Strong Family History Of Diabetes Research Articles

A Study of Diabetes in Young Individuals with Special Reference to Type 2 Diabetes Mellitus

Abstract Background: Type 2 diabetes mellitus (T2DM) in young individuals is a serious concern for the society. Literature suggests that the incidence of T2DM is not only increasing, but also there is a shift of age of onset of T2DM toward younger age groups in India and worldwide. However, data about the frequency of T2DM among young subjects below 25 years of age are sparse in the Indian subcontinent. Hence, the current study was undertaken to find out the frequency and clinical profile of young individuals with T2DM in the departments of internal medicine and pediatrics in a tertiary care hospital. Aims and Objectives: The aim of the study was to study the frequency and clinical profile of T2DM among young individuals with diabetes mellitus. Materials and Methods: The study was a cross-sectional observational study conducted in the Departments of General Medicine and Pediatrics at JSS Hospital, Mysuru, Karnataka, India, over a 2-year period. The subjects with age of onset of diabetes mellitus below 25 years were included in the study. They were categorized according to the C-peptide values as type 1 diabetes mellitus (T1DM) and T2DM. Maturity-onset diabetes of the young (MODY) was diagnosed with the age of onset of diabetes below 25 years with a strong family history of diabetes for three generations and no insulin requirement for metabolic control for 5 years after diagnosis. The statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS version 25). Results: Of the 250 patients included in the study, 208 (83.2%) subjects were T1DM, 38 (15.2%) T2DM, and 4 (1.6%) with MODY. The mean age of onset of T1DM was 13.7 ± 6.201 years and T2DM was 23.28 ± 3.68 years. Body mass index (BMI) and waist circumference of young T2DM patients were more compared to T1DM, which were statistically significant P < 0.0001, and family history showed strong positivity in patients with young T2DM compared to T1DM. Low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), and total cholesterol (TC) were more in young T2DM patients compared to T1DM which were statistically significant with P = 0.003 (LDL), P = 0.0015 (TG), and P = 0.03 (TC), respectively. Conclusions: T2DM, previously considered a middle-aged or elderly condition, is now commonly occurring in young adults and children, probably due to a growing epidemic of childhood obesity and lifestyle. Obesity and dyslipidemia were more in T2DM compared to T1DM among young diabetics.

THU151 Undiagnosed MODY In Case Of Morbid Obesity

Abstract Disclosure: A. Abdulkader: None. S.B. Ten: None. MODY is suspected in nonobese subjects with hyperglycemia, negative islet cell antibodies, and a family history of diabetes. Children with morbid obesity and diabetes can still have MODY and require different treatment. Case report The patient was born after a pregnancy complicated with gestational diabetes, treated with insulin, BW 9 1/2 lbs. He had early onset obesity from 3 yrs. of age. At 8 yrs., he developed impaired glucose tolerance, elevated triglycerides, low HDL, and fatty liver. He developed diabetes at 11 yrs. and was treated with Insulin, but treatment was not effective, Hb A1c was 11.4%, and BMI was 51.8 kg/m2. At 12 yrs., he was diagnosed with MODY on the base of normal C-peptide, negative islet cell AB, strong family history of diabetes: mother, uncle and MGM had diabetes. Insulin was discontinued. Glyburide and Metformin were started that improved his glucose level significantly. Hb A1c improved to 6.2%. Diet was changed, physical exercises were added, and he lost 25 lbs., BMI improved to 44.8 kg/m2. His mother, 46 yrs. old, was diagnosed with diabetes type 1 at 18 yrs. and treated with Insulin. She also had morbid obesity with BMI 48 kg/m2. She developed diabetic neuropathy, nephropathy, and had amputation of the left leg below the knee, eGFR 44 mL/min/1.73m2, Hb A1c 10.5%. She was diagnosed with MODY on the base of normal C-peptide 3.21 ng/mL, negative islet cell AB, family history of diabetes: her mother, brother, son have diabetes. Glyburide and pioglitazone were started, Insulin total daily dose was decreased from 90 units to 15 units a day. Her Hb A1c improved to 6 %, insulin was discontinued. She underwent Roux-en-Y Gastric Bypass surgery, lost 30 lbs. BMI improved to 42 kg/m2, Hb A1c became 5.3%. Her current glucose level is normal on Glyburide 2.5 mg and pioglitazone 7.5 mg daily. Results: Patient and his mother had heterozygous gene polymorphism in GLIS3, c.951G>T (p.Glu317Asp). This sequence replaces glutamic acid with aspartic acid at codon 317 of the GLIS3 protein (p.Glu317Asp). GLIS3 is a variant of MODY and is a transcriptional factor in beta cell differentiation and insulin production. Patient and mother had pathogenic heterozygous variant of KSR2 gene, c.1622del, resulting in a frameshift and premature protein termination (p.Lys541Serfs*27). Pathogenic variants in KSR2 are associated with obesity and insulin resistance. Patient was also heterozygous in the NTRK2 gene for a sequence variant c.500C>A, which is predicted to result in the amino acid substitution p.Ser167Tyr, also associated with obesity. Conclusion Genetic analysis of MODY is necessary even in cases of diabetes with morbid obesity, negative islet cell AB, positive family history of diabetes. Diagnosis of MODY helps provide individualized treatment and avoid complications secondary to unnecessary treatment with insulin. Presentation: Thursday, June 15, 2023

