Magdalena Avbelj Stefanija

Nocturnal Glucose Control with an Artificial Pancreas at a Diabetes Camp

BACKGROUND Recent studies have shown that an artificial-pancreas system can improve glucose control and reduce nocturnal hypoglycemia. However, it is not known whether such results can be replicated in settings outside the hospital. METHODS In this multicenter, multinational, randomized, crossover trial, we assessed the short-term safety and efficacy of an artificial pancreas system for control of nocturnal glucose levels in patients (10 to 18 years of age) with type 1 diabetes at a diabetes camp. In two consecutive overnight sessions, we randomly assigned 56 patients to receive treatment with an artificial pancreas on the first night and a sensor-augmented insulin pump (control) on the second night or to the reverse order of therapies on the first and second nights. Thus, all the patients received each treatment in a randomly assigned order. The primary end points were the number of hypoglycemic events (defined as a sensor glucose value of <63 mg per deciliter [3.5 mmol per liter] for at least 10 consecutive minutes), the time spent with glucose levels below 60 mg per deciliter (3.3 mmol per liter), and the mean overnight glucose level for individual patients. RESULTS On nights when the artificial pancreas was used, versus nights when the sensor-augmented insulin pump was used, there were significantly fewer episodes of nighttime glucose levels below 63 mg per deciliter (7 vs. 22) and significantly shorter periods when glucose levels were below 60 mg per deciliter (P=0.003 and P=0.02, respectively, after adjustment for multiplicity). Median values for the individual mean overnight glucose levels were 126.4 mg per deciliter (interquartile range, 115.7 to 139.1 [7.0 mmol per liter; interquartile range, 6.4 to 7.7]) with the artificial pancreas and 140.4 mg per deciliter (interquartile range, 105.7 to 167.4 [7.8 mmol per liter; interquartile range, 5.9 to 9.3]) with the sensor-augmented pump. No serious adverse events were reported. CONCLUSIONS Patients at a diabetes camp who were treated with an artificial-pancreas system had less nocturnal hypoglycemia and tighter glucose control than when they were treated with a sensor-augmented insulin pump. (Funded by Sanofi and others; ClinicalTrials.gov number, NCT01238406.).

Night glucose control with MD‐Logic artificial pancreas in home setting: a single blind, randomized crossover trial—interim analysis

Artificial pancreas (AP) systems have shown an improvement in glucose control and a reduced risk of nocturnal hypoglycemia under controlled conditions but remain to be evaluated under daily‐life conditions.

Improved Metabolic Control in Pediatric Patients with Type 1 Diabetes: A Nationwide Prospective 12-Year Time Trends Analysis

BACKGROUND This study estimated temporal trends of metabolic control over 12 years in a national cohort of childhood-onset type 1 diabetes. SUBJECTS AND METHODS Data from the prospective childhood-onset diabetes register, which included 886 case subjects from 0 to 17.99 years of age at diagnosis and at least 1 year of follow-up until the age of 22.99 years, were analyzed using multivariable linear and logistic regression models in the observational period between 2000 and 2011. RESULTS Hemoglobin A1c (HbA1c) significantly decreased over 12 years, from 78 mmol/mol (interquartile range [IQR], 68-88 mmol/mol) (9.26% [IQR, 8.41-10.24%]) in the year 2000 to 61 mmol/mol (IQR, 55-67 mmol/mol) (7.75% [IQR, 7.20-8.30%]) in the year 2011 (P<0.001). HbA1c was significantly associated with age, treatment modality, and duration of diabetes (P<0.001), with females having on average 1.02% higher HbA1c (P=0.01; 95% confidence interval [CI] 1.005-1.035). The overall use of insulin pumps was 74%. The incidence rate of severe acute complications was low: 1.07 per 100 patient-years for severe diabetic ketoacidosis (95% CI 0.81-1.40) and 1.21 per 100 patient-years for severe (requiring intravenous or intramuscular therapy) hypoglycemia (95% CI 0.81-1.40). CONCLUSIONS The metabolic control of the entire nationwide pediatric type 1 diabetes population significantly improved during the 12-year observational period with a low rate of severe acute complications events. The improvement was associated with the treatment modality. Additional efforts and solutions are necessary to further improve metabolic control and the quality of life of young people with type 1 diabetes.

An ancient founder mutation in PROKR2 impairs human reproduction

Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutations age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ~123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.

