1. DR. OLASOPE A.C REGISTRAR ENDOCRINOLOGY UNIT.

2. OUTLINE Introduction. Pathophysiology. Effects. Diabetic Ketoacidosis Vs Hyperglycaemic Hyperosmolar State. Summary. References.

3. Insulin Glucagon Epinephrine Cortisol Growth Hormone INTRODUCTION. Two hormonal abnormalities: – Insulin deficiency and/or resistance. – Glucagon excess increased secretion of catecholamines and cortisol

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

5. Normally… Hyperglycemia ↑Insulin ↑Glucose uptake ↓Glucose production ↓ Gluconeogenesis ↓ Glycogenolysis Normoglycemia

6. Hyperglycemia ↑Insulin ↓Glucose uptake ↑Glucose production ↑Glucose production ↑ Gluconeogenesis ↑ Glycogenolysis Hyperglycemia

7. 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 bodies Ketone bodies Acetoacetate Acetone β-hydroxbutyrate

9. 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

10. 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

11. 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

12. 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

13. Protein metabolism There will be ↑ protein breakdown & production of amino acids, which will be used in gluconeogenesis

16. Events Dehydration – Osmotic Diuresis – blood glucose exceeds the renal threshold (160-180mg/dl) – Vomiting – Hyperventilation – Impaired consciousness – ↓ intake

17. 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.

18. 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

19. PARADOXES OF HYPERGYCAEMIC EMERGENCIES. – Hyperglycaemia despite ↓ intake – Polyuria despite dehydration – Catabolic state despite hyperglycaemia

20. 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.

21. 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.

22. 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 8 th 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 12 th ed. Saunders Elsevier 2011 Fauci et al, 2012; Harrison’s principles of internal medicine 18th edition