FRI637 Missed MODY With Complex Mutation

Abstract Disclosure: S. Bulchandani: None. S. Majety: None. P. Kundra: None. Introduction: The prevalence range of Maturity-Onset Diabetes of the Young (MODY) is 1-5% among all patients diagnosed with diabetes. Strong family history of diabetes is suggestive of autosomal dominant inheritance. The symptoms of MODY range from mild asymptomatic hyperglycemia to overt insulinopenia requiring insulin therapy. Clinical Case: 33-year-old male presented to the endocrinology clinic for evaluation. He was diagnosed with type 2 diabetes mellitus at the age of 13 years and was initially treated with insulin which was subsequently transitioned to repaglinide and metformin. Reported history of hypoglycemia at birth in self and recently born daughter. Family History was significant for diabetes mellitus diagnosed in biological father at the age of 16 years. Genetic testing for monogenic diabetes revealed pathogenic variant in hepatocyte nuclear factor 4 alpha (HNF4a) and variant of unknown significance in Paired Box Gene 4 (PAX4). Therapy was switched to glipizide 2.5 mg orally which resulted in adequate glycemic control. Genetic testing was recommended for his daughter. Conclusion: MODY is a rare condition and because of its wide clinical presentation, it is common for it to be missed. There are about 14 subtypes of MODY with different genetic mutations, each affecting the beta cell function in a different way. Our case is unique given that our patient had two genetic mutations. Amongst all forms of MODY, HNF4a with a prevalence of 5% to 10% is the third most common mutation of MODY. PAX4 is a transcription factor that is critical for the formation of beta cells, and is important as a regulator in commitment of progenitor cells to mature islet cells. Mutations in PAX gene associated with monogenic diabetes were first identified in two patients of Thai origin, who did not present with mutations in the other known MODY genes. There should be high vigilance and low threshold for genetic testing for MODY in patients who have high likelihood of possessing a form of MODY, particularly as the treatment can be tailored to the clinical presentation of the patient.

IDENTIFICATION OF A NOVEL APPL1 GENE MUTATION IN A SAUDI ARABIAN PATIENT WITH MATURITY-ONSET DIABETES OF THE YOUNG (MODY 14): A CASE REPORT

Introduction:The need of genetic testing and individualized treatment for diabetic individuals with a family history of the condition is discussed in this case study. It emphasizes the significance of early detection and therapy of maturity-onset diabetes of the young (MODY) and the potential advantages of identifying unique mutations that may contribute to the development of diabetes. Case Presentation:A Saudi Arabian woman of 50 years old with a strong family history of diabetes was discovered to have a new mutation in the APPL1 gene related with MODY 14. Prior to age 30, the patient had a history of elevated blood sugar, but had never used diabetes medication. Gliclazide and metformin were prescribed to the patient, resulting in a decrease in HbA1c levels. Conclusion:This case study illustrates the significance of genetic testing in finding novel mutations that may contribute to the development of diabetes and in adapting treatment to the specific needs of individual patients. Detection and treatment of MODY at an early stage helps reduce complications associated with poorly managed diabetes. To completely comprehend the functional repercussions of the APPL1 gene mutation and its impact on the patients long-term health, additional research is required.

