Cerebral glycogen in humans following acute and recurrent hypoglycemia: Implications on a role in hypoglycemia unawareness

Abstract

Supercompensated brain glycogen levels may contribute to the development of hypoglycemia-associated autonomic failure (HAAF) following recurrent hypoglycemia (RH) by providing energy for the brain during subsequent periods of hypoglycemia. To assess the role of glycogen supercompensation in the generation of HAAF, we estimated the level of brain glycogen following RH and acute hypoglycemia (AH). After undergoing 3 hyperinsulinemic, euglycemic and 3 hyperinsulinemic, hypoglycemic clamps (RH) on separate occasions at least 1 month apart, five healthy volunteers received [1-C]glucose intravenously over 80+ h while maintaining euglycemia. C-glycogen levels in the occipital lobe were measured byC magnetic resonance spectroscopy at ∼8, 20, 32, 44, 56, 68 and 80 h at 4 T and glycogen levels estimated by fitting the data with a biophysical model that takes into account the tiered glycogen structure. Similarly, prior C-glycogen data obtained following a single hypoglycemic episode (AH) were fitted with the same model. Glycogen levels did not significantly increase after RH relative to after euglycemia, while they increased by ∼16% after AH relative to after euglycemia. These data suggest that glycogen supercompensation may be blunted with repeated hypoglycemic episodes. A causal relationship between glycogen supercompensation and generation of HAAF remains to be established.

Glycogen Supercompensation in the Rat Brain After Acute Hypoglycemia is Independent of Glucose Levels During Recovery

“…Oz et al [18] used 13 C magnetic resonance spectroscopy in conjunction with [1-13 C]glucose administration measure brain glycogen content and metabolism in patients with type 1 diabetes and hypoglycemia unawareness, as well as healthy volunteers. This study also did not support the hypothesis that post-hypoglycemia glycogen supercompensation is the driver for hypoglycaemia unawareness [18], although a single hypoglycaemia episode was shown to elicit glycogen supercompensation in healthy subjects [12,16]. Nevertheless, increased brain glucose storage could be favoured by increased glucose uptake after hypoglycaemia.…”

“…Evidence supporting this post-hypoglycemia supercompensation has been reported in the human [12,16], rat [9,14], mouse [10] and rainbow trout [15]. However, the re-establishment of glycogen content in the brain after hypoglycaemia has been involved in controversy: (1) not all studies confirmed glycogen supercompensation after acute hypoglycaemia [11], (2) there have been reports suggesting that repeated hypoglycaemia does not result in increased glycogen levels [11,16,17], and (3) patients with type 1 diabetes and hypoglycaemia unawareness display brain glycogen levels similar to those in healthy subjects [18].…”

Use of a Continuous Glucose Monitor for Preoperative Monitoring and Treatment of Hypoglycemia in a Case of Pancreatic Neuroendocrine Tumor

“…Various mechanisms, including changes in glucose uptake or metabolism by the brain, the use of alternate fuels, and changes in hypothalamic neurotransmitter release have been proposed. Excessive compensation of brain glycogen levels during recurrent hypoglycemia could contribute to the development of hypoglycemia-associated autonomic failure in humans (15). Inhibition of the counterregulatory response by suppressed adrenal activity has been observed in animal models (16).…”

Impaired hypoglycaemia awareness in type 1 diabetes: lessons from the lab

“…However, many of these studies were conducted in people or rodents without type 1 diabetes. More recent work suggests no increase in cerebral glucose metabolism during hypoglycaemia in people with type 1 diabetes and IAH [30] and no increase in brain glycogen stores [31]. Moreover, compared with control animals, detailed tracer studies in rodents indicate that, after recurrent hypoglycaemia, neuronal glucose metabolism is actually decreased during subsequent hypoglycaemia [32].…”