a preprandial rise in plasma ghrelin levels suggests a ...wadepage.org/files/file/2012 annual...
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Metabolic Surgery:
Endocrine Mechanisms of Diabetes
Remission After “Bariatric” Operations
David E. Cummings, M.D.
University of Washington, VA Puget Sound,
Diabetes & Obesity Center of Excellence, Seattle
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I am P.I. on the COSMID trial
(Comparison of Surgery vs.
Medicines for Indian Diabetes),
funded by Johnson & Johnson
Disclosure
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Adjustable
Gastric
Banding (LAGB)
Some Clinically Used Bariatric Operations
Roux-en-Y
Gastric
Bypass (RYGB)
Bilio-
Pancreatic
Diversion (BPD)
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Roux-en-Y Gastric Bypass (RYGB)
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Swedish Obese Subjects Study
Years of Follow Up
Total Body
Weight Loss
(%)
Sjöström L, et al. JAMA 307:56 (2012)
Gastric Bypass
Gastroplasty
Banding
Usual
Care
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Clev Clin J Med, 2006
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Bariatric Operative Mortality
• Pure Restrictive Procedures: <0.1%
• Lap Gastric Bypass: 0.2%
• BPD or DS: 1.1%
Most perioperative mortality from PE or sepsis
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Effect of Bariatric Surgery on Long-Term Mortality
Compared With Non-Operated Controls
72% 12 yr LAGB Dixon, 2007
31% 14 yr VBG/other Sjostrom, 2007
40% 8.4 yr RYGB Adams, 2007
63% 4.4 yr RYGB Sowemimo, 2007
89% 5 yr RYGB Christou, 2004
33% 4.4 yr RYGB Flum, 2004
88% 9 yr RYGB MacDonald, 1997
Mortality
Reduction F/U Procedure Study
Perry, 2008 48% 2 yr RYGB/LAGB
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Cost per QALY
• Bariatric surgery: $3,200 – $6,300
• Renal Dialysis: $50,000
(accepted societal std)
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Bariatric Operations in USA
Steinbrook R. NEJM 350:1075 (2004)
# B
ari
atr
ic S
urg
eri
es i
n t
he U
SA
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003
Year
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How does gastric
bypass cause type 2
diabetes remission?
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Gastric Bypass Reverses Diabetes
• 80-85% full remission of type 2 DM after RYGB
– Buchwald meta-analysis 22,094 patients
– Schauer, et al. 1,160 patients
– Whitgrove, et al. 1,029 patients
– Pories, et al. 608 patients
– Buchwald meta-analysis 2 135,246 patients
– Many others
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How does it work?
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Swedish Obese Subjects Study
Years After Surgery
Total Body
Weight Loss
(%)
Gastric Bypass
Gastroplasty
Gastric Banding
Medical
Management
Sjostrom L, et al, NEJM 357:741 (2007)
15 10 8 6 4 3 2 1 0
–30%
–20%
–10%
0
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Insulin Sensitivity After RYGB
– hepatic, muscle, and adipose insulin sensitivity
– HMW adiponectin, apelin
– inflammatory cytokines, ER stress, YKL-40
– hepatic steatosis-inducing factor CIDEC
– intramuscular & hepatic lipids & FACoA
– muscle insulin receptor concentration
– muscle PGC1 and its target Mfn2
* All Long-Term Effects * DE Cummings
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insulin sensitivity
with weight loss
undoubtedly plays
an important role
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0
100
200
300
400
500
0 4 8 12 16 20 24 28
Days After Surgery
Blood
Glucose
(mg/dl)
Rapid Improvement of Diabetes After RYGB
90 units insulin
0 insulin 0 0
4
8
4
8
8
16
Adapted from
Pories W, 1980
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Rapid Resolution of Diabetes After RYGB
• Prospective study of
1160 RYGB patients
• 240 with DM on oral
meds and/or insulin,
80% F/U
• 83% DM resolution 0
5
10
15
20
25
30
35
Overall <5 6-10 >10
% Diabetes
Resolved
Upon Initial
Hospital
Discharge
Duration of DM
Schauer PR et al , Ann Surg 238:467
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Just Starvation
& Weight Loss
or
Something Special?
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Biliopancreatic
Diversion
>95% (Immediate)
48% (Slow)
Roux-en-Y
Gastric Bypass
84% (Immediate)
Adjustable
Gastric Banding
Rates of Remission of Diabetes
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• Fast kinetics of diabetes resolution
• Glucose homeostasis improves more with RYGB
than with equal weight loss from other means
Poor correlation between amount of weight lost
and DM remission rates after RYGB
DE Cummings
Evidence for Weight-Independent Anti-DM Effects
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Bypass
Band
% W
eig
ht
Lo
ss
Time (months)
Percentage Weight Loss Percentage With Diabetes
Time (months)
Long-Term Follow-Up of Gastric Bypass vs. Gastric Banding
Bypass
Band
% W
ith
Dia
bete
s
C. le Roux, et al
Ann Surg 252:966 (2010)
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Francois Pattou
(Lille, France)
Inclusion
10% weight loss
HbA1c
HOMA-IR
Insulin (test meal)
Incretins
BMI > 35 kg/m2 and type 2 diabetes
1 year
Controlled,
non-randomized,
prospective study
50 Patients
AGB RYBG
Trial of Gastric Banding vs. Bypass
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Gastric Banding
Gastric Bypass
F Pattou, et al
Plasma
Glucose
Glycemic Responses to Post-op Test Meal
After 10% Weight Loss in Both Groups
Time After Test Meal
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Effects on Glucose Homeostasis of
Equivalent Weight Loss from RYGB vs. Diet
Type 2 diabetes patients
matched for BMI, age, degree of diabetes
Studied at
9.7 kg
Studied at
9.2 kg
RYGB Diet
Laferrère et al
JCEM 93:2479, 2008
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Before RYGB Before Diet
After Diet
After RYGB
Time (min)
Glu
co
se (
mg
/dL
) OGTT
Laferrère et al
JCEM 93:2479, 2008
250
200
150
100
50
-15 0 15 30 45 60 75 90 105 120 135 150 165 180
More Improved Glucose Tolerance After RYGB
Than After Equivalent Dietary Weight Loss
*
* *
*
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Randomized Trial for T2DM Treatment:
Sleeve Gastrectomy vs. Gastric Bypass
Type 2 diabetes patients
HbA1c > 8%
BMI 27-35
Sleeve Gastrectomy Sleeved Gastric Bypass
Randomization
n = 15 n = 15
BMI: 30
HbA1c: 10%
LDL, TG, age, gender
Matched
Lee WJ
et al 2009
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0
5
10
15
20
30
35
25
0 1 2 3 4 5 6
Months After Surgery
BMI
(kg/m2)
Gastric bypass
Sleeve Gastrecomy
No Differences in Body Weight or Weight Loss at 6 mo.
