Bariatric Surgery for Obesity and Type 2 Diabetes Sangeeta R. Kashyap, MD

Sunday, March 6, 2016 11:30 a.m. – 12:15 p.m.

Obesity has reached epidemic levels in the world and accelerates the development of metabolic diseases including Metabolic Syndrome, Pre-diabetes and Type 2 Diabetes. Obesity is strongly linked to insulin resistance and subsequent hyperinsulinemia that promotes the mitogenic effects of insulin in the development of various cancers, CAD and NAFLD/NASH. This presentation will provide an overview of the therapeutic benefits of various bariatric surgery procedures for the treatment of severe obesity and type 2 diabetes. Data from the Swedish Obesity Study (1,2) that compared bariatric procedures to conventional lifestyle therapy demonstrate reduction in mortality of 30% related to reduction in cancer and CAD deaths as well as, 10 year durable reduction in body weight and co-morbidities of obesity following surgery. Data from the Cleveland Clinic STAMPEDE trial (3) and others(4,5) demonstrate the superiority of bariatric procedures to intensive medical therapy for the treatment of type 2 diabetes in moderate and severe obesity. Other topics covered include mechanisms of action of bariatric surgery to restore beta cell function in type 2 diabetes and determinants of remission vs. non-remission of diabetes post-surgery.

Improvement of glycemic control following bariatric surgery must be considered in the setting of weight independent mechanisms (ie. Incretin hormone stimulation, bile acids, gut microbiota)(6,7) and those related to massive weight loss with subsequent effects on reduction of lipotoxicity, ectopic lipids and adipokines. In some cases, a dramatic lowering in glucose levels has been observed days to weeks following surgery, before major weight loss but in the setting of enforced caloric restriction (8,9). Persistent cases of diabetes after this initial period gradually improve in parallel with weight loss(10). Patients who undergo RYGB and BPD procedures improve sooner and maintain glucose control for longer periods than do patients treated by banding or sleeve gastrectomy procedures. However compared with patients following a very low calorie diet who achieved similar weight loss, patients who underwent RYGB have increased secretion of insulin, c-peptide, glucagon like peptide (GLP-1) and gastric inhibitory peptide (GIP) after oral glucose challenge consistent with an incretin effect(8). Over-stimulation of the incretin axis (primarily GLP-1) has been noted to underlie exaggerated prandial insulin responses leading to post-RYGB hypoglycemia (11) that may be reversed by gastrostomy tube feeds (12), suggesting that altered nutrient-intestinal transit rather than ß-cell hyperplasia (13) may be responsible for this under-recognized condition.

References:

1. Sjostrom L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, Dahlgren S, Larsson B, Narbro K, Sjostrom CD, Sullivan M, Wedel H: Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 351:2683-2693, 2004

2. Sjostrom L, Narbro K, Sjostrom CD, Karason K, Larsson B, Wedel H, Lystig T, Sullivan M, Bouchard C, Carlsson B, Bengtsson C, Dahlgren S, Gummesson A, Jacobson P, Karlsson J, Lindroos AK, Lonroth H, Naslund I, Olbers T, Stenlof K, Torgerson J, Agren G, Carlsson LM: Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 357:741-752, 2007

3. Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, Thomas S, Abood B, Nissen SE, Bhatt DL: Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes. N Engl J Med 2012

4. Mingrone G, Panunzi S, De GA, Guidone C, Iaconelli A, Leccesi L, Nanni G, Pomp A, Castagneto M, Ghirlanda G, Rubino F: Bariatric Surgery versus Conventional Medical Therapy for Type 2 Diabetes. N Engl J Med 2012

5. Ikramuddin S, Korner J, Lee WJ, Connett JE, Inabnet WB, Billington CJ, Thomas AJ, Leslie DB, Chong K, Jeffery RW, Ahmed L, Vella A, Chuang LM, Bessler M, Sarr MG, Swain JM, Laqua P, Jensen MD, Bantle JP: Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA 309:2240-2249, 2013

