Les systèmes de boucle fermée hybride validés dans le DT1 ont été expérimentés dans le DT2, montrant une amélioration du temps passé dans la plage cible et une réduction de l’HbA1c, sans survenue d’hypoglycémies. Au cours de la dernière décennie, un algorithme pour une boucle fermée complète sans bolus repas manuel a été développé et les essais cliniques menés à l’hôpital et en ambulatoire ont démontré une amélioration du temps dans la plage cible sans survenue d’hypoglycémies. Ces données suggèrent la faisabilité, la sécurité et l’efficacité de la boucle fermée pour traiter le DT2.

Objective Data on pituitary neuroendocrine tumours (PitNETs) surgically treated during pregnancy are limited, and no studies have compared these cases to those treated in non-pregnant women. This study aimed to describe the clinical, radiological, and histological profiles of patients treated surgically for PitNETs during pregnancy and evaluate long-term prognosis.Design This study was multicentric, observational, and retrospective.Methods We included 10 patients from 5 university hospitals who underwent surgical treatment for PitNETs during pregnancy or within 12 months postpartum, along with 30 matched non-pregnant controls treated surgically for PitNETs. Clinical and histological data, as well as progression-free survival without additional treatment, were compared between pregnant and non-pregnant patients.Results and conclusions Among the 10 PitNETs, 4 were corticotropic, 2 gonadotropic, 2 lactotropic, and 2 somatotropic. The primary surgical indication (tumour syndrome with or without failure of medical treatment) was similar between the two groups: 7/10 vs 19/30 (P = 1.00). There was no statistically significant difference in volume (P = .072) or radiological invasion markers (optic chiasm compression, P = .059, and cavernous sinus invasion, P = .274). However, PitNETs in pregnant women showed higher mitotic activity (P = .038) and were more frequently classified as grade 2b (Trouillas clinicopathological classification; P = .049). The need for second-line treatment was also more frequent (P = .005). PitNETs requiring surgical treatment during pregnancy are characterized by increased proliferative activity and progression after surgery. Despite this, the long-term prognosis remains favourable. These results need confirmation in a larger study.

BACKGROUND:Adrenal incidentalomas are found in 3-10% of adults undergoing abdominal imaging. Of these, 30-50% are responsible for mild autonomous cortisol secretion (MACS), which is frequently associated with hypertension. The impact of adrenalectomy on hypertension in patients with unilateral incidentalomas and MACS remains uncertain. The aim of the CHIRACIC study was to prospectively assess the impact of surgical excision of the incidentaloma on blood pressure with a randomised trial combining accurate blood pressure measurement and standardisation of antihypertensive treatment. METHODS:CHIRACIC was a multicentre, superiority, open-label, parallel, randomised controlled trial performed at 17 university hospitals in France, Italy, and Germany. Adults with hypertension with MACS entered a run-in phase to confirm hypertension with multiple home blood pressure measurements (HBPM) before blood pressure was normalised with standardised stepped-care antihypertensive treatment. Eligible participants were then randomly assigned (1:1) to adrenalectomy or conservative management. Randomisation was blocked (random block size of 4 and 6) and stratified by intensity of antihypertensive treatment. Participants were followed up for 13 months and systematic attempts were made to gradually reduce antihypertensive treatment. The primary endpoint was the proportion of normotensive participants using HBPM who reduced their antihypertensive treatment in the intention-to-treat population at study completion. Key secondary endpoints included 24 h ambulatory blood pressure measurement (ABPM), mean change in antihypertensive treatment, and the proportion of participants with antihypertensive treatment at study completion. This study was registered with ClinicalTrials.gov, NCT02364089, and is completed. FINDINGS:Between April 9, 2015 and Nov 23, 2022, 78 patients were enrolled, and 52 eligible participants were randomly assigned to adrenalectomy (n=26, 23 underwent adrenalectomy and completed the study) or conservative management (n=26, 25 completed the study). The median age of participants was 63·3 years (IQR 57·4-68·2) and 36 (69%) were female. At study completion, a reduction in antihypertensive treatment with normal HBPM was observed in 12 (46%) of 26 participants treated with adrenalectomy and in four (15%) of 26 treated conservatively (adjusted risk difference [RD] 0·34 [95% CI 0·11 to 0·58]; p=0·0038). Similar results of smaller magnitude were observed for systolic blood pressure during 24 h ABPM. There were ten (43%) of 23 participants still needing antihypertensive treatment in the adrenalectomy group and 24 (96%) of 25 in the conservative management group (adjusted RD -0·58 [95% CI -0·78 to -0·38]; p<0·0001). Mean antihypertensive treatment step was 0·8 (SD 1·1) in the adrenalectomy group and 3·0 (1·4) in the conservative management groups (adjusted difference -2·05 [95% CI -2·61 to -1·50]; p<0·0001]. The number of patients with normal systolic HBPM and no hypertensive treatment was 12 (52%) of 23 in the adrenalectomy group and none in the conservative management group. Serious adverse events occurred in eight (35%) of 23 participants in the adrenalectomy group and eight (31%) of 26 participants in the conservative management group. Three serious adverse events for three (13%) participants were related to the surgery (post-surgical wall pain and hypotension). INTERPRETATION:MACS associated with unilateral adrenal incidentalomas is responsible for secondary hypertension that can be safely improved by minimally-invasive adrenalectomy. FUNDING:French Ministry of Health and the German Research Foundation.

