Type I Diabetes

1. Type I Diabetes

2. Diabetes • Drinking heaps, urinating heaps • Massive weight loss • “Flesh melting into Urine” • Diabetes = ‘Siphon’ • Death inevitable within weeks • Sugar in urine • Diabetes mellitus • Sweet/organic breath

3. Root Cause • -cell destruction • Auto-immune attack • Extent and time-course variable • Appearance of symptoms varies • Still functional -cells at time of diagnosis

4. What does Insulin do? • Anabolic hormone • Stimulates synthesis of macromolecules • Inhibits catabolism

5. Glucose Uptake • Insulin needed for GLUT-4 translocation • Not GLUT-1 or GLUT-2 • So what is affected? • Not basal or liver glucose transport

6. Glucose Disposal • Lipogenesis • Glycogenesis • Key enzymes not stimulated • Nowhere for glucose to go • [G6P] rise inhibits glucose uptake

7. Protein Synthesis • Little stimulus for protein formation • Amino acids oxidised

8. Glycogenolysis • Normally inhibited by insulin

9. Lipolysis • Insulin inhibits lipolysis • Decreases level of cAMP in fat cells • Lack of insulin leads to uncontrolled fat breakdown • Lots of fatty acids released into blood • And lots of glycerol • Fatty acids will inhibit glucose oxidation

10. Proteolysis • Hypoinsulinemia causes widespread proteolysis • Amino acids released into blood

11. Gluconeogenesis • Insulin normally inhibits enzymes that cause glucose production in the liver • Now we have increased substrate supply too… • Lots of glycerol, amino acids, lactate

12. Ketone Bodies • Massive supply of fatty acids to liver • Removal of Krebs cycle intermediates for gluconeogenesis • So massive ketone body production • Brain lowers use of glucose

13. So… • Uncontrolled release of fatty acids, amin acids and glycerol • Inhibition of glucose storage and oxidation everywhere • Hepatic glucose production increases • Ketone body production enormous

14. Acidosis • Ketone bodies • Lactate • Fatty acids • Severe drop in pH • Ultimately fatal

15. Catabolic Meltdown • “Starvation in the face of plenty” • Hyperglycemia • Glucose not disposed of • Hepatic glucose production

16. Explaining Symptoms • Drinking heaps, urinating heaps • Hyperglycemia changes osmotic strength of blood • Draws water out of tissues • Unquenchable thirst • Massive weight loss • Uncontrolled lipolysis and proteolysis • Sugar in urine • Kidneys cannot reabsorb glucose when blood [Glucose] > 10 mM • Sweet/organic breath • Spontaneous decarboxylation of ketone bodies to acetone

17. Treatment • Before 1920s… no treatment • Banting & Best • Dog pancreatic extracts • Minus the digestive enzymes • Leonard Thompson • Aim to stabilize blood glucose • But also to prevent lipolysis/proteolysis

18. Aims of Control • Avoid prolonged hyperglycemia • Very dangerous in the long run • Glycosylated proteins • Damage to capillaries, retina, kidney • Polyol pathway • Accumulation of sorbitol in nerve cells

19. Insulin Therapy • Several types and blends available • Ultra-rapid – 10 min. immediately pre-meal • Short acting – 30 min • Intermediate – 1-2 hr – can take 6 h to peak • Long acting – 3 h to onset, lasts 24 h – Zn2+ core • Mixtures – 70:30 long short • Analogs - Structural modifications • Lispro – swap 28 & 29 • Aspart – pro to asp at 28 • glulisine- lys and glu at 3 & 29 • glargline – replace A21 and add to arg • detemir – binds to albumin via fatty acid Mooradian et al (2006) Narrative review: a rational approach to starting insulin therapy. Ann Intern Med. 145(2):125-34

20. Monitoring • Regular blood glucose readings • Glycated hemoglobin - HbA1c • to assess medium term diabetic control • base changes in management of patients • Red blood cell 120 day life span • Aim for < 7.5% • but note that hypoglycemia is much more dangerous than hyperglycemia!!

21. Hypoglycemia Unawareness • Impending hypoglycemia warning signs • Sweating, trembling, irritability, dizziness… • Better or worse in long term diabetics?