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Zusammenfassung. Chronische Müdigkeit ist ein unspezifisches Symptom, das bei erwachsenen ambulanten Patientinnen und Patienten häufig auftritt. Anhaltende körperliche Müdigkeit, deren Ätiologie nach Ausschluss der üblichen Ursachen unklar ist, sollte die Frage nach seltenen Krankheiten wie angeborene Stoffwechselstörungen (IEM) aufwerfen. Das Hauptmerkmal der chronischen Müdigkeit bei IEM ist ihr dynamischer Charakter, der durch Situationen verschlimmert wird, die den Stoffwechsel erhöhen, wie körperliche Anstrengung, Kälte, Fasten oder biologischer Stress. Angesichts solcher klinischer Anzeichen ist es wichtig, eine gezielte Diagnostik durchzuführen, um Patienten zu identifizieren, die wahrscheinlich eine unerwünschte Arzneimittelwirkung haben, um sie an ein spezialisiertes Zentrum zu überweisen. Zu den IEMs, die zu chronischer Müdigkeit führen, gehören metabolische Myopathien wie Muskelglykogenose, Fettsäure-Beta-Oxidationsstörungen und mitochondriale Erkrankungen. Spezifische biochemische und/oder molekulare Analysen ermöglichen es, die Diagnose zu stellen und ein multidisziplinäres Management einzurichten.

Résumé. La fatigue chronique est un symptôme peu spécifique, fréquent en consultation ambulatoire de l’adulte. Une fatigue physique persistante, d’étiologie indéterminée après élimination des causes courantes, doit faire évoquer des maladies rares telles que les erreurs innées du métabolisme (EIM). La principale caractéristique de la fatigue chronique dans les EIM est son caractère dynamique, aggravée par les situations entrainant une augmentation du métabolisme telles que l’effort physique, le froid, le jeûne ou un stress biologique. Devant de tels indices cliniques, il est important d’entreprendre une démarche diagnostique orientée permettant d’identifier les patients susceptibles d’avoir une EIM afin de les orienter vers un centre spécialisé. Les EIM entrainant une fatigue chronique sont les myopathies métaboliques, notamment les glycogénoses musculaires, les troubles de la béta-oxydation des acides gras et les maladies mitochondriales. Des analyses biochimiques et/ou moléculaires spécifiques permettent de poser le diagnostic et de mettre en place une prise en charge pluridisciplinaire.

Background The Mauriac syndrome was described in 1930 as a peculiar combination of poorly controlled diabetes mellitus type 1, stunted growth and glycogenic hepatopathy. More recently, lactic acidosis was recognized as an additional feature, often induced by insulin treatment. Case presentation A 17-year old girl known for diabetes type 1A and Mauriac syndrome was admitted to the emergency room with hyperglycemia of > 41 mmol/l without ketoacidosis. Under a standard insulin regimen, hyperglycemia was rapidly corrected but marked hyperlactatemia occurred. Conclusions The mechanism of impaired glucose utilization and lactate elevation independent of ketoacidosis in Mauriac syndrome is intriguing. The rarity of Mauriac syndrome and its resemblance to glycogen storage diseases suggest the presence of a specific metabolic or genetic predisposition that remains to be identified.

Hyperuricemia is an independent risk factor for the metabolic syndrome and cardiovascular disease. We hypothesized that asymptomatic carriers for hereditary fructose intolerance (OMIM 22960) would have increased uric acid and altered component of the metabolic syndrome when exposed to fructose overfeeding.Six heterozygotes for HFI (hHFI) and 6 controls (Ctrl) were studied in a randomized, controlled, crossover trial. Participants ingested two identical test meals containing 0.7 g kgHiFruD increased fasting uric acid (p 0.05) and reduced fasting insulin sensitivity estimated by the homeostasis model assessment (HOMA) for insulin resistance (p 0.05), in both groups. Postprandial glucose concentrations were not different between hHFI and Ctrl. However HiFruD increased postprandial plasma uric acid, insulin and hepatic insulin resistance index (HIRI) in hHFI only (all p 0.05).Seven days of HiFruD increased fasting uric acid and slightly reduced fasting HOMA index in both groups. In contrast, HiFruD increased postprandial uric acid, insulin concentration and HIRI in hHFI only, suggesting that heterozygosity for pathogenic Aldolase B variants may confer an increased susceptibility to the effects of dietary fructose on uric acid and hepatic insulin sensitivity. This trial was registered at the U.S. Clinical Trials Registry as NCT03545581.

