7.3 (interquartile range: 0.4) mmol/l vs. 9.5 (1.6) mmol/l, p = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l, p = 0.03). Four participants who discontinued metformin treatment and one diet-treated participant were reevaluated after three months. There was no deterioration of HbA1c or fasting glucose (median baseline HbA1c: 49 (3) vs. 51 (6) mmol/mol after three months, p = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months, p = 0.5). Participants did not consistently fulfill best practice guidelines for GCK screening nor clinical criteria for monogenic diabetes.

Carriers of pathogenic or likely pathogenic GCK variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with GCK-diabetes. Variants of uncertain significance should be interpreted with care. Systematic genetic screening of patients with common T2D receiving routine care can lead to the identification and precise care of patients with misclassified GCK-diabetes who are not identifiable through common genetic screening criteria.

Heterogeneity in type 2 diabetes presentation, progression and treatment has the potential for precision medicine interventions that can enhance care and outcomes for affected individuals. We undertook a systematic review to ascertain whether strategies to subclassify type 2 diabetes are associated with improved clinical outcomes, show reproducibility and have high quality evidence. We reviewed publications that deployed 'simple subclassification' using clinical features, biomarkers, imaging or other routinely available parameters or 'complex subclassification' approaches that used machine learning and/or genomic data. We found that simple stratification approaches, for example, stratification based on age, body mass index or lipid profiles, had been widely used, but no strategy had been replicated and many lacked association with meaningful outcomes. Complex stratification using clustering of simple clinical data with and without genetic data did show reproducible subtypes of diabetes that had been associated with outcomes such as cardiovascular disease and/or mortality. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into meaningful groups. More studies are needed to test these subclassifications in more diverse ancestries and prove that they are amenable to interventions.

Monogenic diabetes includes several clinical conditions generally characterized by early-onset diabetes, such as neonatal diabetes, maturity-onset diabetes of the young (MODY) and various diabetes-associated syndromes. However, patients with apparent type 2 diabetes mellitus may actually have monogenic diabetes. Indeed, the same monogenic diabetes gene can contribute to different forms of diabetes with early or late onset, depending on the functional impact of the variant, and the same pathogenic variant can produce variable diabetes phenotypes, even in the same family. Monogenic diabetes is mostly caused by impaired function or development of pancreatic islets, with defective insulin secretion in the absence of obesity. The most prevalent form of monogenic diabetes is MODY, which may account for 0.5-5% of patients diagnosed with non-autoimmune diabetes but is probably underdiagnosed owing to insufficient genetic testing. Most patients with neonatal diabetes or MODY have autosomal dominant diabetes. More than 40 subtypes of monogenic diabetes have been identified to date, the most prevalent being deficiencies of GCK and HNF1A. Precision medicine approaches (including specific treatments for hyperglycaemia, monitoring associated extra-pancreatic phenotypes and/or following up clinical trajectories, especially during pregnancy) are available for some forms of monogenic diabetes (including GCK- and HNF1A-diabetes) and increase patients' quality of life. Next-generation sequencing has made genetic diagnosis affordable, enabling effective genomic medicine in monogenic diabetes.

Integration of genomic and other data has begun to stratify type 2 diabetes in prognostically meaningful ways, but this has yet to impact on mainstream diabetes practice. The subgroup of diabetes caused by single gene defects thus provides the best example to date of the vision of 'precision diabetes'. Monogenic diabetes may be divided into primary pancreatic beta cell failure, and primary insulin resistance. In both groups, clear examples of genotype-selective responses to therapy have been advanced. The benign trajectory of diabetes due to pathogenic GCK mutations, and the sulfonylurea-hyperresponsiveness conferred by activating KCNJ11 or ABCC8 mutations, or loss-of-function HNF1A or HNF4A mutations, often decisively guide clinical management. In monogenic insulin-resistant diabetes, subcutaneous leptin therapy is beneficial in some severe lipodystrophy. Increasing evidence also supports use of 'obesity therapies' in lipodystrophic people even without obesity. In beta cell diabetes the main challenge is now implementation of the precision diabetes vision at scale. In monogenic insulin-resistant diabetes genotype-specific benefits are proven in far fewer patients to date, although further genotype-targeted therapies are being evaluated. The conceptual paradigm established by the insulin-resistant subgroup with 'adipose failure' may have a wider influence on precision therapy for common type 2 diabetes, however. For all forms of monogenic diabetes, population-wide genome sequencing is currently forcing reappraisal of the importance assigned to pathogenic mutations when gene sequencing is uncoupled from prior suspicion of monogenic diabetes.

