Lipoatrophic diabetes in Familial Partial Lipodystrophy type 2: from insulin resistance to diabetes - 15/11/22

Doi : 10.1016/j.diabet.2022.101409

Guillaume Treiber ^1,², Alice Guilleux ³, Kevin Huynh ⁴, Oriane Bonfanti ¹, Ania Flaus–Furmaniuk ⁵, David Couret ^2,⁶, Natalie Mellet ⁴, Céline Bernard ¹, Nathalie Le-Moullec ¹, Berenice Doray ⁷, Isabelle Jéru ⁸, Jean-Christophe Maiza ¹, Bhoopendrasing Domun ¹, Muriel Cogne ¹, Olivier Meilhac ², Corinne Vigouroux ⁹, Peter J Meikle ^4,^10,¹¹, Estelle Nobécourt ^1,^2,^3,^⁎
¹ Department of Endocrinology, Diabetes and Nutrition, GHSR, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France
² University of La Réunion, INSERM, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Plateforme CYROI, Saint-Denis de, La Réunion, France
³ Centre d'Investigation Clinique – Epidémiologie Clinique (CIC-EC) U1410 INSERM, Centre Hospitalo-Universitaire de la Réunion, La Réunion, France
⁴ Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
⁵ Department of Endocrinology, Diabetes and Nutrition, Felix-Guyon, Centre Hospitalo-Universitaire de la Réunion, Saint-Denis, La Réunion, France
⁶ Neurocritical Care Unit, Centre Hospitalo-Universitaire de la Réunion, University of La Réunion, BP 350, Saint Pierre, 97448, la Réunion, France
⁷ Genetic Department, Felix-Guyon, Centre Hospitalo-Universitaire de la Réunion, Saint-Denis, La Réunion, France
⁸ Sorbonne Université, Inserm UMR S938, Saint-Antoine Research Centre, Institute of Cardiometabolism and Nutrition, AP-HP, Pitié-Salpêtrière Hospital, Department of Medical Genetics, DMU BioGeM, Paris, France
⁹ Sorbonne Université, Inserm UMR S938, Saint-Antoine Research Centre, Institute of Cardiometabolism and Nutrition, AP-HP, Saint-Antoine Hospital, Genetics, Molecular Biology and Endocrinology Departments, National Reference Centre for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Paris, France
¹⁰ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia
¹¹ Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Bundoora, Victoria, Australia

^⁎Corresponding author: Pr Nobécourt Estelle, Hospital Group South Reunion, ReunionHospital Group South ReunionReunion

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HIGHLIGHT

•	OGTT should be performed in all subjects with FPLD2 with normal fasting glucose.
•	OGGT allows to diagnose insulin resistance early in the course of the disease.
•	Glucose tolerance abnormalities are more frequent in women than men with FPLD2.
•	Clinical lipodystrophy is lacking in 75% of patients with FPLD2 without diabetes.
•	Adiponectin levels are low in all subjects bearing FPLD2 even in diabetes absence.

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ABSTRACT

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.

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Keywords : Diabetes, Dunnigan, Insulin resistance, Laminopathy, Lipodystrophy