Blood-to-Brain Glucose Transport, Cerebral Glucose Metabolism, and Cerebral Blood Flow Are Not Increased After Hypoglycemia

Abstract

Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (including adrenomedullary epinephrine), symptomatic, and other responses to subsequent hypoglycemia to lower plasma glucose concentrations. This change in threshold is the basis of the clinical syndromes of hypoglycemia unawareness and, in part, defective glucose counterregulation and the unifying concept of hypoglycemia-associated autonomic failure in type 1 diabetes. We tested in healthy young adults the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport, a plausible mechanism of this phenomenon. Eight subjects were studied after euglycemia, and nine were studied after ϳ24 h of interprandial hypoglycemia (ϳ55 mg/dl, ϳ3.0 mmol/l). The latter were shown to have reduced plasma epinephrine (P ‫؍‬ 0.009), neurogenic symptoms (P ‫؍‬ 0.009), and other responses to subsequent hypoglycemia. Global bihemispheric blood-to-brain glucose transport and cerebral glucose metabolism were calculated from rate constants derived from blood and brain timeactivity curves-the latter determined by positron emission tomography (PET)-after intravenous injection of [1- , respectively), cerebral glucose metabolism (16.8 ؎ 0.9 and 15.9 ؎ 0.9 mol ⅐ 100 g ؊1 ⅐ min ؊1 , respectively) and cerebral blood flow (56.8 ؎ 3.9 and 53.3 ؎ 4.4 ml ⅐ 100 g ؊1 ⅐ min ؊1 , respectively) were virtually identical. These data do not support the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport during subsequent hypoglycemia. They do not exclude regional increments in blood-to-brain glucose transport. Alternatively, the fundamental alteration might lie beyond the blood-brain barrier.

Differential changes in brain glucose metabolism during hypoglycaemia accompany loss of hypoglycaemia awareness in men with type 1 diabetes mellitus. An [11C]-3-O-methyl-d-glucose PET study

“…Our study is small and a type 2 error is possible, reflecting the relatively low signal-to-noise ratio in the data when regional analysis is employed in comparison with FDG. However, power calculations suggest we should have detected any difference greater than 15% between the two groups in K 1 /k 2 ratio measures in the present study, and our data are supported by an earlier PET study which failed to find any change in brain glucose transport rates in a human model of hypoglycaemia unawareness [23]. Thus, if upregulation of glucose transport does occur its net global effect should be less than this.…”

“…These data represent a significant extension of: (1) our earlier FDG study, in which we were unable to measure the effect of hypoglycaemia on the above parameters due to the limitations of FDG kinetic modelling [24]; and (2) the PET study of Segel et al, in which brain glucose metabolic parameters were measured at a plasma glucose of 3.6 mmol/l, at which level neither hypoglycaemia-accustomed or -unaccustomed subjects would experience symptoms [23]. These data offer a potential new insight into the phenomenon of unawareness.…”

“…Increased tracer uptake is shown in a contiguous region involving Brodmann area 10 (an area which survived analysis at p=0.001 and minimum cluster size of 100 voxels; data not shown) and anterior cingulate cortex. Decreased tracer uptake is shown in a contiguous region involving Brodmann area 17 and cerebellar vermis or at modest hypoglycaemia [25]; (2) the negative study in hypoglycaemia-naive and hypoglycaemia-accustomed healthy volunteers using 11 C PET [23]; and (3) data failing to find downregulation of glucose transport in poorly controlled diabetes [42,43]. All these data support an explanation for unawareness that is not dependent on upregulation of neuronal glucose uptake, such as increased efficiency of use of non-glucose metabolic fuels.…”

“…In man, studies measuring brain arteriovenous differences have shown preservation of brain glucose uptake with attenuation of the hormonal counterregulatory response during acute hypoglycaemia in models of hypoglycaemia unawareness [19,20]. However, other studies have shown no robust preservation of cortical function in hypoglycaemia unawareness [1,21,22], and positron emission tomography (PET) neuroimaging studies have not found evidence for increased brain glucose extraction in acute hypoglycaemia in models of counterregulatory failure [23,24]. A recent study using magnetic resonance spectroscopy has demonstrated increased glucose content in hypoglycaemia-unaware subjects compared with non-diabetic subjects under conditions of hyperglycaemia (16.7 mmol/l); however, aware diabetic subjects were not studied, nor were conditions of hypoglycaemia explored [25].…”

Hypoglycaemia unawareness and the brain

“…Early studies with labelled C-O-methyl glucose [86] and a recent study with 11 C-glucose found no indication of altered brain glucose uptake or metabolism in Type I diabetic patients in poor control or in normal volunteers with counterregulatory deficits after antecedent hypoglycaemia exposure [87]. It is likely that a further adaptation of the intracellular glucose metabolic pathway and the subsequent change in neurotransmitter release is involved in changing the plasma glucose concentrations triggering any reaction to hypoglycaemia.…”