Lee WJ
et al, 2009
~15% wgt @ 6 mo
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Sleeve Gastric
Endpoint Gastrectomy Bypass
• % A1c <7.0 46.7% 93.3%
• LDL 23 16 mg/dL
• Triglycerides 107 130 mg/dL
• % at Rx Goals 14% 60%
– A1c < 7%
– LDL < 130
– TG < 150
Lee WJ
et al, 2009
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Meirelles K, et al
Ann Surg 249:277 (2009)
Weight Loss After RYBG in Obese Zucker Rats
RYGB
Pair Fed
Sham
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Better Oral Glucose Tolerance After RYGB Than
After Similar Weight Loss From Food Restriction in Rats
Time After Gavage (min) Meirelles K, et al
Ann Surg 249:277 (2009)
Plasma
Glucose
(mg/dl)
RYGB
Sham Operated Pair-Fed Sham
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• Fast kinetics of diabetes resolution
• Glucose homeostasis improves more with RYGB
than with equal weight loss from other means
• Inconsistent correlation between amount of
weight lost and DM remission rates after RYGB
Evidence for Weight-Independent Anti-DM Effects
DE Cummings
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Asian Indians Have Increased DM Risk
at Lower BMIs Compared with Caucasians
9.1% Body Fat 21.2%
22.3 BMI 22.3
Yajnik & Yudkin
Lancet 363:163
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Chiu M et al. Diabetes
Care 34:1741, 2011
Body Mass Index (kg/m2)
Dia
bete
s I
ncid
en
ce p
er
1000 p
ers
on
-years
Asian Indians Have Increased
Diabetes Risk at Lower BMI Levels
Asian
Indian
Chinese
White
Black
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Asian Indians Are Vulnerable
to Developing Type 2 Diabetes
• High % body fat for a given body weight
• Preferential visceral fat distribution
• Genetic predisposition to:
– ↑ insulin resistance
– ↓ –cell volume
– ↓ glucose-mediated insulin secretion
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W.H.O. Definitions by BMI Level
Most
People
“Overweight” “Obese”
25-29.9 kg/m2 30 kg/m2
Asian
Indians 23-24.9 kg/m2 25 kg/m2
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50.8
Ind
ia
29.4
Ch
ina
22.7 U
SA
13.6
Ind
on
es
ia
8.7
Pa
kis
tan
7.3
Bra
zil
6.4
Ban
gla
desh
7.6
Ja
pa
n
4.8
Ph
ilip
pin
es
4.3
Eg
yp
t
4.3
Tu
rke
y
15.1
IFE
GS
Wild et al, Diabetes Care 27:1047 (2004)
2000 2012
Projected Global Incidence of Type 2 DM
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Prospective Study of RYGB for Type 2 DM
in Asian Indians With BMI < 35 kg/m2
• BMI 22–35 kg/m2
– “Overweight” to “Obese” by Indian-specific
WHO criteria
• Type 2 DM – Confirmed with Abs, C-peptide, FHx
• Severe diabetes – Mean duration: 9 years
– 80% on insulin (the rest on oral DM meds)
– HbA1c: 10.1%
• Other features – Dyslipidemia: 93%
– Hypertension: 60%
Shah S…..
Cummings DE
SOARD 2010
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Results
• Weight Loss
– Mean BMI: 28.9 → 23.0 ( 20% )
• Hypertension Improved
– Mean systolic bp: 136 → 116
– 67% discontinued HTN meds
• Dyslipidemia Improved
– Mean cholesterol: 175 → 135
– Mean HDL: 37 → 50
– 100% discontinued lipid meds
Shah S…..
Cummings DE,
SOARD 2010
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Fasting
Blood
Glucose
(mg/dL)
Months After Surgery
0
50
100
150
200
250
300
0 1 3 6 9
233
89
100% 100% 100% 0% 80% % Off All
DM Meds
Gastric Bypass in Asian Indians
With DM & BMI <35 kg/m2
Shah S…..
Cummings DE,
SOARD 2010
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0
2
4
6
8
10
12
14
HbA1c
(%)
Months After Surgery
0 1 3 6 9
10.1
Gastric Bypass in Asian Indians
With DM & BMI <35 kg/m2
6.1
100% 100% 100% 0% 80% % Off All
DM Meds
Shah S…..
Cummings DE,
SOARD 2010
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UKPDS Risk Engine 10-Year Cardiovascular Risk Predictions (%)
Pre-Op
Post-Op
0
2
4
6
8
10
12
14
16
Coronary
Heart
Disease *
Fatal
Coronary
Heart
Disease
0
2
4
6
8
10
*
Stroke
0
0.5
1
1.5
2
2.5
3
3.5
4
*
Fatal
Stroke
0
0.1
0.2
0.3
0.4
0.5
0.6
*
Shah &
Cummings,
SOARD 2010
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• 100% DM remission by 3 months
– Most by 1 month
– All persisted now to ≥ 2.5 years
• Weight loss: ~ 1/5 total body wgt
• Better than expected for severe obesity
– ~80% DM remission with ~1/3 body wgt loss
F/U of Shah & Cummings, SOARD 6:332 (2010)
RYGB in Asian Indians With BMI <35
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COSMID
Randomized Controlled Trial
Comparison
Of
Surgery vs.
Medicines for
Indian
Diabetes Shah SS,
Kim K,
Cummings DE
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Prospective Study of RYGB for Type 2 DM
in Caucasians With BMI 30–35 kg/m2
• 66 Caucasian patients – 100% F/U to 6 years
• BMI 30–35 kg/m2
– Mild obesity for this population
• Type 2 DM – Confirmed with Abs, C-peptide, FHx
• Severe diabetes – Mean duration: 13 years
– 40% on insulin (the rest on oral DM meds)
– HbA1c: 9.7% at start Cohen RV…..
Cummings DE
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A
5
6
7
8
9
10
11
0 6 12 24 48 60 72
Months After Surgery
Hemoglobin
A1c
(%)
Rapid & Durable Improvement in HbA1c
Cohen RV…..
Cummings DE
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90
100
110
120
130
140
150
160
170
0 6 12 24 48 60 72
Months After Surgery
Rapid & Durable Improvement in Fasting Glucose
Fasting
Plasma
Glucose
(mg/dL)
Cohen RV…..
