Hypoglycemia Flashcards
What is Hypoglycemia?
Hypoglycemia is defined as an abnormal decrease in plasma glucose concentrations less than 2.5mmol/L
The plasma glucose concentration at which observable symptoms of hypoglycemia appear in adult and newborns/infants is at about:
2.8–3.0 mmol/L, Newborns and infants are known to tolerate lower levels of plasma glucose without eliciting any sign of hypoglycemia.
Why is glucose required?
Glucose is an important metabolic fuel
especially brain:
- energy requirements more than twice other cell
- glucose is the normal substrrate
- cannot synthesise glucose
- cannot store more than a few minutes supply
- cannot utilise fatty acids
States of fasting include:
Fed State/Post-absorptive state
- defined as 2 hours after a meal
Fasting State
- exists after (even 10) 12 – 24 hours after the last meal
- overnight fast
Starvation State
- no food intake for greater than 48hours
Glucose absorption from the GIT ceases by_____ hours after a meal
6-8 hours after a meal
How is Euglycaemia maintained in fasting state?
Euglycaemia (normal glucose levels) is maintained by the breakdown of endogenous sources of energy: Glycogen, Triacylglycerols, Amino acids
The pancreas decreases insulin secretion and increases glucagon secretion
Epinephrine levels also increase in response to the falling glucose levels
The lack of insulin also stimulate hormone sensitive lipase on adipose cells
What occurs during Starvation?
No liver glycogen
Only source of glucose is gluconeogenesis
Ketosis becomes more prominent as fuel for the tissues including the brain
Kidney becomes gluconeogenic
Discuss Insulin
Protein hormone produced by the β-cells of the Pancreas
Produced as part of a precursor molecule pre-proinsulin
Preproinsulin - Proinsulin - Insulin and C- peptide
Insulin is secreted in equi-molar amounts with C-peptide.
Imbalance between Insulin and C-peptide can be an indication of exogenous insulin
Function of insulin in the body organs?
Brain : Increase glucose entry into by GLUT-1,3
(Not insulin requiring)
Muscle: Increases glucose entry (GLUT-4). Increases glycogen synthesis
Liver: Enhances glucose entry (via + glucokinase)
(Entry mediated by GLUT-2, not insulin dependent)
Inactivates liver glycogen phosphorylase
Stimulates glycogen synthase
Inhibits gluconeogenesis
Adipose tissue: Promotes glucose entry (by GLUT-4) mainly for glycerol synthesis
How does insulin INCREASE FAT SYNTHESIS AND STORAGE?
- Increased glucose utilization action has fat sparing effect
- Excess glucose converted to fat (when liver glycogen is 5 – 6% concentration)
- Fat synthesized is used to form TG, which is incorporated into LP and secreted
- Insulin activates lipoprotein lipase in the adipose tissue to breakdown LPs to form FAs which are absorbed
- In adipose tissue, Insulin inhibits hormone sensitive lipase
6.Increases glucose entry into cell, forms glycerol to combine with FAs to form TG
Other effects of Insulin
Promotes synthesis of protein and inhibits degradation of proteins
Interacts synergistically with GH to promote growth
Counter-regulatory Hormones
Glucagon
Epinephrine
Norepinephrine
Cortisol
Growth Hormone
Discuss glucagon
Secreted by the α-cells of the pancreas
Stimulates glycogenolysis and ↑ blood glucose conc. within minutes
Stimulates gluconeogenesis, increasing uptake of amino acids into Liver
Activates hormone sensitive lipase in adipose tissue, ↑ FFA conc.
Main counter-regulatory hormone during acute hypoglycaemia
Types of Hypoglycemia
Fasting Hypoglycemia:
Occurs in the fasting state
Non-fasting/Reactive/Postprandial hypoglycemia
Occurs only in response to a meal
Discuss Fasting Hypoglycemia With Hyperinsulinism
Insulin Therapy
Sulfonylurea Overdose (they encourage the release of endogenous insulin)
Factitious Hypoglycemia
Autoimmune Hypoglycemia
Pentamidine-Induced
Pancreatic β- cell tumours
Discuss Fasting Hypoglycemia Without Hyperinsulinism
Hepatic parenchymal damage
Severe Muscle wasting
Chronic starvation
Uremia
Adrenocortical deficiency
Inborn errors of CHO metab. e.g G6PD deficiency
Discuss Non fasting hypoglycemia
- Postgastrectomy alimentary hypoglycemia (revomal of the stomach, glucose enters directly into small intestine. insulin levels shoot up, greatly increases rate of absorption)
- Post gastric bypass hypoglycemia
- Functional alimentary hypoglycemia
- Pancreatic-islet hyperplasia
- Late hypoglycaemia (Occult diabetes)
How does insulin therapt cause hypogycemia?
Insulin treated diabetics are bulk of patients with hypoglycemia
Advent of intensive glycemic control
Several episodes per week
About 2- 4 % deaths associated with hypoglycemia
What are the risk factors of fasting hypoglycemia?
Hypoglycaemia unawareness
Insulin doses are excessive, ill timed or wrong type
Influx of exogenous glucose is reduced (fast or missed meals)
Insulin dependent glucose utilisation is increased
Insulin sensitivity is increased
Endogenous glucose production is reduced (alcohol ingestion)
Insulin clearance is reduced (renal failure)
Sulfonylurea overdose in association with hypoglycemia?
