Impact of recurrent hypoglycemia on brain glucose transport kinetics in type 1 diabetes

CONTEXT: Impaired awareness of hypoglycemia (IAH) significantly impacts efforts to maintain optimal glycemia. IAH occurs when recurrent episodes of hypoglycemia (HG) occur within a short period of time, but the mechanisms are unknown. Upregulation of glucose transport may contribute to the development of IAH. OBJECTIVE: To determine if brain glucose transport is upregulated in response to recurrent HG in people with type 1 diabetes (T1D) and normal awareness of hypoglycemia. DESIGN: Forty-five subjects enrolled and 30 completed the entire 3-day protocol. Participants underwent magnetic resonance spectroscopy scans at 3 tesla during which they were clamped at 150, 225 or 300 mg/dL before and after exposure to three 2-hr HG (target = 50mg/dL) clamps over 2 days between December 2020 and June 2023. The primary metabolite of interest was glucose. Brain glucose transport kinetics were measured in the hypothalamus (HTL) and prefrontal cortex (PFC) during hyperglycemic clamps using reversible symmetric Michaelis-Menten model. SETTING: Academic medical center. PATIENTS OR OTHER PARTICIPANTS: Participants were recruited from a clinical registry. Inclusion criteria were diagnosis of T1D, 18-65 years, hemoglobin A1C <8.5%, and diabetes duration of 2-25 years. Exclusion criteria included IAH on the Clarke and Gold questionnaires. INTERVENTIONS: Three 2-hr HG clamps over 2 days. MAIN OUTCOME MEASURE: The ratio of maximal transport rate to cerebral metabolic rate of glucose (Vmaxt/CMRglc). RESULTS: Brain glucose transport kinetics measured during hyperglycemic clamps were not different before vs. after exposure to recurrent HG clamps. CONCLUSIONS: Short-term exposure to recurrent HG does not upregulate glucose transport kinetics in the setting of T1D.