AIMS:Health-related quality of life (HRQoL) assessment is increasingly integrated into type 1 diabetes (T1D) monitoring to promote a holistic approach. To investigate HRQoL in adults with T1D and to assess the impact of the severity of complications on HRQoL. MATERIALS AND METHODS:This is a cross-sectional analysis of baseline characteristics of adults living with T1D included in Société Francophone du Diabète - Cohorte Diabète de Type 1 (SFDT1), a French longitudinal cohort study. HRQoL was assessed using generic (EuroQol 5-Dimensions 5-Level questionnaire [EQ-5D-5L]) and diabetes-specific (Audit of Diabetes-Dependent Quality of Life) instruments. The severity of diabetes complications was measured using an adapted Diabetes Complication Score Index (DCSI) ranging from 0 to 14. We used multiple imputations to deal with missing data. RESULTS:We included 1892 adults, 48% women, with a median (interquartile range [IQR]) age of 38 (28; 51) years. The mean overall EQ-5D-5L HRQoL score was 71.1 ± 17.7 (maximum 100), with the following number of participants negatively impacted for each domain: 271 (14%) for mobility, 94 (5%) for self-care, 378 (19%) for usual activities, 853 (45%) for pain/discomfort and 983 (52%) for anxiety/depression. The median (IQR) DCSI was 1 (0; 2). In multivariable models, a one-step increase in DCSI was associated with a 1.5% decrease in overall EQ-5D-5L HRQoL. DCSI was also inversely associated with all domains of the generic scale except anxiety/depression and 17 domains of the diabetes-specific scale. CONCLUSIONS:We observed an inverse association between the severity of complications and overall HRQoL and most of its dimensions. Our results highlight the need to reinforce the prevention of complications to improve the overall well-being of people with T1D.

BACKGROUND:Lipohypertrophy is a common skin complication in people with insulin-treated diabetes. Despite its high prevalence and potential impact on diabetes management and outcomes, published data regarding the risk factors for the development of this complication are contradictory. The study aimed to determine risk factors for lipohypertrophy related to patient characteristics and insulin therapy. METHOD:Medical databases (MEDLINE/PubMed, Embase, CENTRAL) were searched from 1990 to August 21, 2023. All relevant studies describing potential risk factors for lipohypertrophy in people with insulin-treated diabetes (eg, sex, age, body mass index [BMI], type of diabetes, and injection technique) were included. Data enabling calculations of prevalence odds ratios (pOR) and mean differences (MD) with 95% confidence intervals [95% CI] were extracted and pooled in meta-analyses. RESULTS:Fifty-one studies of risk factors for lipohypertrophy were identified. Performed meta-analyses indicate that the strongest contributor to lipohypertrophy was incorrect injection site rotation (pOR = 8.85 [95% CI: 5.10-15.33]), followed by needle reuse (3.20 [1.99-5.13]), duration of insulin therapy >5 years (2.62 [1.70-4.04]) and >2 daily injections per day (2.27 [1.58-3.25]). Those with type 1 diabetes and obese/overweight individuals also had significantly higher odds of developing lipohypertrophy. Sex, age, and insulin device (pen, syringes) were not significant risk factors for lipohypertrophy. CONCLUSIONS:This systematic review with meta-analysis revealed that incorrect injection site rotation and needle reuse are the most substantial factors in developing lipohypertrophy. Notably, both factors are modifiable through patient education, emphasizing the importance of teaching proper injection techniques for better diabetes management.

