Familial partial lipodystrophy type 2 and obesity, two adipose tissue pathologies with different inflammatory profiles.

INTRODUCTION: The transition to metabolically unhealthy obesity (MUO) is driven by the limited expandability of adipose tissue (AT). Familial Partial Lipodystrophy type 2 (FPLD2) is an alternative model for AT dysfunction that is suitable for comparison with obesity. While MUO is associated with low-grade systemic inflammation, studies of inflammation in FPLD2 have yielded inconsistent results. Consequently, comparison of inflammation markers between FPLD2 and obesity is of great interest to better understand the pathophysiological defects of FPLD2. OBJECTIVE: To compare the levels of inflammatory biomarkers between a population of patients with FPLD2 due to the same 'Reunionese' LMNA variant and a population of patients with obesity (OB group). METHODS: Adiponectin, leptin, IL-6, TNF-α and MCP-1 plasma levels were measured by enzyme-linked immuno assays for 60 subjects with FPLD2 and for 60 subjects with obesity. The populations were closely matched for age, sex, and diabetic status. RESULTS: Metabolic outcomes were similar between the two populations. Adiponectinemia and leptinemia were lower in the FPLD2 group than in the OB group (p < 0.01 for both), while MCP-1 levels were higher in the FPLD2 than in the OB group (p < 0.01). Levels of other inflammatory markers were not significantly different. CONCLUSIONS: Insulin-resistant patients with FPLD2 and obesity share common complications related to AT dysfunction. Inflammatory biomarker analyses demonstrated that MCP-1 levels and adiponectin levels differ between patients with FPLD2 and patients with obesity. These two AT pathologies thus appear to have different inflammatory profiles.

Dengue clinical features and harbingers of severity in the diabetic patient: A retrospective cohort study on Reunion island, 2019.

AIM: Diabetes mellitus is associated with both the risks of severe dengue and dengue-related deaths, however the factors characterizing dengue in the diabetic patient are ill-recognized. The objective of this hospital-based cohort study was to identify the factors characterizing dengue and those able to early identify dengue severity in the diabetic patient. METHODS: We retrospectively analysed demographic, clinical and biological parameters at admission in the cohort of patients who consulted at the university hospital between January and June 2019 with confirmed dengue. Bivariate and multivariate analyses were conducted. RESULTS: Of 936 patients, 184 patients (20%) were diabetic. One hundred and eighty-eight patients (20%) developed severe dengue according to the WHO 2009 definition. Diabetic patients were older and had more comorbidities than non-diabetics. In an age-adjusted logistic regression model, loss of appetite, altered mental status, high neutrophil to platelet ratios (>14.7), low haematocrit (≤ 38%), upper-range serum creatinine (>100 µmol/l) and high urea to creatinine ratio (>50) were indicative of dengue in the diabetic patient. A modified Poisson regression model identified four key independent harbingers of severe dengue in the diabetic patient: presence of diabetes complications, non-severe bleeding, altered mental status and cough. Among diabetes complications, diabetic retinopathy and neuropathy, but not diabetic nephropathy nor diabetic foot, were associated with severe dengue. CONCLUSION: At hospital first presentation, dengue in the diabetic patient is characterized by deteriorations in appetite, mental and renal functioning, while severe dengue can be early identified by presence of diabetes complications, dengue-related non-severe haemorrhages, cough, and dengue-related encephalopathy.

The clinical and therapeutic profiles of prolactinomas associated with germline pathogenic variants in the aryl hydrocarbon receptor interacting protein (AIP) gene.

Introduction: Prolactinomas are the most frequent type of pituitary adenoma encountered in clinical practice. Dopamine agonists (DA) like cabergoline typically provide sign/ symptom control, normalize prolactin levels and decrease tumor size in most patients. DA-resistant prolactinomas are infrequent and can occur in association with some genetic causes like MEN1 and pathogenic germline variants in the AIP gene (AIPvar). Methods: We compared the clinical, radiological, and therapeutic characteristics of AIPvar-related prolactinomas (n=13) with unselected hospital-treated prolactinomas ("unselected", n=41) and genetically-negative, DA-resistant prolactinomas (DA-resistant, n=39). Results: AIPvar-related prolactinomas occurred at a significantly younger age than the unselected or DA-resistant prolactinomas (p<0.01). Males were more common in the AIPvar (75.0%) and DA- resistant (49.7%) versus unselected prolactinomas (9.8%; p<0.001). AIPvar prolactinomas exhibited significantly more frequent invasion than the other groups (p<0.001) and exhibited a trend to larger tumor diameter. The DA-resistant group had significantly higher prolactin levels at diagnosis than the AIPvar group (p<0.001). Maximum DA doses were significantly higher in the AIPvar and DA-resistant groups versus unselected. DA-induced macroadenoma shrinkage (>50%) occurred in 58.3% in the AIPvar group versus 4.2% in the DA-resistant group (p<0.01). Surgery was more frequent in the AIPvar and DA- resistant groups (43.8% and 61.5%, respectively) versus unselected (19.5%: p<0.01). Radiotherapy was used only in AIPvar (18.8%) and DA-resistant (25.6%) groups. Discussion: AIPvar confer an aggressive phenotype in prolactinomas, with invasive tumors occurring at a younger age. These characteristics can help differentiate rare AIPvar related prolactinomas from DA-resistant, genetically-negative tumors.