Werner syndrome is a premature ageing disorder caused by biallelic variants in the WRN gene. WRN encodes a dual DNA helicase/exonuclease enzyme. Molecular diagnosis is commonly only made at a late disease stage in the third or fourth decade, when cardinal features have become apparent. We describe a 28 year-old woman who presented with early onset diabetes associated with partial lipodystrophy, severe dyslipidaemia and rapidly progressive liver fibrosis related to non-alcoholic steatohepatitis in the absence of progeroid features. Werner syndrome was diagnosed by trio exome analysis, which revealed compound heterozygous WRN mutations: the known variant c.1290_1293del (p.Asn430Lysfs*7) and the novel intronic splice site variant c.2732+5G>A. cDNA analysis demonstrated this to lead to in-frame skipping of exon 22, predicted to delete most of the zinc binding region of the helicase domain. We suggest that including the WRN gene in genetic analysis of early onset diabetes, lipodystrophy or dyslipidaemia would allow for the opportunity to diagnose some cases of Werner syndrome long before clinical criteria are met, thereby allowing early implementation of important primary prevention interventions.

Chronic Fatigue: When to Suspect an Inherited Metabolic Disease?

Background In NANS deficiency, biallelic mutations in the N-acetylneuraminic acid synthase (NANS) gene impair the endogenous synthesis of sialic acid (N-acetylneuraminic acid) leading to accumulation of the precursor, N-acetyl mannosamine (ManNAc), and to a multisystemic disorder with intellectual disability. The aim of this study was to determine whether sialic acid supplementation might be a therapeutic avenue for NANS-deficient patients. Methods Four adults and two children with NANS deficiency and four adult controls received oral NeuNAc acid (150 mg/kg/d) over three days. Total NeuNAc, free NeuNAc and ManNAc were analyzed in plasma and urine at different time points. Results Upon NeuNAc administration, plasma free NeuNAc increased within hours (P

The identification of neurological disorders by next-generation sequencing (NGS)-based gene panels has helped clinicians understand the underlying physiopathology, resulting in personalized treatment for some rare diseases. While the phenotype of distinct neurogenetic disorders is generally well-known in childhood, in adulthood, the phenotype can be unspecific and make the standard diagnostic approach more complex. Here we present three unrelated adults with various neurological manifestations who were successfully diagnosed using NGS, allowing for the initiation of potentially life-changing treatments. A 63-year-old woman with progressive cognitive decline, pyramidal signs, and bilateral cataract was treated by chenodeoxycholic acid following the diagnosis of cerebrotendinous xanthomatosis due to a homozygous variant in CYP27A1. A 32-year-old man with adult-onset spastic paraplegia, in whom a variant in ABCD1 confirmed an X-linked adrenoleukodystrophy, was treated with corticoids for adrenal insufficiency. The third patient, a 28-year-old woman with early-onset developmental delay, epilepsy, and movement disorders was treated with a ketogenic diet following the identification of a variant in SLC2A1, confirming a glucose transporter type 1 deficiency syndrome. This case study illustrates the challenges in the timely diagnosis of medically actionable neurogenetic conditions, but also the considerable potential for improving patient health through modern sequencing technologies.

