Maturity-onset Diabetes Research Articles

Treatment switch from multiple daily insulin injections to sulphonylureas in an African young adult diagnosed with HNF1A MODY: a case report

BackgroundMaturity 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.Case presentationA 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.ConclusionThis 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.

Expanded phenotypic spectrum in MODY 5 patients with 17q12 deletion syndrome: experience from an Indian tertiary care hospital.

To study the clinical and genotypic spectrum of patients with HNF-1ß deletions (MODY 5) at a tertiary care hospital. This study included four patients from the Department of Endocrinology at Sher-i-Kashmir Institute of Medical Sciences Srinagar with a strong clinical suspicion of MODY 5. Genetic analysis, including a monogenic gene panel comprising 78 genes associated with MODY and other similar forms of monogenic diabetes, was done. Dosage analysis of HNF 1B by Multiplex Ligand-dependent Probe Amplification (MLPA) was performed. The mean age of patients was 22.25 years with a male-to-female ratio of 3:1. Associated phenotypic features included neurodevelopmental disorder in all four patients, insulin resistance in two patients (2/4) and alopecia in three patients (3/4). One patient had clinical and biochemical hyperandrogenism. All patients had renal malformations, and one patient had a Mullerian anomaly. Family history was present in 1 patient. All patients had pancreatic abnormalities, the most common type being dorsal agenesis of the pancreas (3/4), followed by annular pancreas (1/4). All patients had a genetic deletion of the gene HNF1B on chromosome 17 with a deletion interval of (?_37686431)_(37745059_?), (?_37687281)-(37744884_?), comprising exons 1 to 9. It is imperative to maintain a high index of suspicion for MODY 5 in patients presenting with renal anomalies and diabetes, even in the absence of a family history. Early identification allows for screening family members and ensures a comprehensive approach to identifying and managing other abnormalities in these patients.

Novel treatment options in patients with maturity onset diabetes of the young.

Maturity onset diabetes of the young (MODY) is the most common monogenetic form of diabetes with an autosomal dominant inheritance pattern. MODY is caused by mutations in genes that are important for the development and function of pancreatic beta cells, resulting in impaired insulin secretion capacity. To date, 14 different types have been described. While GCK-MODY (formerly MODY-2) generally requires no drug therapy, other forms of MODY such as HNF1A-MODY (formerly MODY-3) and HNF4A (formerly MODY-1) usually respond very well to sulfonylurea therapy. However, these MODY forms are characterised by a progressive course, meaning that insulin therapy is often required as the disease progresses. Both sulfonylurea therapy and insulin therapy are associated with an increased risk of hypoglycaemia and frequent weight gain. Newer blood glucose-lowering therapies, such as SGLT2 inhibitors (SGLT2i), DPP-4 inhibitors (DPP4i) and GLP-1 receptor agonists (GLP-1RA), have a much lower risk of hypoglycaemia and usually have a favourable effect on body weight. This review aims to provide an overview of the treatment of MODY patients with SGLT2i, DPP4i and GLP-1RA on the basis of previously published clinical studies, case series and case reports.

Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes.

Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels' limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5 × 10-5. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual's polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes.

