HNF1A Maturity-onset Diabetes Of The Young Research Articles

Different diabetes

In the 2nd century AD, Aretaeus the Cappadocian noted that some people with diabetes were thin, and others were overweight. In the late 19th century Lancereaux called these diabète maigre and diabète gros.1 Since then, these have been named juvenile and maturity-onset diabetes, insulin-dependent and non-insulin-dependent diabetes, type 1 and type 2 diabetes. But of course there are not just two types of diabetes – there may be thousands. In many cases, the cause of a person's diabetes is multifactorial. Sometimes the type of diabetes is unclear. Even when it is clear, diabetes type may be wrongly recorded.2 Don’t miss less common variants of diabetes, especially those that require different treatment or may have an unexpected course. Some diabetes variants are listed in Box 1. Harry was 16 years old when he developed polyuria and polydipsia. His mother had type 2 diabetes as did her father and six more of her relatives. Harry's mother…said: ‘we’d actually taken in a drawn-up family tree, but they didn’t do anything about it, they just said: “He's type 1”.’ Harry was started on insulin. He had great difficulty controlling his blood glucose: ‘The blood glucose levels were all over the place…I didn’t get any warnings, they were just nasty, one minute I’d be kicking a football around and the next minute I’d be flat out on the floor.’ He was often unconscious at night. Seven months after diagnosis an islet-related antibody test proved negative but his consultant still insisted Harry had type 1 diabetes. His mother suspected Harry had maturity-onset diabetes of the young (MODY). She found the expert website www.diabetesgenes.org and a blood test was arranged which confirmed that Harry had a mutation of HNF1A, a cause of MODY. HNF1A mutations cause about 50% of cases of monogenic diabetes. It is estimated that 1–2% of people with diabetes have MODY.3, 4 Harry's insulin was stopped and he was started on a small dose of gliclazide. His life was transformed – from being unsafe to drive and failing at college he passed his exams and got a place in veterinary college. A detailed account of monogenic diabetes was published in this journal recently.5 There were 31,615 children and young people with diabetes in the National Paediatric Diabetes Audit (England and Wales) in 2020–21 but only 162 (0.5%) had a diagnosis of monogenic diabetes. There should have been more.6 Do you have a patient with possible MODY? Use the MODY probability calculator (https://www.diabetesgenes. org/exeter-diabetes-app/ModyCalculator).4 A 37-year-old man, previously well, was admitted with a two-day history of diarrhoea and vomiting. On examination ‘The patient was lucid but in low spirits’; pulse 102 beats/min, respiratory rate 18 breaths/min, and blood pressure 100/58mmHg, but examination was otherwise unremarkable. His blood tests showed diabetic ketoacidosis with a glucose of 74.6mmol/L (1342mg/dl), and HbA1c 6.2% (44mmol/mol). C-peptide and antibodies (ICA, IAA and GAD) were negative. He recovered with standard diabetic ketoacidosis treatment and long-term insulin therapy.7 This man had fulminant type 1 diabetes, first described in Japan where it accounts for about 20% of newly diagnosed acute-onset type 1 diabetes.8 It is seen in other East Asian populations and occasionally in Westerners.9 It is thought that a viral infection in people with genetic susceptibility triggers a rapid immunological process that destroys the beta-cells and damages exocrine pancreas cells. Fulminant diabetes may occur in patients treated with immune checkpoint inhibitors.10 In 70% of patients the hyperglycaemia is preceded by flu-like symptoms or gastrointestinal symptoms. Fulminant diabetes can occur in pregnancy or soon after delivery. Other frequent concomitants are absent islet-related antibodies and raised serum pancreatic enzyme levels (98% of patients).11 ‘Once the diagnosis of this disease is suspected, treatment of diabetic ketoacidosis must be started immediately, as in all other cases of type 1 diabetes. Otherwise, the death of the patient