6. Kashyap SR, Bhatt DL, Wolski K, Watanabe RM, bdul-Ghani M, Abood B, Pothier CE, Brethauer S, Nissen S, Gupta M, Kirwan JP, Schauer PR: Metabolic Effects of Bariatric Surgery in Patients With Moderate Obesity and Type 2 Diabetes: Analysis of a randomized control trial comparing surgery with intensive medical treatment. Diabetes Care 2013

7. Kashyap SR, Schauer P: Clinical considerations for the management of residual diabetes following bariatric surgery. Diabetes Obes Metab 14:773-779, 2012

8. Laferrere B, Teixeira J, McGinty J, Tran H, Egger JR, Colarusso A, Kovack B, Bawa B, Koshy N, Lee H, Yapp K, Olivan B: Effect of weight loss by gastric bypass surgery versus hypocaloric diet on glucose and incretin levels in patients with type 2 diabetes. J Clin Endocrinol Metab 93:2479-2485, 2008

9. Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, Barakat HA, deRamon RA, Israel G, Dolezal JM, .: Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 222:339-350, 1995

10. Dixon JB, O'Brien PE, Playfair J, Chapman L, Schachter LM, Skinner S, Proietto J, Bailey M, Anderson M: Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA 299:316-323, 2008

11. Goldfine AB, Mun EC, Devine E, Bernier R, Baz-Hecht M, Jones DB, Schneider BE, Holst JJ, Patti ME: Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol Metab 92:4678-4685, 2007

12. McLaughlin T, Peck M, Holst J, Deacon C: Reversible hyperinsulinemic hypoglycemia after gastric bypass: a consequence of altered nutrient delivery. J Clin Endocrinol Metab 95:1851-1855, 2010

13. Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV: Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med 353:249-254, 2005

Metabolic Effects of Bariatric Surgery

Sangeeta R. Kashyap MDAssociate Professor of Medicine

Cleveland Clinic Lerner College of Medicine

Department of Endocrinology, Diabetes and Metabolism

ADA Post-graduate course 2016, San Francisco

Presenter Disclosure Information

In compliance with the accrediting board policies, the American Diabetes Association requires the following disclosure to the participants:

Sangeeta Kashyap

Research Support: Ethicon/Covidean

Employee: none

Board Member/Advisory Panel:none

Stock/Shareholder: none

Consultant: Ethicon

Other: na

Objectives

• Recognize the efficacy and safety of bariatric surgery for type 2 diabetes from randomized clinical trials

• Identify the mechanisms of action (GI hormones/physiology) of bariatric surgery on glucose metabolism

• Identify clinical and metabolic determinants of diabetes remission following surgery

Morbid Obesity in the 1700’s

Hunterian Museum; Royal College of Surgeons. London UK

Etiology of Obesity-Complex and Multifactorial

Genetic and epigenetic influences-70%Acquired: 30%

Increased caloric intakeBiological influences of hormones (leptin, adiponectin etc.)Gut microbesImbalance of signals related to energy regulation (gut/adipose vs. hypothalamic)

Regulation of Food IntakeBrain

NPYAGRPgalanin

Orexin-Adynorphin

Stimulateα-MSHCRH/UCNGLP-I

CARTNE5-HT

Inibit

Central Signals

Glucose

CCK, GLP-1,Apo-A-IVVagal afferents

Insulin

Leptin

Cortisol

Peripheral signals Peripheral organs

+

+

Gastrointestinaltract

Adiposetissue

FoodIntake

Adrenal glands

External factorsEmotionsFood characteristicsLifestyle behaviorsEnvironmental cues

Characterization of -cell Failurein T2DM From UKPDS

Fonesca, Vivian A. Diabetes Care; Nov 2009;32, pg. S151

Factors associated with progression of pre-diabetes to

diabetes

Illustration of coefficient of -cell failure over time in relation to

A1C

• Elevated FPG and increase in FPG

• High BMI

• Weight gain

• Younger age

• High plasma insulin

• Decreased insulin response to glucose

• Hypertension

• Poor -cell function

• Choice of treatment

A1

C (

%)

