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.

Cerebral perfusion in pediatric type 1 diabetes: relation to vascular complications, psychological and neurophysiological functions

“…This protective effect may be lost with longer diabetes duration as part of counter regulatory failure and development of hypoglycemic unawareness. Similar findings were reported by Mangia et al, 2012 [26], where significant hypoglycemia-induced cerebral blood flow (CBF) increases occurred in the thalamus of healthy controls but less in patients with type 1 diabetes and hypoglycemic unawareness. Also, epinephrine and glucagon levels were significantly higher during hypoglycemia in healthy controls compared with subjects with T1DM and hypoglycemic unawareness.…”

“…These studies suggest that longer diabetes duration leads to a pattern of premature atherosclerosis which affects the cerebral vasculature, leading to regional cerebral hypo perfusion. In addition, there are other confounding factors that increase with longer diabetes duration, like impaired lipid profile, microangiopathy and impaired neurovascular couplings [26] which might affect the cerebral circulation and thereby decreasing cerebral blood flow.…”

Hypoglycemia unawareness in type 1 diabetes suppresses brain responses to hypoglycemia

“…Furthermore, T1DM individuals with hypoglycemia unawareness may have alterations in cerebral blood flow during hypoglycemia (38,39), which may also affect BOLD signal. Interestingly, a recent study has reported that individuals with T1DM and hypoglycemia unawareness have increased cerebral blood flow during acute hypoglycemia compared with T1DM-Aware and HC subjects (39).…”

Changes in Human Brain Glutamate Concentration during Hypoglycemia: Insights into Cerebral Adaptations in Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes

“…2 Although the mechanisms of HAAF have not been fully elucidated, a picture is emerging in which a series of cerebral adaptations, including altered fuel transport and/or metabolism, lead to defective glucose counter-regulation and impaired hypoglycemia awareness. 3 The cerebral response to hypoglycemia in the healthy brain involves changes in regional blood flow 4,5 and sequential adjustments in cerebral metabolism in order to provide sufficient fuel for brain activity. As the levels of glucose, the principal cerebral energy substrate, drop from 5 to B3 mmol/L in plasma, cerebral metabolic rate of glucose (CMRglc) and cerebral metabolic rate of oxygen (CMRO 2 ) are preserved [6][7][8] despite lower brain glucose uptake.…”