Lipoatrophic diabetes in familial partial lipodystrophy type 2: From insulin resistance to diabetes.

AIM: Subjects with Familial Partial Lipodystrophy type 2 (FPLD2) are at high risk to develop diabetes. To better understand the natural history and variability of this disease, we studied glucose tolerance, insulin response to an oral glucose load, and metabolic markers in the largest cohort to date of subjects with FPLD2 due to the same LMNA variant. METHODS: A total of 102 patients aged > 18 years, with FPLD2 due to the LMNA 'Reunionese' variant p.(Thr655Asnfs*49) and 22 unaffected adult relatives with normal glucose tolerance (NGT) were enrolled. Oral Glucose Tolerance Tests (OGTT) with calculation of derived insulin sensitivity and secretion markers, and measurements of HbA1c, C-reactive protein, leptin, adiponectin and lipid profile were performed. RESULTS: In patients with FPLD2: 65% had either diabetes (41%) or prediabetes (24%) despite their young age (median: 39.5 years IQR 29.0-50.8) and close-to-normal BMI (median: 25.5 kg/m2 IQR 23.1-29.4). Post-load OGTT values revealed insulin resistance and increased insulin secretion in patients with FPLD2 and NGT, whereas patients with diabetes were characterized by decreased insulin secretion. Impaired glucose tolerance with normal fasting glucose was present in 86% of patients with prediabetes. Adiponectin levels were decreased in all subjects with FPLD2 and correlated with insulin sensitivity markers. CONCLUSIONS: OGTT reveals early alterations of glucose and insulin metabolism in patients with FPLD2, and should be systematically performed before excluding a diagnosis of prediabetes or diabetes to adapt medical care. Decreased adiponectin is an early marker of the disease. Adiponectin replacement therapy warrants further study in FPLD2.

Usefulness of Home Screening for Promoting Awareness of Impaired Glycemic Status and Utilization of Primary Care in a Low Socio-Economic Setting: A Follow-Up Study in Reunion Island.

BACKGROUND: Low socio-economic settings are characterized by high prevalence of diabetes and difficulty in accessing healthcare. In these contexts, proximity health services could improve healthcare access for diabetes prevention. Our primary objective was to evaluate the usefulness of home screening for promoting awareness of impaired glycemic status and utilization of primary care among adults aged 18-79 in a low socio-economic setting. METHODS: This follow-up study was conducted in 2015-2016 in Reunion Island, a French overseas department in the Indian Ocean. Enrollment and screening occurred on the same day at the home of participants (N=907). Impaired glycemic status was defined as [glycated hemoglobin (HbA1c) ≥5.7%] OR [fasting capillary blood glucose (FCBG) ≥1.10 g/L] OR [HbA1c=5.5-5.6% and FCBG=1.00-1.09 g/L]. Medical, socio-cultural, and socio-economic characteristics were collected via a face-to-face questionnaire. A one-month telephone follow-up survey was conducted to determine whether participants had consulted a general practitioner (GP) for confirmation of screening results. A multinomial polytomous logistic regression model was used to identify factors independently associated with non-use of GP consultation for confirmation of screening results and nonresponse to the telephone follow-up survey. RESULTS: Prevalence of glycemic abnormalities was 46.0% (95% CI = 42.7-49.2%). Among participants with impaired glycemic status (N=417), 77.7% (95% CI=73.7-81.7%) consulted a GP for confirmation of screening results, 12.5% (95% CI=9.3-15.6%) did not, and 9.8% failed to respond to the follow-up survey. Factors independently associated with non-use of GP consultation for confirmation of screening results were self-reported unwillingness to consult a GP (adjusted odds ratio [OR]: 4.86, 95% CI=1.70-13.84), usual GP consultation frequency of less than once a year (adjusted OR: 4.13, 95% CI=1.56-10.97), and age 18-39 years (adjusted OR: 3.09, 95% CI=1.46-6.57). CONCLUSION: Home screening for glycemic abnormalities is a useful proximity health service for diabetes prevention in low socio-economic settings. Further efforts, including health literacy interventions, are needed to increase utilization of primary care.

A recurrent familial partial lipodystrophy due to a monoallelic or biallelic LMNA founder variant highlights the multifaceted cardiac manifestations of metabolic laminopathies.

