2. “Developing and Nurturing a Career in GI Research” M. Michael Wolfe, M.D. Professor of Medicine Research Professor of Physiology and Biophysics Boston University School of Medicine Chief, Section of Gastroenterology, Boston Medical Center “Developing and Nurturing a Career in GI Research” M. Michael Wolfe, M.D. Professor of Medicine Research Professor of Physiology and Biophysics Boston University School of Medicine Chief, Section of Gastroenterology, Boston Medical Center

3. CAREER OPTIONS IN GI Private practice Pharmaceutical industry Academia Clinician-educator Clinical research Basic research Administration Miscellaneous

4. PRIVATE PRACTICE Advantages Autonomy Financial Satisfaction Disadvantages Intellectual Insecurity “Pure” business Lack of esprit No mobility

5. PHARMACEUTICAL INDUSTRY Advantages Exciting Translational Financial Upward mobility Satisfaction Disadvantages Intellectual Insecurity “Pure” business Goal-oriented No autonomy

6. BASIC RESEARCH Advantages Intellectual Translational Autonomy Upward mobility Satisfaction Contribution to humankind Disadvantages Challenging Frustration Financial Grant dependence

7. BASIC RESEARCH Advantages Intellectual Translational Autonomy Upward mobility Satisfaction Contribution to humankind Disadvantages Challenging Frustration Financial Grant dependence

8. CONTRIBUTION TO HUMANKIND Lives Affected CONTRIBUTION TO HUMANKIND Lives Affected Clinician

9. CONTRIBUTION TO HUMANKIND Lives Affected CONTRIBUTION TO HUMANKIND Lives Affected Clinician Educator

10. CONTRIBUTION TO HUMANKIND Lives Affected CONTRIBUTION TO HUMANKIND Lives Affected Researcher

11. OBESITY IN THE U.S. Epidemiology 61% of adults are overweight (2000) 27% of adults are obese 14% of children are obese Annual mortality due to obesity - 300,000* Expenditures $300 billion $45 billion (consumer) on weight loss products * 450,000 due to tobacco (comparison)

12. INSULIN IS AN EFFICIENCY HORMONE Saltiel AR and Kahn CR. Nature 2001;414:799-806. Insulin is the most potent anabolic hormone known, and promotes the synthesis and storage of carbohydrates, lipids and proteins, while inhibiting their degradation and release into the circulation.

13. INCRETIN Conceptual hormone mediating the enteroinsular axis; released from small intestine by glucose- containing meals and stimulates the release of insulin from pancreatic  -islet cells

14. McIntyre N et al. Lancet 1964;2:20-21. EFFECTS OF ORAL AND IV GLUCOSE ON PLASMA INSULIN AND GLUCOSE EFFECTS OF ORAL AND IV GLUCOSE ON PLASMA INSULIN AND GLUCOSE

15. McIntyre N et al. Lancet 1964;2:20-21. EFFECTS OF ORAL AND IV GLUCOSE ON PLASMA INSULIN AND GLUCOSE EFFECTS OF ORAL AND IV GLUCOSE ON PLASMA INSULIN AND GLUCOSE

16. EFFECT OF ANTGIP ON GIP- STIMULATED INSULIN RELEASE PLASMA INSULIN (  IU/ml) CONDITION 0 10 20 30 40 50 60 70 80 Basal0.9% NaCl ANTGIPGIP GIP GIP 0.5 1.0 1.5 1.5 GIP + ANTGIP * * ** Tseng C-C et al. J Clin Invest 1996;98:2440-5.

17. 0 10 20 30 40 50 60 P L A S M A I N S U L I N (  I U / m l ) TIME (min) 010203040 EFFECT OF ANTGIP ON PLASMA INSULIN AND SERUM GLUCOSE LEVELS ** Tseng C-C et al. J Clin Invest 1996;98:2440-5. ANTGIP No ANTGIP

18. 0 10 20 30 40 50 60 P L A S M A I N S U L I N (  I U / m l ) TIME (min) 010203040 80 100 120 140 160 S E R U M G L U C O S E ( m g / m l ) EFFECT OF ANTGIP ON PLASMA INSULIN AND SERUM GLUCOSE LEVELS ** ANTGIP No ANTGIP Tseng C-C et al. J Clin Invest 1996;98:2440-5.

19. Tseng C-C et al. Am J Physiol 1999;276:E1049-54. EFFECTS OF ANTGIP ON D-GLUCOSE ABSORPTION FROM THE SMALL INTESTINE AUC (  mol/min/g dry wt) *

20. “Overnutrition” GIP Insulin release Storage of fat GIP Antagonist Gut glucose absorption

21. Miyawaki K et al. Nat Med 2002;8:738-42. EFFECT OF HIGH-FAT DIET ON BODY WEIGHT IN GIPR +/+ AND GIPR -/- MICE

22. Miyawaki K et al. Nat Med 2002;8:738-42. EFFECT OF HIGH-FAT DIET ON BODY WEIGHT IN GIPR +/+ AND GIPR -/- MICE

23. Miyawaki K et al. Nat Med 2002;8:738-42. GIPR +/+ GIPR -/-

24. WEIGHT LOSS SURGERY Gastric Bypass

25. WEIGHT LOSS SURGERY Gastric Bypass K-cells (GIP containing)

26. Weeks 024681012 PEPTIDE LEVELS (per ml) -100 0 100 200 300 400 500 GIP (pg/ml) GLP-1 (pmol/ml) Insulin (  U/ml) P = 0.09 P = 0.009 P = 0.003 PEPTIDE LEVELS FOLLOWING GASTRIC BYPASS SURGERY Clements RH et al. Amer Surg 2004;70:1-5. Insulin  by 33%, P=NS; C-peptide  by 29%, P = 0.019; Glucose: 129.3  99.1 n = 20

27. CONTRIBUTION TO HUMANKIND Lives Affected CONTRIBUTION TO HUMANKIND Lives Affected Researcher

28. 5.9 M* 4.5 M* * US diabetes population – 2001 ** Ford ES et al. JAMA 2002;287;356-359. Oral Agents Failing Oral Agents OBESITY AND TYPE 2 DIABETES A Progressive Problem  -cell function Obesity/Diabetes Disease Progression Normal Absent Type 2 Type 1 Insulin only Insulin Weight loss Metabolic syndrome 47 M**

29. BASIC RESEARCH Keys to Success Find the right preceptor/environment Compatible Diverse – MDs, PhDs, others Supportive Identify the project that is interesting to you Spend the necessary time training Other labs Learn as many techniques as possible Learn how to write! Persevere and be patient