Early-onset type 2 diabetes occurring in childhood or early adulthood carries a significant excess burden of microvascular diabetes complications, cardiovascular disease and premature death, compared to later onset type 2 diabetes along with adverse pregnancy outcomes in women of child-bearing age. National audit data in England reveal that 122,780 individuals under the age of 40 years are currently living with type 2 diabetes, with an over-representation of people from minority ethnicities and those in the most socioeconomically deprived quintiles. A diagnosis of type 2 diabetes earlier in life poses some unique challenges to healthcare providers that are not routinely encountered when type 2 diabetes presents later. These include; (1) the need to ensure correct diabetes classification in an age group that carries a higher probability of other types of diabetes, (2) overcoming difficulties in engaging with individuals who are of working age or in full-time education, (3) appreciating and addressing the lower attainment of diabetes treatment targets and (4) proactively supporting women of child-bearing age to optimise their future pregnancy outcomes through better preparation for pregnancy, including achieving optimum glycaemic control at the time of conception. Meanwhile, approaches to prevent type 2 diabetes in younger age groups are challenged by difficulties in identifying those at highest risk, by poorer attendance at lifestyle interventions to prevent or delay the onset of type 2 diabetes and by attenuation of associated weight loss in those that do attend. In this article, we discuss the importance of recognising and addressing the distinct challenges in delivering healthcare to those with early-onset type 2 diabetes, the greater challenges in preventing type 2 diabetes at younger ages, and key components of strategies that might address these challenges to drive improvements in pregnancy outcomes, microvascular and cardiovascular outcomes.

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes diagnosed in young individuals that lack the typical features of type 1 and type 2 diabetes. The genetic subtype of MODY determines the most effective treatment and this is the driver for MODY genetic testing in diabetes populations. Despite the obvious clinical and health economic benefits, MODY is significantly underdiagnosed with the majority of patients being inappropriately managed as having type 1 or type 2 diabetes. Low detection rates result from the difficulty in identifying patients with a likely diagnosis of MODY from the high background population of young onset type 1 and type 2 diabetes, compounded by the lack of MODY awareness and education in diabetes care physicians. MODY diagnosis can be improved through (1) access to education and training, (2) the use of sensitive and specific selection criteria based on accurate prediction models and biomarkers to identify patients for testing, (3) the development and mainstream implementation of simple criteria-based selection pathways applicable across a range of healthcare settings and ethnicities to select the most appropriate patients for genetic testing and (4) the correct use of next generation sequencing technology to provide accurate and comprehensive testing of all known MODY and monogenic diabetes genes. The creation and public sharing of educational materials, clinical and scientific best practice guidelines and genetic variants will help identify the missing patients so they can benefit from the more effective clinical care that a genetic diagnosis brings.

The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers.

The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development.

This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes.

This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.

Correct genetic diagnosis of maturity-onset diabetes of the young (MODY) is beneficial for person's diabetes management compared to no genetic testing. Aim of the present study was a search for optimal time- and cost-saving strategies by comparing two approaches of genetic testing of participants with clinical suspicion of MODY.

A total of 121 consecutive probands referred for suspicion of MODY (Group A) were screened using targeted NGS (tNGS), while the other 112 consecutive probands (Group B) underwent a single gene test based on phenotype, and in cases of negative findings, tNGS was conducted. The study was performed in two subsequent years. The genetic results, time until reporting of the final results and financial expenses were compared between the groups.

