Decreased BCAAs and Elevated Fatty Acids during Repeated Episodes of Hypoglycemia in Individuals with Type 1 Diabetes

Hypoglycemia is a major limiting factor in achieving recommended glycemic target for patients in insulin treatment and can indirectly lead to diabetic complications, morbidity and mortality. While counterregulatory hormonal responses have been studied extensively in patients with type 1 diabetes, a more comprehensive assessment of the metabolic responses has not been done previously. This post-hoc study explored potential responses of the metabolome to hypoglycemia. Twenty-one patients with type 1 diabetes were examined using a hypoglycemic clamp at day one, and 24 hours later, at day two. Blood samples were taken during normoglycemia (5.0-6.0 mmol/L) and hypoglycemia (2.0-2.5 mmol/L). Non-targeted plasma metabolomic analyses was conducted using two-dimensional gas chromatography/time-of-flight mass spectroscopy. Metabolites were analyzed by a linear mixed effect model, adjusting for age and sex. P-values were adjusted for multiple testing using the Benjamini-Hochberg method. A total of 79 metabolites were identified. At day one, two amino acids decreased in response to hypoglycemia, leucine (β±SE: -0.78±0.18, p = 0.004) and isoleucine (β±SE: -0.72±0.16, p = 0.002). At day two, five amino acids including all three branched-chained amino acids decreased: Leucine (β±SE: -0.62±0.13, p = 0.002), isoleucine (β±SE: -0.59±0.19, p = 0.026), valine (β±SE: -0.52±0.12, p=0.002), methionine (β±SE: -0.62±0.19, p = 0.026) and phenylalanine (β±SE: -0.65±0.20, p = 0.026). Two fatty acids were elevated, oleic acid (β±SE: 0.50±0.14, p = 0.016) and tetradecanoic acid (β±SE: 0.63±0.17, p = 0.013). No significant changes were observed between the two days. In conclusion, this study found that the metabolome alternates in response to insulin-induced hypoglycemia resulting in decrement of several amino acids and increment of two fatty acids, contributing to the knowledge of human physiology in individuals with type 1 diabetes. Disclosure R. She: None. N. Al-sari: None. A. Sejling: Employee; Self; Novo Nordisk A/S. I. Mattila: None. P. Henriksen: None. J. Pedersen: None. C. Legido-quigley: None. U. Pedersen-bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi-Aventis, Consultant; Self; Abbott, Speaker’s Bureau; Self; Novo Nordisk A/S.