Hypoglycemia Flashcards
What is diabetes?
Chronic metabolic disease characterised by elevated levels of blood glucose
How many people are affected by diabetes worldwide?
425 million people
How is hypoglycemia defined?
Plasma glucose level ≤ 70mg/dL or ≤ 3.9mmol/L
What is the standard concentration of glucose in plasma?
60 to 100 mg/dL
What two hormones are involved in the regulation of blood glucose levels?
Insulin and glucagon
What is glycogen?
A polysaccharide that is made and stored in the liver
What is the physiological role of glycogen?
It is an energy reserve that can be quickly mobilised if there is a sudden need for glucose
What occurs in the body when blood glucose levels rise?
Insulin secretion from beta cells in the pancreas increases, glucagon production in the liver is inhibited
How is glycogen synthesised?
Glucose enters liver cells from the blood stream and stimulate enzymes to convert glucose to chains of glycogen (glycogenesis)
What are the symptoms of hypoglycemia?
Tremor, tachycardia, hyperphagia, diaphoresis, disorientation, delirium,
At what blood glucose concentration is decreased insulin secretion seen?
~80mg/dL
At what blood glucose concentration is increased glucagon and epinephrine secretion seen?
~70mg/dL
At what blood glucose concentration do symptoms of hypoglycemia tend to be seen?
~55mg/dL
At what blood glucose concentration is functional brain failure seen?
Less than 50mg/dL
What is meant by functional brain failure in hypoglycemia?
Decreased cognition, aberrant behavior, seizure, coma
At what blood glucose concentration is neuronal death seen?
Below 20mg/dL
What neurodegenerative condition is associated with diabetes due to episodes of severe hypoglycemia?
Dementia - Alzheimer’s and vascular
What is meant by the term neuroglycopenia?
Low blood glucose levels in the brain
What pathophysiological process occurs with the hypoglycemic cognitive deficit in diabetic rat models?
Oxidative stress
What is a common rat model of type 1 diabetes and how is it induced?
Streptozotocin - drug mediated depletion of beta cells (necrotic death) followed by insulin injections to induce hypoglycemia
Which brain regions were shown to have an increase in oxidative stress in a rat model of T1D?
Hippocampus, cortex
What rescues the oxidative damage in the hippocampus seen in recurrent moderate hypoglycemic rats?
NOX2 inhibition
What changes to glucose transporters are observed due to hypoglycemia?
Increased GLTU1 mRNA and protein in brain and capillaries/BBB (to increase glucose trafficking to the brain)
Upregulation of GLUT3 (neuronal transporter) and MCT2
What is the typical response to hypoglycemia in healthy individuals?
Initial decrease in cerebral glucose consumption which is more prominent in regions of the brain that is active. Glucose transporters are upregulated. Further hypoglycemic events result in adaptive glucose uptake
How do patients with uncontrolled T1D respond to recurrent hypoglycemic events?
Impaired simulation of hyperinsulinemic hypoglycemia-induced glucose oxidation, poor glucose uptake
How does hypoglycemia impact glycolysis in murine models?
Fasting decreases glucose metabolism and malonyl-coenzyme A production in hypothalamus and cortex which reprograms substrate utilisation from glycolysis to lipid oxidation
What changes to glycolytic enzymes are observed due to hypoglycemia?
Decreased levels of rate-limiting enzymes in the brain
How does hypoglycemia impact the TCA cycle in T1D patients compared to healthy individuals?
Increase in TCA cycle flux
What changes in mitochondrial respiration are induced by hypoglycemia?
Impairment of electron transport chain
Decreases respiratory control ration
What are alternate sources of energy for brain during hypoglycemia?
Lactate and ketone bodies
What are the benefits of utilising alternative fuels during hypoglycemia?
Increase oxidative metabolism
Decrease autonomic and neuroglycopenic symptoms
Enhance glucose counter regulatory mechanisms
What are the energy sources in the initial phases of hypoglycemia?
Lactate initially, then glutamate and glutamine, then aspartate
What are ketone bodies the products of?
Fatty acid metabolism
How do ketone bodies feed into the TCA cycle?
Metabolised into acetyl-CoA
What are the main two ketone bodies used as energy sources?
3-b-hydroxybutyrate and acetone
b-hydroxybutyric acid contributes to the neuronal synthesis of which amino acids?
Glutamate and glutamine
What is glycogen?
Reserve respiratory substrate for the brain during metabolic stress
Where is glycogen stored?
In astrocytes adjacent to synthesis and degradation enzymes
How is glycogen mobilised during hypoglycemia?
Acted upon by glycogen phosphorylase in astrocytes and converted to glucose-1-phosphate and glucose-6-phosphate to feed glycolysis
What is the glycogen supercompensation phenomenon?
Glycogen levels exceeding pre-hypoglycemia levels for a few hours following restoration of euglycemia after hypoglycemia
