Causes:
- requires insulin
deficiency and a relative/absolute increase in
glucagon
- precipitated
by:
- cessation of insulin intake
- glucagon increases
secondary to insulin withdrawal
- physical stress (infection,
surgery) and/or emotional stress -- even
with continued insulin treatment
- glucagon
releases enhanced by increased
circulating catecholamines
- epinephrine
may also block:
- release
of residual insulin
present and some patients
with IDDM
- insulin-induced
glucose transport in the
periphery
- Enhanced Gluconeogenesis -- role of
glucagon:
- Glucagon enhances
gluconeogenesis
 by:
- causes a
 reduction in
fructose-2,6-bisphosphate (a metabolic
intermediate that stimulates glycolysis
and blocks gluconeogenesis)
- Hyperglycemia
Results
- Consequences of hyperglycemia:
- Osmotic diuresis
- Volume depletion/dehydration--
characteristic of ketoacidotic condition
- Hormonal changes (insulin deficiency with
the relative/absolute increase in glucagon) activate ketogenic
process -- leading to metabolic acidosis
Ketosis
- Free fatty acids from fat
stores are primary substrates for ketone
body formation
- High plasma free fatty
acid levels are required for significant
ketogenesis
- Normally the concentration
of plasma free fatty acids are lowered by
the liver where fatty acids are
reesterified and stored as hepatic
triglyceride or converted into VLDL -- unless
the system for hepatic oxidation of fatty
acids becomes activated.
- Release of free fatty
acids is increased by insulin
deficiency;
- accelerated hepatic
fatty acid oxidation is caused by
glucagon-- by acting on carnitine
palmitoyltransferase enzymes (CPT)
- Activation of
carnitine palmitoyltransferase I (CPT I),
normally inactive, is activated by
uncontrolled diabetes (or starvation)
- Activation of
carnitine palmitoyltransferase I (CPT I)
allows long-chain free fatty acids to
reach beta-oxidative enzymes localized in
the mitochondrial matrix where ketone
body production occurs.
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* For more details see: Foster, D. W.,
Diabetes Mellitus, In Harrison's Principles of Internal
Medicine 14th edition, (Isselbacher, K.J., Braunwald, E.,
Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L.,
eds) McGraw-Hill, Inc (Health Professions Division),
1998, pp 2071-2072.
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Regulation
of Ketogenesis
- Ketogenesis:
Significant acetoacetate and beta-hydroxybutyrate
production by the liver require (a) enough free
fatty acid substrate and (b) activation of fatty
acid oxidation. Lipolysis -- enhanced by insulin
deficiency; Fatty acid oxidation sequence --
activated mainly by glucagon; (immediate signal
for oxidation: fall in malonyl-CoA concentration)
-- figure above adapted from:
Figure 334-4 Foster, D. W., Diabetes
Mellitus, In Harrison's Principles of Internal
Medicine 14th edition, (Isselbacher, K.J.,
Braunwald, E., Wilson, J.D., Martin, J.B., Fauci,
A.S. and Kasper, D.L., eds) McGraw-Hill, Inc
(Health Professions Division), 1998, p 2072.
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