Angeborene Stoffwechselkrankheiten (ASK) sind die Folge eines genetischen Defektes von Enzymen oder regulierenden Eiweissen, die in einige metabolische Prozesse eingreifen. Ziel dieses Artikels ist es, eine Übersicht des Netzwerkes zu geben, das sich um die ASK im Erwachsenenalter gebildet hat, und die Besonderheiten der Betreuung dieser Patienten anhand einiger emblematischen Fällen zu beschreiben.

Les maladies héréditaires du métabolisme (MHM), sont la conséquence du déficit d’origine génétique d’une enzyme ou d’une protéine régulatrice impliquées dans certaines voies métaboliques. L’objectif de cet article est de donner un aperçu du réseau Suisse mis en place autour des MHM de l’adulte et d’illustrer les particularités de prise en charge de ces patients avec quelques cas emblématiques.

Anhand zweier Patienten, die wegen Muskelschmerzen und Farbveranderungen des Urins nach korperlicher Belastung vorstellig wurden, werden Diagnose und Management der belastungsinduzierten Rhabdomyolyse aufgezeichnet.

Background: Classic cerebrotendinous xanthomatosis (CTX; OMIM #213700) manifests itself in childhood with chronic diarrhea, juvenile cataracts, tendon xanthomas and neurological symptoms. Biallelic inactivation of CYP27A1 is responsible for cholesterol 27-hydroxylation, leading to cholestanol accumulation in the central nervous system, eyes and tendons. Less commonly, the disease can present in young adults as spastic paraparesis in the absence of xanthomas. Methods: We report on a 28-year old woman diagnosed with CTX who worsened, under treatment, a spinal form of CTX. A review of spinal CTX in the literature is also described. Spinal CTX patients were identified by searching in Pubmed, EMBASE™ and Web of Science databases. Only patients with clinical features of spinal CTX and/or with a typical spinal MRI were included.Results: A woman presented with chronic diarrhea and progressive spastic paraparesis in her twenties. Brain magnetic resonance imaging (MRI) showed cerebral atrophy with diffuse periventricular white matter hyperintensities. Spinal MRI was normal. CYP27A1 gene sequencing confirmed the diagnosis of CTX. Chenodeoxycholic acid (CDCA) treatment was introduced with remission of diarrhea. Treatment was discontinued several times and patient developed psychosis and an ataxospastic gait. Spinal MRI revealed new linear hyperintensities of the corticospinal and gracile tracts, compatible with spinal CTX. Thirty-three patients with spinal CTX were identified in the literature. All patients presented pyramidal signs and 48% dorsal column signs. Juvenile cataracts were described in 78% of patients, chronic diarrhea in 65%, and tendon xanthomas in 31%. Disease improvement or stabilization with chenodeoxycholic acid was observed in 69% of patients. A higher prevalence of the Arg395Cys allele was observed in patients with spinal CTX as compared to CTX in general (ᵡ2; pConclusions: The diagnosis of spinal CTX can be easily missed or delayed in absence of xanthomas. There is a higher prevalence of the Arg395Cys allele in spinal CTX as compared to classic childhood-onset CTX. CDCA treatment seems to stabilize or improve clinical symptoms in most patients. However, as seen in our patient and in two previously reported cases, sudden interruption of CDCA may lead to irreversible neurological complications.