MD-Logic overnight type 1 diabetes control in home settings: A multicentre, multinational, single blind randomized trial

To evaluate the safety, efficacy and need for remote monitoring of the MD‐Logic closed‐loop system during short‐term overnight use at home.

Decreased prevalence of hypercholesterolaemia and stabilisation of obesity trends in 5-year-old children: possible effects of changed public health policies

BACKGROUND Overweight/obesity in children is a worldwide public health problem. Together with hypercholesterolaemia they are associated with early atherosclerotic complications. OBJECTIVES In this study, we aimed to investigate the anthropometric characteristics and total cholesterol (TC) levels in a population of 5-year-old children, to determine trends in the prevalence of overweight/obesity and hypercholesterolaemia in 5-year-old children over a period of 8 years (2001-2009) and to assess the impact of modified national nutritional guidelines for kindergartens implemented in 2005. DESIGN Cross-sectional studies of overweight/obesity prevalence in the years 2001, 2003-2005 and 2009, and hypercholesterolaemia in years 2001 and 2009, in 5-year-old children. SUBJECTS Altogether, 12 832 (6308 girls/6524 boys) children were included. METHODS Overweight/obesity was defined by IOTF criteria. Hypercholesterolaemia was defined by TC level >5 mmol/l. Multivariable logistic regression models were used. RESULTS NO CORRELATION BETWEEN BMI VALUES AND TC LEVELS WAS FOUND. OVERWEIGHT AND OBESITY PREVALENCE WERE STABILISED FROM 2001 TO 2009 (ODDS RATIO (OR) (95% CI): 1.13 (0.99-1.3) and 1.13 (0.89-1.42) respectively). Girls were more frequently overweight/obese than boys (OR (95% CI): 0.71 (0.65-0.79) and 0.75 (0.64-0.89) respectively). Prevalence of hypercholesterolaemia significantly decreased from 2001 to 2009 (OR (95% CI): 0.47 (0.41-0.55)). It was less frequent in boys than in girls (OR (95% CI): O.7 (0.61-0.8)). CONCLUSIONS This is the first study to describe a negative trend in the prevalence of hypercholesterolaemia in pre-pubertal children. In addition, the prevalence of overweight/obesity in these children has been stabilised. Nationwide changes in public health policies could have influenced these observations.

Novel Mutations in HESX1 and PROP1 Genes in Combined Pituitary Hormone Deficiency

Background/Aims: The HESX1 gene is essential in forebrain development and pituitary organogenesis, and its mutations are the most commonly identified genetic cause of septo-optic dysplasia (SOD). The PROP1 gene is involved in anterior pituitary cell lineage specification and is commonly implicated in non-syndromic combined pituitary hormone deficiency (CPHD). We aimed to assess the involvement of HESX1 and PROP1 mutations in a cohort of patients with SOD and CPHD. Methods: Six patients with sporadic SOD and 16 patients with CPHD from 14 pedigrees were screened for mutations in HESX1 and PROP1 genes by exon sequencing. Half of the CPHD patients had variable associated clinical characteristics, such as hearing loss, orofacial cleft, kidney disorder or developmental delay. Novel variants were evaluated in silico and verified in SNP databases. Results: A novel heterozygous p.Glu102Gly mutation in the HESX1 gene and a novel homozygous p.Arg121Thr mutation in the PROP1 gene were detected in 2 pedigrees with CPHD. A small previously reported deletion in PROP1 c.301_302delAG was detected in a separate patient with CPHD, in heterozygous state. No mutations were identified in patients with SOD. Conclusions: Our results expand the spectrum of mutations implicated in CPHD. The frequency of 15% of the PROP1 mutations in CPHD was low, likely due to the clinical heterogeneity of the cohort.

Medium-chain acyl-CoA dehydrogenase deficiency: Two novel ACADM mutations identified in a retrospective screening:

Objective The aim of this study was to determine whether an expanded newborn screening programme, which is not yet available in Slovenia, would have detected the first two patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the country. Two novel ACADM mutations are also described. Methods Both patients were diagnosed clinically; follow-up involved analysis of organic acids in urine, acylcarnitines in dried blood spots, and genetic analysis of ACADM. Cut-off values of acylcarnitines in newborns were established using analysis of 10,000 newborns in a pilot screening study. Results In both patients, analysis of the organic acids in urine showed a possible β-oxidation defect, while the specific elevation of acylcarnitines confirmed MCAD deficiency. Subsequent genetic analysis confirmed the diagnosis; both patients were compound heterozygotes, each with one novel mutation (c.861 + 2T > C and c.527_533del). The results from a retrospective analysis of newborn screening cards clearly showed major elevations of MCAD-specific acylcarnitines in the patients. Conclusions An expanded newborn screening programme would be beneficial because it would have detected MCAD deficiency in both patients before the development of clinical signs. Our study also provides one of the first descriptions of ACADM mutations in Southeast Europe.