MODY was confirmed in 30.6% and 40.2% probands from Groups A and B, respectively; GCK-MODY was predominant (72.2% in Group A and 77.8% in Group B). The median number of days until results reporting was 184 days (IQR 122-258) in Group A and 91 days (44-174) in Group B (p < 0.00001). Mean costs per person were higher for Group A (639 ± 30 USD) than for Group B (584 ± 296 USD; p = 0.044).

The two-step approach represented a better strategy for genetic investigation of MODY concerning time and costs compared to direct tNGS. Although a single-gene investigation clarified the diabetes aetiology in the majority of cases, tNGS could reveal rare causes of MODY and expose possible limitations of both standard genetic techniques and clinical evaluation.

The coexistence of autoimmune diabetes and maturity-onset diabetes (MODY) is rare. The absence of pancreatic autoantibodies is a key factor prompting MODY genetic testing. In this study, we report three cases of young-onset diabetes with progressive beta-cell dysfunction, strongly positive glutamic acid decarboxylase (GAD) antibodies, and genetic confirmation of pathogenic gene variants of HNF-1A, HNF-4A, and ABCC8-MODY. The first case is a woman diagnosed with HNF-1A-MODY diabetes more than 30 years after her diagnosis of adult-onset diabetes at 25 years. She required insulin after her fourth pregnancy. She became ketotic on oral hypoglycaemic agents (OHAs) and subsequently, her GAD antibodies tested positive. The second case is a woman diagnosed with diabetes at 17 years who was subsequently diagnosed with HNF-4A-MODY after many hypoglycaemic episodes on low-dose insulin. GAD antibodies were strongly positive. The last case is a man diagnosed with diabetes at 26 years who was well controlled on OHAs and required insulin years later due to sudden deterioration in glycaemic control. His ABCC8-MODY was diagnosed upon realisation of strong family history and his GAD antibodies tested positive. All subjects are now treated with insulin. Less than 1% of subjects with MODY have positive autoantibodies. These cases highlight individuals who may have two different types of diabetes simultaneously or consecutively. Deterioration of glycaemic control in subjects with MODY diabetes should highlight the need to look for the emergence of autoantibodies. At each clinic visit, one should update the family history as MODY was diagnosed in each case after the development of diabetes in their offspring.

These cases highlight the rare coexistence of autoimmune diabetes and MODY. Deterioration of glycaemic control in subjects with MODY diabetes should highlight the emergence of autoantibodies. One should revise and update the family history as the diagnosis of MODY was made after the development of diabetes in offspring. Understanding the spectrum of diabetes allows for precision medicine.

To describe the clinical and genetic characteristics and long-term follow-up of a cohort with maturity-onset diabetes of the young (MODY), and to evaluate how molecular diagnosis impacted on treatment.

A large observational, retrospective, cohort study included individuals referred to the University of São Paulo's Monogenic Diabetes Unit between 2011 and 2020. Comprehensive clinical and genetic evaluations were performed.

Overall, 228 individuals (190 GCK-MODY and 38 HNF1A-MODY) were enrolled. Sixty-two different GCK gene mutations (5 novel) and 17 HNF1A gene mutations (2 novel) were found. Data were available on treatment status for 76 index individuals with GCK-MODY. Before molecular diagnosis, nutritional intervention alone was used in 41 cases (53.9%). After molecular diagnosis, this number increased to 72 (94.8%). Glycated haemoglobin (HbA_1c) remained stable over the 6-year follow-up period: 6.5% (47 mmol/mol) at the first and 6.3% (45 mmol/mol) at the final visit (p = 0.056). Prior to molecular diagnosis, 7/21 (33.3%) HNF1A-MODY individuals were using sulfonylurea compared to 17/21 (81%) after testing. After a median of 5 years on sulfonylureas, HbA_1c values improved from 7.5% (58 mmol/mol) to 6.5% (48 mmol/mol) (p = 0.006).

Molecular diagnosis resulted in appropriate adjustment of treatment in approximately 80% of participants with GCK-MODY or HNF1A-MODY.

