Hybrid closed Loop improved glucose control compared to sensor-augmented pumps in outpatients with type 1 diabetes in real-life conditions with telehealth monitoring.

OBJECTIVES: The study aims at evaluating glucose metrics and HbA1C values after pump initiation in outpatient settings. RESEARCH DESIGN AND METHODS: This single center observational study enrolled 121 subjects with type 1 diabetes between September 2020 and May 2021 initiating sensor-augmented pump therapy with stand-alone CGM (n = 26) or pump users who only changed their device (n = 51), with predictive low glucose management (n = 8) or with Hybrid Closed Loop using Medtronic 780G (n = 36) systems. Changes in HbA1C levels and glucose metrics were analyzed after 3 months. All subjects received diabetes and carbohydrate-counting education if needed at time of initiation and were proposed a telehealth monitoring by a diabetic nurse educator. RESULTS: There was no episodes of severe hypoglycemia or diabetic ketoacidosis nor serious pump-related adverse events despite outpatient model of care. While only 18/121 (14.8%) participants reached initially the recommended HbA1C levels, 23/85 (27%) in the conventional group and 33/36 (91%) subjects in the Hybrid Closed Loop group reached target levels after 3 months of follow-up. Time in target range 3.9-10 mmol/L (70-180 mg/dl) also improved and was optimal with closed loop with 30/36 (83%) subjects with time in range above 70%. CONCLUSIONS: Initiation of insulin pump therapy for outpatients is safe with a dedicated facility. Telehealth monitoring after outpatient initiation provides tools for improvement in glucose control with an insulin pump. Outpatient pump initiation is compatible with Hybrid Closed Loop systems which provide the largest improvements in glucose control.

GNAS mutated thyroid carcinoma in a patient with Mc Cune Albright syndrome.

Mc Cune-Albright syndrome (MAS) is a rare disorder defined by the triad of polyostotic fibrous dysplasia, "café au lait" skin hyperpigmentation and hyperfunctioning endocrinopathies, such as precocious puberty. MAS is caused by an activating post zygotic somatic mutation of GNAS gene, coding for the alpha-subunit of the stimulatory G protein (Gsalpha). In endocrine tissues, this mutation results in overproduction of hormones and endocrine cell hyperfunction and proliferation. Whereas the association of hyperthyroidism and thyroid adenomas is well known in MAS, the relation with thyroid carcinoma has rarely been observed. We report the occurrence of a thyroid carcinoma in an 18-years old woman with MAS, revealed by subclinical hyperthyroidism detected during her systematic annual follow-up. Ultrasound and thyroid scintigraphy revealed the presence of a nodule in the right lobe. Pathology on hemithyroidectomy revealed an unexpected thyroid follicular carcinoma. Neoplastic thyroid cells harbored the GNAS R201C activating mutation. This observation suggests that MAS may predispose patients to thyroid carcinomas and supports the importance of thyroid assessment by physical examination, hormonal blood test and ultrasound, in the follow-up of patients with MAS. Because ultrasound diagnostic is challenging in MAS, needle puncture of palpable nodules should be advised.

Elevated ratio of acylated to unacylated ghrelin in children and young adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. Hyperghrelinemia may be involved in the underlying mechanisms of the switch. The purpose of this study is to evaluate acylated ghrelin (AG) and unacylated ghrelin (UAG) levels in PWS and investigate their associations with hyperphagia. This is a cross-sectional clinical study conducted in three PWS expert centers in the Netherlands and France. Levels of AG and UAG and the AG/UAG ratio were determined in 138 patients with PWS (0.2-29.4 years) and compared with 50 age-matched obese subjects (4.3-16.9 years) and 39 healthy controls (0.8-28.6 years). AEBSF was used to inhibit deacylation of AG. As a group, PWS patients had higher AG but similar UAG levels as healthy controls (AG 129.1 vs 82.4 pg/ml, p = 0.016; UAG 135.3 vs 157.3 pg/ml, resp.), resulting in a significantly higher AG/UAG ratio (1.00 vs 0.61, p = 0.001, resp.). Obese subjects had significantly lower AG and UAG levels than PWS and controls (40.3 and 35.3 pg/ml, resp.), but also a high AG/UAG ratio (1.16). The reason for the higher AG/UAG ratio in PWS and obese was, however, completely different, as PWS had a high AG and obese a very low UAG. PWS patients without weight gain or hyperphagia had a similar AG/UAG ratio as age-matched controls, in contrast to those with weight gain and/or hyperphagia who had an elevated AG/UAG ratio. The switch to excessive weight gain in PWS seems to coincide with an increase in the AG/UAG ratio, even prior to the start of hyperphagia.