The role of specific pancreatic antibodies in the differential diagnosis of complete clinical and laboratory remission of type 1 diabetes mellitus and MODY in children

BACKGROUND: T1D is characterized by autoimmune destruction of pancreatic β-cells, which develops due to genetic and environmental risk factors. Shortly after initiating the treatment with insulin, 80% of children with T1D may require smaller doses of insulin and develop clinical and laboratory remission of the disease so called «honeymoon». The issue of whether there is a need of differential diagnosis between autoimmune DM and non-immune forms of DM raises in cases of preclinical diagnosis of T1D and laboratory remission for more than 6 months.AIM: To study the clinical, immunological, genetic characteristics of T1D remission phase and MODY in children, to determine the diagnostic criteria for T1D and MODY in children.MATERIALS AND METHODS: A single-centre, cross sectional noncontrolled comparative study of two independent cohorts. Data of 150 children examined in the Endocrinology Research Center (January 2016–June 2021). First cohort included patients with complete clinical and laboratory remission of T1D (n=36), second cohort included patients with MODY, confirmed by genetic study (n=114).RESULTS: The median age of diabetes manifestation was significantly higher in patients with T1D — 11.25 years [8.33; 13.78] than in patients with MODY — 7.5 years [4.6; 12.2] (p=0.004). In patients with T1D remission the level of glycated hemoglobin was 6.0% [5.6; 6.4], in group with MODY — 6.5% [6.2; 6.7] (p<0.001). Patients with monogenic diabetes had impaired fasting glucose — 6.27 mmol/l [5.38; 6.72], while patients with remission phase had normoglycemia — 5.12 mmol/l [4.17; 5.87]. The oral glucose tolerance test was perform to all patients, two-hour glucose level did not significantly differ in two groups (p=0.08). A strong family history of diabetes in patients with MODY registered more often (93% vs. 66.7%). A positive autoantibody titer detected more often in patients with remission of T1D (77.8%) than in patients with MODY (11.4%). In addition, no more than 1 type of autoantibodies was detected in patients with MODY.CONCLUSION: Antibodies ZnT8 and IA2 showed the greatest significance for the differential diagnosis of T1D and MODY in cases with long absents of insulin requirement in children with diabetes mellitus. Genetic test is recommended in seronegative cases. If only one type of AT is detected, specialist should decide on the need to do diagnostic genetic test based on a comprehensive analysis of the patient’s clinic characteristics, including family history, manifestation and blood glucose levels.

Glucagon-like peptide-1 therapy for youth with type 2 diabetes.

Glucagon-like peptide-1 therapy for youth with type 2 diabetes.

Inter-relationship of Pro- and Anti- inflammatory Biomarkers with the development of Type 2 Diabetes Mellitus

PurposeThere has been growing evidence that inflammatory markers play a role in the development as well as severity of Type 2 diabetes mellitus (T2DM). This study has been designed to decipher the involvement of C-Reactive Protein (CRP), Tumor Necrosis Factor (TNFα), Interleukin-6 (IL-6) and Interleukin-10 (IL-10) in the etiopathogenesis of T2DM. Basic proceduresA total of 480 T2DM cases and 540 healthy controls were recruited for the study. Blood samples were collected from each study subject to measure the serum levels of CRP, TNFα, IL-6 and IL-10. Main findingsWe found that serum levels of CRP in mg/dl (4.2 ± 0.9), TNFα in pg/ml (34.5 ± 8.8), IL-6 in pg/ml (19.2 ± 7.2) in T2DM patients were significantly high as compared to control participants (CRP; 1.4 ± 0.6, TNFα; 12.7 ± 3.4, IL-6; 3.1 ± 1.4; P < 0.0001). The serum levels of IL-10 in pg/ml were lower in T2DM cases compared to controls (4.35 ± 1.2 vs. 9.6 ± 1.2). In addition, we observed a significant association of CRP levels with insulin resistance, obesity and dyslipidemia. Increased TNFα levels were strongly associated with female gender, Poor glycemic control and strong family history of diabetes. Poor glycemic control was significantly associated with elevated IL-6 levels. Moreover, significantly reduced IL-10 levels were found in T2DM patients with sedentary lifestyle; low educational and rural background. ConclusionsThis study showed a strong relationship between TNFα, IL-6, CRP, IL-10 and T2DM patients of Kashmiri ethnicity, treated at SMHS Hospital. Thus, supporting other studies and showing that cytokines may be good markers for T2DM development.

Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene

Pathogenic variants in more than 14 genes have been implicated in monogenic diabetes; however, a significant fraction of individuals with young-onset diabetes and a strong family history of diabetes have unknown genetic etiology. To identify novel pathogenic alleles for monogenic diabetes, we performed whole-genome sequencing (WGS) on four related individuals with type 2 diabetes – including one individual diagnosed at the age of 31 years – that were negative for mutations in known monogenic diabetes genes. The individuals were ascertained from a large case-control study and had a multi-generation family history of diabetes. Identity-by-descent (IBD) analysis revealed that the four individuals represent two sib-pairs that are third-degree relatives. A novel missense mutation (p.P81S) in the PAX6 gene was one of eight rare coding variants across the genome shared IBD by all individuals and was inherited from affected mothers in both sib-pairs. The mutation affects a highly conserved amino acid located in the paired-domain of PAX6 - a hotspot for missense mutations that cause aniridia and other eye abnormalities. However, no eye-related phenotype was observed in any individual. The well-established functional role of PAX6 in glucose-induced insulin secretion and the co-segregation of diabetes in families with aniridia provide compelling support for the pathogenicity of this mutation for diabetes. The mutation could be classified as “likely pathogenic” with a posterior probability of 0.975 according to the ACMG/AMP guidelines. This is the first PAX6 missense mutation that is likely pathogenic for autosomal-dominant adult-onset diabetes without eye abnormalities.

1290-P: A Rare Case of HNF1A-MODY

Introduction: Maturity onset diabetes of the young (MODY) is a monogenic nonimmune type of diabetes mellitus. It is rare and sometimes misdiagnosed as type 1 or type 2 diabetes (T2DM) . The age of onset is usually below 25 years. It is more common in the European population. Hepatocyte nuclear factor 1-alpha (HNF1A) is one of the most common mutations and is associated with cardiovascular and renal complications.1 Genetic testing in patients with strong hereditary factors results in definitive diagnosis and subsequent appropriate treatment.2 The aim of this report is to emphasize the importance of distinguishing MODY by considering the family history of diabetes and relative clinical features. Case presentation: A 58-year-old Filipino woman was diagnosed with T2DM at age 15. Her mother, 5 of 8 siblings and her daughter all had diabetes. They all died in the 2nd or 3rd decades of their life due to diabetes complications. Her grandfather was European. She has renal insufficiency, coronary heart disease and heart failure. Treatment included glimepiride 2 mg daily and sitagliptin 25 mg daily. The physical exam was unremarkable. Body mass index (BMI) was 21. GAD 65 antibody and Islet cell antibody were negative, C peptide: 3.6 ng/mL, blood sugar: 1mg/dL, HbA1c: 7.3%, creatinine: 2.15 mg/dL and GFR: 25 mL/min/1.73m2. A diagnosis of MODY was considered due to strong family history of diabetes, young age at the onset of diabetes and normal BMI. DNA sequencing demonstrated positive HNF1A mutation compatible with HNF1A-MODY. Due to post prandial hyperglycemia, glimepiride was replaced with pre-meal lispro. Conclusion: This is a rare case of HNF1A-MODY found in a Filipino patient. MODY should be included in the differential diagnosis of diabetic patients with an extensive family history of diabetes, young age of onset of diabetes and negative pancreatic antibodies. Early diagnosis with genetic profiling can guide therapy and hopefully decrease the vascular complications of long-term poor glycemic control. Disclosure S.Velayati: None. M.Shanik: Consultant; Bigfoot Biomedical, Inc., Proteomics International, Research Support; Better Therapeutics, Speaker's Bureau; Abbott, Boehringer Ingelheim International GmbH, Novo Nordisk, Xeris Pharmaceuticals, Inc. I.J.Romao: None.

Management of Type 1 Diabetes in Children in the Outpatient Setting.

Management of Type 1 Diabetes in Children in the Outpatient Setting.

NEUROD1 mutation in an Italian patient with maturity onset diabetes of the young 6: a case report