L’assciation d’un diabète de type 1 avec une insuffisance surrénale s’inscrit dans le cadre des polyendocrinopathies auto-immunes (PAI). Onze à 14 % des personnes ayant une insuffisance surrénale auto-immune développent un diabète de type 1 alors que 0.4 % des personnes vivant avec un diabète de type 1 développent une insuffisance surrénale. L’association des 2 affections multiplie par 4 le risque de décès prématuré et par 2,5 le risque d’insuffisance surrénale aiguë. La PAI-2 est la plus fréquente avec une prépondérance de thyroidopathies, de diabète de type 1 dans 50 % des cas et d’insuffisance surrénale dans 20–40 % des cas. La PAI-1 est rare et associe candidose cutanéo-muqueuse, hypoparathyroïdie primaire et insuffisance surrénale, le diabète de type 1 étant rare (2–12 %) et l’association des 2 affections survenant chez 1–18 %. Les facteurs prédictifs de survenue d’une insuffisance surrénale chez une personne vivant avec un diabète de type 1 sont l’apparition d’une rétinopathie, d’infections sévères avec hospitalisation, une prescription d’hormone thyroïdienne ou d’anti-thyroïdiens de synthèse, de glucagon ou de psychotropes dans les 2 ans précédant l’insuffisance surrénale, enfin une baisse des besoins en insuline. Les personnes vivant avec les 2 affections sont confrontées à un challenge dans leur prise en charge respective, qui justifie une éducation thérapeutique pour les prises de décision portant sur l’ajustement des doses substitutives des glucocorticoïdes et de l’insuline. La substitution glucocorticoïde classiquement réalisée avec l’hydrocortisone pourrait être améliorée par les nouvelles galéniques d’hydrocortisone à libération retardée.

BACKGROUND:Lipohypertrophy is a common skin complication in individuals with insulin-treated diabetes, but this condition in those using insulin pumps (continuous subcutaneous insulin infusion, CSII) remains poorly understood. This study aimed to identify and summarize scientific evidence regarding the risk factors and clinical consequences of lipohypertrophy in people using CSII. METHODS:Medical databases (MEDLINE/PubMed, Embase, CENTRAL) were searched to identify relevant studies published in English from 1990 to March 19, 2024. If possible, extracted data were cumulated in meta-analyses. This systematic review was registered on PROSPERO (CRD42024554127). RESULTS:Nine studies reporting risk factors for lipohypertrophy or its consequences in people treated with CSII were identified. In the included studies, only individual risk factors were reported, which in most cases prevented the conduct of a meta-analysis. Meta-analyses could be performed for two factors, that is, improper cannula site rotation and male sex. The odds of developing lipohypertrophy were higher in individuals incorrectly rotating (prevalence odds ratio, pOR = 2.59 [95% Confidence interval, CI: 1.39-4.83]), whereas gender had no impact on the prevalence of lipohypertrophy (pOR = 1.13 [95% CI: 0.62-2.06]). Due to the limitations of the available data, it was not possible to draw conclusions about the clinical consequences of lipohypertrophy in people on CSII. CONCLUSIONS:This systematic review demonstrated that studies on the risk factors and clinical consequences of lipohypertrophy in CSII users are limited and that the currently published data are insufficient to draw definitive conclusions. There is a need for more comprehensive and well-designed clinical studies to better understand this issue in CSII users.

Introduction Type 1 diabetes is burdensome, requiring complex daily management and making people more prone to emotional distress. To better detect diabetes-related distress (DD) and identify at-risk patients, we aimed to provide an in-depth characterization of DD in people with type 1 diabetes.Research design and methods We included adults with type 1 diabetes from the Suivi en France des personnes avec un Diabète de Type 1 cohort who filled in the Problem Areas in Diabetes questionnaire (PAID ≥40 indicates high DD). Age and sex-adjusted multivariable logistic regression models analyzed individual characteristics, clinical indicators, diabetes-related complications and psychological factors. We further analyzed DD according to six data-driven subdimensions: emotional distress, fear of complications, social distress, eating distress, management distress, and diabetes burnout.Results In total, 1220 participants (50.6% female, age 42 years (SD 13.9), diabetes duration 24.7 years (13.6)) had a total mean PAID score of 39.6 (21.7) and 592 (48.5%) reported high DD. Leading subdimensions of DD included fear of complications (50.1 (24.4)) and diabetes burnout (45.9 (24.5)). Females, younger age, social vulnerability, smoking, and the presence of retinopathy were positively associated with high DD (p<0.05). We observed similar DD levels across HbA1c levels and treatment modalities, including automated insulin delivery and continuous glucose monitoring use. Several psychological factors, such as anxiety/depression, poor sleep quality, and treatment burden, were strongly associated with DD (p<0.001).Conclusions We provide a holistic clinical phenotyping approach that enables the identification of determinants and prevalence of DD, overall and according to key DD subdimensions, in a large and diverse population. Our results underscore the importance of developing DD-targeted prevention and intervention strategies focused specifically on high-risk groups and the most impactful distress subdimensions to reduce the impact of type 1 diabetes burden.Trial registration number NCT04657783.