[Ketoacidosis at time of diagnosis of type 1 diabetes in children and adolescents: effect of a national prevention campaign]. / Effet à un an de la campagne nationale de prévention de l'acidocétose au moment du diagnostic de diabète de type 1 chez l'enfant et l'adolescent.

The aim of the study was to evaluate, after the first year of a national information campaign, the effect on the frequency and severity of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) in children and adolescents in France. The following data were collected during a 2-year period in people younger than 15 years of age at diagnosis of T1D, in 146 pediatric centers: age, sex, duration of symptoms, patient's previous care, clinical and biological signs, and family history of T1D. DKA was defined as pH<7.30 or bicarbonate<15mmol/L, severe DKA as pH<7.10 or bicarbonate <5mmol/L. During the 2nd year, an information campaign targeting health professionals and families was launched with the objective of reducing the time to diagnosis. Data were compared between the year before the campaign (year 0) and the first year of the campaign (year 1). The number of new cases of T1D was 1299 for year 0 and 1247 for year 1. Between year 0 and year 1, the rate of DKA decreased from 43.9% to 40.5% (P=0.08), exclusively due to the decrease of severe DKA from 14.8 to 11.4% (P=0.01). In the 0- to 5-year-old and 5- to 10-year-old age groups, the relative decrease in the rate of DKA was 13% and 15%, and 23% and 41% for severe DKA, respectively. In patients referred to the hospital by a pediatrician or who came at the family's initiative, the decrease was 34% and 7%, and 39% and 32% for severe DKA, respectively. No change was observed in the 10- to 15-year-old group or in those children who were referred by a general practitioner. In multivariate analyses, a higher DKA rate was associated with the young age of the child (<5 years), being hospitalized at the parents' initiative rather than being referred by a doctor, and the absence of a family history of T1D. A higher rate of severe DKA was associated with these last two factors but not with the child's age. The frequency of DKA at diagnosis of type 1 diabetes remains high in children and adolescents, but the first year of an information campaign decreased it. The results have also helped better define the strategy and targets of the continuing prevention campaign, to more efficiently reduce the morbidity and mortality of T1D at diagnosis in children and adolescents in France.

Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders.

WFS1 mutations are responsible for Wolfram syndrome (WS) characterized by juvenile-onset diabetes mellitus and optic atrophy, and for low-frequency sensorineural hearing loss (LFSNHL). Our aim was to analyze the French cohort of 96 patients with WFS1-related disorders in order (i) to update clinical and molecular data with 37 novel affected individuals, (ii) to describe uncommon phenotypes and, (iii) to precise the frequency of large-scale rearrangements in WFS1. We performed quantitative polymerase chain reaction (PCR) in 13 patients, carrying only one heterozygous variant, to identify large-scale rearrangements in WFS1. Among the 37 novel patients, 15 carried 15 novel deleterious putative mutations, including one large deletion of 17,444 base pairs. The analysis of the cohort revealed unexpected phenotypes including (i) late-onset symptoms in 13.8% of patients with a probable autosomal recessive transmission; (ii) two siblings with recessive optic atrophy without diabetes mellitus and, (iii) six patients from four families with dominantly-inherited deafness and optic atrophy. We highlight the expanding spectrum of WFS1-related disorders and we show that, even if large deletions are rare events, they have to be searched in patients with classical WS carrying only one WFS1 mutation after sequencing.

Ketoacidosis at diagnosis of type 1 diabetes in French children and adolescents.

