Insulin Analogs

1. Insulin Analogs A Probative Look at the Hormone in Structure, Function, and Future Structure of Human Insulin 1 B chain A chain • 51 amino acids • 2 chains • 3 disulfide bonds

2. Function of Human Insulin • Glucoregulation • Cell Type • Hormones • Duration of Contact • Metabolism • Carbohydrates • Lipids • Proteins • Growth • Differentiation • Energy Homeostasis • Leptin • Ghrelin 2

3. Important Organs 3 Insulin is made in the pancreas Insulin is absorbed primarily through the liver The kidneys are also insulin clearing organs, especially in people with IDDM

4. How Insulin Works • Blood Glucose Levels >100mg\dL • Released in Phases • Early Phase • Cephalic stage… 2 min • First stage… 5-10min • Late Phase • 2-3 hours • Typical doses • 1.8U/2.7U/7.2U secreted for 10g/25g/100g of glucose 4

5. NON-Diabetic Insulin concentrations peak at 30-45 min Basal secretion of insulin lasts 2-3 hours Diabetic (IDDM) Insulin concentrations peak at 3-4 hours There is no basal effect The Problem

6. Analogs! The Solution… • Short-Acting Analogs • Lispro (LysB28, ProB29) • Novolog (AspB28) • Apidra (LysB3, GluB29) • Pros • Faster peak times • Shorter duration • Cons • Increased risk of ketoacidosis • Still no basal coverage 5 • Long-Lasting Analogs • Lantus (GlyA21, ArgB31, ArgB32) • Pros • 24 hour basal line coverage • No peaking effects • Cons • Must be used with a short-acting insulin • http://www.lantus.com/hcp/works.aspx

7. New Analog Possibilities • Ultra-rapid insulin • Ultra-long insulin • Weight differentiated insulin • Insulin as a preventative treatment

8. Sources Used Duckworth, William C., Robert G. Bennett, and Frederick G. Hamel. “Insulin Degradation: Progress and Potential.” The Endocrine Society. 19.5 (1998). 22 Oct. 2007 <http://edrv.endojournals.org/cgi/ content/full/19/5/608?>. Vajo, Zoltan, Janet Fawcett, and William C. Duckworth. “Recombinant DNA Technology in the Treatment of Diabetes: Insulin Analogs.” The Endocrine Society. 22.5 (2001). 21 Oct. 2007 <http://edrv.endojournals.org/cgi/content/full/22/5/ 706?>. Nakagawa, Satoe H. and Howard S. Tager. “Role of the COOH-terminal B-chain Domain in Insulin-Receptor Interactions: Identification of Perturbations involving the Insulin Mainchain.” The Journal of Biological Chemistry. 262.25 (1987). 21 Oct. 2007 <http://www.jbc.org/cgi/reprint/262/25/ 12054>. Ciaraldi, Theodore P., Susan A. Phillip, Leslie Carter, Vanita Aroda, Sunder Mudaliar, and Robert R. Henry. “Effects of the Rapid-Acting Insulin Analog Glulisine on Cultured Human Skeletal Muscle: Comparisons with Insulin and Insulin-Like Growth Factor I.” The Journal of Clinical Endocrinology & Metabolism. 90.10 (2005). 22 Oct. 2007 <http://jcem.endojournals.org/cgi/content/full/90/10/5 551>. DiCostanzo, Catherine A., Mary Courtney Moore, Margaret Lautz, Melanie Scott, Ben Farmer, Carrie A. Everett, J. Gordon Still, Alan Higgins, and Alan. D. Cherrington. “Simulated First-phase Insulin Release Using Humulin or Insulin Analog HIM2 is Associated with Prolonged Improvement in Postprandial Glycemia.” American Journal of Physiology- Endocrinology and Metabolism. 289 (2005). 23 Oct.2007 <http://ajpendo.physiology.org/cgi/content/full/289/1/E46>. Griffen, Steven C., Kimberly Oostema, Kimber L. Stanhope, James Graham, Dennis M. Styne, Nicole Glaser, David E. Cummings, Matthew H. Conners, and Peter J. Havel. “Administration of Lispro Insulin with Meals Improves Glycemic Control, Increases Circulating Leptin, and Supresses Chrelin, Compared with Regular/NPH Insulin in Female Patients with Type 1 Diabetes.” The Journal of Clinical Endocrinology & Metabolism. 91.2 (2006). 22 Oct. 2007 <http://jcem.endojournals. org/cgi/content/full/91/2/485>. Noble, Sara L., Elizabeth Johnston, and Bill Walton. “Insulin Lispro: A Fast-Acting Insulin Analog.” American Family Physician. 57.2 (1998). 22 Oct. 2007 <http://www.aafp.org/afp/980115ap/noble. html>. Ciaraldi, T. P., L. Carter, G. Seipke, S. Mudaliar, and R. R. Henry. “Effects of the Long-Acting Insulin Analog Insulin Glargine on Cultured Human Skeletal Muscle Cells: Comparisons to Insulin and IGF-I.” The Journal of Clinical Endocrinology & Metabolism. 86.12 (2001). 19 Oct. 2007 <http://jcem.endojournals.org/cgi/content/full/86/12/5838>. Plank, Johannes, Andrea Siebenhofer, Andrea Berhold, Klaus Jeitler, Karl Horvath, Peter Mrak, Thomas R. Pieber. “Systemic Review and Meta-analysis of Short-Acting Insulin Analogues in Patients with Diabetes Mellitus.” Archives of Internal Medicine. 165.2 (2005). 22 Oct. 2007 <http://archinte.ama-assn.org/cgi/content/full/165/12/1337>. Schwartz, Gerald P., G. Thompson Burke, and Panayotis G. Katsoyannis. “A Superactive Insulin: [B 10-aspartic Acid] Insulin (Human).” Proceedings of the National Academy of Sciences of the United States of America. 84.18 (1987). 21 Oct. 2007 <http://www.pnas.org/cgi/content/abstract/84/18/ 6408>. Guerci, Bruno, Laurent Meyer, Agnes Salle, Anne Charrie, Brigitte Dousset, Olivier Ziegler, and Pierre Drouin. “Comparison of Metabolic Deterioration between Insulin Analog and Regular Insulin after a 5-Hour Interruption of a Continuous Subcutaneous Insulin Infusion in Type 1 Diabetic Patients.” The Journal of Clinical Endocrinology & Metabolism. 84.8 (1999). 19 Oct. 2007 <http://jcem. endojournals. org/cgi/content/full/84/8/2673?>.

9. Pictures Used • “Sequence of Insulin” from www.ysbl.york.ac.uk/.../thesis-tth/chapter1.html • “Solution structures of the R6 human insulin hexamer” from http://www.lcsc.edu/rjameton/chem10805/chem10805.htm • “Subdivisional surface model of the human liver, kidneys, pancreas and bladder” from http://www.turbosquid.com/FullPreview/Index.cfm/ ID/274335 • “Image of an Insulin Vile” from http://www.cdc.gov/diabetes/pubs/ tcyd/control.htm • “Insulin Lispro” from http://www.rxlist.com/cgi/generic/insulinlispro.htm