Cerebral blood flow response to hypoglycemia is altered in patients with type 1 diabetes and impaired awareness of hypoglycemia

Abstract

It is unclear whether cerebral blood flow responses to hypoglycemia are altered in people with type 1 diabetes and impaired awareness of hypoglycemia. The aim of this study was to investigate the effect of hypoglycemia on both global and regional cerebral blood flow in type 1 diabetes patients with impaired awareness of hypoglycemia, type 1 diabetes patients with normal awareness of hypoglycemia and healthy controls ( n = 7 per group). The subjects underwent a hyperinsulinemic euglycemic-hypoglycemic glucose clamp in a 3 T MR system. Global and regional changes in cerebral blood flow were determined by arterial spin labeling magnetic resonance imaging, at the end of both glycemic phases. Hypoglycemia generated typical symptoms in patients with type 1 diabetes and normal awareness of hypoglycemia and healthy controls, but not in patients with impaired awareness of hypoglycemia. Conversely, hypoglycemia increased global cerebral blood flow in patients with impaired awareness of hypoglycemia, which was not observed in the other two groups. Regionally, hypoglycemia caused a redistribution of cerebral blood flow towards the thalamus of both patients with normal awareness of hypoglycemia and healthy controls, consistent with activation of brain regions associated with the autonomic response to hypoglycemia. No such redistribution was found in the patients with impaired awareness of hypoglycemia. An increase in global cerebral blood flow may enhance nutrient supply to the brain, hence suppressing symptomatic awareness of hypoglycemia. Altogether these results suggest that changes in cerebral blood flow during hypoglycemia contribute to impaired awareness of hypoglycemia.

Keywords: Arterial spin labeling; cerebral blood flow; diabetes; hypoglycemia; magnetic resonance imaging.

Figures

Figure 1.

Schematic overview of the study protocol. ASL measurements were performed just prior to initiating the glucose clamp (i.e., at baseline (BL)), at the end of the euglycemic phase and at the end of the hypoglycemic phase. Hypoglycemic symptom scores (Symp) were acquired just prior to positioning the subject in the MR scanner and at the end of the hypoglycemic phase.

Figure 2.

Hypoglycemia-induced changes in glucagon (a) and adrenaline (b). Glucagon and adrenaline levels were assessed at the end of the euglycemic (open bars) and hypoglycemic (gray bars) phase. Means (with SEM) as well as individual values (dots) are depicted. *p < 0.05 for euglycemia versus hypoglycemia.

Figure 3.

Hypoglycemia-induced changes in global CBF (%). Mean (with SEM) change as well as individual values (dots) are depicted. *p < 0.05 for hypoglycemia versus euglycemia and #p < 0.05 versus healthy controls.

Figure 4.

Redistribution of CBF normalized to its global gray matter mean in response to hypoglycemia for T1DM subjects with IAH (top row), T1DM subjects with NAH (middle row) and healthy controls (bottom row). Colors represent z-scores of hypoglycemia-induced significant changes in regional CBF, superimposed on the transverse view of the MNI-152 atlas (from left to right column: z = −8 mm, 2 mm, 12 mm, 22 mm, 42 mm in MNI-152 coordinate space) and indicate a significant increase (red to yellow) or decrease (dark to light blue) in relative regional CBF in hypoglycemia versus euglycemia.

Figure 5.

Mean quantitative redistribution of CBF in response to hypoglycemia for T1DM subjects with IAH (top row), T1DM subjects with NAH (middle row) and healthy controls (bottom row). Colors represent mean changes in regional CBF, superimposed on the transverse view of the MNI-152 atlas (from left to right column: z = −8 mm, 2 mm, 12 mm, 22 mm and 42 mm in MNI-152 coordinate space) and indicate an increase (red to yellow) or decrease (dark to light blue) in relative regional CBF in hypoglycemia versus euglycemia. Note that statistical significance was only reached for the increase in regional CBF in the left and right thalamic area in healthy controls and T1DM NAH, the redistribution towards the bi-lateral frontal lobes in T1DM NAH and the relative decreases in CBF in the right occipital lobe, temporal lobe and the right insular cortices in T1DM NAH and in the left lateral occipital lobe in T1DM IAH (as depicted in Figure 4).