BackgroundMaturity Onset Diabetes of the Young (MODY) is a monogenic, autosomal, dominant disease that results in beta-cells dysfunction with consequent hyperglycaemia. It represents a rare form of diabetes (1–2% of all the cases).Sulphonylureas (SUs) represent the first-line treatment for this form of diabetes mellitus.NEUROD1 is expressed by the nervous and the pancreatic tissues, and it is necessary for the proper development of beta cells. A neurogenic differentiation factor 1 (NEUROD1) gene mutation causes beta-cells dysfunction, inadequate insulin secretion, and hyperglycaemia (MODY 6).Case presentationWe have documented a new missense mutation (p.Met114Leu c.340A > C) of the NEUROD1 gene, pathogenetic for diabetes mellitus, in a 48 years-old man affected by diabetes since the age of 25 and treated with insulin basal-bolus therapy. Unfortunately, an attempt to replace rapid insulin with dapagliflozin has failed. However, after the genetic diagnosis of MODY6 and treatment with SUs, he was otherwise able to suspend rapid insulin and close glucose monitoring. Interestingly, our patient had an early onset dilated cardiomyopathy, though no data about cardiac diseases in patients with MODY 6 are available.ConclusionsDiagnostic criteria for MODY can overlap with other kinds of diabetes and most cases of genetic diabetes are still misdiagnosed as diabetes type 1 or 2. We encourage to suspect this disease in patients with a strong family history of diabetes, normal BMI, early-onset, and no autoimmunity. The appropriate therapy simplifies disease management and improves the quality of the patient’s life.

A case of digenic maturity onset diabetes of the young with heterozygous variants in both HNF1Α and HNF1Β genes

BackgroundMaturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now. Case reportA female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant. ConclusionDigenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.

An Unusual Form of Type 1 Diabetes With an Elevated Proinsulin Level

Introduction: Diabetes is one of the most prevalent diseases in the world. We recognize the three most common types of diabetes: type1, type2 and gestational diabetes. It is estimated that around 425 million of people worldwide have diabetes and about 90% of those represent type 2 diabetes. The most common types of diabetes are polygenic -- they are caused by a defect in multiple genes. Monogenic diabetes is caused by a mutation in a single gene. We currently have over 10 different types of monogenic diabetes called MODY (Maturity Onset Diabetes of the Young). Sun et al. states that over the past few years, 30 different insulin gene mutations were reported to cause a new syndrome called MIDY (Mutant INS-gene-induced Diabetes of Youth). Most of these mutations lead to proinsulin misfolding in the endoplasmic reticulum. We present a rare case of a young obese female with an elevated proinsulin level and low C-peptide level diagnosed with type 1 diabetes requiring therapy with insulin. Case Description: A 21 year old female with past medical history of chronic diarrhea initially presented with a complaint of dry mouth, dizziness, excessive urination, and thirst. She was found to have hyperglycemia of 203 mg/dL, A1C 8.3, and negative ketones. Patient had a strong family history of diabetes. She had a family history of: father with type 1 diabetes; mother with a past medical history of gestational diabetes who became diabetic postpartum; and three of the patient’s grandparents with a history of diabetes. Patient was started on the oral hypoglycemic agents metformin and glipizide, but she only had partial response to these medications. Because of her strong family history and incomplete response to oral hypoglycemic agents, additional testing was performed. Patient was found to have a low C-peptide level (1.6 ng/mL), elevated proinsulin (72.9 pmol/L), positive GAD antibody (10.3 units/mL) and negative islet cell autoantibody. Patient had a very good response to insulin and subsequently became insulin dependent. She is currently on an insulin pump. Conclusion: Sun et al. reports that proinsulin misfolding causes beta cell failure. Increased misfolding occurs under certain pathological conditions that are currently unknown. We think that there might be some increased proinsulin misfolding abnormality that might be occurring in this patient. There are most likely many epigenetic modifiers that would trigger certain individuals to be more prone to this phenomena of misfolded proinsulin. Future research in diabetes may one day yield antibodies that would specifically recognize misfolded proinsulin in the plasma. Further research is required to elucidate how defective proinsulin folding may lead to beta cell dysfunction and subsequent evolution of diabetes mellitus.

Comparison of clinical features, complication profile, and achievement of guideline targets in early- and late-onset type 2 diabetes patients from North India

The prevalence of diabetes in young people is rising in India. The risk factors are high body mass index, lack of physical activity, and a positive family history. Young patients with type 2 diabetes mellitus are at a higher risk of longer disease duration and enhanced risk for chronic complications. We have studied the difference between early- and late-onset type 2 diabetes mellitus with respect to various glycemic and non-glycemic parameters. This is an observational cross-sectional study conducted from November 2018 to October 2019. A total of 5142 patients were included in the study. The demographic, anthropometric, clinical, and biochemical information was obtained from the record of the patients. The number of patients diagnosed before 40 years of age was 1574 and 3568 patients after 40 years of age. There was female preponderance, 75.7% of the study subjects were from the urban area, and 60% had an income of < 2 lakh rupees per annum. Two-third (77%) of the patients were either overweight or obese. Significantly higher proportion of patients achieved glycemic and blood pressure targets in the early-onset type 2 diabetes mellitus group. The younger group had higher weight and body mass index, strong family history of diabetes, and more severe dyslipidemia. The comorbid conditions were significantly higher in the older age group. Our study has revealed that about one-third of type 2 diabetes mellitus patients are diagnosed before 40 years of age. The younger patients are more obese. Two-third (73%) of these patients have uncontrolled diabetes.

