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DR. OLASOPE A.CREGISTRAR ENDOCRINOLOGY UNIT.
HYPERGLYCAEMIC EMERGENCIES: Pathophysiology
OUTLINE
• Introduction.• Pathophysiology.• Effects.• Diabetic Ketoacidosis Vs Hyperglycaemic
Hyperosmolar State.• Summary.• References.
Insulin
GlucagonEpinephrine
CortisolGrowth Hormone
INTRODUCTION.
• Two hormonal abnormalities:– Insulin deficiency and/or resistance.–Glucagon excess • increased secretion of catecholamines and cortisol
• These will result in abnormal Metabolism of:– Fat–Carbohydrate–Protein
Normally…Hyperglycemia ↑Insulin
↑Glucose uptake↓Glucose production
↓Gluconeogenesis ↓Glycogenolysis
Normoglycemia
Hyperglycemia ↑Insulin
↓Glucose uptake↑Glucose production
↑ Gluconeogenesis ↑ Glycogenolysis
Hyperglycemia
Fat metabolism• ↓insulin & ↑cathecholamines → Lipolysis • ↑lipolysis →→ elevation of Free Fatty Acids in
plasma– mobilization to the liver– Normally, these would be converted into
Triglycerides & Very Low Density Lipoproteins, – but the presence of GLUCAGON alters the hepatic
metabolism to form ketone bodiesKetone bodies
AcetoacetateAcetone
β-hydroxbutyrate
Acetyl-CoA Acetyl-CoA
Acetoacetyl-CoA
HMG-CoA
Acetoacetate
Acetone β-Hydroxybutyrate
CoA-SH
Acetyl-CoA
CoA-SH
H2O
Acetyl-CoANADH+H+
NADCO2
Thiolase
HMG-CoA synthase
HMG-CoA lyaseβ-Hydroxybutyrate dehydrogenase
EFFECTS OF KETONES
• Weak acids which dissociate completely at normal pH
• Create a major H+ load that soon exceeds normal buffering mechanisms
• Hyperventilation eliminates some of the acid• Some are lost in urine buffered by phosphate
and ammonia• While some have Na+ as the accompanying
cation
EFFECT OF EXCESS H+
• Negative ionotropic effect causing peripheral vasodilation, resulting in ↓ BP, warm extremities & ↑ or normal body temp
• If pH falls below 7.0, there may be inhibition of the CNS →→ paradoxical normal RR
CARBOHYDRATE METABOLISM
Insulin deficiency • ↓ hepatic level of fructose-2,6-bisphosphate,
which alters phosphofructokinase & fructose-1,6-bisphosphatase activity thus promoting GLYCOLYSIS.
• Decrease in GLUT-4 Transporter
CARBOHYDRATE METABOLISM.
Glucagon excess • Depresses GLYCOLYSIS by↓ pyruvate kinase
activity causing the intermediates to be shuttled in gluconeogenesis.
• Activates GLUCONEOGENESIS by↑phosphoenolpyruvate carboxykinase activity
• Promotes GLYCOGENOLYSIS
Protein metabolism
• There will be ↑ protein breakdown & production of amino acids, which will be used in gluconeogenesis
Events
• Dehydration – Osmotic Diuresis – blood glucose exceeds the
renal threshold (160-180mg/dl)– Vomiting– Hyperventilation– Impaired consciousness – ↓ intake
Events contd.
• Metabolic acidosis – due to ↑ ketones – Compensatory mechanisms
(1) respiratory compensation, (2) intracellular buffering – excess H+ goes into cells in exchange for potassium. (3) HCO3- buffering system.
Events contd.
• Ionic changes – – A general loss of electrolytes due to osmotic
diuresis. – K+ – intracellular buffering mechanism shifts K+ out
of cells so even if there is ↓ total K+ in the body, serum K+ may initially be normal or even ↑ This K+ is further lost through the kidneys
PARADOXES OF HYPERGYCAEMIC EMERGENCIES.
– Hyperglycaemia despite ↓ intake– Polyuria despite dehydration– Catabolic state despite hyperglycaemia
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 – Absent/Minimal in HHS….why?
• Minimal insulin may be sufficient to minimize ketosis but does not control hyperglycemia.
• Decreased adipocytes in the elderly.
In summary….
• HEs result from imbalance between Insulin and Counter regulatory hormones.
• Hyperglycaemia results from ↑ hepatic glucose production and its ↓ uptake.
• Ketoacidosis results from lipolysis with release of FFA which serves as precursors for ketone bodies.
• Insulin levels in HHS are insufficient to allow appropriate glucose utilization but are adequate to prevent lipolysis.
REFERENCES.
• Gale EAM, Anderson JV Diabetes mellitus and other disorders of metabolism in Kumar P, Clark M, Kumar and Clark’s Clinical Medicine, pp 1001-1031, ch. 20 8th ed. Saunders Elsevier 2012
• Eisenbarth GS,Buse JB Type 1 diabetes mellitus in Melmed S, Polonsky KS, Larsen PR, Kronenberg HM Williams Textbook of Endocrinology pp 1436-1457 ch 32 12th ed. Saunders Elsevier 2011
• Fauci et al, 2012; Harrison’s principles of internal medicine 18th edition