Associated with agents with prolonged half life (chlorpropamide,35hrs)
Also older patients with impaired hepatic or renal function
Factitious hypoglycemia
Self induced hypoglycemia (with insulin or sulfonylurea)
Common in health professionals, diabetics or their relatives
Call for attention, psychiatric disturbances
Also patient error, or pharmacist prescription mishap
Pancreatic β-cell tumours (Insulinomas)
Commonest cause in an otherwise healthy adult
Most are benign and single
May be familial (MEN 1)
Hepatic parenchymal disease
Reduced hepatic gluconeogenesis
Fulminant viral hepatitis or toxic damage
Severe muscle wasting
Reduced amino acid supply for gluconeogenesis
Ethanol hypoglycemia
Ethanol impairs gluconeogenesis, not glycogenolysis
Due to reduced conversion of lactate to pyruvate (altered NADH/NAD ratio from alcohol dehydrogenase activity
Non Pancreatic tumours
Usually large mesenchymal tumours
Retroperitoneal fibrosarcomas, hepatocellular carcinoma, adrenocortical carcinomas, hypernephromas
Basis is production of IGF-II which binds to insulin receptors
Postgastrectomy Alimentary hypoglycemia,
Postgastric bypass & Functional Alimentary hypoglycemia
Postgastrectomy Alimentary hypoglycemia
Consequence of hyperinsulinism
Rapid gastric emptying with overstimulation of insulin production
Postgastric bypass (As above)
Functional Alimentary hypoglycemia
Alimentary type hypoglycemia in a patient who has not had surgery
NEUROGLYCOPENIA
NEUROGLYCOPENIA
The essence of the counter-regulatory response is to ensure adequate supply of glucose to the CNS.
Failure results in neuroglycopenia (insufficient glucose supply to the brain)
impaired cognition weakness
lethargy confusion
incoordination blurred vision
Failure to correct at this stage may result in convulsion, coma, brain damage and death
Autonomic Signs & Symptoms of Hypoglycemia
Symptoms:
Palpitations
Tremors
Anxiety
Sweating
Hunger
Paresthesias
Signs:
Pallor
Diaphoresis(Prof sweating)
↑ Heart Rate
↑ Blood pressure
Neuroglycopenic Signs & Symptoms of Hypoglycemia
Symptoms:
Behavioural changes
Confusion
Fatigue
Seizure
Loss of Consciousness
Death
Signs:
Non-specific
Transient focal neurologic deficit
Onset of symptoms depends on
Status of blood supply to the brain
Rapidity of drop in blood glucose
Chronic hyperglycaemia, hypoglycaemia
Physiologic Responses to Decreasing Plasma Glucose Concentrations
Insulin 4.4–4.7 First defense against hypoglycemia
Glucagon 3.6–3.9 Pry glucose CR factor/ 2nd defense
Epinephrine 3.6–3.9 3rd defense against hypoglycemia, critical when glucagon is deficient
Cortisol & GH 3.6–3.9 Defense against prolonged hypoglycemia,
Symptoms 2.8–3.1 Prompt behavioral defense against hypoglycemia (food ingestion)
Cognition <2.8 Compromises behavioral defense
DIAGNOSIS
Whipple’s triad needed for diagnosis
Symptoms consistent with hypoglycemia
Low plasma glucose concentration
Relief of symptoms after plasma glucose level is raised
Determine Etiology
Investigation of hypoglycemia
Plasma Glucose levels
Not just low blood glucose but Whipple’s triad, so measure when there are symptoms.
Provocation Tests
Overnight fast (18hrs), done on 3 different occasions, to provoke, if necessary
Prolonged fast (up to 48hrs)
Exercise test (Insulin-induced hypoglycemia)
{Measurements in the laboratory, not with glucose meters ( in a/e)}
Plasma insulin assay
Plasma C-peptide assay (when Pl glu is low)
Rule out artefactual causes
*Wrong bottle
*Increased metabolism eg. Leukaemia, Leukemoid or polycythemia
Liver Glycogenoses
Problem with enzymes associated with glycogen metabolism
Liver Glycogenoses (hepatomegaly and hypoglycemia)
Ia (Von Gierke): Glucose-6-phosphatase
Ib: Glucose-6-phosphate translocase
IIIa (Cori or Forbes) - Liver and muscle debranching enzyme
IIIb: Liver debranching enzyme (normal muscle debrancher activity)
VI (Hers): Liver phosphorylase
Disorders with liver cirrhosis
IV(Andersen): branching enzyme
Muscle Glycogenoses
Muscle Glycogenoses
V (McArdle) – Muscle phosphorylase
VII (Tarui) – Phosphofructokinase
II (Pompe) – Lysosomal acid -glucosidase
Discuss Galactose Disorders
Galactosemia with uridyl transf — Def Galac 1-P uridyl transf
Galactokinase deficiency —- Galactokinase
Uridine diphosphate galactose 4-epimerase deficiency—-
UDP galactose 4-epimerase
Fructose Disorders
Essential fructosuria —- Fructokinase
Hereditary fructose intolerance – Fructose 1-phosphate aldolase B
Fructose 1,6-diphosphatase deficiency —Fruct1,6-diphostase