7316 A Unique Presentation of Diabetes Mellitus in an 8-Year-Old Male Positive For 3 Different Mutations Related to MODY

Abstract Disclosure: R. Senguttuvan: None. A. Pamfil: None. Background: Maturity-Onset Diabetes of the Young (MODY) is the most common form of inherited non-autoimmune diabetes mellitus, characterized by autosomal dominant inheritance, young age at onset and beta cell dysfunction. There are at least 14 MODY mutations and we present a pediatric case not meeting criteria for type 1[T1DM] or type 2 diabetes mellitus[T2DM], who tested positive for mutations in 3 different genes known to cause MODY. Case: An 8-year-old male, born full term, 2776 grams and 48.3 cm, without history of neonatal hypoglycemia or hyperglycemia, was referred for new onset diabetes mellitus management. While undergoing evaluation for abdominal pain and constipation, he was found to have a fasting glucose of 126 mg/dL (7 mmol/L) and hemoglobin A1C of 6.5%. He endorsed polyuria, but no polydipsia. He had no clinical signs of insulin resistance (e.g., acanthosis nigricans) and a BMI of 23.65 kg/m2, at the 97th percentile. Family history is positive for diabetes mellitus requiring insulin, in father (diagnosed at 11 years) and paternal grandmother and T2DM in paternal aunt. Laboratory evaluation was negative for all 5 antibodies (GAD, IA-2, Anti-islet cell antibody, Zinc Transporter 8 and Insulin antibodies) and revealed an insulin level of 15.9 uIU/mL (RR: <2.0-13.0) and C peptide: 2.3 ng/mL (RR: 1.1-4.4). Lacking diagnostic criteria for T1DM or T2DM, genetic testing was performed. Patient tested heterozygous for mutations in 3 genes known to cause MODY: GCK [(c.350 G>T p. (G117V)], ABCC8 [(c.2270 C>G p.(T757R)], and HNF1B [(c.68A>G p.(K23R)], all variant of uncertain significance. Over an 8-month period, patient's weight decreased from 98 lbs. (44.9 kg) to 90 lbs. (41.1 kg) after meeting with our dietician and implementing healthy dietary changes, and his beta cell function markers improved from diagnosis: Fasting insulin (4.5 uIU/mL), C peptide (1.3 ng/mL), and glucose 119 mg/dL; Hemoglobin A1C remained relatively stable at 6.1%. A kidney ultrasound was normal. No medical intervention were started yet, and patient is being monitored clinically and biochemically every 3-4 months. Discussion: Clinical monitoring over time, genetic testing in the parents, are critical in this patient’s long-term treatment plan and prognosis. To our knowledge, this may be the first case of diabetes mellitus in a pediatric patient, positive for mutations in 3 different genes known to cause MODY. South Texas has one of the highest incidences of T2DM in the USA. In addition to screening for genetic forms of diabetes, in patients with negative T1DM antibodies and atypical phenotype for T2DM, we should consider genetic screening in mildly obese pediatric and young adult patients without significant acanthosis nigricans, who were already diagnosed as T2DM. Presentation: 6/1/2024

8616 A Novel Mutation of Maturity Onset Diabetes of the Young

Abstract Disclosure: K.H. Weerasinghe: None. N. Branis: None. Background: Maturity onset diabetes of the young (MODY) is an autosomal dominant condition characterized by various subsets (Nkonge et al., 2020). A mutation in the glucokinase gene (GCK), otherwise known as MODY type 2, is often characterized by mild hyperglycemia managed with lifestyle modifications (Nkonge et al., 2020). Novel mutations in this gene may differ in their clinical course and need close clinical monitoring. Clinical Case: A 19 year old male presented for evaluation of his diabetes mellitus. In 2020, the patient was hyperglycemic on routine blood work, with asymptomatic features. His condition was managed with lifestyle modifications. The HbA1c was 6.8 and 7; while fructosamine was 338 mmol/L (normal 205-285 mmol/L). Subsequent workup revealed GAD 65 to be less than 5 U/ml(normal range being 0-5 U/ml) with negative islet antibodies. C-peptide was similarly measured and found to be 1.5 ng/ml, within the limits of 1.1-4.4 ng/ml, demonstrating a good pancreatic reserve. A MODY genetic profile was then conducted which revealed a novel mutation in the GCK gene, variant c.1064T>C (p.L355P). As this is a novel mutation, the probability of MODY was calculated, and found to be 75% using the Exeter maturity-onset diabetes of the young (MODY) probability calculator (EMPC).The patient’s clinical course thus far has been managed conservatively as his hyperglycemia has been mild. However, recently the patient’s post prandial sugars were found to be persistently elevated. Pharmacotherapy such as sulfonylureas was discussed however, as per the patient’s wishes, stricter dietary modifications will be applied prior to the initiation of medication. Conclusion: Patients with novel mutations should be closely monitored as the general expected clinical course may vary. These changes are demonstrated in this case report as the patient started developing elevation in postprandial sugar levels uncharacteristically. Close monitoring of the patient’s future clinical status will be essential in learning more about the differences in prognosis and long term management.

