Indications for islet or pancreatic transplantation: Statement of the TREPID working group on behalf of the Société francophone du diabète (SFD), Société francaise d'endocrinologie (SFE), Société francophone de transplantation (SFT) and Société française de néphrologie - dialyse - transplantation (SFNDT).

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.

Irisin levels in LMNA-associated partial lipodystrophies.

AIM: The adipo-myokine irisin regulates energy expenditure and fat metabolism. LMNA-associated familial partial lipodystrophy (FPLD2) comprises insulin resistance, muscle hypertrophy and lipoatrophy. The aim of this study was to investigate whether irisin could be a biomarker of FPLD2. PATIENTS AND METHODS: This case control study included 19 FPLD2 subjects, 13 obese non-diabetic (OND) patients and 19 healthy controls (HC) of normal weight (median BMI: 26, 39 and 22 kg/m2, respectively). Serum irisin and leptin levels, body composition (DXA/MRI) and metabolic/inflammatory parameters were compared in these three groups. RESULTS: BMI and MRI intra-abdominal fat significantly differed among these three groups, whereas DXA total fat mass and leptin levels were higher in the OND group, but did not differ between HC and FPLD2. Lipodystrophy patients had higher intra-abdominal/total abdominal fat ratios than the other two groups. Irisin levels were higher in FPLD2 and OND patients than in HC (medians: 944, 934 and 804 ng/mL, respectively). However, irisin/leptin ratios and lean body mass percentages were strikingly higher, and lean mass indices lower, in FPLD2 and HC than in the OND (median irisin/leptin ratios: 137, 166 and 21, respectively). In the entire study group, irisin levels positively correlated with BMI, lean body mass and index, intra-abdominal/total abdominal fat ratio, triglyceride, cholesterol, insulin, glucose and HbA1c levels. Also, intra-abdominal/total abdominal fat ratio and lean body mass better differentiated the three groups only in female patients. CONCLUSION: Circulating irisin is similarly increased in FPLD2 and OND patients, who are characterized by higher lean body mass regardless of their clearly different fat mass. However, irisin/leptin ratios, strikingly higher in FPLD2 than in OND patients, could help to make the diagnosis and prompt genetic testing in clinically atypical cases.

[Androgens and cardiovascular risk: A series of case report in the French and Canadian pharmacovigilance databases]. / Androgènes et risque cardiovasculaire : série de cas dans les bases de pharmacovigilance française et canadienne.

INTRODUCTION: Age-related androgenic deficiency (DALA) is a pathology that is increasingly cited in recent publications. The cardiovascular risk of testosterone is debated: present for the FDA, absent for the European Medicines Agency in 2015. Our objective was to analyze the association between androgens and vascular pathologies in adverse reactions reported in pharmacovigilance databases. MATERIAL AND METHOD: We conducted a retrospective case series study of the French and Canadian pharmacovigilance databases for the period 2005-2015. Cases were defined as the association of the occurrence of a cardiovascular event (myocardial infarction or stroke) and the presence of testosterone in the treatment of patients. RESULTS: Of the 10 years analyzed, 12 French cases and 6 Canadian cases (representing 13 MIs and 5 strokes) were recorded in men aged 55 years on average. All were doubtful: differential diagnoses were possible (2.4 confounding conditions on average per patient) and overall cardiovascular risk was high for the majority of cases. CONCLUSION: Our study shows a very low report of cardiovascular effects under testosterone, all doubtful. Pending further studies, it seems reasonable to consider the cardiovascular risk of patients who are candidates for hormone therapy for age-related androgen deficiency. LEVEL OF EVIDENCE: 3.

Actualisation sur l'hypoparathyroïdie : un peu de théorie, beaucoup de pratique: Update on hypoparathyroidism: a little theory, a lot of practice.

Parathormone (PTH), produced by parathyroid glands, is the main regulator of calcium homeostasis. Hypoparathyroidism (hypoPT), due to decrease of PTH production, is a rare disease. Symptoms are multiple, altering function of several organs and leading to a decrease of quality of life. Acquired etiologies, including thyroïdectomy, the main cause of hypoPT, can be distinguished from congenital etiologies, including genetic defects. HypoPT, which is classically treated by supplementation by calcium and active vitamin D, can now be treated by recombinant injection in certain indications as a poor control under classical therapy. Here are summarized current knowledge on etiologies, epidemiology, clinical manifestations and management of hypoPT.