Background: Inborn errors of metabolism (IEMs) are complex medical conditions. Thanks to improvements in diagnostics and treatment, a growing number of pediatric IEM patients reach adulthood. Thus, clinical care for adults with IEM has become an emerging and challenging reality. This purpose of this study of adults with IEM in an adult metabolic clinic at two academic hospitals (Lausanne and Geneva) was to help make informed decisions on the future organization of health care for this group of patients. Methods: All adult patients with a biochemical and/or genetic diagnosis of IEM followed at the Clinic were included in the study. Electronic patient records were reviewed for clinical features, diagnostic studies, treatment and long-term outcome. Data of undiagnosed patients referred for IEM suspicion were analyzed separately.Results: 126 patients were included in the study. The most prevalent group of diseases was small molecules disorders with 83 (66%) patients, followed by energy defects disorders with 28 (22%) patients and complex molecules disorders with 15 (12%) patients. Overall, 64% of patients were diagnosed before, and 37 % after the age 16 years. Among the 126 IEM, 51% suffered from medical complications. 79% of the patients were receiving a specific treatment for their disease. Among the 140 undiagnosed patients referred for suspicion of IEM, investigations lead to a diagnosis in 29 (21%) patients. 24 had confirmation of an IEM and 5 were found to have another genetic condition.Conclusions. This retrospective study reveals significant features of adult IEM cohort. The disorders are heterogeneous, and there is no one-size-fits-all approach – treatment must be tailored to fit each specific disorder in each individual patient. Even patients who are followed tightly are not protected from metabolic decompensations and/or chronic organ-specific complications. While it is commonly assumed that patients with IEMs are more stable once they become adults, our data show that the diseases continue to exact a lifelong toll. A coordinated monitoring of target organs by a multidisciplinary team is needed. To ensure that the success in diagnosis and treatment of individuals with IEMs is sustained, there is a clear requirement for adequately staffed adult IEM clinics.

Data from exome sequencing show that a proportion of individuals in whom a genetic disorder is suspected turn out to have not one, but two to four distinct ones. This may require an evolution in our diagnostic attitude towards individuals with complex disorders. We report a patient with splenomegaly, pneumopathy, bone changes and fronto-temporal dementia (FTD). "Sea-blue histiocytes" in his bone marrow pointed to a lysosomal storage disease. Homozygosity for a pathogenic mutation in the SMPD1 gene confirmed Niemann-Pick disease type B (NPD-B). Mild cognitive impairment and abnormal brain FDG PET were consistent with FTD. We initially tried to fit the skeletal and neurologic phenotype into the NPD-B diagnosis. However, additional studies revealed a pathogenic mutation in the SQSTM1 gene. Thus, our patient had two distinct diseases; NPD-B, and Paget's disease of bone with FTD. The subsequent finding of a mutation in SQSTM1 gene ended our struggle to explain the combination of findings by a singular "unifying" diagnosis and allowed us to make specific therapeutic decisions. SQSTM1 mutations have been reported in association with FTD, possibly because of defective autophagy. Bisphosphonates may be beneficial for PDB, but since they are known to inhibit acid sphingomyelinase activity, we refrained from using them in this patient. While the principle of looking for unifying diagnosis remains valid, physicians should consider the possibility of co-existing multiple diagnoses when clinical features are difficult to explain by a single one. Accurate diagnostic work-up can guide genetic counseling but also lead to better medical management.

Angeborene Stoffwechselerkrankungen (inborn errors of metabolism, IEM) sind einzeln betrachtet selten; zusammengenommen betreffen sie jedoch 1 von 1000 Menschen. Die meisten Erkrankungen werden im Kindesalter klinisch manifest; späte Formen und solche mit längerer Überlebensdauer sind jedoch auch bei Erwachsenen aller Altersstufen zu beobachten. Gewöhnlich manifestiert sich eine IEM nicht primär in der Lunge, allerdings kann es in einigen Fällen zu einer erheblichen pulmonalen Beteiligung mit entsprechend schweren respiratorischen Komplikationen kommen. Die Lungenbeteiligung kann eine späte Manifestationsform einer komplexen multisystemischen Erkrankung darstellen und gelegentlich sogar die einzige Manifestation einer zugrunde liegenden IEM sein. In der vorliegenden Übersichtsarbeit liegt der Fokus auf bestimmten IEM mit Lungenbeteiligung bei Erwachsenen. Der Leser erhält einen Überblick zur Diagnostik, zum allgemeinen Krankheitsmanagement und zu speziellen Therapien für respiratorische Manifestationsformen. Ein klinischer Verdacht, frühzeitiges Erkennen, eine rasche Diagnose und entsprechende Behandlung der respiratorischen Manifestation sind entscheidend, da sie sowohl Auswirkungen auf die Lebenserwartung als auch auf die Lebensqualität der Patienten haben können. Übersetzung aus Respiration 2017;94:2-13 (DOI:10.1159/000475762)