6429 An Unusual Gene Mutation and Clinical Manifestation of MODY 10

Abstract Disclosure: J. Ambalavanan: None. O. Abdulhussein: None. J. Ferri-Guerra: None. G. Madrigal Loria: None. K. Alkwatli: None. A. Iqbal: None. R.R. Correa: None. Introduction: Maturity-Onset Diabetes of the Young (MODY) is a rare monogenic form of diabetes characterized by impaired beta cell function accounting for < 5% of all people with diabetes. About 14 different subtypes of MODY have been described in the. MODY 10 is an extremely rare form with mutation in the INS (insulin) gene. We present a previously unreported genetic mutation in the INS gene, its clinical course and subsequent management. Case: A 23-year-old female presented to us for consultation regarding new diagnosis of diabetes. She came to medical attention for pre-diabetes at the age of 16 years and was managed with diet control. She was officially diagnosed with diabetes by PCP in October 2022 after onset of polyuria and nocturia, and HbA1c of 8.7%. During initial evaluation, we suspected type 1 diabetes due to her age, low BMI of 17.61 kg/m2 and prescribed a CGM while we awaited extensive antibody evaluation. Within a week she reported average blood sugars in the 200-300 mg/dl range. As a result, she was on insulin glargine 5 units at bedtime. Within 3 months, her HbA1c dropped to 6.5% but she started experiencing frequent symptomatic hypoglycemia at work. At this point we suspected MODY due to age at diagnosis; antibody negative status for GAD-65, IA-2, ZnT8 and insulin; detectable C-peptide 1.7 ng/ml (0.81-3.85); low BMI and good glycemic control and frequent hypoglycemia on insulin. On evaluation of family history, she had a history of diabetes in maternal grandmother, paternal grandfather and paternal great uncle. Her parents did not have diabetes. We stopped glargine and started glipizide XL 2.5mg once daily. She was also referred to our clinical genetics team. On genetic evaluation she was found to have one heterozygous variant of uncertain significance in the INS gene. On further evaluation, this was found to be guanine to adenine substitution at c:139 in exon 2 of the INS gene on chromosome 11:2182063 resulting in a variant protein p.Gly47Ser which is a missense change that occurs when glycine (Gly) is replaced by serine (Ser) at position 47. This mutation has not been previously reported to be pathogenic or benign and has not been reported in significant frequency anywhere based on our literature search. Furthermore, in silico analysis supported that this missense variant had a deleterious effect on the insulin structure/function. Given the rarity of this condition, there are no formal guidelines or consensus regarding the management. During a subsequent follow up visit, we discussed that she fit the diagnosis clinically and suggested possible medications. In the end, we decided to change her from glipizide to sitagliptin 50mg daily as she was continuing to have lows at work. This helped avoid hypoglycemia and maintained time in rage at 98%. Conclusion: We present a patient with rare form of MODY 10 with a new mutation in c139:G>A at exon 2 of INS gene managed with sulfonylurea and eventually DPP4 inhibitor. Presentation: 6/2/2024

8182 New Mouse Model Mirrors Human MODY8: Opening Doors to Understanding Exocrine-Endocrine Crosstalk in the Diabetic Pancreas

