Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Should Lead to Testing for MODY: Lessons From a 5-Year Pediatric Swedish National Cohort Study

OBJECTIVEHepatocyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes.RESEARCH DESIGN AND METHODSAdults with diabetes for ≥5years, without renal impairment, were studied (HNF1A MODY [n = 54], HNF4A MODY [n = 23], glucokinase MODY [n = 20], type 1 diabetes [n = 69], and type 2 diabetes [n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes.RESULTSUCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) (<0.02 nmol/mmol [<0.02 to <0.02] vs. 1.72 nmol/mmol [0.98–2.90]; P < 0.0001). ROC curves showed excellent discrimination (area under curve [AUC] 0.98) and identified a cutoff UCPCR of ≥0.2 nmol/mmol for differentiating HNF1A/4A MODY from type 1 diabetes (97% sensitivity, 96% specificity). UCPCR was lower in HNF1A/4A MODY than in type 2 diabetes (1.72 nmol/mmol [0.98–2.90] vs. 2.47 nmol/mmol [1.4–4.13]); P = 0.007). ROC curves showed a weak distinction between HNF1A/4A MODY and type 2 diabetes (AUC 0.64).CONCLUSIONSUCPCR is a noninvasive outpatient tool that can be used to discriminate HNF1A and HNF4A MODY from long-duration type 1 diabetes. To differentiate MODY from type 1 diabetes of >5 years’ duration, UCPCR could be used to determine whether genetic testing is indicated.

Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Are Critical Features of MODY: Lessons from a 5-Year Paediatric Swedish National Cohort Study

Genetic testing for maturity-onset diabetes of the young (MODY) may be relevant for treatment and prognosis in patients with usually early-onset, non-ketotic, insulin-sensitive diabetes and for monitoring strategies in non-diabetic mutation carriers. This study describes the first 10 years of genetic testing for MODY in The Netherlands in terms of volume and test positive rate, medical setting, purpose of the test and age of patients tested. Some analyses focus on the most prevalent subtype, HNF1A MODY. Data were retrospectively extracted from a laboratory database. In total, 502 individuals were identified with a pathogenic mutation in HNF4A, GCK or HNF1A between 2001 and 2010. Although mutation scanning for MODY was used at an increasing rate, cascade testing was only used for one relative, on average, per positive index patient. Testing for HNF1A MODY was mostly requested by internists and paediatricians, often from regional hospitals. Primary care physicians and clinical geneticists rarely requested genetic testing for HNF1A MODY. Clinical geneticists requested cascade testing relatively more often than other health professionals. A substantial proportion (currently 29%) of HNF1A MODY probands was at least 40 years old at the time of testing. In conclusion, the number of individuals genetically tested for MODY so far in The Netherlands is low compared with previously predicted numbers of patients. Doctors' valuation of the test and patients' and family members' response to (an offer of) genetic testing on the other hand need to be investigated. Efforts may be needed to develop and implement translational guidelines.

IDF21-0348 Incidence and risk of diabetic retinopathy in Emirati patients with maturity onset diabetes of the young (MODY)

Different diabetes

AimsSGLT2 inhibitors are a new class of oral hypoglycemic agents used in type 2 diabetes (T2DM). Their effectiveness in maturity onset diabetes of the young (MODY) is unknown. We aimed to assess the response to a single dose of 10 mg dapagliflozin in patients with Hepatocyte Nuclear Factor 1 Alpha (HNF1A)-MODY, Glucokinase (GCK)-MODY, and type 2 diabetes.MethodsWe examined 14 HNF1A-MODY, 19 GCK-MODY, and 12 type 2 diabetes patients. All studied individuals received a single morning dose of 10 mg of dapagliflozin added to their current therapy of diabetes. To assess the response to dapagliflozin we analyzed change in urinary glucose to creatinine ratio and serum 1,5-Anhydroglucitol (1,5-AG) level.ResultsThere were only four patients with positive urine glucose before dapagliflozin administration (one with HNF1A-MODY, two with GCK-MODY, and one with T2DM), whereas after SGLT-2 inhibitor use, glycosuria occurred in all studied participants. Considerable changes in mean glucose to creatinine ratio after dapagliflozin administration were observed in all three groups (20.51 ± 12.08, 23.19 ± 8.10, and 9.84 ± 6.68 mmol/mmol for HNF1A-MODY, GCK-MODY, and T2DM, respectively, p < 0.001 for all comparisons). Post-hoc analysis revealed significant differences in mean glucose to creatinine ratio change between type 2 diabetes and each monogenic diabetes in response to dapagliflozin (p = 0.02, p = 0.003 for HNF1-A and GCK MODY, respectively), but not between the two MODY forms (p = 0.7231). Significant change in serum 1,5-AG was noticed only in T2DM and it was −6.57 ± 7.34 mg/ml (p = 0.04).ConclusionsA single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in T2DM. Whether flozins are a valid therapeutic option in these forms of MODY requires long-term clinical studies.

