Hypoglycemia

Question 1

What is Hypoglycemia?

Answer 1

Hypoglycemia is defined as an abnormal decrease in plasma glucose concentrations less than 2.5mmol/L

Question 2

The plasma glucose concentration at which observable symptoms of hypoglycemia appear in adult and newborns/infants is at about:

Answer 2

2.8–3.0 mmol/L, Newborns and infants are known to tolerate lower levels of plasma glucose without eliciting any sign of hypoglycemia.

Question 3

Why is glucose required?

Answer 3

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

Question 4

States of fasting include:

Answer 4

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

Question 5

Glucose absorption from the GIT ceases by_____ hours after a meal

Answer 5

6-8 hours after a meal

Question 7

How is Euglycaemia maintained in fasting state?

Answer 7

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

Question 8

What occurs during Starvation?

Answer 8

No liver glycogen
Only source of glucose is gluconeogenesis
Ketosis becomes more prominent as fuel for the tissues including the brain
Kidney becomes gluconeogenic

Question 9

Discuss Insulin

Answer 9

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

Question 10

Function of insulin in the body organs?

Answer 10

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

Question 11

How does insulin INCREASE FAT SYNTHESIS AND STORAGE?

Answer 11

1. Increased glucose utilization action has fat sparing effect
2. Excess glucose converted to fat (when liver glycogen is 5 – 6% concentration)
3. Fat synthesized is used to form TG, which is incorporated into LP and secreted
4. Insulin activates lipoprotein lipase in the adipose tissue to breakdown LPs to form FAs which are absorbed
5. In adipose tissue, Insulin inhibits hormone sensitive lipase

6.Increases glucose entry into cell, forms glycerol to combine with FAs to form TG

Question 12

Other effects of Insulin

Answer 12

Promotes synthesis of protein and inhibits degradation of proteins
Interacts synergistically with GH to promote growth

Question 13

Counter-regulatory Hormones

Answer 13

Glucagon
Epinephrine
Norepinephrine
Cortisol
Growth Hormone

Question 14

Discuss glucagon

Answer 14

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

Question 15

Types of Hypoglycemia

Answer 15

Fasting Hypoglycemia:
Occurs in the fasting state

Non-fasting/Reactive/Postprandial hypoglycemia
Occurs only in response to a meal

Question 16

Discuss Fasting Hypoglycemia With Hyperinsulinism

Answer 16

Insulin Therapy
Sulfonylurea Overdose (they encourage the release of endogenous insulin)
Factitious Hypoglycemia
Autoimmune Hypoglycemia
Pentamidine-Induced
Pancreatic β- cell tumours

Question 17

Discuss Fasting Hypoglycemia Without Hyperinsulinism

Answer 17

Hepatic parenchymal damage
Severe Muscle wasting
Chronic starvation
Uremia
Adrenocortical deficiency
Inborn errors of CHO metab. e.g G6PD deficiency

Question 18

Discuss Non fasting hypoglycemia

Answer 18

1. Postgastrectomy alimentary hypoglycemia (revomal of the stomach, glucose enters directly into small intestine. insulin levels shoot up, greatly increases rate of absorption)
2. Post gastric bypass hypoglycemia
3. Functional alimentary hypoglycemia
4. Pancreatic-islet hyperplasia
5. Late hypoglycaemia (Occult diabetes)

Question 19

How does insulin therapt cause hypogycemia?

Answer 19

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

Question 20

What are the risk factors of fasting hypoglycemia?

Answer 20

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)

Question 21

Sulfonylurea overdose in association with hypoglycemia?

Answer 21

Associated with agents with prolonged half life (chlorpropamide,35hrs)
Also older patients with impaired hepatic or renal function

Question 22

Factitious hypoglycemia

Answer 22

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

Question 23

Pancreatic β-cell tumours (Insulinomas)

Answer 23

Commonest cause in an otherwise healthy adult
Most are benign and single
May be familial (MEN 1)

Question 24

Hepatic parenchymal disease

Answer 24

Reduced hepatic gluconeogenesis
Fulminant viral hepatitis or toxic damage

Question 25

Severe muscle wasting

Answer 25

Reduced amino acid supply for gluconeogenesis

Question 26

Ethanol hypoglycemia

Answer 26

Ethanol impairs gluconeogenesis, not glycogenolysis
Due to reduced conversion of lactate to pyruvate (altered NADH/NAD ratio from alcohol dehydrogenase activity

Question 27

Non Pancreatic tumours

Answer 27

Usually large mesenchymal tumours
Retroperitoneal fibrosarcomas, hepatocellular carcinoma, adrenocortical carcinomas, hypernephromas
Basis is production of IGF-II which binds to insulin receptors

Question 28

Postgastrectomy Alimentary hypoglycemia,
Postgastric bypass & Functional Alimentary hypoglycemia

Answer 28

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

Question 29

NEUROGLYCOPENIA

Answer 29

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

Question 30

Autonomic Signs & Symptoms of Hypoglycemia

Answer 30

Symptoms:

Palpitations
Tremors
Anxiety
Sweating
Hunger
Paresthesias

Signs:
Pallor
Diaphoresis(Prof sweating)
↑ Heart Rate
↑ Blood pressure

Question 31

Neuroglycopenic Signs & Symptoms of Hypoglycemia

Answer 31

Symptoms:
Behavioural changes
Confusion
Fatigue
Seizure
Loss of Consciousness
Death

Signs:
Non-specific
Transient focal neurologic deficit

Question 32

Onset of symptoms depends on

Answer 32

Status of blood supply to the brain
Rapidity of drop in blood glucose
Chronic hyperglycaemia, hypoglycaemia

Question 33

Physiologic Responses to Decreasing Plasma Glucose Concentrations

Answer 33

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

Question 34

DIAGNOSIS

Answer 34

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

Question 35

Investigation of hypoglycemia

Answer 35

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

Question 36

Liver Glycogenoses

Answer 36

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

Question 37

Muscle Glycogenoses

Answer 37

Muscle Glycogenoses
V (McArdle) – Muscle phosphorylase
VII (Tarui) – Phosphofructokinase
II (Pompe) – Lysosomal acid -glucosidase

Question 38

Discuss Galactose Disorders

Answer 38

Galactosemia with uridyl transf — Def Galac 1-P uridyl transf
Galactokinase deficiency —- Galactokinase
Uridine diphosphate galactose 4-epimerase deficiency—-
UDP galactose 4-epimerase

Question 39

Fructose Disorders

Answer 39

Essential fructosuria —- Fructokinase
Hereditary fructose intolerance – Fructose 1-phosphate aldolase B
Fructose 1,6-diphosphatase deficiency —Fruct1,6-diphostase