1. Type I Diabetes by Jinbao Cao Department of Chemistry 03/29/2011

2. Universal Symbol for Diabetes Diabetes is a group of diseases marked by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Type 1: results from the body's failure to produce insulin Type 2: results from insulin resistance, a condition in which cells fail to use insulin properly

3. Introduction Current situation  Diabetes affects 25.8 million people, 8.3% of U.S polulation  Diabetes is the leading cause of kidney failure  Diabetes is a major cause of heart disease and stroke  Diabetes is the seventh leading cause of death in the United States National Diabetes Fact Sheet, 2011

5. TYPE 1 Signs and Symptoms Polydipsia(increased thirst) Polyphagia(Increased hunger) Fatigue Weight loss Polyuria(frequent urination)

6. Cause of Type 1 Dibetes Genetic: many different genes contribute to it Enviromental Diet: Wheat, Cow’s milk, Vitamin D, Brest milk etc. Chemicals and Drugs: Vacor, Zanosasr Virus Vacor Zanosar

7. Pathophysiology Glucose concentration increase Glucose concentration decrease Insulin concentration increase Activate Beta cell convert glucose × Glucose concentration increase

8. Diagnose Fasting plasma glucose level at or above 7.0mmol/L (126mg/dL) Plasma glucose at or above 11.1 mmol/L (200mg/dL) two hours after a 75 g oral glucoes load as in a glucose tolerance test

9. Treatment Daily injection of insulin － Under skin － Before meal － Several times － Can’t be swallowed Insulin pump Oral meditation: Pramlintide (Symlin) Health diet: fruits, vegetables, whole wheat Excise: consume glucose

10. New Methods Polymeric materials used as drug delivery Drugs can be bind to biodegradable polymer pedant groups, when polymer breaks down, drug will be released continuously Stimuli responsive polymers. Temperature, pH, glucose etc.

11. Insulin A hormone regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle. When insulin is absent, body begins to use fat as energy source. Lose weight, high blood glucose concentration

12. Insulin history 1921 Frederick Banting and John Macleod first isolated insulin and successfully used to treat diabetes 1923 - MacLeod and Banting received Nobel Prize in Physiology and Medicine for insulin discovery 1955 Frederick Sanger won Nobel Prize in Chemistry for determining first order structure of insulin

13. Primary Structure of Insulin Amino acid sequence

14. Secondary Structure of Insulin Hydrogen bonding stabilizes insulin Blue: chain A Red: chain B

15. Tertiary Structure of Insulin Disulfide bond(yellow) -SH+-SH S-S Disulfide bond formed Between 6 CYS residues Two disulfide bond between Chain A and Chain B, one between Chain A In addition salt bridge and Van de Waals force also exist

16. Quaternary structure of Insulin Hydrophobic interaction between molecules General form in beta cell and blood Dimers also formed Active form is single molecular

17. Synthesis of Insulin In vivo, produced within pancreas by  cells. Pig insulin and cattle insulin are very similar to human insulin Chinese scientists firstly synthesized insulin 1965 Today, insulin is mostly made biosynthetically by recombinant DNA technology or 'genetic engineering'.

18. Release of Insulin First phase: triggered by increase blood GLU -Glucose enters the β-cells through the glucose transporter GLUT2 -Glucose goes into glycolysis and the respiratory cycle, where multiple high-energy ATP molecules are produced by oxidation -Dependent on the ATP:ADP ratio, and hence blood glucose levels, the ATP- dependent potassium channels (K + ) close and the cell membrane depolarizes -On depolarization, voltage controlled calcium channels (Ca 2+ ) open and calcium flows into the cells -An increased calcium level causes activation of phospholipase C, which cleaves the membrane phospholipid phosphatidyl inositol 4,5-bisphosphate into inositol 1,4,5-triphosphate and diacylglycerol. -Inositol 1,4,5-triphosphate (IP3) binds to receptor proteins in the membrane of endoplasmic reticulum (ER). This allows the release of Ca 2+ from the ER via IP3 gated channels, and further raises the cell concentration of calcium. -Significantly increased amounts of calcium in the cells causes release of previously synthesized insulin, which has been stored in secretory vesicles Second phase: slowly release of newly formed insulin

19. Oscillations Insulin release from pancreas is not continuous Oscillates within a period of 3-6min Concentration from 100pmol/L—800pmol/L (A picomole is one-trillionth of a mole) Guidance for injection of insulin

20. Degradation of Insulin Degraded one hour after release After work, either release back into extracellular environment or degraded by the cell Usually happens in liver or kindney

21. Questions What are the difference between type 1 and type 2 diabetes? To the level of the causes of two types. What are signs of type I diabetes? What is major force for the secondary structure of insulin?

22. Assigned reading Goodman and Gillman, Chapter 43, pp. 1237- 1254 (large type only). Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia (This a report of a WHO/IDF consultation, which introduces diabetes mellitus. You can read this report if you are interested. The precious questions are not based on this paper.)

23. Reference http://en.wikipedia.org/wiki/Diabetes_mellitus_type_1 http://en.wikipedia.org/wiki/Insulin National Diabetes Fact Sheet, 2011 Jeffrey A. Bluestone1, Vol 464(29) April 2010, Nature Bart O. Roep, Diabetologia (2003) 46:305–321 Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia