Insulin deficiency and excess glucagon lead to abnormal carbohydrate, fat, and protein metabolism resulting in diabetic ketoacidosis (DKA). Specifically: 1) Impaired glucose utilization and increased gluconeogenesis and glycogenolysis cause hyperglycemia. 2) Increased lipolysis and synthesis of ketone bodies in the liver from free fatty acids causes ketoacidosis and metabolic acidosis. 3) Glucose levels are usually lower in DKA compared to hyperosmolar hyperglycemic state (HHS) due to greater urinary glucose excretion in DKA patients, who are usually younger with better kidney function. Insulin levels are sufficient to prevent ketogenesis in H

1. Bethelhem Berhanu

2. • Two hormonal abnormalities:
– Insulin deficiency and/or resistance.
– Glucagon excess – required???
• increased secretion of catecholamines and cortisol
Insulin
Glucagon
Epinephrine
Cortisol
Growth Hormone

3. • These will result in abnormal Metabolism
of:
– Carbohydrate
– Fat
– Protein
• Inflammatory process

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

5. DKA
Hyperglycemia
↑Insulin
↑Glucose production
↑ Gluconeogenesis
↓Glucose uptake
↑ Glycogenolysis
Hyperglycemia

6. Carbohydrate contd.
• The decrease in glucose uptake alone does not
give us the degree of hyperglycemia in DKA or
HHS.
• Gluconeogenesis, why?
– Providing the substrates (glycerol, alanine)
– Increase in glucagon

7. • Glucosuria helps in reducing the serum
glucose initially, but later….
Osmotic diuresis,
Volume depletion
↓GFR
↓ glucose excretion

8. On fat metabolism
• ↓insulin & ↑cathechilamines → Lipolysis
– There will be free fatty acid mobilization to the
liver
– Normally, these would be converted into TGLs and
VLDL, but the presence of glucagon alters the
hepatic metabolism to form ketone bodies.
Ketone
bodies
Acetone
Acetoacetate
β-hydroxbutyrate

9. • The acidic ketone bodies will cause metabolic
acidosis.
– Dehydration from osmotic diuresis also
exacerbates the acidosis.
• A second product of lipolysis, glycerol, will be
used as a substrate for gluconeogenesis in the
liver.

10. On protein metabolism
• There will be increased protein breakdown
and production of amino acids, which will be
used in gluconeogenesis (alanine).

13. Events
• Dehydration – 6 litres or more, 15-20% of
their weight. Why?
– Osmotic Diuresis – blood glucose exceeds the
renal treshold (160-180mg/dl)
– Vomiting
– Hyperventilation
– Impaired consciousness – decreased intake.

14. Events contd.
• Metabolic acidosis – initially due to the excess
ketones.
– Compensatory mechanisms
(1) respiratory compensation,
(2) intracellular buffering – excess H+ goes into
cells in exchange for potassium.
(3) bicarbonate buffering system.

15. Events contd.
• Ionic changes –
– A general loss of electrolytes due to osmotic
diuresis.
– Potassium – intracellular buffering mechanism
shifts potassium out of cells so even if there is
decreased total potassium in the body, serum
potassium may initially be normal or even high.
This potassium is further lost through the kidneys.

16. • Paradoxes of DKA
– Hyperglycemia despite decreased intake
– Polyuria despite dehydration
– Catabolic state despite hyperglycemia

17. DKA Vs HHS
• Degree of hyperglycemia
– 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
– Not found in HHS….why?
• Minimal insulin may be sufficient to minimise ketosis
but does not control hyperglycemia

18. In summary….
• Hyperglycemia results from impaired glucose
utilization, increased gluconeogenesis and increased
glycogenolysis
• Ketoacidosis results from lipolysis, with synthesis of
ketones from free fatty acids in the liver
mitochondria.
• Glucose concentrations are most often lower
(usually <800 mg/dL [44 mmol/L]) in DKA compared
to HHS.
• Insulin levels in HHS are insufficient to allow
appropriate glucose utilization, but are adequate to
prevent lipolysis and subsequent ketogenesis.

19. References
• Harrison, 18th Edition
• Uptodate 19.3
• The World Wide Web