1. DR. OLASOPE A.C REGISTRAR ENDOCRINOLOGY UNIT.
HYPERGLYCAEMIC EMERGENCIES:
Pathophysiology
DR. OLASOPE A.C
REGISTRAR ENDOCRINOLOGY UNIT.

2. OUTLINE Introduction. Pathophysiology. Effects.
Diabetic Ketoacidosis Vs Hyperglycaemic Hyperosmolar State.
Summary.
References.

3. INTRODUCTION. Two hormonal abnormalities:
Insulin deficiency and/or resistance.
Glucagon excess
increased secretion of catecholamines and cortisol 
Glucagon
Epinephrine
Cortisol
Growth Hormone
Insulin

4. These will result in abnormal Metabolism of:
Fat
Carbohydrate
Protein

5. Normally… Hyperglycemia ↑Insulin ↓Glucose production ↑Glucose uptake
↓Gluconeogenesis
↓Glycogenolysis
Normoglycemia

6. Hyperglycemia ↑Insulin ↑Glucose production ↓Glucose uptake
↑ Gluconeogenesis
↑ Glycogenolysis
Hyperglycemia

7. Fat metabolism ↓insulin & ↑cathecholamines → Lipolysis
↑lipolysis →→ elevation of Free Fatty Acids in plasma
mobilization to the liver
Normally, these would be converted into Triglycerides & Very Low Density Lipoproteins,
but the presence of GLUCAGON alters the hepatic metabolism to form ketone bodies
Ketone bodies
Acetone
Acetoacetate
β-hydroxbutyrate

8. Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetyl-CoA Acetoacetate
CoA-SH
Thiolase
Acetyl-CoA
Acetoacetyl-CoA
HMG-CoA synthase
H2O
CoA-SH
HMG-CoA
NADH+H+
Acetyl-CoA
HMG-CoA lyase
β-Hydroxybutyrate
dehydrogenase
Acetoacetate
CO2
NAD
β-Hydroxybutyrate
Acetone

9. EFFECTS OF KETONES Weak acids which dissociate completely at normal pH
Create a major H+ load that soon exceeds normal buffering mechanisms
Hyperventilation eliminates some of the acid
Some are lost in urine buffered by phosphate and ammonia
While some have Na+ as the accompanying cation

10. EFFECT OF EXCESS H+
Negative ionotropic effect causing peripheral vasodilation, resulting in ↓ BP, warm extremities & ↑ or normal body temp
If pH falls below 7.0, there may be inhibition of the CNS →→ paradoxical normal RR

11. CARBOHYDRATE METABOLISM
Insulin deficiency
↓ hepatic level of fructose-2,6-bisphosphate, which alters phosphofructokinase & fructose-1,6-bisphosphatase activity thus promoting GLYCOLYSIS.
Decrease in Glucose Transpoter -4

12. CARBOHYDRATE METABOLISM.
Glucagon excess
Depresses GLYCOLYSIS by↓ pyruvate kinase activity causing the intermediates to be shuttled in gluconeogenesis.
Activates GLUCONEOGENESIS by↑phosphoenolpyruvate carboxykinase activity
Promotes GLYCOGENOLYSIS

13. Protein metabolism
There will be ↑ protein breakdown & production of amino acids, which will be used in gluconeogenesis

16. Events
Dehydration
Osmotic Diuresis – blood glucose exceeds the renal threshold ( mg/dl)
Vomiting
Hyperventilation
Impaired consciousness – ↓ intake

17. Events contd. Metabolic acidosis – due to ↑ ketones
Compensatory mechanisms
(1) respiratory compensation,
(2) intracellular buffering – excess H+ goes into cells in exchange for potassium.
(3) HCO3- buffering system.

18. Events contd. Ionic changes –
A general loss of electrolytes due to osmotic diuresis.
K+ – intracellular buffering mechanism shifts K+ out of cells so even if there is ↓ total K+ in the body, serum K+ may initially be normal or even ↑ This K+ is further lost through the kidneys

19. PARADOXES OF HYPERGYCAEMIC EMERGENCIES.
Hyperglycaemia despite ↓ intake
Polyuria despite dehydration
Catabolic state despite hyperglycaemia

20. DKA Vs HHS Degree of hyperglycemia Ketoacidosis HHS > DKA
Pts with DKA present earlier due to symptoms of ketoacidosis
DKA pts are usually younger and have a better GFR, thus excreting more glucose through urine
Ketoacidosis
Absent/Minimal in HHS….why?
Minimal insulin may be sufficient to minimize ketosis but does not control hyperglycemia.
Decreased adipocytes in the elderly.

21. In summary….
HEs result from imbalance between Insulin and Counter regulatory hormones.
Hyperglycaemia results from ↑ hepatic glucose production and its ↓ uptake.
Ketoacidosis results from lipolysis with release of FFA which serves as precursors for ketone bodies.
 Insulin levels in HHS are insufficient to allow appropriate glucose utilization but are adequate to prevent lipolysis.

22. REFERENCES.
Fauci et al, 2008; Harrison’s principles of internal medicine 18th edition
Kumar P, Clark M, 2009; Kumar and Clark’s Clinical Medicine, 8th edition
Williams Textbook of Endocrinology 12th Edition.
Greenspan’s Basic & Clinical Endocrinology 12th Edition.

23. What of references?