Background. Maturity-Onset Diabetes of the Young (MODY) has not been previously studied in Ukraine. We investigated the genetic etiology in a selected cohort of patients with diabetes diagnosed before 25 years of age, and in their family members. Methods. Genetic testing of the most prevalent MODY genes (GCK, HNF1A, HNF4A, HNF1B and INS) was undertaken for 48 families (51 affected individuals) by Sanger or targeted next generation sequencing. Results. A genetic diagnosis of MODY was made in 24/51 affected individuals from 21/48 families (44%). HNF1A and HNF4A MODY were the most common subtypes, accounting for 11/24 of MODY cases. Ten patients with HNF1A/ HNF4A and ABCC8 MODY and inadequate glycemic control were successfully transferred to sulfonylureas. Median HbA1c decreased from 7,9% [7,5-8,4] tо 6,3% [5,9-6,7] 3 months after transfer (p=0,0001). Conclusions. Genetic testing identified pathogenic HNF1A and HNF4A variants as the most common cause of MODY in Ukraine. Transfer to sulfonylureas substantially improved the glycemic control of these patients.

PurposeTo investigate the utility of biomarkers of maturity-onset diabetes of the young (MODY), high-sensitivity C-reactive protein (hsCRP), and 1,5-anhydroglucitol (1,5-AG) in conjunction with other clinical and laboratory features to improve diagnostic accuracy and provide a diagnostic algorithm for HNF1A MODY.MethodsWe examined 77 patients with HNF1A MODY, 88 with GCK MODY mutations, 99 with type 1 diabetes, and 92 with type 2 diabetes. In addition to 1,5-AG and hsCRP, we considered body mass index (BMI), fasting glucose, and fasting serum C-peptide as potential biomarkers. Logistic regression and receiver operating characteristic curves were used in marker evaluation.ResultsConcentration of hsCRP was lowest in HNF1A MODY (0.51 mg/l) and highest in type 2 diabetes (1.33 mg/l). The level of 1,5-AG was lowest in type 1 diabetes and HNF1A MODY, 3.8 and 4.7 μg/ml, respectively, and highest (11.2 μg/ml) in GCK MODY. In the diagnostic algorithm, we first excluded patients with type 1 diabetes based on low C-peptide (C-statistic 0.98) before using high BMI and C-peptide to identify type 2 diabetes patients (C-statistic 0.92). Finally, 1,5-AG and hsCRP in conjunction yielded a C-statistic of 0.86 in discriminating HNF1A from GCK MODY. We correctly classified 92.9% of patients with type 1 diabetes, 84.8% with type 2 diabetes, 64.9% HNF1A MODY, and 52.3% GCK MODY patients.ConclusionsPlasma 1,5-AG and serum hsCRP do not discriminate sufficiently HNF1A MODY from common diabetes types, but could be potentially useful in prioritizing Sanger sequencing of HNF1A gene.