The Mauriac syndrome was described in 1930 as a peculiar combination of poorly controlled diabetes mellitus type 1, stunted growth and glycogenic hepatopathy. More recently, lactic acidosis was recognized as an additional feature, often induced by insulin treatment.A 17-year old girl known for diabetes type 1A and Mauriac syndrome was admitted to the emergency room with hyperglycemia of 41 mmol/l without ketoacidosis. Under a standard insulin regimen, hyperglycemia was rapidly corrected but marked hyperlactatemia occurred.The mechanism of impaired glucose utilization and lactate elevation independent of ketoacidosis in Mauriac syndrome is intriguing. The rarity of Mauriac syndrome and its resemblance to glycogen storage diseases suggest the presence of a specific metabolic or genetic predisposition that remains to be identified.

Background Cystationine β-synthase (CBS) deficiency is a genetic disorder characterized by severe hyperhomocysteinemia and thrombotic complications. In healthy individuals, physical exercise may result in a transient increase in plasma total homocysteine (tHcy) raising the possibility that exercise might be detrimental in CBS deficiency. Our main objective was to determine plasma tHcy kinetics in response to physical exercise in homocystinuria patients. Methods Six adult patients (2 males, 4 females) with homocystinuria and 6 age- and gender-matched controls completed a 30-min aerobic exercise of moderate-intensity with fixed power output (50 W for women and 100 W for men). Blood samples were drawn before, immediately, 180 min and 24 h after exercise. tHcy levels were determined by standard procedures; substrate oxidation and energy expenditure were measured using indirect calorimetry. Results Acute exercise was well tolerated and safe in patients and controls. During the exercise bout, heart rate and energy expenditure increased equally in both groups. tHcy levels were higher in patients compared to controls at all time points (p, Highlights • Classical homocystinuria is an inborn error of methionine transsulfuration. • Exercise may cause increase of homocysteine in the general population. • We assessed the impact of exercise on homocysteine in classical homocystinuria. • Exercise was safe with no significant impact on homocysteine levels in our cohort.

Background X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder associated with leukodystrophy, myeloneuropathy and adrenocortical insufficiency. We performed a retrospective cohort study to evaluate long-term outcome of patients with X-ALD. Method All patients with X-ALD diagnosed between 1989 and 2012 were included. Electronic patient charts were reviewed for clinical features, biochemical investigations, molecular genetic testing, neuroimaging, long-term outcome and treatment. Results Forty-eight patients from 18 unrelated families were included (15 females; 33 males). Seventeen patients were symptomatic at the time of the biochemical diagnosis including 14 with neurocognitive dysfunction and 3 with Addison disease only. Thirty-one asymptomatic individuals were identified by positive family history of X-ALD. During follow-up, eight individuals developed childhood cerebral X-ALD (CCALD), one individual developed adrenomyeloneuropathy (AMN), six individuals developed Addison disease only, and five individuals remained asymptomatic. Direct sequencing of ABCD1 confirmed the genetic diagnosis in 29 individuals. Seven patients with CCALD underwent hematopoietic stem cell transplantation (HSCT). Nine patients lost the follow-up. There was no correlation between clinical severity score, Loes score and elevated degree of elevated very long chain fatty acid (VLCFA) levels in CCALD. Conclusion Our study reports forty-eight new patients with X-ALD and their long-term outcome. Only 35% of the patients presented with neurological features or Addison disease. The remaining individuals were identified due to positive family history. Close monitoring of asymptomatic males resulted in early HSCT to prevent progressive lethal neurodegenerative disease. Identification of patients with X-ALD is important to improve neurodevelopmental outcome of asymptomatic males.

