Hypoglycemia-induced increases in thalamic cerebral blood flow are blunted in subjects with type 1 diabetes and hypoglycemia unawareness

Abstract

The thalamus has been found to be activated during the early phase of moderate hypoglycemia. Here, we tested the hypothesis that this region is less activated during hypoglycemia in subjects with type 1 diabetes (T1DM) and hypoglycemia unawareness relative to controls. Twelve controls (5 F/7 M, age 40 ± 14 years, body mass index 24.2 ± 2.7 kg/m(2)) and eleven patients (7 F/4 M, age 39 ± 13 years, body mass index 26.5 ± 4.4 kg/m(2)) with well-controlled T1DM (A1c 6.8 ± 0.4%) underwent a two-step hyperinsulinemic (2.0 mU/kg per minute) clamp. Cerebral blood flow (CBF) weighted images were acquired using arterial spin labeling to monitor cerebral activation in the midbrain regions. Blood glucose was first held at 95 mg/dL and then allowed to decrease to 50 mg/dL. The CBF image acquisition during euglycemia and hypoglycemia began within a few minutes of when the target blood glucose values were reached. Hypoglycemia unaware T1DM subjects displayed blunting of the physiologic CBF increase that occurs in the thalamus of healthy individuals during the early phase of moderate hypoglycemia. A positive correlation was observed between thalamic response and epinephrine response to hypoglycemia, suggesting that this region may be involved in the coordination of the counter regulatory response to hypoglycemia.

Figures

Figure 1

Diagram of the experimental protocol, highlighting the number and timing of the measurements of counter regulatory (CR) hormones along with the MRI measurements (details are in the text). Blood samples for CR measurements were drawn 5 minutes apart at baseline and 10 minutes apart during hypoglycemia. Other blood samples were drawn every 5 minutes during the entire duration of the study to monitor glucose levels (not indicated in the diagram). Measurements of cerebral blood flow (CBF) were performed within a few minutes of blood glucose reaching the target level. Scout, anatomy, and CBF refer to the different MRI acquisitions performed during the study. BG, blood glucose; IV, intravenous.

Figure 2

Cerebral blood flow (CBF) responses to hypoglycemia (ΔSI (%)) in 12 healthy controls (A, C) and 11 hypoglycemia unaware subjects with type 1 diabetes (B, D). T-scores evaluating where ΔSI (%) differed from zero are shown in (A) and (B) for controls and diabetes patients, respectively. Only voxels common to all subjects and belonging to the brain are shown; red to yellow colors (blue to green colors) indicate larger (smaller) CBF in hypoglycemia versus euglycemia. Values of ΔSI (%) are displayed in (C) and (D) for controls and diabetes patients, respectively, only in those brain areas where differences occurred at a significance level of P<0.02, uncorrected for multiple comparisons. Maps in (A) to (D) are superimposed on the mean T1-weighted images of the Tailarach-normalized brain calculated from the 23 subjects. Sagittal, coronal, and transverse views are shown in the top left, top right, and bottom right section of each panel, respectively. SI, signal intensity.

Figure 3

Comparisons of ΔSI (%) induced by hypoglycemia in 12 healthy controls versus 11 hypoglycemia unaware subjects with type 1 diabetes, displayed on different brain sections (A to C). Images show the t-score maps calculated in the overlapping brain volume between controls and patients, as detailed in Figure 2. Parametric maps are superimposed on the mean T1-weighted images of the Tailarach-normalized brain calculated from the 23 subjects. Colors identify brain regions where the hypoglycemia-induced ΔSI (%) were different between controls and hypoglycemia unaware subjects with type 1 diabetes at a significance level of P<0.05, uncorrected for multiple comparisons. Red to yellow colors (blue to green colors) indicate larger (smaller) ΔSI (%) responses of controls as compared with patients. Sagittal, coronal, and transverse views are shown in the top left, top right, and bottom right section of each panel, respectively. R and L indicate right and left, respectively. While larger ΔSI (%) were observed in the thalamus of controls versus patients, smaller ΔSI (%) were observed in the splenium and body of the corpus callosum (CC), in the periventricular white matter (PVWM), and in temporal lobe white matter (TLWM). SI, signal intensity.

Figure 4

(A) Correlation between the average ΔSI (%) induced by hypoglycemia in the thalamus and the average epinephrine response during hypoglycemia. The average ΔSI (%) was calculated in each subject from the thalamic region as shown in (B). Data in (B) are from one representative healthy control, superimposed on the mean T1-weighted images of the Tailarach-normalized brain calculated from the 23 subjects. Sagittal, coronal, and transverse views are shown in the top left, top right, and bottom right section of (B). The thalamic region was outlined once on the Tailarach space, and then applied on the normalized brain of each subject. The correlation was r=0.572, with a significance level of P=0.0043. SI, signal intensity; T1DM, type 1 diabetes.