Time (years)

Codeeicient of failure=0.47 A1C %/yearR2=0.95

0 1 2 3 4 5 6 7 8 9 10 110

2

4

6

8

10

12

1414Liver

Resistancearteries Large

arteries

Sympatheticnervoussystem PlateletsMuscle

Insulin Resistance

Overeating, inactivity(acquired/genetic)

↑↑↑Glucose Predisposition to atherothrombotic vascular disease

Type 2 DiabetesKashyap SR. et al. Diab Vasc Dis Res. 2007

Mar;4(1):13-9

“Lipotoxicity”

l Muscle insulin resistance

l Adipocyte macrophage TNF

l Liver HGP (GN); Steatosis

l Pancreas insulin secretion

l Arteries atherosclerosis

Adipocytes represent a storage depot for energy (i.e., fat). When the capacity of adipocytes to store fat is exceeded, there is an overflow of fat to:

Gastric BypassLap Band

Effectiveness

Risk

Low High

Banding Gastric Bypass

Duodenal Switch

Excess weight loss

47.5% 61.6% 70.1%

Operative mortality

0.1% 0.5% 1.1%

Resolution of diabetes

47.8% 83.6% 97.9%

COMPARISON OF BARIATRIC OPERATIONS: The resolution of diabetes is “dose related”

n = 22,094 patients; 2738 citations 1990-2002

Buchwald, Avidor, Braunwald, Jensen, Pories, Farbach, SchoellesJAMA 2004;292:1724-1737

Weight loss in the SOS

JAMA. 2012;307(1):56-65

Bariatric Surgery is Associated with aReduced Mortality: the SOS Study

Sjostrom L NEJM 2007: 357-741-752

30% lower riskOf dying

MI: 25 in controlGroup 13 in theSurgery group

Cancer: 47 inThe control group29 in the surgerygroup

Sjostrom L et al. N Engl J Med 2004;351:2683-93“SOS STUDY”

• 30-60yrs

• A1C ≥ 7.0%

• A1c = 9.2 ±1.5%

• BMI = 45.2

• DM = 6.1 yrs

• R-Y Bypass, Biliopancreaticdiversion

Fasting BG <100mg/dL &

A1c <6.5% ± drug Rx for 2 yrs

Italian Study Cleveland Study Ikramuddin et al.

Inclusion Criteria

• 20-60yrs• BMI 27-35• A1C ≥ 7.0%

• A1c = 8.7 ±1.5%• BMI = 36.8• DM = 8.5 yrs

• R-Y Bypass• Sleeve GastrectomyA1C<6.0% for 1 yr

Baseline

Surgery

1° endpoint

Bariatric Surgery vs. Intensive Medical Rx for T2DM:

20-60 yrsBMI 30-40A1C >8%

A1c 9.6%BMI 34.6DM 9 yrs

RYGB vs. lifestyle

A1C < 7%; SBP< 130 and LDL <100

Endpoints

Success rate of achieving HbA1c ≤ 6%

Primary

Secondary

• Change in fasting plasma glucose (FPG)

• Change in BMI

• Change in lipids, blood pressure, hs-CRP

• Change in medications

• Safety and adverse events

Bariatric Surgery and Type 2 Diabetes

Schauer et al., N. Eng. J. Med., 370:2002-13, 2014

218 patients screened

50Intensive medical

therapy alone

50 Medical therapy

plussleeve gastrectomy

Population for 3-Year Analysis40 48 49

150 randomized

STAMPEDE Trial: Flow of Patients

50Medical therapy

plusgastric bypass

1 withdrew consent

prior to surgery

8 withdrew consent

2 Lost to follow-up

• HbA1c >7.0%• BMI 27- 43 kg/m2

• Age 20-60 years

91% retention

2 Lost to follow-up

Kashyap, Bhatt, Schauer et al. Diabetes, Obesity Metabolism 2009

Primary and Secondary Endpoints at 36 MonthsPrimary and Secondary Endpoints at 36 Months

ParameterMedical Therapy (n=40)

