DR. OLASOPE A.C REGISTRAR ENDOCRINOLOGY UNIT.. OUTLINE Introduction. Pathophysiology. Effects. Diabetic Ketoacidosis Vs Hyperglycaemic Hyperosmolar State.

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