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“Developing and Nurturinga 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 Nurturinga 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
CAREER OPTIONS IN GICAREER OPTIONS IN GI
• Private practice• Pharmaceutical industry• Academia
Clinician-educator
Clinical research
Basic research
Administration
Miscellaneous
PRIVATE PRACTICEPRIVATE PRACTICE
Advantages
Autonomy
Financial
Satisfaction
Disadvantages
Intellectual
Insecurity
“Pure” business
Lack of esprit
No mobility
PHARMACEUTICAL INDUSTRYPHARMACEUTICAL INDUSTRY
Advantages
Exciting
Translational
Financial
Upward mobility
Satisfaction
Disadvantages
Intellectual
Insecurity
“Pure” business
Goal-oriented
No autonomy
BASIC RESEARCHBASIC RESEARCH
Advantages
Intellectual
Translational
Autonomy
Upward mobility
Satisfaction
Contribution to humankind
Disadvantages
Challenging
Frustration
Financial
Grant dependence
BASIC RESEARCHBASIC RESEARCH
Advantages
Intellectual
Translational
Autonomy
Upward mobility
Satisfaction
Contribution to humankind
Disadvantages
Challenging
Frustration
Financial
Grant dependence
CONTRIBUTION TO HUMANKINDLives Affected
CONTRIBUTION TO HUMANKINDLives Affected
Clinician
CONTRIBUTION TO HUMANKINDLives Affected
CONTRIBUTION TO HUMANKINDLives Affected
ClinicianEducator
CONTRIBUTION TO HUMANKINDLives Affected
CONTRIBUTION TO HUMANKINDLives Affected
Researcher
OBESITY IN THE U.S.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)* 450,000 due to tobacco (comparison)
INSULIN IS AN EFFICIENCY HORMONEINSULIN 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.
INCRETININCRETIN
Conceptual hormone mediating the enteroinsular axis; released from small intestine by glucose-containing meals and stimulates the release of insulin from pancreatic -islet cells
Conceptual hormone mediating the enteroinsular axis; released from small intestine by glucose-containing meals and stimulates the release of insulin from pancreatic -islet cells
McIntyre N et al. Lancet 1964;2:20-21.
EFFECTS OF ORAL AND IV GLUCOSEON PLASMA INSULIN AND GLUCOSE EFFECTS OF ORAL AND IV GLUCOSEON PLASMA INSULIN AND GLUCOSE
McIntyre N et al. Lancet 1964;2:20-21.
EFFECTS OF ORAL AND IV GLUCOSEON PLASMA INSULIN AND GLUCOSE EFFECTS OF ORAL AND IV GLUCOSEON PLASMA INSULIN AND GLUCOSE
EFFECT OF ANTGIP ON GIP-STIMULATED INSULIN RELEASE
EFFECT OF ANTGIP ON GIP-STIMULATED INSULIN RELEASE
PL
AS
MA
INS
UL
IN (I
U/m
l)
CONDITION
0
10
20
30
40
50
60
70
80
Basal 0.9%NaCl
ANTGIP GIP GIP GIP 0.5 1.0 1.5
1.5 GIP + ANTGIP
**
**
Tseng C-C et al. J Clin Invest 1996;98:2440-5.
0
10
20
30
40
50
60P
LA
SM
A I
NS
UL
IN(
IU/ m
l)
TIME (min)0 10 20 30 40
EFFECT OF ANTGIP ON PLASMA INSULIN AND SERUM GLUCOSE LEVELS
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
0
10
20
30
40
50
60P
LA
SM
A I
NS
UL
IN(
IU/ m
l)
TIME (min)0 10 20 30 40
80
100
120
140
160
SE
RU
M G
LU
CO
SE
(mg
/ml)
EFFECT OF ANTGIP ON PLASMA INSULIN AND SERUM GLUCOSE LEVELS
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.
0
10
20
30
40
50
0.9% NaCl ANTGIP
0.9% NaCl
ANTGIP
Tseng C-C et al. Am J Physiol 1999;276:E1049-54.
EFFECTS OF ANTGIP ON D-GLUCOSEABSORPTION FROM THE SMALL INTESTINE
EFFECTS OF ANTGIP ON D-GLUCOSEABSORPTION FROM THE SMALL INTESTINE
AU
C (m
ol/m
in/g
dry
wt)
*
“Overnutrition”
GIP Insulin release
Storage of fatGIPAntagonist
Gut glucose absorption
Miyawaki K et al. Nat Med 2002;8:738-42.
EFFECT OF HIGH-FAT DIET ON BODYWEIGHT IN GIPR+/+ AND GIPR-/- MICE EFFECT OF HIGH-FAT DIET ON BODYWEIGHT IN GIPR+/+ AND GIPR-/- MICE
Miyawaki K et al. Nat Med 2002;8:738-42.
EFFECT OF HIGH-FAT DIET ON BODYWEIGHT IN GIPR+/+ AND GIPR-/- MICE EFFECT OF HIGH-FAT DIET ON BODYWEIGHT IN GIPR+/+ AND GIPR-/- MICE
Miyawaki K et al. Nat Med 2002;8:738-42.
GIPR+/+ GIPR-/-
WEIGHT LOSS SURGERYWEIGHT LOSS SURGERY
Gastric BypassGastric Bypass
WEIGHT LOSS SURGERYWEIGHT LOSS SURGERY
Gastric BypassGastric Bypass
K-cells (GIPK-cells (GIPcontaining)containing)
Weeks
0 2 4 6 8 10 12
PE
PT
IDE
LE
VE
LS
(p
er
ml)
-100
0
100
200
300
400
500
GIP (pg/ml)
GLP-1 (pmol/ml)
Insulin (U/ml)
P = 0.09P = 0.009
P = 0.003
PEPTIDE LEVELS FOLLOWING GASTRIC BYPASS SURGERYPEPTIDE 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 99.1n = 20
CONTRIBUTION TO HUMANKINDLives Affected
CONTRIBUTION TO HUMANKINDLives Affected
Researcher
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
-cellfunction
Obesity/Diabetes Disease Progression
Normal
Absent
Type 2Type 2
Type 1Type 1
Insulin only
Insulin
Weight loss
Metabolic Metabolic syndromesyndrome
47 M**
BASIC RESEARCHKeys to SuccessBASIC RESEARCHKeys 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