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Camille Sollier, Emilie Capel, Caroline Aguilhon, Vasily Smirnov, Martine Auclair, Claire Douillard, Miriam Ladsous, Sabine Defoort-Dhellemmes, Jennifer Gorwood, Laura Braud, Roberto Motterlini, Camille Vatier, Olivier Lascols, Eric Renard, Corinne Vigouroux, and Isabelle Jéru

Objective

The term Multiple Symmetric Lipomatosis (MSL) describes a heterogeneous group of rare monogenic disorders and multifactorial conditions, characterized by upper-body adipose masses. Biallelic variants in LIPE encoding hormone-sensitive lipase (HSL), a key lipolytic enzyme, were implicated in three families worldwide. We aimed to further delineate LIPE-related clinical features and pathophysiological determinants.

Methods

A gene panel was used to identify pathogenic variants. The disease features were reviewed at the French lipodystrophy reference center. The immunohistological, ultrastructural, and protein expression characteristics of lipomatous tissue were determined in surgical samples from one patient. The functional impact of variants was investigated by developing a model of adipose stem cells (ASCs) isolated from lipomatous tissue.

Results

We identified new biallelic LIPE null variants in three unrelated patients referred for MSL and/or partial lipodystrophy. The hallmarks of the disease, appearing in adulthood, included lower-limb lipoatrophy, upper-body and abdominal pseudo-lipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Ophthalmological investigations revealed numerous auto-fluorescent drusen-like retinal deposits in all patients. Lipomatous tissue and patient ASCs showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. LIPE-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction.

Conslusions

Biallelic LIPE null variants result in a multisystemic disease requiring multidisciplinary care. Loss of HSL expression impairs adipocyte differentiation, consistent with the lipodystrophy/MSL phenotype and associated metabolic complications. Detailed ophthalmological examination could reveal retinal damage, further pointing to the nervous tissue as an important disease target.

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Blandine Tramunt, Sarra Smati, Sandrine Coudol, Matthieu Wargny, Matthieu Pichelin, Béatrice Guyomarch, Abdallah Al-Salameh, Coralie Amadou, Sara Barraud, Édith Bigot, Lyse Bordier, Sophie Borot, Muriel Bourgeon, Olivier Bourron, Sybil Charriere, Nicolas Chevalier, Emmanuel Cosson, Bruno Fève, Anna Flaus-Furmaniuk, Pierre Fontaine, Amandine Galioot, Céline Gonfroy-Leymarie, Bruno Guerci, Sandrine Lablanche, Jean-Daniel Lalau, Etienne Larger, Adele Lasbleiz, Bruno Laviolle, Michel Marre, Marion Munch, Louis Potier, Gaëtan Prévost, Eric Renard, Yves Reznik, Dominique Seret-begue, Paul Sibilia, Philippe Thuillier, Bruno Vergès, Jean-Francois Gautier, Samy Hadjadj, Bertrand Cariou, Franck Mauvais-Jarvis, and Pierre Gourdy

Objective:

Male sex is a determinant of severe coronavirus disease-2019 (COVID-19). We aimed to characterize sex differences in severe outcomes in adults with diabetes hospitalized for COVID-19.

Methods:

We performed a sex-stratified analysis of clinical and biological features and outcomes (i.e. invasive mechanical ventilation [IMV], death, intensive care unit [ICU] admission and home discharge at day 7 [D7] or day 28 [D28]) in 2,380 patients with diabetes hospitalized for COVID-19 and included in the nationwide CORONADO observational study (NCT04324736).

Results:

The study population was predominantly male (63.5%). After multiple adjustments, female sex was negatively associated with the primary outcome (IMV and/or death, OR 0.66 [0.49-0.88]), death (OR 0.49 [0.30-0.79]) and ICU admission (OR 0.57 [0.43-0.77]) at D7, but only with ICU admission (OR 0.58 [0.43-0.77]) at D28. Older age and a history of microvascular complications were predictors of death at D28 in both sexes, while chronic obstructive pulmonary disease (COPD) was predictive of death in women only. At admission, CRP, AST and eGFR predicted death in both sexes. Lymphocytopenia was an independent predictor of death in women only, while thrombocytopenia and elevated plasma glucose concentration were predictors of death in men only.

Conclusions:

In patients with diabetes admitted for COVID-19, female sex was associated with lower incidence of early severe outcomes, but did not influence the overall in-hospital mortality, suggesting that diabetes mitigates the female protection from COVID-19 severity. Sex-associated biological determinants may be useful to optimize COVID-19 prevention and management in women and men.