P-426: Genetic insulin-resistant diabetes: a case report of a variant of uncertain significance (VUS) in the INSR gene
A Vervloet da Luz, G Adami, J G Rico, R R Biasi, A Riquetto, L Cudízio, L E CalliariAbstract
Introduction
Diabetes mellitus associated with genetic syndromes of insulin-resistance (IR) is a rare condition (prevalence <1:1,000,000). Usually, they are associated with poorly controlled hyperglycemia, acanthosis nigricans, and features of hyperandrogenism. The diagnosis should be suspected based on clinical history, physical examination, and metabolic profile, but it is usually delayed. Molecular testing allows diagnostic confirmation. The more frequently associated genes with IR are: INSR, AGPAT2, BSCL2, LMNA, PPARG, AKT2, PIK3R1, LMS1, and PCNT.
Objectives
To highlight the importance of considering genetic syndromes with insulin resistance as a possible diagnosis of diabetes mellitus in adolescents with type 2 diabetes
Methods
A 14-year-old obese female (Z-score +2,3) was initially diagnosed with type 2 diabetes at age 11, with a fasting glucose of 400 mg/dL, hypertriglyceridemia (>400 mg/dL), negative diabetes autoantibodies, and normal C-peptide levels. Treatment was initiated with metformin (2 g/day) and later progressed to insulin therapy (1 IU/kg/day), but glycemic control remained inadequate. On physical examination, we noted a predominant centripetal accumulation of adipose tissue in her face and trunk.
Results
A genetic study was performed, identifying a heterozygous variant of uncertain significance (VUS) in the INSR gene (p.Arg1128Cys). Treatment with a GLP-1 analog (liraglutide) was initiated, resulting in improvement in insulin resistance, weight loss (3.6kg in 4 months), reduction in the required daily insulin dose (0.5 UI/kg/day), and a reduction in HbA1c levels (11% to 7.6% in the same period).
Conclusions
Genetic syndromes should be considered in early-onset diabetes when the patient presents with particular clinical characteristics, such as notable insulin resistance. Molecular testing may enable earlier diagnosis and better clinical management.