is likely to occur within 24 h. All medical practitioners must remember that this extremely rapidly progressing type of diabetes does exist, and they must pay special attention not to overlook it.’12 Islet cells can suffer autoimmune damage at any age. LADA, also known as slowly evolving immune-mediated diabetes of adults, affects about 12% of people with adult-onset diabetes. Diagnostic criteria included age >30 years, autoimmune history in patient or family, weight normal or slightly overweight, measurable C-peptide, GAD antibody positive, and not needing insulin at first, although it is likely to be needed eventually. Oral agents and non-insulin treatments can be used initially, such as metformin. The possible benefits of insulin use from the start to preserve beta-cell function have yet to be confirmed. SGLT2 inhibitors may help but such patients have a risk of developing diabetic ketoacidosis. It is suggested that C-peptide is monitored, especially if non-insulin treatment has to be increased to reduce hyperglycaemia. Patient and clinician education is important as illness or surgery, for example, may precipitate ketoacidosis. A management strategy is suggested in a consensus statement from an international expert panel.13 A previously well man in his forties of Central African ethnicity with no family history of diabetes had had polyuria and polydipsia for two months. His weight fell from 106kg to 91kg. On admission he looked well but his plasma glucose was 40mmol/L (720mg/dl) with marked ketosis but no acidosis. He was treated with fluid replacement and insulin. Islet-related antibody tests were negative. He was discharged on a total of 82 units of insulin daily which fell to 14–20 units a week later. At three months he was experiencing frequent hypoglycaemia despite further insulin dose reduction. The insulin was stopped and sitagliptin started.14 This man had ketosis-prone type 2 diabetes, also known as Flatbush diabetes, type-J diabetes, type 1.5 diabetes, phasic diabetes, or prairie diabetes. It is common in people of African ethnicity, for example African-Americans, but can affect other ethnic groups. In sub-Saharan Africa it is estimated to account for up to 15% of new diabetes presenting to hospital. It presents with a relatively short history, in people who are overweight who often have a family history of type 2 diabetes. The presenting glucose level is usually high with ketosis or ketoacidosis; insulin treatment causes a rapid fall in glucose, and patients can stop insulin within days or weeks, sometimes needing other glucose-lowering treatment. They may have further episodes of hyperglycaemia and ketosis needing short-term insulin treatment.15 A UK community study among 206 people diagnosed with diabetes aged <45 years included detailed review of diagnosis, GAD antibodies in type 1 diabetes, and targeted genetic testing. Type 1 diabetes was confirmed in 33%, type 2 in 54%, and other diabetes subtypes in 13%. The latter comprised 9% with LADA, 3% with HNF1A MODY (from five families) and 1% with mitochondrial diabetes. Including the families tested as a result of the project ‘led to an estimated minimum population prevalence of 84 (95% CI 31–136) cases per million for HNF1A-MODY.’16 There are many diabetes variants. Remember them when you see both new and existing patients with diabetes. There are almost certainly patients with unusual diabetes variants in every clinic. Misdiagnosis of diabetes type may lead to the wrong treatment and failure to recognise potential dangers. It can cause patients much misery. Always record a family history of diabetes in people with diabetes. Listen to the patient and their family. Many people with monogenic diabetes do not need insulin. An accurate genetic diagnosis is available. Do the test! Fulminant diabetes comes on fast and can kill fast. Beware ketoacidosis in patients with a short history and a very high glucose. Autoimmune diabetes can occur at any age. Don’t miss LADA. Ketosis-prone type 2 diabetes fluctuates from very high glucose and ketosis mandating insulin to not needing insulin at all. Ketosis can recur.