Bypass (n=48)

Sleeve (n=49)

P Value1

P Value2

HbA1c ≤ 6% 5% 37.5% 24.5% <0.001 0.012

HbA1c ≤ 6% (without DM meds) 0% 35.4% 20.4% <0.001 0.002

HbA1c ≤ 7% 40% 64.6% 65.3% 0.02 0.02

Change in FPG (mg/dL) -6 -85.5 -46 0.001 0.006

Relapse of glycemic control 80% 23.8% 50% 0.03 0.34

% change in HDL +4.6 +34.7 +35.0 <0.001 <0.001

% change in TG -21.5 -45.9 -31.5 0.01 0.01

% change in CIMT 0.048 0.013 0.017 0.36 0.49

1 Gastric Bypass vs Medical Therapy; 2 Sleeve vs Medical Therapy

0

10

20

30

40

50

60

Baseline Month 3 Month 6 Month 12 Month 24 Month 360

10

20

30

40

50

60

Baseline Month 3 Month 6 Month 12 Month 24 Month 36

Percentage of Patients on Insulin

% Patients% Patients

Medical 52 54 44 40 47 55Gastric Bypass 46 25 10 4 7 6Sleeve 45 16 6 8 9 8

Medical 52 54 44 40 47 55Gastric Bypass 46 25 10 4 7 6Sleeve 45 16 6 8 9 8

MedicalSleeve Gastric Bypass

MedicalSleeve Gastric Bypass

ACC 2014; Late Breaking Clinical Trials

Cardiovascular Medications atBaseline and Month 36

Cardiovascular Medications atBaseline and Month 36

CV medications – number (%)

Medical Therapy(n=40)

Bypass (n=48)

Sleeve(n=49)

Baseline

None 0 (0) 3 (6.3) 2 (4.1)

1 - 2 19 (47.5) 17 (35.4) 28 (57.1)

> 3 21 (52.5) 28 (58.3) 19 (38.8)

Month 36

None 1 (2.5) 33 (68.8) * 21 (42.9) *

1 - 2 18 (45) 14 (29.2) 25 (51)

> 3 21 (52.5) 1 (2.1) 3 (6.1)

* P value <0.05 with Medical Therapy group as comparator

Quality of Life

Physical Functioning

Role Limitations

Physical Health Components

Mental Health Components

** **

* <0.05   ** <0.001 (Compared to IMT)

**

*

*

%

%

Adverse Events through 36 MonthsAdverse Events through 36 Months

ParameterMedical Therapy

(n=43)Bypass (n=50)

Sleeve (n=49)

GI complications 2 (5) 13 (26) 5 (4)

Re-op 0 2(4) 2(4)

Stroke 0 0 1 (2)

Retinopathy 0 1 (2) 2 (4)

Nephropathy 4 (9) 7 (14) 5 (10)

Foot ulcers 0 2 (4) 1 (2)

Excessive weight gain 7 (16) 0 0

SummarySummary• Bariatric surgery was more effective than intensive

medical therapy in achieving glycemic control (hbA1c <6.0%) with weight loss as the primary determinant of this outcome.

• Many surgical patients achieved glycemic control without use of any diabetic medications (particularly insulin).

• Metabolic syndrome components (HDL, triglycerides, glucose, BMI) showed greater improvement after surgery.Marked improvement in quality of life.

• Bariatric surgery was more effective than intensive medical therapy in achieving glycemic control (hbA1c <6.0%) with weight loss as the primary determinant of this outcome.

• Many surgical patients achieved glycemic control without use of any diabetic medications (particularly insulin).

• Metabolic syndrome components (HDL, triglycerides, glucose, BMI) showed greater improvement after surgery.Marked improvement in quality of life.