Radiotherapy is advocated for many brain and head and neck tumors close to the pituitary gland. Pituitary hormones govern many vital functions but data of standardized monitoring for deficiencies after irradiation are lacking. We prospectively assessed the latency and frequency of hypothalamo-pituitary radiation dose-effects in patients undergoing proton therapy or mixed photon /proton beams for CNS, skull base and head and neck tumors. Radiation oncologists prospectively were asked to monitor endocrine functions based on a standardized protocol complying with international recommendations at 6, 12 months and yearly during follow-up. Patient, tumor and treatment characteristics were collected. Seventy patients (women 70%, median age 60.1 years) had undergone endocrine monitoring with a median follow-up of 20.7 (12.8–29.5) months. Thirty percent of patients had at least one pituitary deficiency before radiotherapy. Median mean dose to the pituitary gland and hypothalamus were respectively 52.0 (50.4–53.9) Gy and 24.7 (16.8–39.2) Gy. Of these patients with heavily exposed on their pituitary gland, skull base meningiomas (47.1%) and pituitary adenomas were the most represented (28.7%). Twenty-six (37.1%) patients experienced a new pituitary deficiency after a median time of 14.1 [IQR 10.3–23.6] months. Lactotroph and gonadotroph axis deficiencies occurred in 36% and 23.2% of the patients after 13.5 and 24.5 months, respectively. GH deficiency occurred in 9.7% patients after 27.1 months. TSH and ACTH axes occurred in 7.8% and 6.3% of patients after 21.8 and 19.0 months. On univariate analysis, only BMI < 25 was significantly associated with a shorter time to new deficiency onset. In this selected population of patients receiving over 50 Gy RBE to the pituitary gland, patients frequently developed at least one new pituitary deficiency within 2 years. As hormonal deficiencies are frequent after surgery and radiotherapy have functional and quality-of-life consequences and can be substituted medically, baseline and routine annual monitoring of every axis were performed. Educational programs for patients and physicians toward more systematic monitoring in patients, including those receiving < 30 Gy could serve to analyze radiation dose-effects and better predict individual endocrine normal tissue complication probabilities (NTCP).

Craniopharyngiomas are rare hypothalamic-pituitary tumors found in young children, adolescents and adults, and their multidisciplinary management required, calls for consistent practices for practicioners, patients and families. The French Endocrine Society and French Society for Pediatric Endocrinology & Diabetes enlisted and coordinated adult and paediatric endocrinologists, neurosurgeons, pathologists, radiotherapists as well as psychologists, dieticians and a patient association, to draft a reference document on this severe disease. The management of craniopharyngiomas remains complex due to their aggressive nature, invasive behavior, and propensity for recurrence, requiring a sequential and measured therapeutic approach and follow-up in expert centers. Although patient survival rates are high, the consequences of both the tumor and its treatment can lead to serious comorbidities and impaired quality of life, particularly in those patients with lesional hypothalamic syndrome. Recent advances have allowed the two described tumor types - papillary and adamantinomatous - to be associated with distinct molecular signatures, specific pathophysiological mechanisms and ipso facto, distinct therapeutic approaches, including innovative medications for hyperphagia, that will continue to evolve. This consensus statement covers all stages in the management of patients with craniopharyngioma, from diagnosis to therapeutic strategies including the long-term follow-up.

AIMS:Diabetes distress (DD) is prevalent among people with diabetes. While automated insulin delivery systems (AIDs) improve glycaemic control, their impact on DD is unclear. We aimed to investigate the effect of AIDs on DD in people with diabetes and their caregivers. METHODS:We focused on people with diabetes using AIDs versus other insulin delivery systems, with DD as the outcome. We included randomised controlled trials (RCTs), before-after studies (BAS) and observational studies until 4 April 2024. After screening, 40 studies were included in the systematic review, comprising 5426 participants (3210 adults, 1131 paediatric and 1085 caregivers). Twenty-seven studies were selected for the meta-analysis (focusing solely on type 1 diabetes). We used random effects models by population and study design. We also conducted a subgroup analysis by age group (children vs. teenagers). RESULTS:In adults, eight BAS and five RCTs indicated a significant small DD reduction post-AID initiation (standardised mean difference [95% confidence intervals] -0.32 [95% CI: -0.40, -0.24] and [-0.19 (-0.27, -0.11)]). No significant changes were observed in the paediatric population. In caregivers, eleven BAS and five RCTs indicated a significant moderate DD reduction (-0.48 [95% CI: -0.78, -0.18] and (-0.22 [-0.38, -0.06])). Subgroup analysis revealed an increased benefit in parents of children compared to parents of teenagers. CONCLUSIONS:This work suggests that AIDs is associated with a DD reduction in adults and caregivers but not in children/teenagers with type 1 diabetes. More longitudinal studies and better systematic DD assessments are needed.