Childhood Osteoporosis and Presentation of Two Cases with Osteogenesis Imperfecta Type V / Osteoporoza V Otroški Dobi in Predstavitev Dveh Bolnikov Z Osteogenesis Imperfecta Tipa V

Abstract Introduction. Osteogenesis imperfecta (OI) is etiologically heterogeneous disorder characterized by childhood osteoporosis. A subtype OI type V is caused by the same c.-14C>T mutation in the IFITM5 gene. Nevertheless, there is a marked interindividual phenotypic variability in clinical presentation; however, response to bisphosphonates is reported to be good. Methods. Two individuals with OI type V had multiple recurrent fractures with hypertrophic calluses, scoliosis and ossifications of the forearm interosseous membranes. Sequencing of IFITM5, genotyping of variants rs2297480 in farnesyl diphosphate synthase gene (FDPS), and rs3840452 in geranylgeranyl diphosphate synthase 1 gene (GGPS1), both involved in bisphosphonate metabolism, was performed. Results. In patient 1 BMD reached normal values during bisphosphonate treatment and remained normal four years after the treatment discontinuation. In patient 2 no increase in BMD after five years of bisphosphonate treatment was observed and callus formation continued. The c.-14C>T IFITM5 mutation in heterozygous state was detected in both individuals. Additionally, both patients carried FDPS variant rs2297480 in homozygous state, and were heterozygous for GGPS 1 variant rs3840452. Conclusions. The paper presents a short overview of childhood osteoporosis with a special emphasis on OI type V by presenting two cases. Both OI type V patients had identical disease-causing mutation, but marked interindividual phenotypic variability. The striking failure in response to bisphosphonate treatment in one of the patients could not be explained by the variants in genes involved in bisphosphonate metabolism. Izvleček Uvod. Osteogenesis imperfecta (OI) je vzročno heterogena bolezen, katere značilnost je osteoporoza v otroštvu. Pri vseh opisanih bolnikih s podtipom OI tipa V je vzrok bolezni ista mutacija c.-14C>T gena IFITM5. Kljub temu med bolniki obstaja izrazita fenotipska variabilnost v klinični sliki, toda opisan je le dober odgovor na zdravljenje z bisfosfonati. Metode. Oba bolnika z OI tipa V sta imela ponavljajoče se zlome kosti s hipertrofičnimi kalusi, skoliozo in zakostenelo membrano med podlahtnico in koželjnico. Opravili smo sekvenčno analizo gena IFITM5 in genotipizacijo variant rs2297480 gena za farnesil difosfat sintazo (FDPS) in rs3840452 gena za geranilgeranil difosfat sintazo 1 (GGPS1), ki sta vpletena v presnovo bisfosfonatov. Rezultati. Pri bolniku 1 se je ob zdravljenju z bisfosfonati mineralna kostna gostota povečala do normalnih vrednosti in ostala nespremenjena štiri leta po prenehanju zdravljenja. Pri bolniku 2 kljub pet let trajajočemu zdravljenju z bisfosfonati ni prišlo do izboljšanja mineralne kostne gostote, še naprej so se pojavljali zlomi kosti in hipertrofični kalusi. Pri obeh bolnikih smo ugotovili znano mutacijo c.-14C>T v genu IFITM5 v heterozigotni obliki. Oba imata v homozigotni obliki prisotno tudi varianto rs2297480 gena FDPS in v heterozigotni obliki varianto rs3840452 gena GGPS1. Zaključek. V članku je predstavljen kratek pregled osteoporoze v otroštvu s posebnim poudarkom na OI tipa V pri dveh bolnikih. Pri obeh bolnikih z OI tipa V, ki sta imela različno klinično sliko in potek bolezni, smo ugotovili mutacijo c.-14C>T v genu IFITM5. Z analizo genov encimov, vpletenih v presnovo bisfosfonatov, nismo mogli pojasniti neuspešnega zdravljenja z bisfosfonati pri enem od bolnikov.