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

Background: Diabetic retinopathy (DR) is a potentially sight-threatening complication of diabetes mellitus. The incidence and associated risk factors of DR has been studied in primary forms of diabetes but little is known with regards to maturity onset diabetes of the young (MODY), particularly in Middle Eastern populations Aim: We aimed to study the incidence of DR in Emirati patients with MODY and to identify clinical and biochemical risk factors associated with its occurrence. Method: Patients with diabetes mellitus underwent digital retinal photography at Imperial College London Diabetes Centre, United Arab Emirates (UAE). Retinal photographs were graded according to the NHS Diabetic Eye Screening Programme for severity of DR and presence or absence of maculopathy. Forty-eight patients highly suspected to have MODY were tested for mutations in all known monogenic diabetes genes using targeted next generation sequencing. Clinical and biochemical parameters were reviewed. Results: Pathogenic MODY mutations were identified in a total of 30 cases, with HNF1A, GCK, HNF4A, HNF1B, and CEL in 50%, 26.7%, 16.7%, 3.3% and 3.3%, respectively. Retinal disease of any grade was found in 26.7% (n=8) of individuals with a genetic diagnosis of MODY, with 75% (n=6) of HNF1A-MODY patients having background (n=4), proliferative (n=1), or stable-proliferative DR (n=1), and 25% (n=2) of HNF4A-MODY patients having background (n=1) or stable-proliferative (n=1) retinopathy. Maculopathy occurred in half (50%) of the HNF1A-MODY cases and all (100%) with HNF4A-MODY. Overall, the incidence rate of any degree of DR in patients with MODY was 880 (270-1490) cases per 10,000 person-years. Significant differences were found in univariate analysis in mean duration of diabetes (14.2±5.3 vs 5.4±6.3years, p=0.002), HbA1c (9.5±1.8% vs 7.1±1.3%, p=<0.001), total cholesterol (TC) (5.3±1.7 vs 4.1±1.0mmol/L, p=0.030), and triglycerides (1.8±1.1 vs 1.0±0.6mmol/L, p=0.018) between individuals with any degree of retinopathy and those without retinal disease. Treatment modality was significantly different in cases with and without any retinopathy (p=0.001), with 50% vs 9.1% receiving insulin. No significant difference in age at onset of diabetes (p=0.640), LDL (p=0.225), albumin-creatinine ratio (p=0.208) were observed. Mean age at examination, blood pressure (BP), estimated glomerular filtration rate, and BMI in individuals with or without retinopathy were 32.2±9.9 vs 19.9±10.9years, 114.5±9.8/69.4±7.4 vs 112.9±12.1/67.1±10.5mmHg, 122±31.6 vs 120.3±25mL/min/1.73m2, 24.1±2.4 vs 22.5±5.3kg/m2, respectively. In multivariate Cox regression incorporating TC:HDL ratio, systolic BP and HbA1c, increased TC:HDL was independently associated with significantly increased hazard of any degree of retinopathy (HR 3.96 (1.08-14.5)). Discussion: The incidence rate of any degree of retinopathy in Emirati patients with primarily HNF1A and HNF4A MODY appears increased in comparison to recently published incidence rates for Type 2 Diabetes (200 to 300 per 10,000 person-years) and comparable with rates reported in Type 1 Diabetes (500 to 660 cases per 10,000 person-years). The high incidence of retinal disease in HNF1A MODY highlights the importance of retinal screening from the time of diagnosis, along with early identification of potential MODY cases in order to optimise blood glucose quickly and effectively.

Pregnancy Complicated by the Most Frequent Forms of Maturity Onset Diabetes of the Young: A Narrative Review on Its Pharmacological Implications.

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.

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.

OBJECTIVEIdentifying maturity-onset diabetes of the young (MODY) in pediatric populations close to diabetes diagnosis is difficult. Misdiagnosis and unnecessary insulin treatment are common. We aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with glucokinase (GCK), hepatocyte nuclear factor-1A (HNF1A), and HNF4A MODY in the pediatric population.RESEARCH DESIGN AND METHODSSwedish patients (n = 3,933) aged 1–18 years, diagnosed with diabetes May 2005 to December 2010, were recruited from the national consecutive prospective cohort Better Diabetes Diagnosis. Clinical data, islet autoantibodies (GAD insulinoma antigen-2, zinc transporter 8, and insulin autoantibodies), HLA type, and C-peptide were collected at diagnosis. MODY was identified by sequencing GCK, HNF1A, and HNF4A, through either routine clinical or research testing.RESULTSThe minimal prevalence of MODY was 1.2%. Discriminatory factors for MODY at diagnosis included four islet autoantibody negativity (100% vs. 11% not-known MODY; P = 2 × 10−44), HbA1c (7.0% vs. 10.7% [53 vs. 93 mmol/mol]; P = 1 × 10−20), plasma glucose (11.7 vs. 26.7 mmol/L; P = 3 × 10−19), parental diabetes (63% vs. 12%; P = 1 × 10−15), and diabetic ketoacidosis (0% vs. 15%; P = 0.001). Testing 303 autoantibody-negative patients identified 46 patients with MODY (detection rate 15%). Limiting testing to the 73 islet autoantibody-negative patients with HbA1c <7.5% (58 mmol/mol) at diagnosis identified 36 out of 46 (78%) patients with MODY (detection rate 49%). On follow-up, the 46 patients with MODY had excellent glycemic control, with an HbA1c of 6.4% (47 mmol/mol), with 42 out of 46 (91%) patients not on insulin treatment.CONCLUSIONSAt diagnosis of pediatric diabetes, absence of all islet autoantibodies and modest hyperglycemia (HbA1c <7.5% [58 mmol/mol]) should result in testing for GCK, HNF1A, and HNF4A MODY. Testing all 12% patients negative for four islet autoantibodies is an effective strategy for not missing MODY but will result in a lower detection rate. Identifying MODY results in excellent long-term glycemic control without insulin.