Cummings DE
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70
60
50
40
30
20
10
0
Number
Of
Patients
1%
11%
88%
Cohen RV…..
Cummings DE
6-Year Study of RYGB for
Type 2 DM in Patients With BMI 30–35 kg/m2
No
Change
T2DM
Improvement
T2DM
Remission
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Resolved
Cohen RV…….
Cummings DE
80
90
100
110
120
130
140
0 6 12 24 48 60 72
Waist
Circumference
(cm)
80
90
100
110
120
130
140
0 6 12 24 48 60 72
Months After Surgery
Waist
Circumference
(cm)
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
0 6 12 24 48 60 72
Total Body
Weight Loss
(%)
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
0 6 12 24 48 60 72
Months After Surgery
Total Body
Weight Loss
(%)
Improved
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Evidence for Weight-Independent
Beneficial Effects of RYGB on Glycemia
• No relationship at any time point between
the amount of weight lost and:
– Decrease in fasting blood glucose
– Decrease in HbA1c
– Improvement beta-cell responsiveness to glucose
– Increase in estimated insulin sentivitity (HOMA)
• Except at 5 and 6 years
Cohen RV….
Cummings DE
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6 12 24 48 60 72
1 1 5
1 2 0
1 2 5
1 3 0
1 3 5
1 4 0
70
75
80
85
90
0
Months After Surgery Cohen RV…..
Cummings DE
Systolic Blood
Pressure (mmHg)
Diastolic Blood
Pressure (mmHg)
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100
120
140
160
180
200
220
0 6
12 24 48 60
72 70
90
110
130
150
170
190
210
230
0 6 12 24 48 60 72
60
70
80
90
100
110
120
130
140
160
20
25
30
35
40
45
50
55
Cohen RV…..
Cummings DE
Triglycerides
(mg/dL)
Low
Density
Lipoprotein
(mg/dL)
Months After Surgery
Total
Cholesterol
(mg/dL)
High
Density
Lipoprotein
(mg/dL)
Months After Surgery
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Cohen RV…..Cummings DE
10-Year Cardiovascular Risk
Before vs. After RYGB
Cardio-
Vascular
Event
Pre-Surgery
(n=66)
Mean Risk
(%) ± SD
Post-Surgery
(n=66)
Mean Risk
(%) ± SD
Absolute
Risk
Reduction
95%
Confidence
Interval
Relative
Risk
Reduction
P Value
CHD 35.3 ± 10.0 10.3 ± 2.6 25% 8.2–13.3 71% 0.001
Fatal CHD 26.2 ± 8.1 5.4 ± 1.9 21% 3.7–8.0 84% 0.001
Stroke 5.0 ± 0.4 2.5± 1.7 2.5% 1.7–6.0 50% 0.01
Fatal Stroke 0.7 ± 0.3 0.4 ± 0.2 0.3% 0.03–0.1 57% 0.009
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Swedish Obese Subjects Study
Years of Follow Up
Total Body
Weight Loss
(%)
Sjöström L, et al. JAMA 307:56 (2012)
Gastric Bypass
Gastroplasty
Banding
Usual
Care
Multivariate analyses of 20-year data
show additional effects of surgery,
beyond weight loss, to improve
diabetes prevention & remission.
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Preoperative BMI does not predict
DM prevention or remission in
SOS or any other study,
even though heavier
patients lose more weight.
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• Fast kinetics of diabetes resolution
• Glucose homeostasis improves more with RYGB
than with equal weight loss from other means
• Inconsistent correlation between amount of
weight lost and DM remission rates after RYGB
• Some intestinal bypass operations improve
diabetes with little or no weight loss
Evidence for Weight-Independent Anti-DM Effects
DE Cummings
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Novel Anti-Diabetic GI Procedures
Duodenal-Jejunal Bypass Duodenal-Jejunal Bypass Sleeve
Ileal Interposition
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• Fast kinetics of diabetes resolution
• Glucose homeostasis improves more with RYGB
than with equal weight loss from other means
• Inconsistent correlation between amount of
weight lost and DM remission rates after RYGB
• Some intestinal bypass operations improve
diabetes with little or no weight loss
• Hints from hyperinsulinemia
Evidence for Weight-Independent Anti-DM Effects
DE Cummings
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Service et al.
NEJM 353:249 (2005)
Control
Post-RYGB
Hyperinsulinemia Hypoglycemia After Gastric Bypass:
Too much of a good thing for islets?
Late onset:
1-9 years
(typical 2-4)
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Evidence for Increased β-Cell Mass
After Intestinal Bypass Operations
• β-cell area & neogenesis in post-RYGB patients with
hyperinsulinemic hypoglycemia ?
– J. Service; A. Goldfine; others
• PDX-1 & β-cell regeneration (BRDU) at 1, 2, 4, 12 wk
after RYGB in GK rats
– Z. Li
• β-cell area after ileal interposition in rats
– A. Strader; A.Patriti
• β-cell area after DJB in GK rats
– T. Kieffer (by histology); W. Inabnet & J. Korner (by VMAT2 PET)
DE
Cummings
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What Causes RYGB’s
Weight-Independent
Anti-Diabetes Effects?
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Changes
in
Gut Hormones?
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Cummings DE, Overduin J
J Clin Invest 2007
Ghrelin
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• Peptide hormone produced
primarily by stomach & proximal
small intestine
• Powerfully stimulates appetite
and food intake in many species,
including humans
Ghrelin
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Human Plasma Ghrelin Levels
Rise & Fall Shortly Before & After Every Meal
300
400
500
600
700
800
900
PlasmaGhrelin(pg/ml)
06
00
07
00
08
00
09
00
10
00
11
00
12
00
13
00
14
00
15
00
16
00
17
00
18
00
19
00
20
00
21
00
22
00
23
00
24
00
01
00
02
00
03
00
04
00
05
00
Time of Day
B DL
n = 10
Cummings, et al.