AIMS: LMNA-linked familial partial lipodystrophy type 2 (FPLD2) leads to insulin resistance-associated metabolic complications and cardiovascular diseases. We aimed to characterise the disease phenotype in a cohort of patients carrying an LMNA founder variant. METHODS: We collected clinical and biological data from patients carrying the monoallelic or biallelic LMNA p.(Thr655Asnfs*49) variant (n = 65 and 13, respectively) and 19 non-affected relative controls followed-up in Reunion Island Lipodystrophy Competence Centre, France. RESULTS: Two-thirds of patients with FPLD2 (n = 51) and one-third of controls (n = 6) displayed lipodystrophy and/or lean or android morphotype (P = 0.02). Although age and BMI were not statistically different between the two groups, the insulin resistance index (median HOMA-IR: 3.7 vs 1.5, P = 0.001), and the prevalence of diabetes, dyslipidaemia, and non-alcoholic fatty liver disease were much higher in patients with FPLD2 (51.3 vs 15.8%, 83.3 vs 42.1%, and 83.1 vs 33.3% (all P ≤ 0.01), respectively). Atherosclerosis tended to be more frequent in patients with FPLD2 (P = 0.07). Compared to heterozygous, homozygous patients displayed more severe lipoatrophy and metabolic alterations (lower BMI, fat mass, leptin and adiponectin, and higher triglycerides P ≤ 0.03) and tended to develop diabetes more frequently, and earlier (P = 0.09). Dilated cardiomyopathy and/or rhythm/conduction disturbances were the hallmark of the disease in homozygous patients, leading to death in four cases. CONCLUSIONS: The level of expression of the LMNA 'Reunionese' variant determines the severity of both lipoatrophy and metabolic complications. It also modulates the cardiac phenotype, from atherosclerosis to severe cardiomyopathy, highlighting the need for careful cardiac follow-up in affected patients.

Biological and radiological exploration and management of non-functioning pituitary adenoma.

Non-functioning pituitary adenoma may be totally asymptomatic and discovered "incidentally" during radiological examination for some other indication, or else induce tumoral signs with compression of the optic chiasm and pituitary dysfunction. Non-functioning adenomas are mainly gonadotroph, but may also be "silent". Treatment strategy depends on initial clinical, biological, ophthalmological and radiological findings. The present French Society of Endocrinology Consensus work-group sought to update the pitfalls associated with hormone assay and outline a hormonal exploration strategy for diagnosis and follow-up, without overlooking the particularities of silent adenoma. We also drew up basic rules for initial exploration and radiological follow-up of both operated and non-operated pituitary adenomas.

Genetic analysis in young patients with sporadic pituitary macroadenomas: besides AIP don't forget MEN1 genetic analysis.

CONTEXT: Germline mutations in the aryl hydrocarbon receptor interacting protein gene (AIP) have been identified in young patients (age ≤30 years old) with sporadic pituitary macroadenomas. Otherwise, there are few data concerning the prevalence of multiple endocrine neoplasia type 1 (MEN1) mutations in such a population. OBJECTIVE: We assessed the prevalence of both AIP and MEN1 genetic abnormalities (mutations and large gene deletions) in young patients (age ≤30 years old) diagnosed with sporadic and isolated macroadenoma, without hypercalcemia and/or MEN1-associated lesions. DESIGN: The entire coding sequences of AIP and MEN1 were screened for mutations. In cases of negative sequencing screening, multiplex ligation-dependent probe amplification was performed for the detection of large genetic deletions. PATIENTS AND SETTINGS: One hundred and seventy-four patients from endocrinology departments of 15 French University Hospital Centers were eligible for this study. RESULTS: Twenty-one out of 174 (12%) patients had AIP (n=15, 8.6%) or MEN1 (n=6, 3.4%) mutations. In pediatric patients (age ≤18 years old), AIP/MEN1 mutation frequency reached nearly 22% (n=10/46). AIPmut and MEN1mut were identified in 8/79 (10.1%) and 1/79 (1.2%) somatotropinoma patients respectively; they each accounted for 4/74 (5.4%) prolactinoma (PRL) patients with mutations. Half of those patients (n=3/6) with gigantism displayed mutations in AIP. Interestingly, 4/12 (33%) patients with non-secreting adenomas bore either AIP or MEN1 mutations, whereas none of the eight corticotroph adenomas or the single thyrotropinoma case had mutations. No large gene deletions were observed in sequencing-negative patients. CONCLUSION: Mutations in MEN1 can be of significance in young patients with sporadic isolated pituitary macroadenomas, particularly PRL, and together with AIP, we suggest genetic analysis of MEN1 in such a population.

Effectiveness and tolerability of 3-year lanreotide Autogel treatment in patients with acromegaly.

OBJECTIVE: During short-term treatment, monthly subcutaneous injections of lanreotide Autogel are effective in controlling GH/IGF-1 hypersecretion and are well tolerated in patients with acromegaly. This study reports the effectiveness and the tolerability of lanreotide Autogel for at least 3 years in acromegalic patients. PATIENTS: Fourteen patients (nine females, five males) were treated with titrated doses of lanreotide Autogel. DESIGN: This clinical study was an extension of a previous trial. After three fixed-dose lanreotide Autogel injections, treatment was adjusted according to mean GH and IGF-I levels. After 3 years of treatment, patients were receiving 120 (n=7), 90 (n=2) and 60 mg (n=4) monthly injections of lanreotide Autogel. MEASUREMENTS: Acromegalic symptoms, GH and IGF-1 concentrations were analysed at the end of lanreotide microparticle treatment, and after 4, 8, 12, 24, 30 and 36 months of lanreotide Autogel therapy. Tolerance and side-effects were monitored throughout the 3-year study. RESULTS Hormonal control (GH