MON-130 Optimal Glycemic Control in a Patient with HNF1A MODY with GLP1-RA Monotherapy: Implications for Future Therapy

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.

A decision algorithm to identify patients with high probability of monogenic diabetes due to HNF1A mutations

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.

MODY in Ukraine: genes, clinical phenotypes and treatment

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.

A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in type 2 diabetes mellitus

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.

The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.

HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 × 10(-21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations.

Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a(-/-) Model.

Sulfonylurea derivatives are widely used for clinical treatment of human subjects with Maturity Onset Diabetes of the Young (MODY) caused by mutations in HNF-1α or HNF-4α despite the mechanism leading to their hypersensitivity is incompletely understood. In Hnf1a(-/-) mice, serum concentrations and half-life of sulfonylurea derivatives are strongly increased. We thus hypothesized that reduced sulfonylurea derivatives clearance stands behind their therapeutic potential in human HNF1A/HNF4A MODY subjects. Single doses of 3 mg glipizide and 5 mg glibenclamide/glyburide were administered sequentially to seven HNF1A/HNF4A MODY subjects and six control individuals matched for their age, BMI and CYP2C9 genotype. Pharmacokinetic (plasma concentration levels, Cmax, tmax, t1/2, AUC) and pharmacodynamic parameters (glycemia, C-peptide and insulin plasma levels) were followed for 24 hours after drug administration. We provide the first evidence on the pharmacokinetics and pharmacodynamics of sulfonylurea derivatives in human MODY subjects. The half-life of glipizide did not change, and reached 3.8±0.7 and 3.7±1.8 h in the MODY and control subjects, respectively. The half-life of glibenclamide was increased only in some MODY subjects (t1/2 9.5±6.7 and 5.0±1.4 h, respectively). Importantly, the intra- individual responses of MODY (but control) subjects to glipizide and glibenclamide treatment were highly correlated. With regards to pharmacodynamics, we observed a differential response of control but not MODY subjects to the doses of glipizide and glibenclamide applied. We rejected the hypothesis that all human MODY-associated mutations in HNF1A / HNF4A induce changes in the pharmacokinetics of sulfonylureas in humans analogically to the Hnf1a(-/-) mouse model.

A decade of molecular genetic testing for MODY: a retrospective study of utilization in The Netherlands.

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.

A case of hepatocyte nuclear factor‐1β (TCF2) maturity onset diabetes of the young misdiagnosed as type 1 diabetes and treated unnecessarily with insulin (一例肝细胞核因子‐1b (TCF2)突变的青年人中的成年发病型糖尿病（MODY）被误诊为1型糖尿病并且被不必要地使用胰岛素治疗)

Maturity onset diabetes of the young (MODY) is a heterogeneous group of monogenic diabetes subtypes characterized by onset before 25 years of age, residual b-cell function, and autosomal dominant inheritance. In addition to diabetes, hepatocyte nuclear factor (HNF) 1b MODY (formerly MODY5) exhibits a phenotype of structural renal abnormalities, abnormal liver function tests, hyperuricemia, and abnormalities of the pancreas, genital tract, and gastrointestinal system. In contrast with HNF-1a and HNF-4a MODY patients, who are sensitive to sulfonylureas, patients with HNF-1b MODY usually require insulin. There is no report of the successful use of metformin or insulin sensitizers in this setting.