OBJECTIVES: This study aimed to evaluate the frequency of diabetic ketoacidosis (DKA) and its associated factors at the diagnosis of type 1 diabetes (T1D) in French children and adolescents prior to launching a public-health campaign of information to prevent DKA. PATIENTS AND METHODS: Over a 1-year period, 1299 youngsters (aged < 15 years) were diagnosed with T1D at 146 paediatric centres in all regions of France. Age, gender, duration of symptoms, patient's pathway to diagnosis, clinical and biological signs, and family history of T1D were collected for each newly diagnosed patient. DKA was defined as pH < 7.30 or bicarbonate < 15 mmol/L, and severe DKA as pH < 7.10 or bicarbonate < 5 mmol/L. RESULTS: At the time of diagnosis, 26% of the children were aged 0-5 years, 34% were 5-10 years and 40% were 10-15 years. The overall prevalence of DKA was 43.9% (0-5 years: 54.2%; 5-10 years: 43.4%; and 10-15 years: 37.1%) and 14.8% for severe DKA (0-5 years: 16.6%; 5-10 years: 14.4%; and 10-15 years: 13.9%; < 2 years: 25.3%). Severe DKA was more frequent when the child was hospitalized at the family's behest (26.6%) than when referred by a general practitioner (7.6%) or paediatrician (5.1%; 30.6%, 53.7% and 9.2%, respectively, by patients' age group). The frequency of DKA decreased to 20.1% (severe DKA: 4.4%) in families with a history of T1D. Multivariate analysis showed that age, pathway to diagnosis, duration of polyuria/polydipsia (< 1 week) and family history of T1D were associated with the presence of DKA, while pathway to diagnosis and family history of T1D were associated with severe DKA. CONCLUSION: DKA at the time of T1D diagnosis in children and adolescents is frequent and often severe. Patients' age, pathway to hospitalization and family history of diabetes were the main factors associated with DKA. These data suggest that a public-health campaign to prevent DKA at diagnosis can help reduce the frequency of DKA and also provide baseline data for evaluating the efficacy of such a campaign.

Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects.

OBJECTIVES: The aim of this study was to investigate whether the quadrivalent human papillomavirus (HPV) vaccine Gardasil is associated with a change in the risk of autoimmune disorders (ADs) in young female subjects. DESIGN: Systematic case-control study of incident ADs associated with quadrivalent HPV vaccination in young women across France. PARTICIPANTS AND SETTING: A total of 113 specialised centres recruited (from December 2007 to April 2011) females aged 14-26 years with incident cases of six types of ADs: idiopathic thrombocytopenic purpura (ITP), central demyelination/multiple sclerosis (MS), Guillain-Barré syndrome, connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus and autoimmune thyroiditis. Control subjects matched to cases were recruited from general practice. ANALYSIS: Multivariate conditional logistic regression analysis; factors included age, geographical origin, smoking, alcohol consumption, use of oral contraceptive(s) or vaccine(s) other than Gardasil received within 24 months before the index date and personal/family history of ADs. RESULTS: Overall, 211 definite cases of ADs were matched to 875 controls. The adjusted odds ratio (OR) for any quadrivalent HPV vaccine use was 0.9 [95% confidence interval (CI) 0.5-1.5]. The individual ORs were 1.0 (95% CI 0.4-2.6) for ITP, 0.3 (95% CI 0.1-0.9) for MS, 0.8 (95% CI 0.3-2.4) for connective disorders and 1.2 (95% CI 0.4-3.6) for type 1 diabetes. No exposure to HPV vaccine was observed in cases with either Guillain-Barré syndrome or thyroiditis. CONCLUSIONS: No evidence of an increase in the risk of the studied ADs was observable following vaccination with Gardasil within the time periods studied. There was insufficient statistical power to allow conclusions to be drawn regarding individual ADs.

A novel ABCC8 mutation illustrates the variability of the diabetes phenotypes associated with a single mutation.

AIM: ATP-sensitive potassium channels are important regulators of insulin secretion. They consist of four sulphonylurea receptor (encoded by ABCC8) and four inwardly rectifying protein (encoded by KCNJ11) subunits. Activating ABCC8 mutations lead to decreased insulin secretion and to diabetes. Wide phenotype variability is associated with single ABCC8 mutations, ranging from transient or permanent neonatal diabetes (ND) with or without developmental delay (DEND syndrome) to very mild phenotypes. This report describes the case of a Caucasian infant diagnosed with ND at the age of 2 months due to a novel ABCC8 missense mutation. METHODS: ABCC8 was analyzed by sequence analysis. The mutation was present in the patient and her family and was found to be associated with phenotypes ranging from ND to asymptomatic impaired fasting glucose (IFG). RESULTS: A novel His863Tyr ABCC8 mutation was identified in a 2-month-old girl diagnosed with ND. After an initial insulin treatment, treatment with glibenclamide was initiated and the treatment with insulin discontinued. The same mutation was found in her father, who had been fortuitously diagnosed with diabetes and had an HbA(1c) level of 9% (74.8 mmol/mol). The patient's brother and mother both had normal fasting glucose, and were not found to be carriers of the mutation. However, the same mutation was found in her grandmother, who had been asymptomatic and discovered IFG (6.9 mmol/L) with an HbA(1c) of 6.8% (50.8 mmol/mol). CONCLUSION: This case describes a novel ABCC8 mutation and offers a further illustration of the highly variable phenotypes associated with an identical mutation present across three generations.