Multiple endocrine neoplasia (MEN) is a group of syndromes with a genetic predisposition to the appearance of endocrine tumors, and shows autosomal dominant transmission. The advent of molecular genetics has led to improvements in the management of MEN in terms of diagnosis, prognosis and therapy. The genetics of MEN is the subject of regular updates, which will be presented throughout this paper. MEN1, the first to be described, is associated with the MEN1 gene. MEN1 is well known in terms of the observed phenotype, with genetic analysis being conclusive in 90% of patients with a typical phenotype, but is negative in around 10% of families with MEN1. Improvement in analysis techniques and the identification of other genes responsable for phenocopies allows the resolution of some, but not all, cases, notably non-familial forms suspected to be fortuitous assocations with tumors. MEN4 is a rare phenocopy of MEN1 linked to constitutional mutations in the CDKN1B gene. Though it closely resembles the phenotype of MEN1, published data suggests the appearance of tumors is later and less frequent in MEN4. MEN2, which results from mutations in the RET oncogene, shows a strong genotype-phenotype correlation. This correlation is particularly evident in the major manifestation of MEN2, medullary thyroid carcinoma (MTC), in which disease aggressiveness is dependent on the pathogenic variant of RET. However, recent studies cast doubt on this correlation between MTC and pathogenic variant. Lastly, the recent description of families carrying a mutation in MAX, which is known to predispose to the development of pheochromocytoma and paraganglioma, and presents a phenotypic spectrum that evokes MEN, suggests the existence of another syndrome, MEN5.

Context : Renin is a marker of blood volume. There is no consensus on the validity of plasma renin measurement for adjusting mineralocorticoid (MC) substitution in patients with primary adrenal insufficiency (PAI). Objective This work aimed to investigate if plasma renin could be used to adjust MC substitution in patients with PAI. Methods: A total of 150 patients with at least one measurement of plasma renin followed for PAI at 2 tertiary expert centers between 2008 and 2022 were retrospectively included. As supraphysiological hydrocortisone might have additional MC activity, we integrated the individual hydrocortisone dose to obtain the MC equivalent dose (Eq-MC). Renin less than 20 mIU/L was considered oversubstituted, renin between 20 and 60 mIU/L as correctly substituted, and renin over 60 mIU/L as undersubstituted. Results: The mean dose of fludrocortisone was 82.3 +/- 46 mu g/day. Plasma renin was abnormal in 56.7% of cases (7 patients oversubstituted and 78 patients undersubstituted). Abnormalities in electrolyte levels were observed in only 12.7% of patients. Plasma renin correlated negatively with sodium (P < .01) and systolic blood pressure (P = .026), and positively with potassium (P < .01). Doses changes in Eq-MC had a statistically significant effect on renin levels (P = .0037), with an increase of MC dose correlating with a decrease in renin level and vice versa; no correlation was observed using electrolytes or blood pressure. Conclusion: Plasma renin correlates with electrolytes and blood pressure. While dose changes significantly alter renin levels, electrolytes and blood pressure do not, suggesting that renin may provide more information about MC replacement therapy than electrolytes and blood pressure.

Objective: Pituitary stalk interruption syndrome (PSIS) is a rare cause of congenital hypopituitarism. Limited data exist on the gonadotropic status and fertility of adult women with PSIS. Our study aims to describe pubertal development and the evolution of gonadotropic function and fertility in adult women with PSIS. Design: A retrospective multicentric French study. Methods: We described gonadotropic function in 56 adult women with PSIS from puberty onward. We compared live birth rates per woman with PSIS with age-matched controls from the large French epidemiological cohort (CONSTANCES). Additionally, we assessed height, body mass index (BMI), blood pressure, other metabolic parameters, and socioeconomic status. Results and Conclusions: Among 56 women with PSIS, 36 did not experience spontaneous puberty. Of these, 13 underwent ovarian stimulation, resulting in 7 women having a total of 11 children. In the subgroup with spontaneous puberty (n = 20), 4 had a total of 8 pregnancies, while 6 developed secondary gonadotropic deficiency. Women with PSIS had fewer children than controls (0.33 vs 0.63, P = .04). Median height was also lower (160.5 vs 165.0 cm, P < .0001). Although mean blood pressure was lower in women with PSIS compared with controls (111.3/65.9 +/- 11.2/8.1 vs 118.7/72.1 +/- 10.1/7.7 mmHg, P < .001), there were no significant differences in other metabolic parameters, notably BMI and lipid profile. Employment/academic status was not different in the 2 groups, but fewer women with PSIS were in relationships (42% vs 57.6% in controls, P = .02). The fertility prognosis in patients with PSIS needs optimization. Patients should be informed about the likelihood of declining gonadotropic function over time.