Abstract Disclosure: K. El Jellas: None. V. Salerno: None. L.S. Katz: None. J. Hu: None. G. Fogarty: None. A. Mandal: None. A. DiStefano-Forti: None. D. Scott: None. M. Lowe: None. A. Molven: None. R.N. Kulkarni: None. Maturity-onset diabetes of the young, type 8 (MODY8) is a dominantly inherited form of monogenic diabetes, caused by heterozygous mutations in the carboxyl ester lipase (CEL) gene expressed in pancreatic acinar cells. MODY8 is characterized by chronic pancreatitis and exocrine dysfunction. Despite the intimate anatomical relationship between the endocrine and exocrine pancreas, little is known about the biological components mediating exocrine-endocrine communication in regulating glucose homeostasis. Here, we report a refined mouse model that bears the mutation present in MODY8 patients on one allele, and the humanized normal variable number of tandem repeat (VNTR) of CEL with 16 repeats (16R) on the other, mimicking the genetic make-up seen in MODY8 patients. Examination of glucose homeostasis revealed that inducing stress (e.g. by high-fat diet) leads to glucose intolerance in MODY8/16R mice and a blunted glucose-stimulated insulin-secretion compared to their control littermates. Histopathological analyses demonstrated features of chronic pancreatitis in some pancreatic lobes, including inflammation, acinar atrophy, acinar-to-ductal metaplasia, fibrosis and fat infiltration, mirroring the morphology of the human disease. Moreover, we applied immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) to intact pancreata and found that beta-cell mass was significantly decreased in the MODY8/16R mice, with a large number of islets located within fatty lobes. These results are coupled with comparative proteomics and lipidomic profiling with the aim of understanding the molecular signatures of exocrine and endocrine cells during pathogenesis. In conclusion, we have generated a mouse that recapitulates several features of the exocrine and endocrine phenotype characteristic of human MODY8. This novel model provides a unique opportunity, not possible in humans, to characterize pancreatic endocrine-exocrine communication in a longitudinal manner as a response to diverse environmental stressors. Presentation: 6/2/2024

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

HNF1B Transcription Factor: Key Regulator in Renal Physiology and Pathogenesis.

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype-phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care.

A novel mutation in HNF1B promotes ferroptosis-mediated renal mesangial cells fibrosis

Maturity onset diabetes of the young type 5(MODY5) is typically attributed to mutations in the HNF1B gene, which encodes transcription factors that play a significant role in kidney development and function maintenance. In this study, we identified a novel HNF1B gene mutation (c.445C>A) in a young male MODY5 patient exhibiting elevated serum creatinine levels and albuminuria. Through transfection of wild type and mutant HNF1B plasmids into mouse mesangial cells (MMCs), we investigated the impact on molecular indicators related to proliferation, fibrosis and oxidative stress. The results revealed that the HNF1B novel mutation promoted the expression of fibronectin, type 1 collagen, and CyclinD1, as well as increasing cellular oxidative stress and susceptibility to ferroptosis in MMCs. Our findings established a novel association between HNF1B mutant diseases and mesangial cell proliferation and fibrosis, suggesting that mutations of HNF1B may contribute to the progression of renal function in MODY5 patients. Additionally, our results implicate potential therapeutic targets for restraining fibrosis.

Management Strategies for Children and Adolescents with Diabetes Mellitus

The principles of treatment for diabetes in children and adolescents cannot simply be derived from care routinely provided to adults with diabetes. The major consideration is that the epidemiology, pathophysiology, developmental considerations, and response to treatment of pediatric diabetes are often different from those of adult diabetes. Second, recommended treatments for children and adolescents with type 1 diabetes (T1DM), type 2 diabetes (T2DM), and other pediatric conditions such as monogenic diabetes (neonatal diabetes and MODY [maturity-onset diabetes of the young]) also differ. HbA1c goals in T1DM and T2DM must be individualized and reassessed over time. A HbA1c < 7% is appropriate for many children and adolescents with T1DM. In a case with hypoglycemia, hypoglycemic unawareness, lack of access to analog insulins, advanced insulin delivery technology and/or continuous glucose monitoring, a less stringent HbA1c < 7.5% will be required. A reasonable HbA1c goal for T2DM is < 7%. If possible, a strict HbA1c target of < 6.5% can be implemented. Metformin is the first-line treatment of choice in T2DM. In a case with ketosis or HbA1c > 8.5%, insulin will be required with once daily basal insulin (0.25~0.5 IU/kg). If the glycemic goal is not attained, the addition of a second agent is considered in adult patients but might not be applicable or safe in pediatric cases. Therefore, the efficacy and safety of these drugs used in adult patients, including glucagon-like peptide-1 receptor agonists and sodium glucose cotransporter 2 inhibitors, should be evaluated in pediatric patients worldwide.