Mutations in the Genes Encoding the Transcription Factors Hepatocyte Nuclear Factor 1 Alpha and 4 Alpha in Maturity-Onset Diabetes of the Young and Hyperinsulinemic Hypoglycemia

Maturity-onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young-onset (typically <25 years), noninsulin-dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding hepatocyte nuclear factor-4 alpha are a rarer cause of MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in ∼50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of an HNF1A or HNF4A gene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost-effective gene analysis for all patients with young onset diabetes.

Rapamycin protects against dominant negative-HNF1A-induced apoptosis in INS-1 cells

HNF1A-maturity onset diabetes of the young (HNF1A-MODY) is caused by mutations in Hnf1a gene encoding the transcription factor hepatocyte nuclear factor 1alpha (HNF1A). An increased rate of apoptosis has been associated with the decrease in beta-cell mass that is a hallmark of HNF1A-MODY and other forms of diabetes. In a cellular model of HNF1A-MODY, we have recently shown that signalling through mammalian target of rapamycin (mTOR) is decreased by the overexpression of a dominant-negative mutant of HNF1A (DN-HNF1A). mTOR is a protein kinase which has important roles in cell metabolism and growth, but also in cell survival, where it has been shown to be both protective and detrimental. Here, we show that pharmacological inhibition of mTOR activity with rapamycin protected INS-1 cells against DN-HNF1A-induced apoptosis. Rapamycin also prevented DN-HNF1A-induced activation of AMP-activated protein kinase (AMPK), an intracellular energy sensor which we have previously shown to mediate DN-HNF1A-induced apoptosis. Conversely, activation of mTOR with leucine potentiated DN-HNF1A-induced apoptosis. Gene silencing of raptor (regulatory associated protein of mTOR), a subunit of mTOR complex 1 (mTORC1), also conferred protection on INS-1 cells against DN-HNF1A-induced apoptosis, confirming that mTORC1 mediates the protective effect. The potential relevance of this effect with regards to the clinical use of rapamycin as an immunosuppressant in diabetics post-transplantation is discussed.

Bone Morphogenetic Protein 3 Controls Insulin Gene Expression and Is Down-regulated in INS-1 Cells Inducibly Expressing a Hepatocyte Nuclear Factor 1A–Maturity-onset Diabetes of the Young Mutation

Inactivating mutations in the transcription factor hepatocyte nuclear factor (HNF) 1A cause HNF1A-maturity-onset diabetes of the young (HNF1A-MODY), the most common monogenic form of diabetes. To examine HNF1A-MODY-induced defects in gene expression, we performed a microarray analysis of the transcriptome of rat INS-1 cells inducibly expressing the common hot spot HNF1A frameshift mutation, Pro291fsinsC-HNF1A. Real-time quantitative PCR (qPCR), Western blotting, immunohistochemistry, reporter assays, and chromatin immunoprecipitation (ChIP) were used to validate alterations in gene expression and to explore biological activities of target genes. Twenty-four hours after induction of the mutant HNF1A protein, we identified a prominent down-regulation of the bone morphogenetic protein 3 gene (Bmp-3) mRNA expression. Reporter assays, qPCR, and Western blot analysis validated these results. In contrast, inducible expression of wild-type HNF1A led to a time-dependent increase in Bmp-3 mRNA and protein levels. Moreover, reduced protein levels of BMP-3 and insulin were detected in islets of transgenic HNF1A-MODY mice. Interestingly, treatment of naïve INS-1 cells or murine organotypic islet cultures with recombinant human BMP-3 potently increased their insulin levels and restored the decrease in SMAD2 phosphorylation and insulin gene expression induced by the HNF1A frameshift mutation. Our study suggests a critical link between HNF1A-MODY-induced alterations in Bmp-3 expression and insulin gene levels in INS-1 cells and indicates that the reduced expression of growth factors involved in tissue differentiation may play an important role in the pathophysiology of HNF1A-MODY.

Urinary C-Peptide Creatinine Ratio Is a Practical Outpatient Tool for Identifying Hepatocyte Nuclear Factor 1-α/Hepatocyte Nuclear Factor 4-α Maturity-Onset Diabetes of the Young From Long-Duration Type 1 Diabetes

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.