Introduction: Most continuous subcutaneous insulin infusion (CSII) catheters (KT) are changed every 3 days. This study aims at evaluating whether KT changes impact glucose control while under open-loop (OL) or automated insulin delivery (AID) modes. Methods: We included patients with type 1 diabetes who used Tandem t:slim x2 insulin pump and Dexcom G6 glucose sensor for 20 days in OL, then as AID. CSII and sensor glucose data in OL and for the past 20 days of 3-month AID were retrospectively analyzed. The percentage of time spent with sensor glucose above 180 mg/dL (%TAR180) was compared between the calendar day of KT change (D0), the next day (D1), and 2 days later (D2). Values were adjusted for age, gender, body mass index (BMI), hemoglobin A1c (HbA1c) at inclusion, and %TAR180 for the 2 h before KT change. Results: A total of 1636 KT changes were analyzed in 134 patients: 72 women (54%), age: 35.6 ± 15.7 years, BMI: 25.2 ± 4.7 kg/m2, and HbA1c: 7.5 ± 0.8%. %TAR180 in the 2 h before the KT change was 51.3 ± 37.0% in OL and 33.2 ± 30.0% in AID mode. In OL, significant absolute increases of %TAR180 at D0 versus D1 (+6.9%; P < 0.0001) or versus D2 (+6.8%; P < 0.0001) were observed. In AID, significant absolute increases of %TA180R at D0 versus D1 (+4.8%; P < 0.0001) or versus D2 (+4.2%; P < 0.0001) were also observed. Conclusion: This study shows an increase in time spent in hyperglycemia on the day of the KT change both in OL and AID modes. This additional information should be taken into account to improve current AID algorithms. ClinicalTrials.gov: NCT04939766.

Background: Lipohypertrophy is a common complication in patients with diabetes receiving insulin therapy. There is a lack of consensus regarding how much lipohypertrophy affects diabetes management. Our study aimed to assess the potential correlation between lipohypertrophy and glycemic control, as well as insulin dosing in patients with diabetes. Methods: We performed a systematic review followed by a meta-analysis to collect data about glycemic control and insulin dosing in diabetic patients with and without lipohypertrophy. To identify relevant studies published in English, we searched medical databases (MEDLINE/PubMed, Embase, and CENTRAL) from 1990 to January 20, 2023. An additional hand-search of references was performed to retrieve publications not indexed in medical databases. Results of meta-analyses were presented either as prevalence odds ratios (pORs) or mean differences (MDs) with 95% confidence intervals (95% CIs). This study was registered on PROSPERO (CRD42023393103). Results: Of the 5540 records and 240 full-text articles screened, 37 studies fulfilled the prespecified inclusion criteria. Performed meta-analyses showed that patients with lipohypertrophy compared with those without lipohypertrophy were more likely to experience unexplained hypoglycemia (pOR [95% CI] = 6.98 [3.30-14.77]), overall hypoglycemia (pOR [95% CI] = 6.65 [1.37-32.36]), and glycemic variability (pOR [95% CI] = 5.24 [2.68-10.23]). Patients with lipohypertrophy also had higher HbA1c (MD [95% CI] = 0.55 [0.23-0.87] %), and increased daily insulin consumption (MD [95% CI] = 7.68 IU [5.31-10.06]). Conclusions: These results suggest that overall glycemic control is worse in patients with lipohypertrophy than in those without this condition.