Maturity-onset Diabetes of the Young During Pregnancy

Maturity-onset Diabetes of the Young During Pregnancy

Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes

Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis.

Maternal Transmission of 17q12 Microdeletion: Intrafamilial Phenotypic Variability and Diagnostic Hurdles

The relatively rare proximal 17q12 microdeletion, including the deletion of the HNF1B gene, is associated with renal cysts and diabetes syndrome (RCAD). This genomic rearrangement results in a wide range of phenotypes, including renal cysts and diabetes, which are consistent with maturity-onset diabetes of the young type 5 (MODY5), Mullerian aplasia/dysgenesis, autism spectrum disorder and schizophrenia, speech delay, learning difficulties, transient neonatal hypercalcemia, and neonatal cholestasis. We describe a girl with a 17q12 microdeletion identified using CGH array analysis (about 1.4 Mb, including HNF1B and LHX1 genes). The same deletion was identified in her mother. The proband had shown cystic and hypodysplastic bilateral kidneys since birth and hypertension, while her mother had bilateral renal cysts and diabetes. Despite suggestive findings in the girl and in the mother, no clinical suspicion arose, and genetic testing was carried out only after referral to a pediatric nephrologist. In children, the identification of 17q12 microdeletion may have a significant impact on the diagnosis, prognosis, and management of renal disease and early-onset type II diabetes. This family with a 17q12 microdeletion confirms intrafamilial phenotypic variability and highlights the importance of including it early on in the analysis of the diagnostic workup of children with renal cystic diseases.

Striking manifestation and unexpected therapeutic course of diabetes mellitus in a22-year-old male patient

The case of a22-year-old male patient who presented with acute on chronic hyperglycemia in known MODY ("maturity onset diabetes of the young") 12 (ABCC8 gene) after 11months of treatment cessation is reported. To emphasize the importance of the awareness of this therapeutically important entity of diabetes, the essential facts of this inherited disease are summarized.

Modelling human diabetes ex vivo: a glance at maturity onset diabetes of the young.

Diabetes is a complex metabolic disease which most commonly has a polygenic origin; however, in rare cases, diabetes may be monogenic. This is indeed the case in both Maturity Onset Diabetes of the Young (MODY) and neonatal diabetes. These disease subtypes are believed to be simpler than Type 1 (T1D) and Type 2 Diabetes (T2D), which allows for more precise modelling. During the three last decades, many studies have focused on rodent models. These investigations provided a wealth of knowledge on both pancreas development and beta cell function. In particular, they allowed the establishment of a hierarchy of the transcription factors and highlighted the role of microenvironmental factors in the control of progenitor cell proliferation and differentiation. Transgenic mice also offered the possibility to decipher the mechanisms that define the functional identity of the pancreatic beta cells. Despite such interest in transgenic mice, recent data have also indicated that important differences exist between mice and human. To overcome these limitations, new human models are necessary. In the present review, we describe these ex vivo models, which are created using stem cells and organoids, and represent an important step toward islet cell therapy and drug discovery.

Case report of a patient with a biallelic variant in glucokinase (GCK) gene causing maturity onset diabetes of the young

Case report of a patient with a biallelic variant in glucokinase (GCK) gene causing maturity onset diabetes of the young

Diagnostic Inertia in Identifying Maturity-Onset Diabetes of the Young

This case report describes a woman in her mid 30s with diabetes who had been treated with insulin therapy, no history of diabetic ketoacidosis, and normal levels of C-peptide.

Monogenic diabetes screening in the midwest of ireland

Monogenic diabetes screening in the midwest of ireland