PSUN138 Demonstration of Progressive Beta-Cell Failure in Familial Partial Lipodystrophy

Abstract

Abstract Background Familial Partial Lipodystrophy Type 2 (FPLD2) is an autosomal dominant disorder caused by inherited mutations on the LMNA gene, typically on exon 8 and 11. Insulin resistance and diabetes mellitus are common clinical manifestations in patients with partial lipodystrophy. Despite aggressive treatment aiming reduction in insulin resistance, patients usually require insulin treatment, highlighting the presence of insulin secretion defects. The sequence of events to develop metabolic derangement is not well studied. This study aims to compare the metabolic changes and insulin secretion in two generations of patients with FPLD2. Methods In a longitudinal study, we are studying the metabolic and morphometric changes in younger patients carrying the mutation who have not fully expressed the phenotype and comparing their findings to their affected older relatives. In the first year of the study, six affected young patients (age: 17±4 years, 4F/2M) and four affected older relatives (age: 46±7 years, all-female) have completed a 5-hour OGTT with 75g of glucose to determine the metabolic parameters at 30-minute intervals as well as the area under the curve (AUC) for these parameters. Results Patients in the younger group did not have a clinical diagnosis of diabetes (mean HbA1c of 5.3±0.3%), while all patients in the older generation had the diagnosis of diabetes mellitus with higher HbA1c (7.9±3.1%, p=0.05). Younger patients showed a lower AUC for glucose (28703±12037 mg/dL/min), triglycerides (38820±15305 mg/dL/min, p<0.05)) and free fatty acids (FFA) (78±29mmol/L/min) compared to older affected patients (glucose AUC: 67563±39089 mg/dL/min; triglycerides AUC: 96461±39989 mg/dL/min; FFA AUC: 159±125 mmol/L/min). However, insulin and C-peptide AUC were higher in the younger group compared to the older generation (insulin AUC: 60664±66802 vs. 29331±23341 mcU/mL/min; C-peptide AUC: 3466±1646 vs. 2548±1391 mg/L/min). The change in C-Peptide in the first 30 min post glucose was significantly higher in the younger group compared to the older group (12±1.8 vs. 5±4 mg/L; p<0.05). Insulin secretion during the first 30 min of the test was numerically higher in the younger group versus the older group (213±90 vs. 90±115 mcU/mL). Conclusion Our data (albeit limited) show that the clinical manifestation of diabetes mellitus in older patients with FPLD2 is associated with impairments in insulin secretion, therefore highlighting the importance of beta-cell failure in the development of diabetes mellitus in this population. These data draw attention to the need for further investigation of the pancreatic endocrine dysfunction to treat and better understand diabetes mellitus in this population. Strategies to address just insulin resistance may not be sufficient to prevent the development of diabetes in the long run. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.