Diabetes 50:1714
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Plasma Ghrelin Increases After Diet-Induced Weight Loss
300
400
500
600
PlasmaGhrelin(pg/ml)
06
00
08
00
10
00
12
00
14
00
16
00
18
00
20
00
22
00
24
00
02
00
04
00
Clock Time
Before Wgt Loss
After Wgt Loss
LB D
n = 13
Cummings, et al. NEJM 346:1623
1600
1800
2000
2200
2400
0200
0400
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• Ghrelin With Weight Loss
– Caloric restriction
– Cancer anorexia
– Cachexia: cardiac, renal,
pulmonary, or hepatic
– Huntington’s disease
– Anorexia & bulimia nervosa
– Chronic exercise
• Ghrelin With Weight Gain
– Overfeeding
– High fat or sugar diets
– Glucocorticoids
– Atypical anti-psychotics
– Valproic acid
– Rx of celiac disease
– Rx of anorexia nervosa
Plasma Ghrelin Responds to
Chronic Changes in Body Weight
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Roux-en-Y Gastric Bypass
Ingested food bypasses
most of the
ghrelin-producing cells
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100
200
300
400
500
600
700
800
PlasmaGhrelin(pg/ml)
06
00
08
00
10
00
12
00
14
00
16
00
18
00
20
00
22
00
24
00
02
00
04
00
Clock Time
Gastric Bypass
Wgt-Reduced Obese
Normal Weight
DetectionLimit
LB D
Cummings, et al. NEJM 346:1623
Matched Obese
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Effects of Gastric Bypass on Human Ghrelin Levels
Prospective
Decrease
Geloneze Obes Surg 13:17 Fruhbeck NEJM 350:308 Lin Arch Surg 139:780 Couce NAASO 2003 Morinigo Obes Res 12:1108 Chan Obesity 14:194 Foschi J Invest Surg 21:77 Fruhbeck Obes Surg 14:1208
Abnormally
Low
Cummings NEJM 346:1623 Tritos Obes Surg 11:919 Leonetti JCEM 88:4227
Rodieux
Obesity 16:298 Korner JCEM 90:359
No Change
Despite Wgt
Faraj JCEM 88:1594 Stoeckli Obes Res 12:346
Prospective
Increase
Holdstock JCEM 88:3177 Vendrell Obes Res 12:962 Liou Obes Surg 18:84 Karamanakos Ann Surg 247:401
Impaired Ghrelin Response
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How does gastric bypass
impair the normal ghrelin
response to weight loss?
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Hindbrain
Vagal
Efferents
Gut
Adiposity
Signals
Hypo-
thalamus
Insulin
NO Ghrelin
Body
Weight McLaughlin, Cummings,, et al, JCEM 89:1630
Grill, Cummings, et al, unpublished
Williams, Cummings, et al, Endocrinol 144:5184
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What does ghrelin
have to do with
diabetes?
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GHRELIN
GH
ACTH & Cortisol
Epinephrine
Glucagon?
Adiponectin
Insulin Action
Insulin Secretion
Food Intake
GLUCOSE
Cou
nte
r-reg
ula
tory
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Lower Intestinal
Hypothesis
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STOMACH
Ghrelin
Leptin
GRP, NMB
PANCREAS
Amylin
Enterostatin
Glucagon
Insulin
PP
DUODENUM
CCK, GIP
ILEUM
* GLP-1 *
Oxyntomodulin
PYY
COLON
* GLP-1 *
Oxyntomodulin
PYY
JEJUNUM
APOAIV
FOOD Cummings DE
& Overduin J
J Clin Invest 117:13
↑ insulin secretion
↓ food intake
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PANCREAS
Amylin
Enterostatin
Glucagon
Insulin
PP
DUODENUM
CCK, GIP
JEJUNUM
APOAIV
FOOD
Cummings DE
& Overduin J
J Clin Invest 117:13
ILEUM
* GLP-1 *
Oxyntomodulin
PYY
COLON
* GLP-1 *
Oxyntomodulin
PYY
↑ insulin secretion
↓ food intake
STOMACH
Ghrelin
Leptin
GRP, NMB
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Cummings DE, Overduin J
J Clin Invest 117:13
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ILEUM
GLP-1
COLON
GLP-1
Nutrient-responsive
neural relay from the
duodenum to distal
intestine stimulates
GLP-1 secretion
Based on P. Brubaker et al
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Roux-en-Y Gastric Bypass (RYGB)
Ingested food
bypasses the
duodenal site
of nutrient-
mediated GLP-1
stimulation.
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Does gastric bypass
increase GLP-1
and/or PYY levels?
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Korner J, et al
JCEM 90:359
Increase in Postprandial GLP-1 and PYY After RYGB
Korner J, et al
SOARD 3:597
Meal
PYY
Meal
GLP-1
↓ DPP IV Alam ML…LaFerrère B. 2011
Diabetes Obes Metab 13:378
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0
50
100
150
200
-15 0 15 30 45 60 75 90 105 120 135 150 165 180
Time (min)
GL
P-1
To
tal (p
M) pre-GBP
1M post-GBP
6M post-GBP
1Y post-GBP
2Y post-GBP
3Y post-GBP
GLP-1 For Up To 3 Years After RYGB
Laferrère et al
unpublished
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STOMACH
Ghrelin
Leptin
GRP, NMB
PANCREAS
Amylin
Enterostatin
Glucagon
Insulin
PP
DUODENUM
CCK
ILEUM
* GLP-1 *
PYY
Oxyntomodulin
COLON
* GLP-1 *
PYY
Oxyntomodulin
JEJUNUM
APOAIV
Cummings DE
& Overduin J
J Clin Invest 2007
All after RYGB
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Does elevated GLP-1
after RYGB improve
glucose control?
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Jejuno-ileal
Bypass
Operations That Rapidly Reverse DM
All Expedite Nutrient Delivery to the Ileum
Biliopancreatic
Diversion
Roux-en-Y
Gastric Bypass
… and All GLP-1 Levels GLP @ 20 yrs
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Post-GI Surgery ↑ GLP-1 Can Engage Key Neural Pathways
Holst and Deacon
Diabetologia 2005
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Are elevated GLP-1 levels
after RYGB associated with
an increased incretin effect?