Clinical, Genetic and Immunological Characteristics of Paediatric Autoimmune Polyglandular Syndrome Type 1 Patients in Slovenia / Klinične, Genetske nn Imunološke Značilnosti Otrok In Mladostnikov Z Avtoimunskim Poliglandularnim Sindromom Tipa 1 V Sloveniji

Abstract Introduction. Autoimmune polyglandular syndrome type 1 (APS-1) is an autosomal recessive disorder, caused by mutations in the AIRE gene. The major components of APS-1 are chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP) and Addison’s disease (AD). Clinical, genetic and immunological characteristics of Slovenian paediatric APS-1 patients were investigated. Methods. Existing medical records of 15 APS-1 patients were rewieved, when necessary, additional clinical and laboratory investigations were issued. AIRE gene analysis was performed to identify causative mutations, and autoantibodies against type I interferons were measured by luminescence immunoprecipitation system. Results. Patients had one to eight different manifestations of the disease. CMC was present in all, HP in 12/15 (80 %) and AD in 8/15 (53 %) patients. Growth retardation, due to hyposomatotropism, growth hormone resistance, autoimmune thyroiditis, corticosteroid treatment, malabsorption or secretory failure of exocrine pancreas, was observed in altogether 7 (46 %) patients. Six different AIRE gene mutations were detected and p.R257X mutation was present in 63.3 % of pathological alleles. Antibodies against type I interferons were detected in all patients. Conclusion. APS-1 is a rare disorder with a broad spectrum of clinical manifestations, which, if unrecognized or inadequately treated may be fatal. AIRE gene mutational analysis and autoantibodies against type I interferons are important in early identification of the disease. The aetiology of growth retardation was shown to be extremely diverse, frequently caused by less characteristic manifestations. APS-1 may affect patients’ quality of life in numerous ways, and may cause great psychosocial burden leading to depression and suicidal thoughts even in paediatric patients. Izvleček Uvod. Avtoimunski poliglandularni sindrom tipa 1 (APS-1) je redka avtosomno recesivna bolezen, povezana z mutacijami gena AIRE. Tri najpomembnejše komponente APS-1 so kronična mukokutana kandidiaza (CMC), hipoparatiroidizem (HP) in Addisonova bolezen (AD). Raziskali smo klinične, genetske in imunološke značilnosti slovenskih pediatričnih bolnikov z APS-1. Metode. Pregledali smo obstoječo medicinsko dokumentacijo 15 bolnikov z APS-1, v izbranih primerih smo opravili dodatne klinične in laboratorijske preiskave. Z genetsko analizo smo prepoznali vzročne mutacije gena AIRE, s sistemom luminiscenčne imunoprecipitacije (LIPS) pa smo določili avtoprotitelesa proti interferonom tipa 1. Rezultati. Bolniki so imeli izraženo eno do osem različnih komponent bolezni. CMC je bila prisotna pri vseh bolnikih, HP pri 12 od 15 (80 %) in AD pri 8 od 15 (53 %). Zastoj rasti je bil prisoten pri 7 (46 %) bolnikih zaradi hiposomatotropizma, rezistence proti rastnemu hormonu, avtoimunskega tiroiditisa, zdravljenja s kortikosteroidi, malabsorbcije ali sekretorne okvare eksokrinega pankreasa. Prepoznanih je bilo 6 različnih mutacij gena AIRE, najpogostejša mutacija p.R257X je bila opredeljena pri 63,3 % mutiranih alelov. Avtoprotitelesa proti interferonom tipa 1 so bila prisotna pri vseh bolnikih. Zaključki. APS-1 je redka bolezen s širokim naborom kliničnih značilnosti in je lahko smrtna, če ni prepoznana ali je neprimerno zdravljena. Za zgodnje odkrivanje sta ključnega pomena genetska analiza in določanje protiteles proti interferonom tipa 1. Pri bolnikih z APS-1 je zastoj rasti pogosta komponenta bolezni z različnimi vzroki, pogosto povezanimi z manj značilnimi manifestacijami. APS-1 na različne načine vpliva na kvaliteto življenja bolnikov in je veliko psihološko breme, ki lahko vodi v depresijo in samomorilne misli celo pri mladih bolnikih.