The need to address the emotional impact of diabetes has received growing attention over the last two decades and psychological care is now integrated into guidelines for diabetes management.1 As distinct from major depressive disorders, diabetes distress results from the interaction between the elevated mental load associated with the constraints and consequences of diabetes, the cognitive and psychological capacities of people living with diabetes to cope with multiple tasks, and concerns about their disease. A review focusing on people with type 1 diabetes (T1D) reported a prevalence of severe diabetes distress of 20%–30%,2 which impacted on self-care, management of diabetes, glycaemic control and quality of life (QoL). The development of hybrid closed-loop (HCL) systems offers the potential to improve glucose control but also to reduce diabetes burden thanks to the automation of multiple daily tasks. The present study was designed to assess, in a large cohort of people with T1D, the impact of an HCL system on diabetes distress, QoL and a panel of patient-reported outcome measures. IMPLIQUE was a multicentre longitudinal real-life study conducted in French university hospitals. Adults and adolescents were eligible if they had T1D treated by an insulin pump and a continuous glucose monitoring (CGM) system for at least 6 months, if they used the Tandem t:slim X2 insulin pump (Tandem Diabetes Care, USA) and Dexcom G6 CGM (Dexcom, USA) for at least 4 weeks before study inclusion and if Control-IQ initiation was planned by their diabetologist. Exclusion criteria were pregnancy, lactation, and severe retinopathy. At the end of a 3-week run-in period, the HCL system was activated and participants attended follow-up visits at 3 and 6 months, and received phone calls on Days 7, 14 and 42. The study was reviewed by an independent scientific board and approved by an institutional French Ethics Committee (CPP Ile de France X, 31 August 2021). Written informed consent was obtained as required. The trial was registered at ClinicalTrials.gov under NCT 04939766. Participants completed questionnaires assessing diabetes-related distress (Problem Areas in Diabetes questionnaire [PAID]-20 or PAID-5), QoL (Audit of Diabetes-Dependent Quality-of-Life [ADDQoL]), stress (Perceived Stress Scale [PSS]), anxiety (seven-item Generalized Anxiety Disorder questionnaire [GAD7]), depression (QSP9), fear of hypoglycaemia (Hypoglycaemia Fear Survey [HFS] II) including the behaviour (HFS-B) and worry (HFS-W) scales, physical activity (Godin), sleep (Pittsburgh Sleep Quality Index [PSQI]) and fatigue (Fatigue Severity Scale [FSS]; Appendix S1). The primary outcomes, PAID and ADDQoL scores, were assessed at baseline, 3 months (PAID-5) and 6 months during the study period. Secondary outcome scores were assessed at baseline and 6 months. Glycaemic outcomes were assessed at baseline and 6 months. Adverse events were reported throughout the study (Figure S1, Appendix S2). For statistical analyses, the population set included all enrolled participants with available baseline CGM data and completed questionnaires. Statistical analyses were run separately for adults and adolescents, and were considered significant if p values were <0.05. Missing data were minimal, therefore, only the results of analyses on complete cases are presented. Unless otherwise specified, results for quantitative data are expressed as mean ± SD. For the determination of differences in PAID and ADDQoL scores from inclusion until follow-up visit, paired Student tests were used. A total of 257 people with T1D were enrolled across 55 French centres. The participant characteristics are presented in Table 1. Of this study cohort, 250 participants completed the study (97%), while seven participants (five adults and two adolescents) withdrew. At baseline, 64% of adults had a PAID score above 40 indicating severe diabetes distress (Table 2). The most severe subscores (mean score >2/4) were obtained for concerns regarding serious diabetes complications, feelings of guilt, and anxiety regarding diabetes management, worry about hypoglycaemia, and mental and physical exhaustion caused by diabetes. In adults, PAID score decreased significantly after 3 months of HCL system use and remained stable at 6 months (p < 0.001), resulting in a 16% improvement in mean diabetes distress score. All subscores improved, with the exception of one, the feeling of being burned out by diabetes management. After 6 months of HCL system use, 50% of adults still had severe diabetes distress. Among adolescents, 40% had severe diabetes distress at baseline and the mean PAID score did not change significantly with HCL system use (Figure S2). Concerning QoL, ADDQoL global score improved rapidly in adults after 3 months of HCL system use (p < 0.001) and remained stable at 6 months. In adolescents, ADDQoL global score remained stable during the study (Figure S3). Concerning fear of hypoglycaemia, HFS-B score improved significantly in both adults (p < 0.001) and adolescents (p < 0.05) after 6 months of HCL system use, while HFS-W score improved only in adults (p < 0.001). The PSS global stress score also improved only in adults. GAD7 anxiety score improved in adults (p = 0.05) but remained stable in adolescents. In both adults and adolescents, neither QSP9 score nor PSQI score, nor FSS scores changed significantly. Godin physical activity score improved only in adolescents (p < 0.05). Outcomes for glucose control are summarized in Table S1. During the study period, one episode of severe hypoglycaemia and two episodes of ketoacidosis occurred in adolescents, while seven episodes of severe hypoglycaemia and one episode of ketoacidosis occurred in adults. Regarding device-related adverse events, five occurred in adolescents and 26 in adults, due to catheter occlusions (n = 8), sensor failures (n = 14), or pump failures (n = 9). In adults, severe diabetes distress at baseline was associated with female sex (p = 0.05), presence of retinopathy (p < 0.05), and neuropathy (p < 0.01). In adolescents, severe diabetes distress was associated with female sex (p < 0.01), low physical activity (p < 0.0) and pump use for fewer than 