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Effects on Glucose Homeostasis of
Equivalent Weight Loss from RYGB vs. Diet
Type 2 diabetes patients
matched for BMI, age, degree of diabetes
Studied at
9.7 kg
Studied at
9.2 kg
RYGB Diet
Laferrère et al
JCEM 93:2479, 2008
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Pre-GBPIn
su
lin
(u
U/m
L)
100
80
60
40
20
0-15 0 15 30 45 60 90 120
OGTT
IsoG IVGT
100
80
20
60
40
0-15 0 3015 45 60 90 120 180
Pre-Diet
100
80
60
40
20
0
Ins
uli
n(u
U/m
L)
-15 0 15 30 45 60 90 120 180
Post-GBP
Time (min)
100
80
60
40
20
0-15 0 15 30 45 60 90 120 180
Time (min)
Post-Diet
180
Incretin Effect Increases After RYGB in Patients With T2DM
Before RYGB OGTT
IsoGlu IVGTT Before Diet
After Diet After RYGB
Insulin
(uU/mL)
Insulin
(uU/mL)
Laferrère et al
JCEM 93:2479, 2008
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0
10
20
30
40
50
60
70In
sulin Incre
tin E
ffect %
Lean Control
Pre-GBP
1M Post-GBP
6M Post-GBP
1Y Post-GBP
#
**
*
0
10
20
30
40
50
60
70In
sulin Incre
tin E
ffect %
Lean Control
Pre-GBP
1M Post-GBP
6M Post-GBP
1Y Post-GBP
#
**
*
Incretin Effect on Insulin Secretion
Remains Normal Up to One Year After RYGB
Bose M & Laferrere B. J Diabetes 2:47 (2010)
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0
10
20
30
40
50
60
70In
sulin Incre
tin E
ffect %
Lean Control
Pre-GBP
1M Post-GBP
6M Post-GBP
1Y Post-GBP
#
**
*
0
10
20
30
40
50
60
70In
sulin Incre
tin E
ffect %
Lean Control
Pre-GBP
1M Post-GBP
6M Post-GBP
1Y Post-GBP
#
**
*
Incretin Effect on Insulin Secretion
Remains Normal Up to One Year After RYGB
Bose M & Laferrere B. J Diabetes 2:47 (2010)
No change in incretin
effect from equal
dietary weight loss
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RYGB increases the
incretin effect, but equal dietary
weight loss does not
Laferrère et al , JCEM 93:2479, 2008
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Laferrère et al , JCEM 93:2479, 2008
0
2
4
6
8
10
-15 0 15 30 45 60 75 90 105 120 135 150 165 180
Time (min)
C-P
ep
tid
e (
ng
/mL
)
Pre-RYGB
Pre-Diet
Higher C-Peptide Response to Oral Glucose
After RYGB vs. Equivalent Dietary Weight Loss
Post-RYGB
Post-Diet
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Prandial GLP-1 response increases
immediately after RYGB, along
with insulin
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Jens Holst, et al
Type 2 Diabetes Normal Glucose Tolerance
↑↑ GLP-1 Meal Responses by 3 Days After RYGB To
tal G
LP
-1 (
pM
)
To
tal G
LP
-1 (
pM
)
Time (min) Time (min)
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Jens Holst, et al
Type 2 Diabetes Normal Glucose Tolerance
↑ C-Peptide Responses by 3 Days After RYGB
Time (min) Time (min)
C-P
ep
tid
e (
pM
)
C-P
ep
tid
e (
pM
)
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Jens Holst, et al
Type 2 Diabetes Normal Glucose Tolerance
↑ Glucose Tolerance by 3 Days After RYGB
Time (min) Time (min)
Glu
co
se (
nM
)
Glu
co
se (
nM
)
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Acute Improvement in β-Cell Function
4 Weeks After RYGB vs. Gastric Restriction
0
200
400
600
800
1000
6 7 8 9 10
Glucose (mmol/l)
Insu
lin
secreti
on
rate
(p
mo
l/m
in)
PRE
1 month
GR
Kashyap SR….Schauer PR. IJO 34:462 (2010)
Gastric Restriction
0
200
400
600
800
1000
4 5 6 7 8 9 10
Glucose (mmol/l)
Insu
lin
secreti
on
rate
(p
mo
l/m
in)
PRE
1 month
RYGBRYGB
(during MMTT)
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Improved insulin secretion after
RYGB is not only fast but also
very durable
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Prospective Study of RYGB for Type 2 DM in
Caucasians With BMI 30–35 kg/m2
• 66 Caucasian patients
– 100% F/U to 6 years
• BMI 30–35 kg/m2
– Mild obesity for this population
• Type 2 DM
– Confirmed with Abs, C-peptide, FHx
• Severe diabetes
– Mean duration: 13 years
– 40% on insulin (the rest on oral DM meds)
– HbA1c: 9.7% at start Cohen RV…..
Cummings DE
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A
5
6
7
8
9
10
11
0 6 12 24 48 60 72
Months After Surgery
Hemoglobin
A1c
(%)
Rapid & Durable Improvement in HbA1c After RYGB in BMI 30-35
Cohen RV…..
Cummings DE
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Before RYGB
After RYGB
0
50
100
150
200
250
0
1
2
3
4
5
6
*
*
*
Fasting
Glucose
(mg/dL)
C-Peptide
(ng/mL)
Post-Meal Cohen RV…..
Cummings DE
Improved β–Cell Function for Up to 6 Years After RYGB
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How much of the effects of RYGB on
glucose homeostasis results from
GLP-1?.
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GLP-1 After RYGB
• Released in correct location to engage neural
(e.g., vagal) pathways to improve glucose
homeostasis
• Associated with increased incretin effect
• Occurs immediately, lasts for years
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Ileal Interposition
10-cm distal
transection
Vascularly intact
Innervated
Isoperistaltic
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Ileal Interposition
• No gastric restriction or malabsorption
• GLP-1 & PYY
• Improved glucose homeostasis
– Beyond expected for degree of weight loss
– ↑ Glucose-stimulated insulin secretion (GLP-1 dep)
– ↑ β-cell mass in rats
– Delays diabetes onset by 4 mo in rat T2DM model
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Intestinal Bypass Operations That Increase
Postprandial GLP-1 and Insulin Responses
• Gastric Bypass
– e.g., LaFerrere, LeRoux, Korner, Holst, Schauer,
Mingrone, Miller, Morinigo, Peterli, Cummings
• Biliopancreatic Diversion
– e.g., Briatore, Mingrone, Ferrannini
• Ileal Interposition
– e.g., Strader, Patriti, DePaula
• Duodenal-Jejunal Bypass
– e.g., Ramos
…but not seen with
gastric banding or
dietary weight loss
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What about GIP?
