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Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented.

Context Dercum’s disease (DD) and Roch-Leri mesosomatic lipomatosis (LMS) are rare and poorly characteri -zed diseases. The clinical presentation combines multiple lipomas, painful in DD in contrast with LMS, without lipoatrophy. ObjectiveTo identify any specific metabolic and immune phenotype of DD and LMS with the aim to improve their treatment.Design & PatientsThis monocentric retrospective study included 38 patients: 9 DD, 11 LMS and 18 healthy controls. Metabolic and immunohematological characteristics of each group were compared.Results The median age of the patients was similar in the 3 groups (31 years). The number of women, and of basophils, and CD3+, CD4+ and CD8 + T lymphocytes was significantly higher in the DD versus the LMS group, without any difference of the metabolic parameters. Weight, BMI, blood pressure, gamma-GT, leptin, fasting insulin and C-peptide levels, fat mass percentage, and intra/total abdominal fat ratio were significantly higher in each lipomatosis group compared with the control group. Compared with the control group, the DD group had significantly higher fasting blood glucose, LDL-cholesterol, platelets, leukocytes, basophils, and a lower NK cell count, whereas the LMS group had a significantly lower rate of CD3, CD4, and CD8 lymphocytes.ConclusionDD and LMS show a common background of obesity and metabolic phenotype, but a distinct immunohematological profile characterized by a higher number of platelets, leukocytes and basophils in DD patients, an inflammatory profile that could contribute to pain. T lymphocyte depletion was present in LMS. These findings could offer specific therapeutic opportunities, especially for painful DD.NCT0178428

Background and Aims In patients with type 1 diabetes and end-stage renal disease, kidney transplantation improves both quality of life and survival. When simultaneous kidney-pancreas transplantation appears too invasive, or after failure of the pancreatic graft, an islet after kidney transplantation (IAK) may be considered to restore a stable endocrine function. The aim of our work was to assess the impact of islet transplantation on kidney transplantation outcomes versus insulin alone. Method In this retrospective parallel-arm cohort study in Lille, we included all type 1 diabetes patients who received a kidney graft from 2000 to 2017, followed by an islet transplantation after kidney (IAK) or not (kidney alone, KA). The primary study endpoint was the change of renal function (estimated glomerular filtration rate, eGFR). Secondary endpoints were glycemic control-related markers, such as HBA1c. Results During the period of study, 14 patients were included in the KA group versus 15 in the IAK group (including 5 after failure of a simultaneous pancreatic graft) were enrolled. At baseline, kidney donor sex, BMI, cause of death, cold ischemia time and recipient sex, waiting time on dialysis, type of dialysis, and number of previous kidney transplantation, were similar between the two groups. Yet, there were significant differences between KA and IAK, considering donor age (resp. 56.0±15.0 vs 35.2±13.7 years, p Conclusion In patients with type 1 diabetes and a functioning kidney graft, IAK was associated with a better glucose control and a slower decrease of eGFR than standard insulin therapy. Our results suggest that IAK should be proposed to type 1 diabetes patients with a functional kidney graft.

Islet allotransplantation has been shown to be effective in restoring endogenous insulin secretion. Many initial reports showed, however, a sharp decline of islet graft function with time. In the late 1990s we hypothesized that islet transplantation success could be significantly prolonged by increasing islet primary graft function, through the deliberate repetition of islet infusions. We report here the favorable long-term outcome of this strategy in patients with type 1 diabetes and severe hypoglycemia unawareness or after a kidney graft with the Edmonton immunosuppressive regimen. Our results suggest that optimizing initial graft function is essential for the long-term success of beta cell replacement.

The names of the working groups that collaborated in the study reported in this article were inadvertently omitted from the byline. The corrected byline should … 2019;42

OBJECTIVE The long-term outcome of allogenic islet transplantation is unknown. The aim of this study was to evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes and hypoglycemia unawareness and/or a functioning kidney graft. RESEARCH DESIGN AND METHODS We enrolled in this prospective parallel-arm cohort study 28 subjects with type 1 diabetes who received islet transplantation either alone (ITA) or after a kidney graft (IAK). Islet transplantation consisted of two or three intraportal infusions of allogenic islets administered within (median [interquartile range]) 68 days (43–92). Immunosuppression was induced with interleukin-2 receptor antibodies and maintained with sirolimus and tacrolimus. The primary outcome was insulin independence with A1C ≤6.5% (48 mmol/mol). Secondary outcomes were patient and graft survival, severe hypoglycemic events (SHEs), metabolic control, and renal function. RESULTS The primary outcome was met by (Kaplan-Meier estimates [95% CI]) 39% (22–57) and 28% (13–45) of patients 5 and 10 years after islet transplantation, respectively. Graft function persisted in 82% (62–92) and 78% (57–89) of case subjects after 5 and 10 years, respectively, and was associated with improved glucose control, reduced need for exogenous insulin, and a marked decrease of SHEs. ITA and IAK had similar outcomes. Primary graft function, evaluated 1 month after the last islet infusion, was significantly associated with the duration of graft function and insulin independence. CONCLUSIONS Islet transplantation with the Edmonton protocol can provide 10-year markedly improved metabolic control without SHEs in three-quarters of patients with type 1 diabetes, kidney transplanted or not.