One-year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes.

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.

Treating diabetes with islet transplantation: lessons from the past decade in Lille.

Type 1 diabetes (T1D) is due to the loss of both beta-cell insulin secretion and glucose sensing, leading to glucose variability and a lack of predictability, a daily issue for patients. Guidelines for the treatment of T1D have become stricter as results from the Diabetes Control and Complications Trial (DCCT) demonstrated the close relationship between microangiopathy and HbA1c levels. In this regard, glucometers, ambulatory continuous glucose monitoring, and subcutaneous and intraperitoneal pumps have been major developments in the management of glucose imbalance. Besides this technological approach, islet transplantation (IT) has emerged as an acceptable safe procedure with results that continue to improve. Research in the last decade of the 20th century focused on the feasibility of islet isolation and transplantation and, since 2000, the success and reproducibility of the Edmonton protocol have been proven, and the mid-term (5-year) benefit-risk ratio evaluated. Currently, a 5-year 50% rate of insulin independence can be expected, with stabilization of microangiopathy and macroangiopathy, but the possible side-effects of immunosuppressants, limited availability of islets and still limited duration of insulin independence restrict the procedure to cases of brittle diabetes in patients who are not overweight or have no associated insulin resistance. However, various prognostic factors have been identified that may extend islet graft survival and reduce the number of islet injections required; these include graft quality, autoimmunity, immunosuppressant regimen and non-specific inflammatory reactions. Finally, alternative injection sites and unlimited sources of islets are likely to make IT a routine procedure in the future.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on adrenal insufficiency and osteoporosis]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: insuffisance corticotrope et ostéoporose.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview on secondary adrenal insufficiency and osteoporosis post-transplant.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on dyslipidemia and thyroid disorders]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: dyslipidémie et thyropathie.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview on dyslipidemia and thyroid disorders post-transplant.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on gonadal failure and fertility]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: insuffisance gonadique et fertilité

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview gonadal failure, fertility preservation and post-transplant.

[Hypoglycemia and endocrine effects of adults' inborn errors of metabolism]. / Hypoglycémies et manifestations endocriniennes des maladies héréditaires du métabolisme chez l'adulte.

Inborn errors of metabolism (IEM) are rare diseases, most often inherited as an autosomal recessive disorder. They may be associated with endocrine dysfunction, the most frequent of them being disorders of carbohydrate metabolism (hypoglycemia, diabetes). The endocrinologist might be led to screen these complications in a patient whose diagnosis has been done during childhood. In some rare cases, he should evoke the diagnosis in front of an endocrine disorder most often associated to a multisystemic involvement. This spreading field is new, not yet very well known in adulthood. Long-term consequences of IEM on fertility and bone metabolism are still poorly understood. Diagnosis orientation relies on a few specific lab investigations encompassing blood lactate, free fatty acids and 3-hydroxy-butyrate, ammoniemia, carnitine and acylcarnitines, aminoacid and urinary organic chromatography. Hyperinsulinism, glycogenosis, fatty acid ss-oxydation, carnitine cycle and glycosylation (CDG syndrome) disorders, fructose intolerance, tyrosinemia, organic aciduria may explain hypoglycemia. These diagnosis should be evoked in front of unexplained adult hypoglycemia. Diabetes is related to iron overload, mitochondriopathy and thiamine sensitive diabetes. Clinical spectrum of some forms of IEM switch from hypoglycemia in childhood to diabetes in adulthood. Mitochondriopathies can be associated to all types of endocrine disorders, the most frequent being diabetes and dysthyroidism. Hypothyroidism is encountered in mitochondriopathies, cystinosis and primary hyperoxaluria. Hypogonadism is almost constant in galactosemia, frequent in CDG syndromes, cystinosis and iron overload. Most of the time, a specialized advice is required, which is one of the mission of reference centres.

TSH-secreting adenoma improved with cabergoline.

TSH-secreting adenomas are rare tumors, representing only 0.5 to 2.5% of pituitary adenomas. Their main clinical characteristics include signs of thyrotoxicosis, diffuse goiter and a compressive syndrome. Biologically, free T4 and T3 serum levels are elevated, contrasting with inadequate serum TSH levels and increased alpha chains. Magnetic resonance (MR) imaging shows a pituitary tumor, the main differential diagnosis being resistance to thyroid hormones. Treatment is based on surgery, possibly associated with somatostatin analogs and radiotherapy. Though the long-term evolution of this rare pathology seems to have improved, some clinical situations are still a challenge to treat. We report one such case that was resistant to both stereotactic radiotherapy and somatostatin analogs, but surprisingly improved with cabergoline. We suggest that cabergoline should be considered as an alternative treatment in cases of pituitary adenomas that resist traditional treatments.

