A Novel Approach for Screening of Hypoglycemia-Associated Autonomic Failure Using c-FOS and Beclin-1: A Multicenter Study

Background Iatrogenic hypoglycemia constitutes a significant barrier to optimal glycemic control in type 1 diabetes mellitus (T1DM). Recurrent hypoglycemic leads to defective glucose counter-regulation and impaired awareness of hypoglycemia. These two conditions are the major characteristics of hypoglycemia-associated autonomic failure (HAAF). This study aimed to identify novel biomarkers for screening HAAF and examine clinical characteristics of hypoglycemia in patients with T1DM. Methods This cross-sectional, multicenter study was conducted at the Diabetes and Endocrinology Clinics (DECs) at the University of Sharjah Hospital (UHS), Al Qassimi Hospital, and Dubai Hospital (DH). A total of 75 T1DM patients aged 18–60 years, without comorbidities, were recruited. Participants were divided into three groups: no evidence of hypoglycemia (25.3%), hypoglycemia awareness (34.7%), and hypoglycemia unawareness (40%). A comprehensive assessment of hypoglycemia frequency, severity, and status was conducted using the Hypoglycemia-Awareness Questionnaire. Blood samples were analysed for gene expression levels of cFOS and Beclin-1 using ΔCt values (a higher ΔCt value indicates lower gene expression). Results Patients with hypoglycemia unawareness had significantly higher expression of Beclin-1 (ΔCt Mean ± SD: 1.5781 ± 2.2903) compared to the hypoglycemia awareness group (ΔCt Mean ± SD: 2.2903 ± 0.93280; p < 0.0001 ). Moreover, cFOS expression was significantly higher in patients with hypoglycemia awareness (ΔCt Mean ± SD: 14.7696 ± 1.9741) in compared to those with hypoglycemia unawareness (ΔCt Mean ± SD: 24.6290 ± 4.55669; p < 0.0001 ) and those at no evidence of hypoglycemia (ΔCt Mean ± SD: 28.1868 ± 3.12772; p < 0.0001 ). A significant association of impaired awareness of hypoglycemia was detected in those with older age (p = 0.032) , longer diabetes duration (p = 0.025) , lower HbA1c level (p = 0.006) , lower heart rate (p = 0.006) , lower triglyceride levels (p = 0.01) , and higher frequency of recurrent hypoglycemia. Conclusion This study identified cFOS and Beclin-1 as potential biomarkers for HAAF. Impaired awareness of hypoglycemia in T1DM is linked to distinct molecular and clinical characteristics.