While either pancreas or pancreatic islet transplantation can restore endogenous insulin secretion in patients with diabetes, no beta-cell replacement strategies are recommended in the literature. For this reason, the aim of this national expert panel statement is to provide information on the different kinds of beta-cell replacement, their benefit-risk ratios and indications for each type of transplantation, according to type of diabetes, its control and association with end-stage renal disease. Allotransplantation requires immunosuppression, a risk that should be weighed against the risks of poor glycaemic control, diabetic lability and severe hypoglycaemia, especially in cases of unawareness. Pancreas transplantation is associated with improvement in diabetic micro- and macro-angiopathy, but has the associated morbidity of major surgery. Islet transplantation is a minimally invasive radiological or mini-surgical procedure involving infusion of purified islets via the hepatic portal vein, but needs to be repeated two or three times to achieve insulin independence and long-term functionality. Simultaneous pancreas-kidney and pancreas after kidney transplantations should be proposed for kidney recipients with type 1 diabetes with no surgical, especially cardiovascular, contraindications. In cases of high surgical risk, islet after or simultaneously with kidney transplantation may be proposed. Pancreas, or more often islet, transplantation alone is appropriate for non-uraemic patients with labile diabetes. Various factors influencing the therapeutic strategy are also detailed in this report.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since lundi 14 novembre 2016

Introduction. The diagnosis of non-HIV lipodystrophies is challenging, especially since borderline forms with type 2 diabetes have been described (Strickland Diabetes Care 2013). Aim: to identify the most specific anthropometric and biological parameters enabling to differentiate lipodystrophic from obese and control subjects. Methods. This prospective study (clin.gov 2009-AO-1169-48) included 94 patients divided in 3 groups adjusted for age and gender: 52 lipodystrophic patients (among whom 16 LMNA –mutated lipodystrophies (LDM), 16 non- LMNA mutated partial lipodystrophies (LDNM), and 20 other types of lipodystrophies), 28 obese (O; 12 diabetic (OD) and 16 non-diabetic (OND)) and 14 normal-weighed healthy subjects (C). The anthropometric (DEXA, MRI) characteristics and leptin levels of the patients were recorded. Three ratios were calculated to assess the respective part of fat and lean mass (FM/LM), intra- and whole abdominal fat (IAF/WAF) and adipose tissue function (leptin/WAF). Results. The three groups differed by the FM, LM, IAF, WAF, leptinemia, trunk FM/LM ( P

Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.

Les etats de resistance a la PTH se caracterisent ordinairement par des signes d’hypocalcemie chronique avec hyperphosphoremie qu’explique l’alteration de la sensibilite renale a l’action de la PTH. Eventuellement l’intensite de la riposte parathyroidienne rend compte d’une expression majeure au niveau des recepteurs osseux, determinant une situation qualifiee de pseudo-hypohyperparathyroidie. Nous rapportons l’observation d’un patient de 34 ans evalue a l’occasion d’une fracture phalangienne survenue pour un traumatisme minime : osteoporose (T-score vertebral : –2,9 DS, T-score femoral : –2,1 DS), calcemie et phosphoremie normales mais net accroissement des marqueurs du remodelage osseux et augmentation considerable de la PTH (3121 pg/mL, N = 12–65). Les radiographies des mains revelaient un aspect feuillete des corticales, des signes de resorption sous-periostee. Un nodule palpe dans la region cervicale gauche etait identifie par l’echographie, la scintigraphie au MIBI-Technetium et la TDM comme une tres volumineuse lesion parathyroidienne en situation latero-œsophagienne gauche. La discretion des atypies morphologiques sans habitus typique d’osteodystrophie d’Albright et la notion d’hypocalcemie familiale ont conduit a evoquer un etat de PSHP de type 1B, authentifie par l’analyse genetique : anomalie de methylation des DMRA/B du gene GNAS et deletion de la syntaxine 16. L’intervention chirurgicale a permis l’exerese d’un volumineux adenome parathyroidien (6330 mg) sans signe histologique de malignite. Les suites operatoires ont ete marquees par une hypocalcemie severe (minimum a 49 mg/L) mais peu symptomatique, attribuee a un « hungry bone syndrome », necessitant de tres fortes doses d’apports calciques (alimentaires et medicamenteux) et vitaminiques durant plusieurs semaines. Une amelioration des parametres osteodensitometriques (T-score vertebral : -1,8 DS, T-score femoral : –1,8 DS) a ete constatee apres 8 semaines. Cette situation inedite d’hyperparathyroidie tertiaire compliquant une PSHP de type 1B elargit le spectre phenotypique des situations de resistance a la PTH.

International audience; Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. This review aims to summarize the main gonadal side effects of immunosuppressants, to detail the effects on fertility and pregnancy of each class of drug, and to provide recommendations on the management of patients who are seen prior to starting or who are already receiving immunosuppressive treatment, allowing them in due course to bear children. The recommendations for use are established with a rather low level of proof, which needs to be taken into account in the patient management. Methotrexate, mycophenolate, and le- and teri-flunomide, cyclophosphamide, mitoxanthrone are contraindicated if pregnancy is desired due to their teratogenic effects, as well as gonadotoxic effects in the case of cyclophosphamide. Anti-TNF-alpha and mTOR-inhibitors are to be used cautiously if pregnancy is desired, since experience using these drugs is still relatively scarce. Azathioprine, glucocorticoids, mesalazine, anticalcineurins such as cyclosporine and tacrolimus, ß-interferon, glatiramer-acetate and chloroquine can be used during pregnancy, bearing in mind however that side effects may still occur. Experience is limited concerning natalizumab, fingolimod, dimethyl-fumarate and induction treatments. Conclusion: At the time of prescription, patients must be informed of the possible consequences of immunosuppressants on fertility and of the need for contraception. Pregnancy must be planned and the treatment modified if necessary in a pre-conception time period adapted to the half-life of the drug, imperatively in relation with the prescriber of the immunosuppressive drugs.