Bethelhem Berhanu

Diabetic Keto-cidosis: Pathophysiology

Insulin

GlucagonEpinephrine

CortisolGrowth Hormone

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

• These will result in abnormal Metabolism of:–Carbohydrate– Fat–Protein

• Inflammatory process

Normally…Hyperglycemia ↑Insulin

↑Glucose uptake↓Glucose production

↓Gluconeogenesis ↓Glycogenolysis

Normoglycemia

DKAHyperglycemia ↑Insulin

↓Glucose uptake↑Glucose production

↑ Gluconeogenesis ↑ Glycogenolysis

Hyperglycemia

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

• Glucosuria helps in reducing the serum glucose initially, but later….

Osmotic diuresis,

↓GFR

↓ glucose excretion

Volume depletion

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

AcetoacetateAcetone

β-hydroxbutyrate

• 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.

On protein metabolism

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

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.

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.

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.

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

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

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.

References

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