The FINNMODY study : clinical characterization of maturity-onset diabetes of the young (MODY) in Finland

The most common form of monogenic diabetes is called Maturity-onset Diabetes of the Young (MODY), which accounts for 1–3% of all cases of diabetes. Initially, MODY was a diagnosis for a familial form of diabetes that occurred in the lean and the young, demonstrated no dependence on exogenous insulin, and followed a dominant pattern of inheritance. Today, the clinical manifestation is more heterogeneous, and MODY has increasingly become a genetic diagnosis. More than 90% of the pathogenic gene variants responsible for MODY reside in GCK, HNF1A, HNF4A, or HNF1B. Although classical Mendelian diseases involve fully penetrant and distinctive phenotypes, heterogeneity in patients with MODY is pronounced. Even those with the same gene variant manifest with diverse clinical presentations. The characterization of gene–disease associations and heterogeneity in patients with MODY have inspired the three studies included in this thesis. In Study I, our aim was to systematically assess hepatobiliary and pancreatic manifestations in 14 Finnish patients affected by pathogenic gene variants of HNF1B. The patients underwent magnetic resonance imaging and magnetic resonance cholangiopancreatography. In conclusion, half of the patients (7 of 14) had an anomalous finding of the biliary system, and 6 of them had bile duct cysts (BDCs). Although untreated BDCs have generally been associated with a substantial risk of malignant transformation, it is not known whether the BDCs of genetic origin are similarly premalignant. In Study II, the aim of the international effort was to establish whether heterozygous protein-truncating variants (PTVs) in RFX6 are a novel genetic aetiology for MODY. Comparing between independent patient and control cohorts, we found that the RFX6 PTVs were enriched among the patients, whose clinical presentation was strongly suggestive of MODY, and among those routinely referred to genetic testing for MODY. In addition, the individuals heterozygous for the RFX6 PTVs demonstrated dysglycaemia and lower levels of serum glucose–dependent insulinotropic polypeptide (a.k.a. gastric inhibitory polypeptide, GIP). Study III was a multigenerational, longitudinal and cross-sectional family-based characterization study with a specific focus on the clinical and metabolic presentation of HNF1A p.(Gly292fs), the most common pathogenic variant responsible for HNF1A-MODY. The 12 families studied included 145 heterozygous carriers of the variant and their 139 first-degree relatives without the variant. Three of the 12 families were large multigenerational families who have continued their extensive follow-up ever since they were first identified and reported by our group in the 1990s. In conclusion, the carriers were leaner than the non-carriers, and they demonstrated enhanced lipolytic activity. Plasma glucose levels were higher in carriers than in non-carriers throughout the OGTT, and suggestive of insulin deficiency, serum insulin levels were lower in carriers than in noncarriers during the OGTT response. Although most carriers developed diabetes at a young age, one-third remained free of diabetes at 33 years. The polygenic risk score for type 2 diabetes also modified the age at onset of diabetes in patients with HNF1A-MODY. Studies I–III and numerous previous studies have indicated that patients with MODY are vastly heterogeneous. National efforts, including the studies conducted in