Anesthesia Pharmacology Chapter 23:  Co-Existing Disease:  Diabetes

Diabetic Ketoacidosis

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Diabetic Ketoacidosis

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:

        1. release of residual insulin present and some patients with IDDM

        2. insulin-induced glucose transport in the periphery

Effects of these hormonal changes:

  • cause maximal gluconeogenesis

  • impair peripheral glucose utilization-- resulting in severe hyperglycemia

  • 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.

* 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.

 

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.
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 2060-2080
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