Questionnaire-based Survey of Demographic and Clinical Characteristics, Health Behaviors, and Mental Health of Young Korean Adults with Early-onset Diabetes.

BackgroundThe incidence of early-onset diabetes is increasing among young adults. However, there are limited data on the characteristics and management of young Korean adults with diabetes. This study assessed the clinical and demographic characteristics, health behaviors, and mental health among young Korean adults with diabetes mellitus.MethodsThis cross-sectional study included young Korean adults with diabetes (n = 225) with an onset age of 20–39 years from four university hospitals. Demographic characteristics, management of diabetes, and mental health were assessed using a questionnaire survey.ResultsType 2 diabetes was the most common type (73.3%), and 13.8% of participants were classified as other types or unknown. Approximately, 64.7% of participants had a strong family history of diabetes, and 76% had treatment within three months of diagnosis. Approximately, 11.1% of participants had diabetic complications; 39.1% of participants received insulin injections, including oral anti-diabetic medications. Additionally, 30.4% were smokers, and only 28% had active physical activity; 26.5% of participants had >3 hours of screen time. One third of participants never had breakfast, and 60.5% went out to eat at least three times a week. Half of the participants showed moderate to severe stress perception, and 21.4% of patients had moderate to severe levels of depression based on the Korean version of Beck Depression Inventory score.ConclusionEarly-onset diabetes was associated with a strong family history and early insulin treatment. Young adults with diabetes had poor health behaviors and frequent mental depression. These findings suggest the necessity of health policies for improving health behaviors and mental distress.

Clinical experience from a regional monogenic diabetes referral centre in Singapore

AimsMonogenic diabetes (also known as maturity-onset diabetes of the young or MODY) affects a subset of individuals with young-onset diabetes. We report our diagnostic work-up experience for such individuals. MethodsServing as a regional secondary-care diabetes centre in a multi-ethnic population, we receive referrals to evaluate MODY from endocrinologists in both public and private practice. Key criteria for consideration of genetic-testing are onset age ≤ 35, negative GAD antibody, no history of diabetic ketoacidosis, strong family history of diabetes and BMI < 32.5 kg/m2. A monogenic diabetes registry was set up since 2017 to study their disease trajectories. ResultsWe identified 30 out of 175 (17.1%) individuals with likely pathogenic/pathogenic variants. Importantly, 29 out of 30 (96.7%) occurred in clinically actionable genes. A continuous scale combining BMI, hs-CRP and HDL provided 80% (P < 0.001) diagnostic accuracy for MODY in our cohort, achieving a negative predictive value of 0.93 and sensitivity at 0.76. Subtyping MODY prior to genetic testing (if desired) will require specialist domain knowledge and additional biomarkers due to its genetic heterogeneity. ConclusionsThrough systematic and structured evaluation, the prevalence of MODY is non-trivial (17.1%) in a referral centre. Diagnostic algorithm combining clinical criteria and readily available biomarkers can support clinical decision for MODY genetic testing.

P1697MULTI- NATIONAL SURVEY AMONG NEPHROLOGISTS AND TRANSPLANT SURGEONS ABOUT THE SUITABILITY AND ACCEPTABILITY OF MARGINAL LIVE KIDNEY DONORS WITH OBESITY OR ABNORMAL BLOOD SUGAR PROFILE

