High Frequency of Glucose Intolerance in Lean Patients with Noonan and Noonan-like Syndromes Links RAS/MAPK Pathway and Metabolism

Presentation Number: MON 597
Date of Presentation: April 3rd, 2017

Alexsandra C Malaquias*1, Renata Maria Noronha2, Michelle B Moraes3, Mariana F A Funari4, Alexandre C Pereira5, Sandra MF Villares6, Debora R Bertola7 and Alexander A L Jorge3
1Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo, Sao Paulo, Brazil, 2Faculdade de Medicina da Universidade de Sao Paulo (FMUSP), Sao Paulo, Brazil, 3Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil, 4Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo - SP, Brazil, 5Instituto do Coraçao (InCor) da FMUSP, Sao Paulo, Brazil, 6Hospital das Clinicas da FMUSP, Sao Paulo, Brazil, 7Instituto da Crianca da Faculdade de Medicina da USP, Sao Paulo, Brazil

Abstract

Introduction: Noonan syndrome (NS) and Noonan-like syndromes (NLS) are autosomal dominant disorders caused by heterozygous mutations in genes of the RAS/MAPK pathway. Noonan syndrome related proteins, such as SHP2, may regulate insulin signaling and could have an influence on metabolism and control of energy storage. It is of great interest to understand the glucose metabolism in patients with NS and NLS. Objectives: To estimate the insulin sensitivity, using plasma glucose and insulin responses derived from the OGTT, in NS and NLS patients. Subjects and Methods: We selected 53 patients (31 females; from 14.5 to 61.2 years) clinically diagnosed with NS/NLS, 40 of them harboring mutation in RAS/MAPK-related genes (29 PTPN11, 4 BRAF, 3 SOS1, 2 SOS2, 1 SHOC2 and 1 LZTR1) to undergo a standard 75g OGTT. Demographic parameters for age, height, weight, and BMI were expressed as SDS for age and sex. To estimate insulin sensitivity, we used indexes from fasting- or OGTT-derived measurements. Results: Height-SDS was -2.5 ± 1.3 and BMI-SDS was -0.5 ± 1.4 in all patients. Fasting glucose levels were normal in patients with NS/NLS. In contrast, 4 patients disclosed fasting insulin levels > 15 µUI/mL; 5 showed Insulin Sensitivity Index (ISI)-composite < 2.5 and 2 showed HOMA-IR > 2.71. Nine patients (17%) had impaired glucose tolerance (IGT), 6 with previously identified pathogenic mutation (4 PTPN11, 1 LZTR1 and 1 SHOC2), and would have been missed if only fasting glucose level, ISI and/or HOMA-IR had been considered alone as diagnostic criteria. IGT and normal glucose tolerance (NGT) patients were similar in relation to age, gender, BMI-SDS, fasting glucose and insulin levels, HOMA-IR, ISI-composite and HOMAβ%. The glucose area under the curve (AUCglu) was higher in IGT than NGT patients (1013 ± 154 vs 791 ± 154, p<0,001) whereas the ratio insulin AUC (AUCins) to AUCglu was lower in IGT patients (67 ± 45 vs 40 ± 17, p=0,047). Conclusion: It is worth noting that impaired glucose tolerance was diagnosed in 17% of patients with NS or NLS despite BMI SDS within the normal range along with fasting glucose and insulin levels. Since RAS/MAPK-related proteins seem to have a role in insulin signaling through PI3K/AKT pathway, patients with NS or NLS should be considered at risk for developing insulin resistance and its complications.

 

Nothing to Disclose: ACM, RMN, MBM, MFAF, ACP, SMV, DRB, AALJ