Does the RET variant G691S influence the features of sporadic medullary thyroid carcinoma?

OBJECTIVE: The RET (rearranged during transfection) proto-oncogene G691S variant is over-represented in the germline of patients with sporadic medullary thyroid carcinoma (sMTC) vs. normal controls but so far is not associated with any medical or pathological features of the tumour. The aim of our study was to assess the influence of this variant on the age of onset, clinical, biological and pathological features of sMTC. DESIGN AND PATIENTS: One hundred patients with histologically proven MTC, for whom the germline genetic analysis of RET was negative and medical records were available, were included in the study. RESULTS: Patients with the heterozygous GS variant or the homozygous SS variant (n = 36) were on average 8.0 years younger than patients with the wild-type GG variant (n = 64, mean age 43.9 vs. 51.9 years, P < 0.01). The former group did not differ from the wild-type group in terms of MTC size, prevalence of C-cell hyperplasia (CCH) or papillary thyroid carcinoma (PTC). However, the prevalence of an increased preoperative basal calcitonin (bCT) level (> 1000 pg/ml) was 2.75-fold higher in the patients with the GS or SS variant than in those with the wild-type variant (P < 0.001). The proportion of patients with lymph node metastases was also higher in the former group (P < 0.05). Multivariate analysis confirmed that the presence of the RET variant is independently associated with higher preoperative bCT values (P = 0.011). CONCLUSIONS: Our data demonstrate that the RET G691S variant could modulate the age of onset of sMTC as demonstrated previously for familial tumours. Moreover, this variant is an independent predictor of a higher basal calcitonin synthesis rate in patients with sMTC.

[11beta-hydroxysteroide dehydrogenases. Recent advances]. / 11beta-hydroxystéroïde déshydrogénases. Avancées récentes.

11beta-hydroxysteroide dehydrogenase (11beta-OHSD) enzymes exhibit a regulating action upon cortisol metabolism before access to its receptors. Two types of isoenzymes have been described, type 2 being the most anciently known. Type 2 11beta-OHSD, which changes cortisol into cortisone, is a unidirectional dehydrogenase mainly located in kidney, that protects mineralocorticoid receptors from illicit activation by glucocorticoids. Mutations of the gene coding for this enzyme has been demonstrated in apparent mineralocorticoid excess, which induces hypertension and hypokalemia with low renin and aldosterone levels. Polymorphisms of this gene could modulate essential hypertension and also be responsible for certain forms of acquired apparent mineralocorticoid excess especially after liquorice intoxication, in hypothyroidism, Cushing syndrome, and chronic renal insufficiency. Type 1 11beta-OHSD, which changes cortisone into cortisol, is a reductase, mainly located in liver and adipose tissue. Functional defects of this enzyme have been shown in polycystic ovaries and cortisone reductase deficiency. By contrast, metabolic syndrome, corticoid-induced osteoporosis, and glaucoma are linked to a local over-activity of this enzyme. The understanding of action mechanisms of these two enzymes currently leads to 11beta-OHSD inhibitors development, therefore opening new therapeutic strategies, especially in metabolic syndrome.

Effects of non-steroid immunosuppressive drugs on insulin secretion in transplantation.

Post-transplantation diabetes (PTD) is a serious complication in organ transplantation: not only does it increase the risk of graft dysfunction; it also increases cardiovascular morbidity and mortality. PTD incidence is correlated with age, non-Caucasian ethnic background, a family history of diabetes, excess weight, hepatitis C infection and steroid boluses for potential rejection. Different mechanisms might explain post-transplantation glucose metabolism disorders: ischemia-reperfusion disorders, whether renal, hepatic or cardiac, are responsible for insulin-resistance, which is increased by post-transplantation steroids; the detrimental effect of non-steroid immunosuppressive drugs on insulin-secretion could also be involved, especially with calcineurin inhibitors. In vivo and in vitro studies have shown that tacrolimus has inhibitory effects on insulin-secretion, while these effects are less obvious for cyclosporin, and were mainly demonstrated in vitro. Mycophenolate has no overt effect on insulin-secretion. Sirolimus and everolimus, two mTOR inhibitors, have shown controversial results in this realm. The effects of sirolimus (most often studied mTOR inhibitor) appear to depend on serum levels, cell type (ss cell or cell line), species (human or animal) and also environmental nutrients. At therapeutic concentrations, a stimulatory effect on insulin secretion was observed on human beta cells. This might explain the success of islet cell transplantation with the Edmonton protocol. Finally, steroids are mainly detrimental because they accentuate insulin resistance whereas anticalcineurins, in particular tacrolimus, lower insulin synthesis.