Finland, might play a major role due to possible population differences. Personalized tailoring of medical therapy (e.g. a switch from insulin treatment to oral agents) is often possible regardless of the clinical presentation and origin of a patient, but further research is essential to explore individual predictors of the treatment response. Although the response has only rarely been assessed in engineered human cell line models, in vitro studies could provide novel mechanistic insights concerning MODY and other monogenic forms of diabetes. To summarize, systematic studies on individuals with a pathogenic gene variant can uncover profound heterogeneity associated with monogenic diabetes. These studies provide a valuable source for genetic laboratories to produce high-quality gene reports. Precision medicine in monogenic diabetes is progressively becoming a reality.Yleensä diabeteksen taustalla on yksittäisen syyn sijaan monen perintö- ja ympäristötekijän ryväs, mutta monogeeninen diabetes vaatii kehittyäkseen vain yksittäisen geenimuutoksen. Monogeenisen diabeteksen yleisin muoto on MODY (Maturity-Onset Diabetes of the Young), joka kattaa noin 1-3 % diabetestapauksista. Alkujaan MODY viittasi harvinaiseen ja perheittäin esiintyvään diabetekseen, joka kehittyi hoikille nuorille ja periytyi vallitsevasti (dominantisti) puolille jälkeläisistä. Insuliinihoitoa ei tarvittu. Viime vuosikymmenten geenitutkimukset ovat kuitenkin paljastaneet, että yhä useamman MODY-potilaan oirekuva ja ilmiasu ovat huomattavasti alkuperäistä määritelmää monenkirjavampia. Kahdella perheenjäsenellä voi olla hyvin erilainen ilmiasu, vaikka molemmat kantavat samaa geenimuutosta. Väitöskirjan ensimmäiseen osatyöhön osallistui 14 potilasta, jotka kantavat muutosta HNF1B-geenissä. MODY-diabeteksen lisäksi HNF1B-potilailla todetaan useamman elinjärjestelmän muutoksia. Kartoitimme potilaiden sappiteitä magneettikuvauksella, ja puolella tutkimukseen osallistuneista todettiin sappiteiden kystia. Sappitiekystojen on uskottu vaativan leikkaushoitoa. Toisessa osatyössä etsimme uusien geenien yhteyttä MODY-diabetekseen. Osallistujien diabetes oli MODY-tyyppinen, mutta geeniseulonta ei paljastanut muutoksia tunnetuissa MODY-geeneissä. Poikkeuksellisen monella osallistujalla todettiin kuitenkin harvinainen RFX6-geenimuutos. Kansainvälisen yhteistyön tuloksena RFX6-muutokset voitiin yhdistää MODY-diabetekseen, joka kehittyi vain osalle kantajista. Kantajilla todettiin myös alhainen GIP-suolistohormonin taso. Kolmannessa osatyössä jatkoimme 1990-luvulla käynnistynyttä monisukupolvista tutkimusta perheissä, joissa MODY-diabetesta aiheuttaa yleisin MODY-geenimuutos HNF1A p.(Gly292fs). Perheisiin kuului 145 geenimuutoksen kantajaa ja heidän 139 perheenjäsentään ilman muutosta. Tulokset paljastivat kantajien olevan perheenjäseniään hoikempia. Lipolyysi eli kehon rasvan hajoaminen oli kantajilla aktiivisempaa. Vaikka kantajien diabetes alkoi usein nuorena, heistä kolmanneksella ei ollut diabetesta vielä 33-vuotiaana. Tyypin 2 diabeteksen riski vaikutti MODY-diabeteksen alkamisikään. Tämän väitöskirjan tutkimukset vahvistavat aiempia havaintoja MODY-diabeteksen monimuotoisuudesta. Vaikka MODY-diabeteksen tunnistaminen onkin haastavaa, yksittäisen potilaan diagnoosi saattaa mullistaa diabeteksen hoidon. Joskus insuliinipistokset voidaan esimerkiksi korvata tablettilääkkein. MODY-tutkimus on tärkeää myös kansallisella tasolla, jotta Suomessakin yhä useampi pääsee oikeaan diagnoosiin ja siten yksilöllisen hoidon piiriin