Background: Among those diagnosed with maturity-onset diabetes of the young (MODY), the most common form is hepatocyte nuclear factor 1α MODY (HNF1A MODY). Individuals with HNF1A MODY typically respond very well to treatment with sulfonylureas (SU) which are recommended as first line therapy. Clinical Case: A 23 year old Caucasian woman with presumed type 1 diabetes since age 14 presented for diabetes care during pregnancy where she maintained an A1c between 5.9% - 7.5% on full basal-bolus insulin therapy. In the immediate post-partum period a diagnosis of MODY was suspected, despite no family history of diabetes, given frequent hypoglycemia on a low total daily dose of insulin of 0.2u/kg/day with minimal basal insulin requirement, absence of development of DKA in the setting of complete cessation of insulin for several days, random c-peptide 2.15 ng/mL (ref. range 0.80-3.10 ng/mL) with concurrent glucose 181mg/dl, and absent anti-GAD and islet cell antibodies. Genetic sequencing revealed a de novo heterozygous mutation for variant c.827C>A; p.Ala276Asp in exon 4 of the HNF1A gene consistent with HNF1A MODY. In 2014, insulin was discontinued and SU therapy was started with A1c ranging 7.1% - 8.8% in the setting of variable adherence. Given consistently elevated A1c, dulaglutide 0.75mg weekly was started in 2017 with subsequent improvement in glycemic control allowing a decrease in SU dose. In early 2018, she discontinued SU therapy entirely given frequent hypoglycemia on glimepiride 1mg daily and dulaglutide 0.75mg weekly. After SU discontinuation, dulaglutide was increased to 1.5mg weekly and her A1c improved to 6.6% without hypoglycemia, the best A1c of her adult life with the exception of during her pregnancy. Conclusion: There is little data on the use of GLP1-RA as monotherapy for patients with HNF1A MODY and no long term studies of GLP1-RA monotherapy or parallel group, head-to-head studies of GLP1-RA vs. SU have been published. In this case, dulaglutide monotherapy was more effective than glimepiride monotherapy in achieving short term glycemic targets in an individual with HNF1A MODY.

Practical Aspects of Monogenic Diabetes: A Clinical Point of View.

Monogenic Diabetes (MFD) represents close to 2% of all the cases of diabetes diagnosed in people younger than 45 years old. Maturity-Onset Diabetes of the Young (MODY), neonatal diabetes, and several syndromic forms of diabetes are included among the most accounts for about typical forms of MDF. MODY is the most frequent type of MFD, with MODY 1, 2, 3, and 5 being the most prevalent forms. The aim of this narrative review is to describe pregnancy associated changes in the pharmacological profile of the antidiabetic drugs used in women with the most frequent MODY subtypes. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/ PubMed, EMBASE, and SCIELO databases from 1970 to 2019 first semester. Pregnancy introduces changes in the pharmacodynamic and pharmacokinetic profile of some of the treatments used in MODY. MODY 3 (also known as HNF1-A MODY) is the most frequent MDF. MODY 3 patients are highly sensitive to Sulfonylureas (SU). This is also the case for MODY pregnant women. This high sensitivity to SU is also registered in patients with MODY 1 (HNF4-A MODY). Pharmacodynamic changes have been proposed to explain this behavior (Epac2 hyperactivity). However, changes in expression/activity of the metabolizing CYP2C9 cytochrome and/or alterations in the drug transporters oatp1 (Slc21a1), Lst-1 (Slc21a6), OATPD (SLC21A11), and oat2 may better explain, at least in part, this phenomenon by an increase in the concentration of the active drug. The impact of changes in the pharmacological behavior of drugs like SU and other metabolized/transported by mechanisms altered in a pregnancy complicated by MODY is unknown. However, switching-to-insulin recommendation formulated for MODY 1 and 3 seems to be justified. Further research in this field is needed for a better understanding of changes in drug activity associated with this particular subset of patients with MFD.

Current practice guidelines recommend considering a diagnosis of MODY in patients with a strong family history but without typical features of type 2 diabetes (T2D) (i.e., obesity, insulin resistance, high-risk ethnicity) or type 1 diabetes (T1D) (i.e., islet autoantibodies). We aimed to test if these criteria apply to a racially diverse pediatric patient population. Using EPIC Population Health, we retrospectively reviewed electronic medical records (IRB H-41512) of youth diagnosed with MODY between 2013-2017 in a large academic pediatric hospital in Southwestern U.S. We found that, out of 46 patients with MODY, 50% (n=23) had MODY 2, 17.3% (n=8) MODY 3, 17.3% (n=8) MODY 5, 8.6% (n=4) MODY 1, 2.1% (n=1) MODY 4, and 8.6% of patients had a clinical diagnosis of MODY due to inability to perform molecular testing. The mean (SD, range) age of diabetes diagnosis was 10.1 years (4.4, 2-17); 52% of patients were females; 50% were non-Hispanic white, 32.5% Hispanic, 6.5% African American, 6.6% Lebanese, 2.2% Asian and 2.2% others/unknown. Notably, 15.2% (n=7, all with a molecular diagnosis of MODY) had positive islet antibodies, 8.6% (n=4) Hashimoto’s thyroiditis and 2.1% (n=1) vitiligo. Obesity/overweight was present in 23.8%, 15.2% had hypertension / prehypertension and 21.7% had dyslipidemia. Diabetes was absent in parents and siblings of 26% (n=12) of patients, although in 5 patients, the mother had gestational diabetes. Persistent microalbuminuria was found in 2 youth with MODY 2 and diabetic neuropathy in 1 patient with MODY 2. The mean (SD, range) time between the diagnoses of diabetes and MODY was 14.3 months (22.3, 1-120). In conclusion, youth with MODY often were of ethnic minorities, lacked a family history of diabetes and had characteristics typical of T1D or T2D, suggesting that the current guidelines to consider a diagnosis of MODY may not apply to a racially diverse U.S. pediatric population. Furthermore, in contrast to previous studies, we identified microvascular complications in youth with MODY 2. Disclosure S. Relan: None. F.C. Hessel: None. K.D. Timmons: None. R. Sonabend: None. M.J. Redondo: None.