5 years (p < 0.05). No other variables were associated with severe diabetes distress. The psychosocial impact of HCL systems is now a matter of debate and worthy of clinical evaluation. In the present study, the main findings were a high prevalence of severe diabetes distress in adults and its improvement after 6 months of HCL system use. Importantly, despite the positive effect of HCL devices, half of the adults still exhibited severe diabetes distress scores and altered QoL at the study end, emphasizing that some of the difficulties in coping with diabetes burden are not modifiable by HCL technology. Previous studies have reported an improvement in diabetes distress with HCL devices,3-5 while others did not.6, 7 In contrast to adults, the HCL system did not modify the level of diabetes distress and QoL in adolescents, in accordance with some published studies6, 8 but not others.9, 10 HCL devices also improved QoL in adults only, in agreement with previous studies.3, 5 Concerning fear of hypoglycaemia, trials performed with second-generation HCL systems have shown improvements in both behaviour and worry about hypoglycaemia in children and their parents,11 as seen in the present study, while findings have been controversial in adults.6, 12 Other benefits of HCL systems were a reduction of anxiety and stress in adults and an improvement of physical activity level in adolescents. The strengths of the present study include the large panel of psychosocial outcomes investigated, the fact that most adults were using a sensor-augmented pump before the study and the 6-month duration of the study, while the main limitation was the lack of a control group. We conclude that HCL system use is associated with improvement in several psychosocial outcomes. The high percentage of residual distress despite HCL use suggests unmet needs which should be handled in an alternative way with psychotherapeutic approaches. Yves Reznik, Jean-Pierre Rivelin, Guy Fagherazzi and Mihaela Mihaileanu conceived the study. Yves Reznik wrote the manuscript. Yves Reznik, Elisabeth Bonnemaison, Guy Fagherazzi and Jean-Pierre Riveline interpreted the data. Guy Fagherazzi and Eric Renard reviewed the manuscript. Yves Reznik, Elisabeth Bonnemaison, Hélène Hanaire, Pauline Schaepelynck and Jean-Pierre Riveline provided the patient medical data. Yves Reznik is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors thank Dr Eric Leutenegger, freelance medical writer, for help with preparing the manuscript, and Cecile Caballol, VitalAire France, for her support. Editorial assistance was provided by Dr Ian Darby, Editingbiomed, Melbourne, Australia. The promoter of the study was VitalAire France. Study monitoring was conducted by Qualees, a contract research organization. Yves Reznik has received consultant/speaker fees from Medtronic, Insulet, Embecta, Abbott, Novo Nordisk, Eli-Lilly, Sanofi-Aventis, TIMKL, Vitalaire, ORKYN and Air Liquide Santé International. Elisabeth Bonnemaison has received consultant/speaker fees from Abbott, Eli-Lilly, Medtronic, Novo Nordisk, Sanofi-Aventis and Air Liquide Santé International. Guy Fagherazzi has received consultant/speaker fees from MSD, Eli-Lilly, Roche Diabetes Care, AstraZeneca, Danone Research, Diabeloop, Bristol Myers Squibb, L'Oréal R&D, AbbVie Pharmaceutical, Pfizer, Vitalaire and Sanofi-Aventis. Eric Renard has received consultant/speaker fees from A. Menarini Diagnostics, Abbott, Air Liquide SI, AstraZeneca, Becton-Dickinson, Boehringer-Ingelheim, Cellnovo, Dexcom Inc., Eli-Lilly, Hillo, Insulet Inc., Johnson & Johnson (Animas, LifeScan), Medtronic, Medirio, Novo Nordisk, Roche and Sanofi-Aventis and research support from Abbott, Dexcom Inc., Insulet Inc., Roche and Tandem Diabetes Care. Hélène Hanaire has received lecturer and scientific advisor fees from Insulet, Abbott, AstraZeneca, Novo Nordisk, Lilly, Sanofi A, Lifescan, Medtronic, and research grants from Novo Nordisk, Lifescan, Abbott, Sanofi-Aventis. Pauline Schaepelynck has received consultant/speaker fees from Medtronic, Abbott Diabetes Care, Novo Nordisk, Eli-Lilly, Sanofi-Aventis, TIMKL, Vitalaire and ORKYN. Mihaela Mihaileanu is an employee of VitalAire France. Jean-Pierre Riveline is an advisory panel member for Sanofi Aventis MSD, Eli Lilly, Novo Nordisk, AstraZeneca, Abbott, Dexcom, Alphadiab and Medtronic, and has received research funding from Abbott, Air Liquide Santé International, Sanofi-Aventis and Novo Nordisk. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15462. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. TABLE S1. Glycaemic outcomes. FIGURE S1. Flow chart. FIGURE S2. PAID scores in adults and adolescents at baseline and 3 and 6 months after AID system use. Panel A: adults, panel B: adolescents. FIGURE S3. ADDQoL scores at baseline and 3 and 6 months after AID system use. APPENDIX S1. Descriptive of the psychosocial scales. APPENDIX S2. Descriptive of the Study sample calculation and statistical methods. DATA S1. STROBE statement—IMPLIQUE study. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUND: Pathogenic variants in PLIN1 -encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1 -related FPL. METHODS: We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1 -mutated FPL and 3 controls. RESULTS: Patients with PLIN1 -mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P =0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P <0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P =0.006). Compared with controls, patients with PLIN1 -related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P =0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P =0.005). VLDL-apoB100 production was not different between patients with PLIN1 -related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1 -related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 ( P =0.031) and IDL-apoB100 ( P =0.031). Plasma LPL mass was significantly lower in patients with PLIN1 -related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P <0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass. CONCLUSIONS: We show that hypertriglyceridemia associated with PLIN1 -related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.