Biology of Disease

reducing the action of insulin. The pathogenesis of DKA is outlined in Figure
7.25. In DKA, glucose uptake by cells decreases whereas gluconeogenesis
and glycogenolysis are both stimulated, causing severe hyperglycemia.
Increased breakdown of proteins occurs and the released amino acids enter
gluconeogenesis or are degraded to form urea. As a result of insulin deficiency,
there is a shift of both K+ and Pi from the intracellular to the extracellular
compartments causing hyperkalemia and hyperphosphatemia respectively
(Chapter 8). The insulin deficiency also stimulates lipolysis producing free fatty
acids (FFAs) and glycerol. In the liver, FFAs are converted to acetyl CoA which
is then converted to acetoacetate and finally acetone and B-hydroxybutyrate.
Acetoacetate, acetone and B-hydroxybutyrate are called ketone bodies even
thoughB-hydroxybutyrate is not a ketone. The liver cannot utilize ketone
bodies and they accumulate in the blood (ketonemia) and may be excreted in
the urine (ketonuria). The ketone bodies in the blood are moderately strong
acids, H+Ketone–, and react with buffers, such as NaHCO 3 (Chapter 9),

H+Ketone– + NaHCO 3 Na+Ketone– + H 2 CO 3

decreasing the concentration of hydrogen carbonate but increasing that of
carbonic acid producing an acidosis. The carbonic acid dissociates to CO 2 and
H 2 O and the blood PCO 2 increases. Thus the lung ventilation rate increases
as the body attempts to remove the excess CO 2. The ketonemia is believed to
be responsible for the abdominal pain, vomiting and acidosis associated with
DKA. Severe hyperglycemia in DKA exerts a high osmotic pressure causing
water to move out of the cells leading to cellular dehydration. Blood volume
rises and the kidneys respond with polyuria. If blood glucose levels exceed
the renal threshold, glucose is lost in the urine causing glycosuria. Eventually
an osmotic diuresis may occur with loss of water and electrolytes. The blood
volume therefore declines further (hypovolemia) reducing the glomerular

REGULATION OF BLOOD GLUCOSE

CZhhVg6]bZY!BVjgZZc9Vlhdc!8]g^hHb^i]:YLddY &,.

Figure 7.25 An overview of the factors causing

diabetic ketoacidosis (DKA). See text for details.

Increased

Decreased

INSULIN

Glucose uptake

K+ uptake

Hyperkalemia

Hyperphosphatemia

Phosphate

release

Protein

catabolism

Gluconeogenesis

Glycogenolysis

Loss of

Na+

K+

H 2 O

Plasma

osmolality

Thirst

Acidosis

Hypovolemia

GFR

Uremia

Hyperglycemia

Glycosuria

Osmotic

diuresis

Lipolysis

Free fatty acids

Ketosis

Ketonemia

Ketonuria