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STOMACH
Ghrelin
Leptin
GRP, NMB
PANCREAS
Amylin
Enterostatin
Glucagon
Insulin
PP
DUODENUM
CCK, GIP
ILEUM
GLP-1
Oxyntomodulin
PYY
COLON
GLP-1
Oxyntomodulin
PYY
JEJUNUM
APOAIV
FOOD Cummings DE
& Overduin J
J Clin Invest 117:13
↑ insulin secretion
↓ food intake
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STOMACH
Ghrelin
Leptin
GRP, NMB
PANCREAS
Amylin
Enterostatin
Glucagon
Insulin
PP
DUODENUM
CCK, GIP
ILEUM
GLP-1
Oxyntomodulin
PYY
COLON
GLP-1
Oxyntomodulin
PYY
JEJUNUM
APOAIV
Cummings DE
& Overduin J
J Clin Invest 117:13
↑ insulin secretion
↓ food intake
FOOD
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Abolished Postprandial GIP Response to Oral
Glucose in GK Rats With Duodenal Bypass Sleeve
Complete
Sleeve
Fenestrated
Sleeve
No
Sleeve
Complete
Sleeve
Fenestrated
Sleeve
No
Sleeve
GIP
Min After Glucose Load 30 0
Rubino F
Minutes After Oral Glucose Load
0 Minutes 30 Minutes
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Sustained Elevation of GIP in Response to Oral
Glucose for Up to 1 Year After RYGB
0
50
100
150
200
250
300
350
0 15 30 45 60 75 90 105 120 135 150 165 180
Time (min)
GIP
(p
g/m
L)
Before Surgery
1 M after Surgery
6 M after Surgery
1 Y after Surgery
Bose M & Laferrere B, J Diabetes, 2:47-55 (2010)
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No Change in GIP Levels After RYGB in Type 2 DM
Jens Holst, et al
To
tal G
IP (
pM
)
To
tal G
IP (
pM
)
Time (min) Time (min)
Type 2 Diabetes Normal Glucose Tolerance
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GIP seems unlikely to be a critical
participant in the
anti-diabetes effects of RYGB.
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GLP-1
insulin secretion
RYGB
body weight
insulin sensitivity
TIME
A Simple Model
LAGB
body weight
insulin sensitivity
TIME
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FOOD
Cummings DE
& Overduin J
J Clin Invest 117:13
ILEUM
GLP-1
Oxyntomodulin
PYY
COLON
GLP-1
Oxyntomodulin
PYY
↑ insulin secretion
↓ food intake
Does this
explain
everything?
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NO.
Acute insulin response to I.V. glucose
in IVGTT starting very early after RYGB
(but not with similar weight loss from LAGB)
E. Lin, et al. AJP 299:E706, 2010
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Elevated
Postprandial
GLP-1
As per R. Seeley, et al
Sleeve
Gastrectomy
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Effects of GI Surgery
on Insulin Sensitivity
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Gastric Restriction RYGB
*
*
Pre-
Surg
1 Wk
Post
4 Wk
Post
Pre-
Surg
1 Wk
Post
4 Wk
Post
M/I M/I
Kashyap SR….Schauer PR
IJO 34:462 (2010) * Similar weight loss between groups *
Insulin Sensitivity by Hyperinsulinemic Clamp
in Patients with Type 2 Diabetes
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Hyperinsulinemic Clamp Studies
Early After GI Surgery
• Biliopancreatic Diversion
– Ferrannini & Mingrone 2005 & 2006: Fast ↑ Si is not explained by
weight loss, whereas slower ↑ insulin sensitivity after RYGB is
explained by weight loss
• Gastric Bypass
– Campos 2009: No Δ Si at 2 weeks c/w caloric restriction
– Geloneze 2010: No Δ Si at 1 month
– Kashyap & Schauer 2010: ↑ Si at 1 & 4 weeks
– (Cummings & Flum 2011: ↑ Si at 2 weeks?)
No DM in RYGB groups
No DM
Mostly No DM
All DM
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Upper Intestinal
Hypothesis
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Roux-en-Y
Gastric Bypass
Duodenal (Jejunal)
Bypass
Rubino F, et al
x
x
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Duodenal (Jejunal) Bypass
Rubino F, et al
• No gastric restriction
• No calorie malabsorption
• No change in food intake
• No change in body weight
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Goto-Kakizaki Rat (GK)
• Polygenic
• -cell defects
• Some insulin resistance
• Non-obese
• Normolipidemic
Most widely used lean model
in type 2 diabetes research
Animal Model of Type 2 Diabetes
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P=0.001
42% reduction of AUC (P<0.001)
Blood
Glucose
(mg/dl)
OGTT
(DJB RATS)
0
50
100
150
200
250
300
350
400
450
Baseline 10 min 30 min 60 min 120 min 180 min
Preop
1 week p.o.
P < 0.001
Blood
Glucose
(mg/dl)
Rubino F, et al
Ann Surg 239:1
Similar results at
1 week through
9 months after surgery
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Duodenal (Jejunal) Bypass
F Rubino, D Pacheco, Y Wang, M Speck, Kindel & Tso, others
Major, durable ↑ in
glucose tolerance with
little or no weight loss in
several rat DM models
(but not in non-DM rats)
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Does duodenal bypass
ameliorate type 2 diabetes in
humans?
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Patient 1
Patient 2 0
20
40
60
80
100
120
140
160
180
200
0 1 2 3 4 5 6 7 8 9
Patient 1
Patient 2 0
5
10
15
20
25
30
0 1 2 3 4 5 6 7 8 9
Fasti
ng
Glu
co
se (
mg
%)
Fasti
ng
In
su
lin
(m
mo
l/l)
Months After Surgery Months After Surgery
Fasting Glucose Fasting Insulin
Resolution of Human Diabetes After Duodenal Bypass
Cohen RV, Rubino F,
et al. SOARD 2007
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Patient 1
Patient 2
Patient 1
Patient 2 4
5
6
7
8
9
0 1 2 3 4 5 6 7 8 9
26
27
28
29
30
0 1 2 3 4 5 6 7 8 9
Hb
A1
c (
%)
Months After Surgery Months After Surgery
Hemoglobin A1c Body Mass Index
Bo
dy M
as
s In
de
x (
kg
/m2)
Resolution of Human Diabetes After Duodenal Bypass
Off all
diabetes
meds
Cohen RV, Rubino F,
et al. SOARD 2007
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Duodenal-Jejunal Bypass in Humans
(“Gastric-Sparing Gastric Bypass”)
~1.5 ft
~2.4 ft
~12–18 ft Cohen RV,
et al.
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Prospective Study of DJB for Type 2 DM
in Patients With BMI < 35 kg/m2
• 46 patients
• BMI 22–35 kg/m2
• Severe Diabetes
– Confirmed type 2: negative -GAD, ICA
– Duration of DM: 2–10 years
– 70% on insulin; others on oral DM meds
– Mean HbA1c = 8.9%
Cohen RV,
Cummings DE,
et al.
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Duodenal-Jejunal Bypass in
Patients with DM & BMI <35 kg/m2
Cohen RV,
Cummings DE,
et al.
0
2
4
6
8
10
12
0 3 6 12
Months After Surgery
HbA1c
(%)
8.9
6.5
100% off
insulin Rx
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No Relationship Between Change in
Body Weight and Improvement in Glycemia
Change in BMI (kg/m2)
Ch
an
ge i
n H
bA
1c
HbA1c
Data at 1 year
Cohen RV,
Cummings DE,
et al.