Inborn errors of metabolism (IEM) are rare individually, but taken together, they affect 1 in 1,000 people. Most of the disease becomes apparent at the pediatric age; however, with the identification of late-onset forms, and with improved survival, several of these conditions may be found in adults of all ages. While the lung is not typically a primary site of clinical disease in patients with IEM, in some of them it can be a significantly affected organ with associated severe respiratory complications. Lung involvement can be a late- onset feature of a complex multisystemic disease, but sometimes it can also be the only manifestation of underlying IEM. The aim of this review is to focus on specific IEM associated with lung disease in adults and to provide the reader with an overview of the diagnostic workup, overall disease management, and specific treatments for the respiratory manifestations. Clinical suspicion, early recognition, prompt diagnosis, and appropriate care of the respiratory manifestation are crucial, as they can affect both the life expectancy and the quality of life of these patients.

Obesity and type 2 diabetes have a constantly increasing prevalence in industrialized countries, and both are associated with an increased risk of developing certain cancers. The mechanisms that contribute to this association are probably multiple and are based mainly on hormonal and inflammatory changes. In view of this unequivocal relationship, it is necessary to act upstream by optimizing diabetes prevention and cancer screening measures in at-risk populations. This article reviews the epidemiological data, the physiopathological link between these entities and the concrete measures to be applied in clinical practice.L’obésité et le diabète de type 2 ont une prévalence en constante augmentation dans les pays industrialisés, et tous deux sont associés avec un risque accru de développer certains cancers. Les mécanismes qui contribuent à cette association sont probablement multiples et reposent principalement sur des modifications hormonales et inflammatoires. Face à cette relation sans équivoque, il est nécessaire d’agir en amont en optimalisant les mesures de prévention du diabète et de dépistage du cancer dans les populations à risque. Cet article fait le point sur les données épidémiologiques, le lien physiopathologique entre ces entités ainsi que les mesures concrètes à appliquer en pratique clinique.

The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes. We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters. We observed a significant inverse correlation (ρ = −0.592; p

Background: Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. Methods: Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. Results: Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. Conclusion: This study describes the natural history of classic galactosemia based on the hitherto largest data set. The initial GalNet meeting to discuss the registry was financially supported by a grant to M.E.R-G. from The Netherlands Organisation for Scientific Research (NWO). Development, implementation and maintenance were supported by grants from the Dutch Galactosemia Research foundation, European Galactosemia Society and Metakids grants to M.E. R-G. Data entry for 6 of the 7 participating Dutch centers was done by the coordinating center and was financially supported by a Stofwisselkracht grant to M.E.R-G. in 2016. Analysis and interpretation of data was financially supported by Stofwisselkracht and Metakids grants to M.E.R-G. (2017 and 2018). The Irish data entry was supported by a national Health Research Board (HRB) grant to E.P.T. The British inherited Metabolic Disease Group supported access to the registry in the UK. M.G. was supported by a grant from the Batzebär foundation of the University Hospital Bern, and one from the Galaktosämie Schweiz patient organization for the set-up of the registry and data entry for all patients of Switzerland. The Spanish Galactosemia foundation financially supported data entry for Spanish patients. SI

Eine 43-jahrige Patientin kommt aufgrund sich verschlimmernder Lumbalgien mit Schmerzausstrahlung in den suprapubischen Bereich und die Oberschenkel in die Notaufnahme. Sie berichtet ferner von rotem Urin.

Une patiente de 43 ans consulte les urgences en raison de pejoration de lombalgies avec irradiations douloureuses dans la region sus-pubienne et vers les cuisses. Elle rapporte egalement la presence d’urines rouges.

The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes.We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters.We observed a significant inverse correlation (ρ = -0.592; p 0.05) between HbAWe provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans.RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.