Report of Prolonged Neonatal Hypoglycemia in Three Infants of Mothers With Variants in HNF1A

Ghrelin is a hormone that regulates appetite. It is likely to be involved in the pathophysiology of varying forms of diabetes. In animal studies, the ghrelin expression was regulated by the hepatocyte nuclear factor 1 alpha (HNF1A). Mutations of the HNF1A gene cause maturity onset diabetes of the young (MODY). We aimed to assess the circulating ghrelin levels in HNF1A–MODY and in other types of diabetes and to evaluate its association with HNF1A mutation status. Our cohort included 46 diabetic HNF1A gene mutation carriers, 55 type 2 diabetes (T2DM) subjects, 42 type 1 diabetes (T1DM) patients, and 31 glucokinase (GCK) gene mutation carriers with diabetes as well as 51 healthy controls. Plasma ghrelin concentration was measured using the immunoenzymatic assay with polyclonal antibody against the C-terminal fragment of its acylated and desacylated forms. Ghrelin concentrations were 0.75 ± 0.32, 0.70 ± 0.21, 0.50 ± 0.20, and 0.40 ± 0.16 ng/ml in patients with HNF1A–MODY, GCK–MODY, T1DM, and T2DM, respectively. The ghrelin levels were higher in HNF1A–MODY and GCK–MODY than in T1DM and T2DM (p < 0.001 for all comparisons) but lower than in non-diabetic controls (1.02 ± 0.29 ng/ml, p < 0.001 for both comparisons). In the multivariate linear model, the differences between both MODY groups and common diabetes types remained significant. Analysis by a HNF1A mutation type indicated that ghrelin concentration is similar in patients with different types of sequence differences. Plasma ghrelin level is higher in HNF1A–MODY and GCK–MODY than in the common polygenic forms of diabetes.

The differential diagnosis for children with diabetes includes a group of monogenic diabetic disorders known as maturity-onset diabetes of the young (MODY). So far, six underlying gene defects have been identified. The most common subtypes are caused by mutations in the genes encoding the transcription factor HNF-1a (MODY 3) and the glycolytic enzyme glucokinase (GCK) (MODY 2). MODY 2 is the most benign form of diabetes as the threshold for glucose sensing is elevated resulting in mild, regulated hyperglycemia. MODY 2 may usually be treated with diet alone without risk of microvascular complications. Patients with MODY usually present as children or young adults. Genetic testing for MODY in diabetic subjects is often not performed because of the costs and its unavailability in Switzerland. We describe the impact of the genetic analysis for MODY 2 on diabetes management and treatment costs in a five-year-old girl. The patient and her diabetic mother were both found to have a heterozygous missense mutation (V203A) in the glucokinase gene. The five-year-old girl was started on insulin therapy for her diabetes but because her HbA1c remained between 5.8-6.4% (reference 4.1-5.7%) and her clinical presentation suggested MODY insulin was discontinued. She is now well controlled on a carbohydrate controlled diet regimen only. Omission of insulin treatment made regular blood glucose monitoring unnecessary and removed her risk of hypoglycemia. Costs for the genetic analysis were 500 Euro. At our centre costs for diabetes care of a patient with type 1 diabetes are approximately 2050 Euro/year compared to 410 Euro/year for the care of a patient with MODY 2. In addition, a diagnosis of MODY 2 may reassure patients and their families, as microvascular complications are uncommon. Thus there are both health and financial benefits in diagnosing MODY 2. We recommend genetic testing for MODY 2 in clinically selected patients even though this analysis is currently not available in Switzerland and costs are not necessarily covered by the health insurances.