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Ileal Interposition +
Sleeve Gastrectomy
35%
HbA1c <6%
Ileal Interposition +
Sleeve Gastrectomy +
Duodenal Bypass
Equal Weight Loss
DePaula et al
SOARD 6:296 (2010)
81%
HbA1c <6%
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Can the same thing be
accomplished with
an endoscopically implantable
device?
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Duodenum + 1/3 Jejunum Only Duodenum
Intraluminal Duodenal Sleeve Duodenal/Jejunal Bypass
Rubino F
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Duodenal Sleeve
Rubino F
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GK Rats (diabetic)
1. Complete tube (n=12)
2. Fenestrated tube (n=12)
3. No tube (Sham) (n=6)
2 & 3 pair-fed to 1
Rubino F
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Complete Duodenal Sleeve
Rubino F
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Fenestrated Duodenal Sleeve
Rubino F
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Duodenal Sleeve
• No change in D-xylose absorption test
– Indicates no carbohydrate malabsorption
• No difference from controls in GLP-1 response to
oral nutrient load
Rubino F
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STOMACH
Ghrelin
Leptin
GRP, NMB
PANCREAS
Amylin
Enterostatin
Glucagon
Insulin
PP
DUODENUM
CCK, GIP
ILEUM
GLP1
Oxyntomodulin
PYY
COLON
GLP1
Oxyntomodulin
PYY
JEJUNUM
APOAIV
What about GIP?
Cummings DE
& Overduin J
J Clin Invest 2007
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Abolished Postprandial GIP Response to Oral Glucose in GK
Rats With Duodenal Bypass Sleeve
Complete
Sleeve
Fenestrated
Sleeve
No
Sleeve
Complete
Sleeve
Fenestrated
Sleeve
No
Sleeve
GIP
Min After Glucose Load 30 0
Rubino F
Minutes After Oral Glucose Load
0 Minutes 30 Minutes
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Postoperative Body Weight
Rubino F
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Preoperative OGTT
PREOPERATIVE OGTT
0
50
100
150
200
250
300
350
400
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Complete
Fenestrated
No tube
Rubino F
Blood
Glucose
(mg/dl)
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Postoperative OGTT: No Sleeve (Sham Surgery)
Rubino F
Blood
Glucose
(mg/dl)
0
50
100
150
200
250
300
350
400
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Pre
Post
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Postoperative OGTT: Fenestrated Sleeve
Fenestrated Sleeve
0
50
100
150
200
250
300
350
400
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Pre
Post
Rubino F
Blood
Glucose
(mg/dl)
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Postoperative OGTT: Complete Sleeve
Rubino F
P < 0.001
Blood
Glucose
(mg/dl)
Time After Glucose Load (min)
Pre-op
Post-op
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Pre-study
0
100
200
300
400
500
600
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Pre-study
Before Surgery
A Very Instructive Rat
Rubino F
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Postop complete intraluminal tube
0
100
200
300
400
500
600
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Pre-study
Post sleeve
A Less Successful Rat:
Has a Duodenal Sleeve Leak
Rubino F
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0
100
200
300
400
500
600
BASE 10 min 30 min 60 min 90 min 120 min 180 min
Pre-study
9th pop tube
2nd post lac
9th post lac
Diabetes Resolved 9 Days After the Repair
Rubino F
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Duodenal-Jejunal Bypass Sleeve
Substantially
improves glucose
homeostasis in
several rat models
of type 2 DM
L Kaplan, F Rubino, others
Food bypasses the duodenum &
proximal jejunum, as it does in RYGB
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Can an upper intestinal sleeve
ameliorate type 2 diabetes in
humans?
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Duodenal-Jejunal Bypass Sleeve
• Anchor – Nitinol
– Large proximal opening
– Barbs in each direction
– Retrieval drawstrings
• Liner – Impermeable fluoropolymer
– 2 feet long
– Bypasses duodenum &
small amt proximal jejunum
– Radiopaque (RO) markers EndoBarrierTM
G.I. Dynamics, Inc.
Humans tested to date:
~220 implanted, ~160 controls
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* P=0.004 vs. Sham
DJBS
Sham
-1.3%
-0.8%
-2.9% *
-0.8%
3 months 7 months
-0.5%
-1.5%
-2.5%
-3.5%
HbA1c
(change
from
baseline)
Sorli C, et al.
& GI Dynamics
Baseline HbA1c: 8.9% Baseline HbA1c: 9.0%
Duodenal-Jejunal Bypass Sleeve Lowers HbA1c
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0.00
-4.66-5.28
-7.06
-8.55-9.00
-11.44
0.00
-5.38-5.72
-7.28-7.76 -7.52 -7.62
-14
-12
-10
-8
-6
-4
-2
0
0 2 4 8 12 16 20
Weeks
Ab
solu
te W
eig
ht
Lo
ss (
Kg
)EndoBarrier Sleeve Sham
Body Weight Curves After
DJB Sleeve or Sham Endoscopy
Body
Weight
Change
(kg)
Weeks After Implantation Sorli C, et al.
& GI Dynamics
DJBS Sham
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Rodríguez L, et al. Diabetes Technol Ther 11:725 (2009)
Improved Glucose Tolerance
One Week After DJB Sleeve
Sham Endoscopy DJB Sleeve
Time After Meal (min) Time After Meal (min)
Po
stp
ran
dia
l G
luco
se (
mg
/dL
)
Po
stp
ran
dia
l G
luco
se (
mg
/dL
) Baseline 1 Week Baseline 1 Week
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Rodríguez L, et al. Diabetes Technol Ther 11:725 (2009)
Immediate, Durable Lowering of Fasting
Blood Glucose After Endoluminal Sleeve
Sham
ELS
Fa
sti
ng
Pla
sm
a G
luc
os
e
Ch
an
ge
fro
m B
as
elin
e (
mg
/dL
)
Treatment (Weeks)
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Substantial improvements
in glucose homeostasis,
before and out of
proportion to weight loss
Duodenal-Jejunal Bypass Sleeve for Humans
EndoBarrierTM
G.I. Dynamics, Inc.
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Lower Intestinal
vs.
Upper Intestinal
Hypothesis?
Rubino F, et al
Duodenal (Jejunal)
Exclusion
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Duodenal (Jejunal)
Exclusion
Gastro-jejunal
Anastamosis
Rubino F, Cummings DE, et al
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OGTT GK rats
0
100
200
300
400
500
600
0 50 100 150 200
Time (min)
Glu
co
se
le
ve
ls (
mg
/dl)
GK DJB
GK Sham
GK GJ
Oral Glucose Tolerance
Rubino F, et al
Ann Surg 244:741
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1
Hyperglycemic Normoglycemic?