Abstract Background and Aims There are no clear guidelines about the suitability and acceptance of living- kidney donors with obesity or abnormal blood sugar profile. Method To form a consensus about the acceptance of these donors, a survey was distributed to nephrologists and transplant surgeons in different countries and through AST and ERA-EDTA. Results Of a total of (n=122) respondents from 22 countries: 80% (N= 96) were nephrologists and 20% (N=23) were transplant surgeons. The majority were heavily involved in pre-transplant evaluations of donors and recipients and have &amp;gt; 6 years in practice. 75% of the respondents will accept obese donors (BMI 30-35) if donors show some weight loss before donation or at least show commitment to lose weight in the future. However, the presence of a strong family history of diabetes ( DM) in obese donors (even with normal fasting blood sugar (FBS) and hemoglobin A1C [ Hgb A1C]) mandates weight lose preferably to BMI of 30 ( n=46, 38% ) or at least to lose some weight before being considered for donation (n=30, 25%). On the other hand, morbidly obese donors (BMI 36-40) with normal FBS, Hgb A1C and negative family history of DM thought to need to decrease their weight to BMI 30 ( 47% of the respondents) or at least lose some weight before being considered for donation ( n=30, 25%). However, 22% of the respondents would decline these donors due to the risk of relapse of obesity. If an obese donor started to have impaired fasting blood sugar ( IFG), the majority (47%) will decline him/her because of the higher risk to develop DM. (33%) will delay the donation till BMI reaches below 30 and IFG is resolved as a result of weight reduction. Most of the respondents (52%) will not rely solely on isolated mildly elevated Hgb A1C (e.g. Hgb A1C = 5.7- 6) or isolated (IFG) as the critical indicator to decline a young donor with normal weight and normal FBS. Instead 2hrs- glucose tolerance test will be indicated. The presence of even mild and controlled diabetes in a middle age (e.g. 55 years old donor) thought to be a contraindication for kidney donation in 62% of the respondents. However, such donors might be allowed to donate if no alternative donor is available after clearly explaining the risks (23%). In regard to resolved DM after bariatric surgery and weight loss, 43% of the respondents said they will consider them for donation if two years passed after bariatric surgery without obesity relapse (43%). Up to one forth may consider these donors earlier (once BMI is below 30). Despite the surgical difficulties related to obesity in kidney donors, transplant surgeons seem more likely than nephrologists to accept obese donors (P= 0.046), morbidly obese ( P=NS). Conclusion Living kidney donors with isolated obesity, (IFG), mildly abnormal HgbA1C or history of bariatric surgery are still considered for kidney donation by many centers. However, donors with more than one abnormality especially at young age are not considered for donation.

SUN-128 Novel Mutation in the HNF1A Gene in Siblings Previously Diagnosed with Type 1 Diabetes

Introduction: Maturity Onset Diabetes of the Young (MODY) is a monogenic type of diabetes, frequently misdiagnosed as Type 1 diabetes. Previous studies have shown that MODY makes up about 1.1% of all diabetes cases among children 0-14 years. MODY can potentially be managed with dietary changes and/or oral medications. Case Presentation: A 16 year old girl who presented with elevated hemoglobin A1c was diagnosed with Type 1 diabetes with negative antibodies and started on insulin therapy. She also had negative screening for thyroid autoimmunity and celiac markers. Family history was positive for an older sister with antibody negative Type 1 diabetes, and their mother with diabetes of unknown etiology. The older sister was on insulin for 8 years. Given strong family history of diabetes and negative pancreas autoimmunity, the diagnosis of MODY was considered. Genetic testing on both sisters revealed a heterozygous variant in the HNF1A gene designated c.981del, suggesting MODY-3. This variant is predicted to result in a frameshift and premature protein termination (p.Ser328Valfs*14). To the best of our knowledge this mutation has not been reported as an etiology of MODY-3 and is expected to be pathogenic. Both siblings were started on oral sulfonylurea (SU) that has improved their hemoglobin A1c. The younger sister (index case) was completely weaned off insulin while the older sister had improvement in her diabetes control. Conclusion: We report a novel mutation in HNF1A gene in 2 siblings who were misdiagnosed as Type 1 diabetes and had significant improvement in their diabetes control after initiation of oral SU treatment. Strong family history of diabetes and negative autoimmune markers in affected individuals should alert the provider to consider MODY in the differential diagnosis particularly if the phenotype does not fit either type 1 or type 2 diabetes. Appropriately classifying type of diabetes will help choose the best treatment plan for the patient which can lead to improvement in quality of life and better health outcomes.

