1. Insulin Use in Diabetes Mellitus Jennifer Beggs

2. Introduction History of insulin Manufacture and secretion The insulin receptor Homeostatic role Insulin and diabetes mellitus Types of insulin in DM Rx Insulin use in Type 1 DM Insulin use in Type 2 DM

3. History of insulin 1922: Bovine insulin first extracted 1923: Nobel Prize in physiology and Medicine awarded to Toronto based team – F Banting and JJR MacLeod (shared with Best and Colling) International recognition of Paulescu as the true discoverer of insulin 50 years later 1958: Primary structure determined by British molecular biologist Frederick Sanger (Nobel Prize in Chemistry). First protein to have its sequence be determined 1969: Tertiary structure (conformation) determined by Dorothy Crowfoot Hodgkin, using X-ray diffraction studies

4. Insulin Formation and Secretion Endogenous peptide hormone Coded for on chromosome 11 Controlled release of chemical energy from food Secreted by beta islet cells of pancreas Intracellular conversion: pre-proinsulin to proinsulin to insulin Two pathways: constitutive and regulated Secretion into portal circulation Primary target is liver

5. Insulin Receptor Cell membrane glycoprotein Insulin binding to alpha-subunits Conformational change leads to cascade response Glucose transporter moves to cell surface Increased glucose uptake into cell Receptor complex recycled

6. Glucose homeostasis Homeostasis of blood glucose (63-144 mg/dL) FASTING – Insulin secretion reduced – Regulation of glucose release by liver POSTPRANDIAL – Insulin secretion increased – Increased glucose uptake by fat and muscle Insulin antagonised by ‘anti-insulins’ – Gluycagon – Adrenaline – Human growth hormone – Cortisol

7. Insulin and Diabetes Mellitus Diabetes mellitus: Syndrome of chronic hyperglycaemia due to insulin deficiency, resistance, or both Type 1 DM: Absolute insulin deficiency Type 2 DM: Relative insulin deficiency and/or insulin resistance

8. Types of Insulin Rx Animal versus biosynthetic human insulin Short acting insulin – Soluble insulin – Rapid acting insulin analogues Intermediate/long acting – Protamine/zinc formulations – Long acting insulin analogues Mixed insulin (biphasic)

9. Short Acting Insulins Soluble – SC administration Onset 30-60 mins Peak 2-4 hrs Duration <8 hrs Rapid analogues – Lispro, Aspart – Quicker onset, shorter half-life – Reduced hypoglycaemia

10. Intermediate / Long acting Addition of protamine/zinc – crystal formation SC administration – Onset 1-2 hrs – Peak 4-12 hrs – Duration 16-35 hrs Analogues – Glargine – Reduced solubility at lower pH

11. Mixed (Biphasic) Pre-mixed insulin containing a short and intermediate/long acting insulin Usually 30:70 ratio Fewer injections Less flexibility of lifestyle

12. Example Regimens in Type 1 DM Mixed insulin bd before meals Short acting td before meals and intermediate/long od before bed Adjustment of insulin as appropriate for blood glucose result

13. Treatment Pathway in Type 2 DM HB1Ac >7.5% Non-Obese Obese HB1Ac >7.5% @ 3 mths Risk factor reduction Sulphonylurea Metformin Combination oral therapy ADD INSULIN

14. Hypoglycaemia Most common complication of insulin Rx Precipitated by alcohol, irregular eating habit, raised exertion levels Symptoms and signs develop over a few minutes – Sweating – Tremor – Palpitations – Drowsiness – Behavioural changes – Coma – Rarely – convulsions, hemiparesis Most DM sufferers experience symptoms 1/3 with at least one episode of coma

15. Thank you! Questions?