MODY-diabetes

Diabetes. English summary

Ennustaako varhaisraskauden yhdistelmäseulonnan poikkeava tulos ainoastaan aneuploidian riskin?

TARKOITUS: Retrospektiivisen tutkielman tarkoituksena on selvittää, vaikuttako varhaisraskauden yhdistelmäseulonnan väärä positiivinen tulos raskausajan ennusteeseen. Tulos on väärä positiivinen, jos positiivisesta seulontatuloksesta huolimatta jatkotutkimuksissa ei todeta sikiön aneuploidiaa. Tutkielman tarjoamaa tietoa voitaisiin parhaimmillaan käyttää osana laadukasta raskausneuvontaa. MENETELMÄT: Aineisto kootaan HYKS:in sikiötutkimusyksikön rekisterin perusteella. Rekisterin lisäksi suuri osa tiedoista poimitaan sähköisistä potilastietojärjestelmistä. Yhdistelmäseulonnat on tehty vuosina 2009-2012. Selvitettäviä tekijöitä ovat vastasyntyneen pieni- tai suuripainoisuus, keskenmenot, syntymän ennenaikaisuus, kohtukuolemat, äidin ikä, synnytyksen käynnistymistapa, synnytystapa ja 21-trisomian riskiarvio. 21-trisomian riskiarvion mukaan aineisto voidaan jakaa kahteen tai viiteen alaluokkaan. Tutkielma vertailee ennustetekijöitä riskialaluokkien välillä. Tuloksia verrataan myös laajempiin ulkopuolisiin tilastoihin. TULOKSET: Tutkielman perusteella yhdistelmäseulonnan väärä positiivinen tulos lisää lievästi ennenaikaisuuden riskiä korkeimmissa riskiluokissa, jos äiti on yli 35-vuotias tai sikiö on miespuolinen. Yleisesti raskauden ennuste vaikuttaa kuitenkin hyvältä väärän seulontapositiivisen tuloksen jälkeen. Tätä tietoa voitaisiin käyttää raskausajan potilasneuvonnassa

Human Physiology of Genetic Defects Causing Beta-cell Dysfunction

The last decade has revealed hundreds of genetic variants associated with type 2 diabetes, many especially with insulin secretion. However, the evidence for their single or combined effect on beta-cell function relies mostly on genetic association of the variants or genetic risk scores with simple traits, and few have been functionally fully characterized even in cell or animal models. Translating the measured traits into human physiology is not straightforward: none of the various indices for beta-cell function or insulin sensitivity recapitulates the dynamic interplay between glucose sensing, endogenous glucose production, insulin production and secretion, insulin clearance, insulin resistance-to name just a few factors. Because insulin sensitivity is a major determinant of physiological need of insulin, insulin secretion should be evaluated in parallel with insulin sensitivity. On the other hand, multiple physiological or pathogenic processes can either mask or unmask subtle defects in beta-cell function. Even in monogenic diabetes, a clearly pathogenic genetic variant can result in different phenotypic characteristics-or no phenotype at all. In this review, we evaluate the methods available for studying beta-cell function in humans, critically examine the evidence linking some identified variants to a specific beta-cell phenotype, and highlight areas requiring further study. (C) 2020 The Authors. Published by Elsevier Ltd.Peer reviewe

Biliary Anomalies in Patients With HNF1B Diabetes

Context: The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. Objective: To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Setting and Patients: Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Main Outcome Measure(s): Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Results: Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Conclusions: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.Peer reviewe

MODY-diabetes ja raskaus

English summaryPeer reviewe

A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY

Correction: Volume65, Issue5 Page: 912-912 DOI: 10.1007/s00125-022-05663-z Published: MAY 2022 Early Access: MAR 2022Aims/hypothesis Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum. Methods We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT. Results Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17-35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m(2) units of BMI, p=2.2 x 10(-4), using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 mu mol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 mu mol/l, p=3.1 x 10(-5)). Conclusions/interpretation The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.Peer reviewe

Identification of monogenic variants in more than ten per cent of children without type 1 diabetes-related autoantibodies at diagnosis in the Finnish Pediatric Diabetes Register

Peer reviewe

An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells

MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients. Unexpectedly, MODY3 patient-specific HNF1A+/R272C β cells hypersecrete insulin both in vitro and in vivo after transplantation into mice. Consistently, we identified a trend of increased birth weight in human HNF1A mutation carriers compared with healthy siblings. Reduced expression of potassium channels, specifically the KATP channel, in MODY3 β cells, increased calcium signaling, and rescue of the insulin hypersecretion phenotype by pharmacological targeting ATP-sensitive potassium channels or low-voltage-activated calcium channels suggest that more efficient membrane depolarization underlies the hypersecretion of insulin in MODY3 β cells. Our findings identify a pathogenic mechanism leading to β cell failure in MODY3.Peer reviewe