2 weeks
Normal
Oral Feeding
Hyperglycemic?
2 weeks
Gastric Feeding
With G-tube
4
Normoglycemic?
2 weeks
RYGB
Human RYGB
Mechanisms Study
2 3 Normal
Oral Feeding
Patients: severely obese
type 2 diabetics
Tests: meal tolerance tests
FS-IVGTT
hyperinsulinemic clamps
(with tracers)
Gastrostomy Tube
Remove DM Meds
DE Cummings & DR Flum
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Novel Roles of the Gut to
Regulate Hepatic Insulin
Sensitivity
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Thaler & Cummings
Nature 452:941, 2008
Relating to:
Wang PY et al.
Nature 452:1012, 2008
Nutrient sensing
in the gut
regulates insulin
secretion
&
sensitivity
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A Model
body weight
insulin sensitivity
GLP-1
insulin secretion
RYGB TIME
body weight
insulin sensitivity
LAGB
intestinal nutrient sensing & metab
hepatic insulin sensitivity
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Weight-Independent Anti-Diabetes Candidate
Mechanisms of RYGB
GLP-1 (& PYY & OXM)
Ghrelin
Amylin
Duodenal factor?
Intestinal LCFACoA & CCK
Intestinal Gluconeogenesis
Bile acids
Ceramides
Δ in Gut Microbiome
Inflamm & oxidative stress
Branched Chain AA in blood
Intestinal SGLT-1
Others?
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What’s the clinical role for
RYGB to treat type 2 DM in
less obese patients?
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NIH Consensus Development Panel Criteria
for Bariatric Surgery (1991)
• BMI > 40
• BMI > 35 and life-threatening obesity-associated cardiopulmonary complications or severe diabetes
• Approved: RYGB, VBG, Banding
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Diagnosis
Lifestyle Intervention and Metformin
HbA1c 7% No Yes
Add Basal Insulin − (most effective)
Add Sulfonylurea − (least expensive)
Add Glitazone − ( no hypoglycemia)
Add Glitazone Intensify Insulin Add Basal Insulin Add Sulfonylurea
Add Basal or intensify insulin
Intensive insulin + metformin ± glitazone
Yes Yes
Yes HbA1c 7% No Yes
HbA1c 7% No HbA1c 7% No HbA1c 7% No Yes
HbA1c 7% No
Check HbA1c every 3 months and act until HbA1c is <7%
Although 3 oral agents can be used, insulin therapy is preferred based on effectiveness and expense
ADA/EASD Consensus Algorithm for Type 2 DM
Nathan D, et al., 2006
Diabetologia 49:1711−21
Bariatric surgery not
mentioned for anyone!
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Diabetes Surgery Summit
Rome 2007
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Diabetes Surgery Summit Conclusions
• Gastric bypass improves diabetes via mechanisms
beyond reduced food intake & body weight
• Gastric banding improves diabetes only via its effects
on food intake and body weight
Rubino, Schauer, Kaplan, & Cummings, Ann Surg 2010 & Ann Rev Med 2010
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• American Society for Metabolic and Bariatric Surgery
• Brazilian Society for Bariatric and Metabolic Surgery
• Italian Society for Surgery of Obesity and Metabolic Diseases
• Venezuelan Society of Bariatric & Metabolic Surgery
• International Federation for Surgery of Obesity and Metabolic Diseases
• Asia-Pacific Metabolic & Bariatric Surgery Society
Societies Changing Their Names
in ~2007 to Include “Metabolic Surgery”
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Diabetes Surgery Summit Conclusions
• Gastric bypass improves diabetes via mechanisms
beyond reduced food intake & body weight
• Gastric banding improves diabetes only via its effects
on food intake and body weight
• Gastric bypass should be considered to treat type 2
diabetes in patients with BMI ≥ 30 kg/m2
Rubino, Schauer, Kaplan, & Cummings, Ann Surg 2010 & Ann Rev Med 2010
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Distribution of T2DM According to BMI
Bays et al. Int J Clinical Prac 61:737 (2007)
Thin Normal Overweight Obese I Obese II III
>50% of patients
with diabetes
worldwide have
BMI <35 kg/m2
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Management Algorithm for Metabolic Control in Type 2 Diabetes
Basal Premixed
Basal Bolus insulin
Sulphonylurea
Acarbose DPP-4 inhibitor Glitazone
Insulin
Lifestyle Modification •diet modification •weight control •physical activity
Metformin
Bariatric Surgery BMI > 30 eligible & BMI > 35 prioritized *If HbA1c >7.5% despite optimized conventional therapy, especially if weight is increasing, or if other weight responsive comorbidities are not reaching target on conventional therapy.
Bariatric Surgery
BMI > 35 eligible BMI > 40 prioritised
Bariatric Surgical and Procedural Interventions in the Treatment of Obese Patients with Type 2 Diabetes
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What’s the Proper Role for GI Surgery in the
Treatment of Type 2 Diabetes?
• Randomized controlled trials are needed
• Randomizing surgery vs. medical care is very
difficult
• Nevertheless, pivotal RCTs are on their way
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Randomized controlled trials are needed.
And they’re on their way!
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CROSSROADS Trial (an RCT)
Calorie Reduction Or Surgery: Seeking
Remission for Obesity And Diabetes
Cummings, Flum, Arterburn
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CROSSROADS Trial
• RCT of T2DM Rx in BMI 30−40
• Standard RYGB & Medical Care OR
• Intensive Medical−Lifestyle Rx
– Aerobic exercise
– Diet (low-calorie, low-fat)
– State-of-the-art DM Rx per ADA/EASD
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Contributors U. Washington
– Joost Overduin
– Molly Carlson
– Karen Foster-Schubert
– Scott Frayo
– Ian Townsend
– Dave Flum
– David Arterburn
– Allison Rhodes
– Skye Steptoe
– Diana Williams
– Adrian Heap
– Jon Purnell
– Scott Weigle
Funding: NIH/NIDDK
Elsewhere
– Francesco Rubino (Cornell)
– Ricardo Cohen (Sao Paulo, Brazil)
– Phil Schauer (Cleveland Clinic)
– Blandine LaFerrere (Columbia U.)
– Judy Korner (Columbia U.)
– Carel LeRoux (U. London)
– Shashank Shah (Pune, India)
– Jaya Todkar (Pune, India)
– Francois Pattou (U. Paris)
– April Strader (U. Cincinnati)
– Lars Sjostrom (Sweden)
– G.I. Dynamics (Boston)
– Jens Holst (U. Copenhagen)