Henrik Hill: Investigations of hypoglycemic events and the role of GABA in type 1 diabetes

Abstract

Introduction: Hypoglycemia in type 1 diabetes (T1D) ranges from mild to life-threatening events, yet most studies of hypoglycemia frequency rely on self-reported or aggregated data. Residual endogenous insulin production is associated to fewer severe hypoglycemic events, highlighting the potential benefit of preserving or restoring insulin production. For this purpose, gamma-aminobutyric acid (GABA) has emerged from experimental studies as a potential therapeutic drug candidate.

Aim: This thesis aimed to investigate the real-world frequency of hypoglycemia in children and adolescents with T1D, and to evaluate GABA’s therapeutic potential in a clinical trial.

Methods: Five studies were included. Endogenous GABA, C-peptide, counter-regulatory hormones and cytokine levels were analyzed in plasma. A controlled-release oral formulation of GABA (Remygen®) was assessed in a randomized controlled Phase I/II clinical trial in individuals with long-standing T1D (n=35) for safety, effect on endogenous insulin production and hypoglycemic counter-regulation.

The real-world frequency of hypoglycemia and its relationship to overall metabolic control and age was evaluated using retrospective continuous glucose monitoring (CGM)-data and clinical records. More than 50,000 hypoglycemic events were analyzed. Additionally, a single-metric scoring model for CGM-data evaluation was developed based on n=82,114 days of CGM-data by assessing three dimensions of glucose control. The models validity was evaluated against clinical treatment targets and interpretations of a clinical expert board (CEB). 

Results: GABA levels did not differ between individuals with T1D and healthy controls, but correlated with anti-GAD and cytokines. GABA treatment showed no improvements in endogenous insulin production or hypoglycemic counter-regulation, but side-effects were commonly observed. In the retrospective studies on CGM-data, mild hypoglycemic events (<3.9 mmol/L) were common. On average occurring on a near daily basis, regardless of age or metabolic control. However, no increased risk of severe- or serious (<3.0 mmol/L) hypoglycemia was observed in children achieving HbA1c ≤48 mmol/mol. The developed CGM scoring model correlated well with CGM-metrics and CEB interpretations.

Conclusions: Despite technological advancements, hypoglycemia remains a persistent challenge in T1D. GABA failed to regain beta-cell function, underscoring the need for alternative therapies in this aspect. Meanwhile, models for enhanced CGM analyses may aid in optimizing glucose management.