PMC

Neuronal death in the cerebral cortex and hippocampus after severe or moderate hypoglycemia in diabetic rats. (A) In sham hypoglycemia-operated rats, neuronal death (FJB (+) neurons) was not detected in diabetic rats. In both diabetic and non-diabetic rats, recurrent/moderate (R/M) hypoglycemia shows only occasional neuronal death in the cerebral cortex while acute/severe (A/S) hypoglycemia shows widespread neuronal death in the superficial layer of cortex at 7 days after hypoglycemia. Bar = 100 μm. (B) Bar graph represents counted degenerating neurons in the cerebral cortex. Data are mean + s.e.m.; n = 5 in R/M hypoglycemia, n = 7 in A/S hypoglycemia * P < 0.05. (C) R/M hypoglycemia shows no neuronal death (FJB (+) neurons) in the hippocampal CA1 and DG cell layer while severe hypoglycemia shows substantial neuron death in the hippocampus at seven days after hypoglycemia. Bar = 100 μm. (D) Light microscopic images represent hematoxylin & eosin (H&E) stained hippocampus from CA1 and DG cell layer. R/M hypoglycemia shows no neuronal death (eosinophilic) in the hippocampal CA1 and DG cell layer while severe hypoglycemia shows substantial neuronal death in the hippocampus at seven days after hypoglycemia. Bar = 100 μm.

Effect of exposure to antecedent euglycemia (black circles) and antecedent hypoglycemia (white circles) on thermal detection thresholds and thermal pain detection thresholds.Panel A: Day 3 cold detection thresholds were similar after antecedent euglycemia and antecedent hypoglycemia. Panel B: There is a higher cold-pain detection threshold (increased sensitivity) after antecedent hypoglycemia. Panel C: There is a lower heat detection threshold (increased sensitivity) after antecedent hypoglycemia. Panel D: There is a lower heat-pain detection threshold (increased sensitivity) after antecedent hypoglycemia.

Frequency and content of discussions of interval hypoglycemia and anticipatory guidance for hypoglycemia prevention. Interval hypoglycemia discussions were defined as clinician queries about hypoglycemic events or symptoms that elicited a response by the patient, or patient reports of hypoglycemic events or symptoms that were followed up by the clinician. Discussions of hypoglycemia unawareness were any discussion of the patient’s symptoms (or lack thereof) during hypoglycemic events. Anticipatory guidance for hypoglycemia was categorized as behavior change to prevent hypoglycemia (changes in diet, exercise, medication timing, or blood glucose monitoring), general hypoglycemia counseling (the definition of hypoglycemia, its causes and sequelae, or its relationship to diabetes treatment), treatment of hypoglycemic events (ingesting carbohydrate), and avoidance of driving with hypoglycemia. a Discussions of interval hypoglycemia. b Discussions of anticipatory guidance.

Hypoglycemia is a state of energy depletion that leads to metabolic stress. Sympathetic activation leads to symptoms of hypoglycemia awareness and the adrenomedullary response. The normal response to hypoglycemia is a cellular adaptation, assuming the energy depletion and metabolic stress was not enough to induce cell death. The mechanism by which cellular adaptation occurs is unclear but may include the use of alternate fuels (such as lactate) and/or an enhanced glucose transport/phosphorylation/metabolism. During a subsequent hypoglycemic episode, the adapted cell experiences less marked energy depletion and less metabolic stress thus making the cells less susceptible to death. Less intracellular energy depletion leads to impaired sympathetic activation resulting in hypoglycemia unawareness and a reduced adrenomedullary response to subsequent hypoglycemia, collectively known as hypoglycemia associated autonomic failure (HAAF). Preconditioning through recurrent hypoglycemia, paradoxically, acts to render an individual more prone to, but less vulnerable to, an episode of severe hypoglycemia.