Hypothalamic Glucose Transport in Humans During Experimentally Induced Hypoglycemia-Associated Autonomic Failure.

Context: Upregulated brain glucose transport in response to recurrent hypoglycemia may contribute to the development of hypoglycemia-associated autonomic failure (HAAF) and impaired awareness of hypoglycemia. Whether recurrent hypoglycemia alters glucose transport in the hypothalamus is unknown. Objective: To test the hypothesis that hypothalamic glucose transport will increase in healthy volunteers preconditioned with recurrent hypoglycemia to induce HAAF. Setting: University medical center. Design and Participants: Thirteen healthy subjects underwent paired euglycemic and hypoglycemic preconditioning studies separated by at least 1 month. Following preconditioning, hypothalamic glucose transport was measured by magnetic resonance spectroscopy (MRS) in the afternoon on day 2 of each preconditioning protocol. Outcome Measure: The ratio of maximal transport rate to cerebral metabolic rate of glucose (Tmax/CMRglc), obtained from MRS-measured glucose in the hypothalamus as a function of plasma glucose. Results: HAAF was successfully induced based on lower epinephrine, glucagon, and cortisol during the third vs first hypoglycemic preconditioning clamp (P ≤ 0.01). Hypothalamic glucose transport was not different following recurrent euglycemia vs hypoglycemia (Tmax/CMRglc 1.62 ± 0.09 after euglycemia preconditioning and 1.75 ± 0.14 after hypoglycemia preconditioning; P was not significant). Hypothalamic glucose concentrations measured by MRS were not different following the two preconditioning protocols. Conclusions: Glucose transport kinetics in the hypothalamus of healthy humans with experimentally induced HAAF were not different from those measured without HAAF. Future studies of patients with diabetes and impaired awareness of hypoglycemia will be necessary to determine if the existence of the diabetes state is required for this adaptation to hypoglycemia to occur.

Measurement of Hypothalamic Glucose Under Euglycemia and Hyperglycemia by MRI at 3T.

PURPOSE: To evaluate the feasibility of using a clinical magnetic resonance (MR) system and MR spectroscopy (MRS) to measure glucose concentration changes in the human hypothalamus, a structure central to whole-body glucose regulation. SUBJECTS AND METHODS: A time series of MR spectra (semi-LASER, TE = 28 msec), localized to the bilateral hypothalamus (∼1.6 ml) were obtained at 3T in six healthy subjects at baseline (euglycemia) and during a ∼65-70-minute-long hyperglycemic clamp in 11-minute blocks with interleaved T1 FLASH images to retrospectively assess head motion, and track changes in cerebrospinal fluid (CSF) partial volume. The LCModel was used to quantify the sum of glucose and taurine concentrations, [Glc+Tau], along with their associated Cramér-Rao lower bounds (CRLB). RESULTS: Spectral quality allowed quantification of [Glc+Tau] (sum reported due to high negative correlation between these metabolites) with CRLB <25% in 35/36 timepoints during hyperglycemia. Increased [Glc+Tau] was observed with hyperglycemia in all subjects, but most reliably in those with plasma glucose targets ≥300 mg/dl. For these subjects, [Glc+Tau]baseline (n = 4) was 1.5 (±0.3, SD) mM, and increased to 4.5 (±1.1) mM (n = 16) for timepoints acquired ≥25 minutes after onset of the clamp, with 15/16 timepoints having no overlap of 95% confidence intervals (CIs) between baseline and hyperglycemia. Preliminary analysis revealed a linear (1:5) relationship between hypothalamus-blood glucose concentrations. CONCLUSION: It is feasible to measure glucose concentration changes in the human hypothalamus using a standard 3T scanner and a short-echo semi-LASER sequence by utilizing retrospective motion tracking, CSF correction, predetermined quality acceptance criteria, and hyperglycemic blood glucose levels ≥300 mg/dl. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:681-691.