INS-1 Cells Undergoing Caspase-Dependent Apoptosis Enhance the Regenerative Capacity of Neighboring Cells

OBJECTIVEIn diabetes, β-cell mass is not static but in a constant process of cell death and renewal. Inactivating mutations in transcription factor 1 (tcf-1)/hepatocyte nuclear factor1a (hnf1a) result in decreased β-cell mass and HNF1A–maturity onset diabetes of the young (HNF1A-MODY). Here, we investigated the effect of a dominant-negative HNF1A mutant (DN-HNF1A) induced apoptosis on the regenerative capacity of INS-1 cells.RESEARCH DESIGN AND METHODSDN-HNF1A was expressed in INS-1 cells using a reverse tetracycline-dependent transactivator system. Gene(s)/protein(s) involved in β-cell regeneration were investigated by real-time quantitative RT-PCR, Western blotting, and immunohistochemistry. Pancreatic stone protein/regenerating protein (PSP/reg) serum levels in human subjects were detected by enzyme-linked immunosorbent assay.RESULTSWe detected a prominent induction of PSP/reg at the gene and protein level during DN-HNF1A–induced apoptosis. Elevated PSP/reg levels were also detected in islets of transgenic HNF1A-MODY mice and in the serum of HNF1A-MODY patients. The induction of PSP/reg was glucose dependent and mediated by caspase activation during apoptosis. Interestingly, the supernatant from DN-HNF1A–expressing cells, but not DN-HNF1A–expressing cells treated with zVAD.fmk, was sufficient to induce PSP/reg gene expression and increase cell proliferation in naïve, untreated INS-1 cells. Further experiments demonstrated that annexin-V–positive microparticles originating from apoptosing INS-1 cells mediated the induction of PSP/reg. Treatment with recombinant PSP/reg reversed the phenotype of DN-HNF1A–induced cells by stimulating cell proliferation and increasing insulin gene expression.CONCLUSIONSOur results suggest that apoptosing INS-1 cells shed microparticles that may stimulate PSP/reg induction in neighboring cells, a mechanism that may facilitate the recovery of β-cell mass in HNF1A-MODY.

Dipeptidyl Peptidase-IV Inhibitors Are Efficient Adjunct Therapy in HNF1A Maturity-Onset Diabetes of the Young Patients—Report of Two Cases

In HNF1A maturity-onset diabetes of the young (MODY), sulfonylurea (SU) is the first-line treatment. Over time, such therapy fails, and additional treatment is required. Dipeptidyl peptidase IV (DPP-IV) inhibitors are new agents that lower blood glucose by prolonging the activity of circulating incretins. We applied DPP-IV inhibitors in two HNF1A MODY patients whose earlier therapeutic regimen included SU. Case 1, a 39-year-old woman, a carrier of the ArgR171X HNF1A mutation, with a 7-year history of diabetes was on 160 mg of gliclazide and 2,000 mg of metformin. Her initial hemoglobin A1c (HbA1c) level was 7.2%, while the mean glucose level on the CGMS((R)) (Medtronic, Northridge, CA) record was 162 mg/dL. Sitagliptine, in a dose of 100 mg/day, was added to the previous treatment. Case 2, a 62-year-old woman, a carrier of the IVS7nt-6G>A mutation, with a 41-year history of diabetes was treated with 240 mg/day gliclazide and 6 IU of insulin/day. Her initial HbA1c was 8.8%, and average glycemia reached 172 mg/dL. In her case, we started the combined therapy with 50 mg of vildagliptine twice daily. Patients were reexamined after 3 months, and HbA1c fell to 6.3% in both subjects. Similarly, significant improvement in glycemic control on CGMS was observed as the average glycemia decreased to 114 mg/dL and 134 mg/dL in Case 1 and Case 2, respectively. No episodes of hypoglycemia or other side effects were recorded. As intravenous glucose tolerance tests (IVGTTs) were performed before and after DPP-IV implementation, we were able to assess their impact on insulin secretion under fasting conditions. We saw a substantial rise in insulin level increment during IVGTT (by 9.8 and13.4 mIU/L in Case 1 and Case 2, respectively). DPP-IV inhibitors may be an effective tool of combined therapy in HNF1A MODY, and they seem to improve beta-cell function under fasting conditions.