Contribution of genetic analysis in screening for MEN1 among patients with sporadic disease and one or more typical manifestation.

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant hereditary syndrome (OMIM 131100) due to MEN1 gene mutations, predisposing to the development of hyperplasic and tumoral lesions of neuroendocrine tissues. Since the identification of the gene in 1997, more than 400 different mutations of MEN1 have been registered. Genotypic analysis of MEN1 remains fastidious and must be reserved to targeted situations. If the lesions appear in a familial assessed context, there is a strong argument to search for MEN1 mutation. This is not the case in a sporadic context. With experience acquired in our laboratory, we evaluated the frequency of MEN1 mutations in patients with sporadic presentations. Our aim was to better define criteria for MEN1 genotypic analysis. One hundred and twenty four blood samples from unrelated patients, who gave their written informed consent, were analyzed. These patients exhibited 1 to 4 manifestations of MEN1 without any familial context. After DNA extraction, the analysis was undertaken by PCR-sequencing of all the MEN1 coding exons and exon/intron boundaries or by PCR of the pre-screened fragments alone, a technique made possible by indirect screening mutation methods. Mutations were identified by comparing the sequences to the reference MEN1 sequence available from GENBANK (U93237.1). Mutations were identified in 19 patients, with variable prevalence according to clinical manifestations: 100% for patients with 4 manifestations, 45.5% for patients with 3 manifestations, 19% for patients with 2 manifestations and 2% for patients with only one manifestation. Mutations were: 11 point variations (58%), including 2 splicing sites and 8 frameshift mutations (42%) including 5 deletions, 2 insertions and 1 insertion/deletion; one mutation was identified twice. We showed a relationship between clinical presentation and MEN1 mutation identification, especially with the number of clinical manifestations but also with the type of manifestation. Pancreatic manifestations were significantly linked with probability of mutation. In a sporadic context with at least two established manifestations of MEN1, the overall probability of identifying a mutation was 26%, warranting MEN1 genotypic analysis.

Management strategies for brittle diabetes.

Type 1 diabetes is an intrinsically unstable condition. However, the term "brittle diabetes" is reserved for those cases in which the instability, whatever its cause, results in disruption of life and often recurrent and/or prolonged hospitalization. It affects 3/1000 insulin-dependent diabetic patients, mainly young women. Its prognosis is poor with lower quality of life scores, more microvascular and pregnancy complications and shortened life expectancy. Three forms have been described: recurrent diabetic ketoacidosis, predominant hypoglycemic forms and mixed instability. Main causes of brittleness include malabsorption, certain drugs (alcohol, antipsychotics), defective insulin absorption or degradation, defect of hyperglycemic hormones especially glucocorticoid and glucagon, and above all delayed gastric emptying as a result of autonomic neuropathy. Psychosocial factors are very important and factitious brittleness may lead to a self-perpetuating condition. The assessment of brittle diabetes requires quantification of the variability of blood glucose levels. To quantify instability, measures which have been developed, include Mean Amplitude of the largest Glycemic Excursions (MAGE), Mean Of Daily Differences (MODD), Lability Index (LI), Low Blood Glucose Index (LBGI), Clarke's score, Hyposcore, and continuous blood glucose monitoring. Once psychogenic problems have been excluded, therapeutic strategies require firstly, the treatment of underlying organic causes of the brittleness whenever possible and secondly optimising standard insulin therapy using analogues, multiple injections and consideration of Continuous Subcutaneous Insulin Infusion. Alternative approaches may still be needed for the most severely affected patients. Isolated islet transplantation (IIT), which restores glucose sensing, should be considered in cases of hypoglycaemic unawareness and/or lability especially if the body mass index is < 25, but with current immunosuppressive protocols patients must have normal renal function and preferably no plans for pregnancy. Implantable pumps have advantages for patients who either weigh more than 80 kgs or have abnormalities of kidney or liver function or are highly sensitised.