Maturity Onset Diabetes of Young (MODY), characterized by the pancreatic b-cell dysfunction, the autosomal dominant mode of inheritance and early age of onset (often ≤25 years). It differs from normal type 1 and type 2 diabetes in that it occurs at a low rate of 1-5%, three-generational autosomal dominant patterns of inheritance and lacks typical diabetic features such as obesity. MODY patients can be managed by diet alone for many years, and sulfonylureas are also recommended to be very effective for managing glucose levels for more than 30 years. Despite rapid advancements in molecular disease diagnosis methods, MODY cases are frequently misdiagnosed as type 1 or type 2 due to overlapping clinical features, genetic testing expenses, and a lack of disease understanding. A timely and accurate diagnosis method is critical for disease management and its complications. An early diagnosis and differentiation of MODY at the clinical level could reduce the risk of inappropriate insulin or sulfonylurea treatment therapy and its associated side effects. We present a broader review to highlight the role and efficacy of biomarkers in MODY differentiation and patient selection for genetic testing analysis.

Monogenic diabetes is a genetic disorder caused by one or more variations in a single gene. It encompasses a broad spectrum of heterogeneous conditions, including neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes, affecting 1-5% of patients with diabetes. Some of these variants are harbored by genes whose altered function can be tackled by specific actions ("actionable genes"). In suspected patients, molecular diagnosis allows the implementation of effective approaches of precision medicine so as to allow individual interventions aimed to prevent, mitigate or delay clinical outcomes. This review will almost exclusively concentrate on the clinical strategy that can be specifically pursued in carriers of mutations in "actionable genes", including ABCC8, KCNJ11, GCK, HNF1A, HNF4A, HNF1B, PPARG, GATA4 and GATA6. For each of them we will provide a short background on what is known about gene function and dysfunction. Then, we will discuss how the identification of their mutations in individuals with this form of diabetes, can be used in daily clinical practice to implement specific monitoring and treatments. We hope this article will help clinical diabetologists carefully consider who of their patients deserves timely genetic testing for monogenic diabetes.

Heterozygous loss-of-function variants of the glucokinase (GCK) gene are responsible for a subtype of maturity-onset diabetes of the young (MODY). GCK-MODY is characterized by a mild hyperglycemia, mainly due to a higher blood glucose threshold for insulin secretion, and an up-regulated glucose counterregulation. GCK-MODY patients are asymptomatic, are not exposed to diabetes long-term complications, and do not require treatment. The diagnosis of GCK-MODY is made on the discovery of hyperglycemia by systematic screening, or by family screening. The situation is peculiar in GCK-MODY women during pregnancy for three reasons: 1. the degree of maternal hyperglycemia is sufficient to induce pregnancy adverse outcomes, as in pregestational or gestational diabetes; 2. the probability that a fetus inherits the maternal mutation is 50% and; 3. fetal insulin secretion is a major stimulus of fetal growth. Consequently, when the fetus has not inherited the maternal mutation, maternal hyperglycemia will trigger increased fetal insulin secretion and growth, with a high risk of macrosomia. By contrast, when the fetus has inherited the maternal mutation, its insulin secretion is set at the same threshold as the mother's, and no fetal growth excess will occur. Thus, treatment of maternal hyperglycemia is necessary only in the former situation, and will lead to a risk of fetal growth restriction in the latter. It has been recommended that the management of diabetes in GCK-MODY pregnant women should be guided by assessment of fetal growth by serial ultrasounds, and institution of insulin therapy when the abdominal circumference is ≥ 75th percentile, considered as a surrogate for the fetal genotype. This strategy has not been validated in women with in GCK-MODY. Recently, the feasibility of non-invasive fetal genotyping has been demonstrated, that will improve the care of these women. Several challenges persist, including the identification of women with GCK-MODY before or early in pregnancy, and the modalities of insulin therapy. Yet, retrospective observational studies have shown that fetal genotype, not maternal treatment with insulin, is the main determinant of fetal growth and of the risk of macrosomia. Thus, further studies are needed to specify the management of GCK-MODY pregnant women during pregnancy.