SUN-132 Investigating the Accuracy of Risk Factor Calculators in Diagnosing Maturity Onset Diabetes of the Young (MODY)

MODY is a rare form of diabetes caused by impaired insulin production attributable to autosomal dominant monogenic mutations. It is an important diagnosis as it results in a treatment change for 25% of patients, allows for the screening of 1st degree relatives and identifies patients who have MODY subtypes associated with reduced rates of micro- and macro-vascular complications. Diagnosing MODY is challenging and several MODY risk factor calculators have been proposed to guide rational genetic testing. The aim of this study was to retrospectively apply the MODY risk factor calculators to patients with diagnosed MODY who attended the diabetes service at a tertiary hospital in the West of Ireland to identify the most accurate calculator in predicting MODY in this patient cohort. MODY risk factor calculators in the literature focus on young age at diagnosis, low BMI and low HbA1c as defining features of MODY. Ellard, Bellanne-Chantelot et al. (2008) proposed age at diagnosis ≤25, BMI <30 and HbA1c ≤58.8 mmol/L as the recommended criteria for genetic testing in MODY, and this captured 6/21 (28.57%) patients with MODY in our cohort. Thanabalasingham, Pal et al. (2012) proposed age at diagnosis ≤30, BMI <30 and HbA1c ≤63.9 mmol/L, which accounted for 8/21 (38.1%) of our MODY patients. The MODY Probability Calculator proposed by Shields et al. (2012) was developed using logistic regression to determine the probability of MODY. Variables include current age, age at diagnosis, sex, treatment with insulin, time to insulin treatment, BMI, HbA1c and parental history of diabetes. The MODY Probability Calculator cannot be directly compared to the other calculators, as it does not define clinical criteria in a binary fashion but assigns a weighting to each factor. Patients have to be aged ≤35 at diagnosis for this calculator to be applied, which resulted in the exclusion of 3/22 patients in our cohort. 9/22 (40.9%) patients had a positive predictive value (PPV) of >50%, which conferred a 0.47/100 false negative rate and a 3/100 false positive rate if used as the basis for referring for genetic testing. 5/22 (22.73%) patients had a PPV of >75%, which conferred a 0.9/100 false negative rate and a 1.2/100 false positive rate, which is highly sensitive and specific. 12/22 (54.55%) patients had a PPV of >20%, which conferred a 0.14/100 false negative rate and a 16.8/100 false positive rate. This work demonstrates that the MODY Probability Calculator currently achieves the best balance of sensitivity / specificity in diagnosing patients with MODY. Nevertheless, a significant portion (10/22) of known MODY patients were not identified. Limitations include excluding patients aged >35 at diagnosis and excluding patients with a strong family history of diabetes who do not have an affected parent. These calculators are diagnostic adjuncts in the Endocrinologist’s toolbox to stratify MODY risk but do not replace clinical judgement.

The MODY Masquerade

Introduction: Maturity Onset Diabetes of the Young (MODY) is a relatively uncommon, but increasingly recognized cause of diabetes. Many MODY patients are misdiagnosed as type 1 or type 2 diabetes mellitus (DM) and may be treated suboptimally for many years before they are recognized. We present one such patient who went 49 years before accurate diagnosis. Case: A 59 year-old female with a history of type 2 DM presented with complaints of difficulty controlling her blood sugar. She was being treated with metformin, and had been recently started on low dose glimepiride due to persistently elevated hemoglobin A1c (HbA1c). She was diagnosed as type 2 DM at 10 years of age. Her weight was normal at the time of diagnosis, and she did not require insulin. Family history included many family members diagnosed as type 2 DM, including her maternal grandmother, mother, brother, sister, son, and two nieces. All were diagnosed in their teens, and only her son currently requires insulin. On exam, she was not obese (BMI 26 kg/m2) with no signs of insulin resistance. Antibodies to glutamic acid decarboxylase (GAD Ab) were undetectable, and C-peptide was elevated to 4.04 ng/mL in response to mild hyperglycemia. Genetic testing revealed a defect in the Hepatocyte Nuclear Factor 4 Alpha (HNF4A) gene, consistent with MODY subtype 1. The dose of glimepiride was increased, and her HbA1c improved from 8.1% to 6.1% after two months. Discussion: MODY is a form of diabetes caused by single gene mutations related to beta cell development, regulation, and function. These defects lead to impaired glucose sensing and insulin release. MODY should be suspected in patients with a strong family history of diabetes, lack of signs of insulin resistance, onset at young age, and absence of features of type 1 DM (i.e., negative GAD Ab and detectable C-peptide). MODY subtype 1 patients are typically sensitive to sulfonylurea therapy, and this is considered first-line treatment. However, some patients may develop progressive beta cell dysfunction as they age and will ultimately require insulin therapy. Disclosure D. Englert: None. J. Dendy: None.