Diabetes Complications?• Retinal data was negative at 2 years (Singh R et

al. ADA scientific sessions, oral presentation 2014)

• Nephropathy/CKD; No worsening of GFR but ?improvement--Pilot study (N=15, Crt>1.3mg/dl) demonstrate no change in proteinuria, measured GFR (iothalamatetesting), Cystatin C, or ß2 microglobulin 1 year following surgery (Navaneethan et. al. AJKD, in press)

• Fractures- Bone density drops by 10%; 31% in surgical and 25% in medical. (Magrabi A et al. ADA scientific sessions, 2013)

LimitationsLimitations• Single-center trial – multicenter studies needed to determine if

results can be generalized.

• Duration of Follow-up limited to 3 years so far

• Larger studies will need to determine potential benefit on cardiovascular events and diabetes related microvascularcomplications.

• Sample size insufficient to detect uncommon but significant complications of surgery or medical Rx

• Single-center trial – multicenter studies needed to determine if results can be generalized.

• Duration of Follow-up limited to 3 years so far

• Larger studies will need to determine potential benefit on cardiovascular events and diabetes related microvascularcomplications.

• Sample size insufficient to detect uncommon but significant complications of surgery or medical Rx

BMJ Oct 22, 2013

• 11 studies, 796 patients, BMI 27-53

• Surgery superior to med Rx

– Wt. loss, HbA1c, T2DM remission, TG, HDL, remission of metabolic syndrome, QOL, medication reduction

• No difference in BP or LDL

• No CV events or death after surgery

• Anemia (15%), Reoperation (8%)

• Based on the complete case analysis, the

relative risk to achieve diabetes remission

was 22 times higher (relative risk 22.1 (3.2 to

154.3, P=0.002) after bariatric surgery

compared with non-surgical treatment.

Mortality Rates (%) of 8 Procedures in Diabetics, 2008-2012

Aminian A, Brethauer SA, Kirwan JP, Kashyap SR, Burguera B, Schauer PR. How safe is metabolic/diabetes surgery? Diabetes Obes Metab. 2014 Oct 29.

.0%

.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

2008 2009 2010 2011 2012

CABG

Infrainguinal Bypass

Lap Colectomy

Lap CholecystectomyLap AppendectomyLRYGBKnee ArthroplastyLap Hysterectomy

Observed

Mortality (%

)

Mortality Rate of LRYGB = 3 in 1000

Mo

rtal

ity

Adverse Events of Surgery

• Hyperinsulinemic hypoglycemia

• Osteomalacia/osteoporosis and bone fractures

• Kidney stone (calcium oxalate)

• Other vitamin and mineral deficiencies (iron, B12, vitamin d)

Risk of Selected Nutritional Deficiencies Resulting from Bariatric Surgery

LAGB = Laparoscopic adjustable gastric banding; RYGB = Roux-en-Y gastric bypass;BPD/DS = biliopancreatic bypass/duodenal switchawith persistent vomiting; bincreased with menstruation

Nutrient LAGB RYGB BPD/DS

Macronutrients √√√

Thiaminea √ √ √

Ironb √√ √

Vitamin B12 √√√ √

Vitamin D √√√ √√√

Vitamin A √ √√

Nutritional Monitoring for the Bariatric Surgical Patient

• Routine

– CBC

– Chemistry profile

– Liver function tests

– Lipid panel

– HbA1c

• Micronutrients

– Iron, TIBC, Saturation

– Ferritin

– Folate

– Vitamin B12

– 25 (OH) vitamin D

– PTH

– DEXA scan

Routine Vitamin & Mineral Supplementation for RYGB Patients

a Depending on dietary calcium intakeb Daily dose determined by serum 25 (OH) vitamin Dc For most menstruating women

Supplement Dosage

Multivitamin-mineral or prenatal

Calcium citratea with vitamin Db

Elemental ironc

Vitamin B12

1-2 daily

1,200-2,000 mg/day + 400-800 U/day

40-65 mg/day

≥350 µg/day orallyor 1,000 µg/mo intramuscularlyOr 3,000 µg every 6 mo intramuscularlyor 500 µg every week intranasally

Time (min)

0 30 60 90 120

Pla

sma

Glu

cose

Co

nc.

(m

M)

4

5

6

7

8

9

10Before Surgery

1 Month

6 Months

12 Months

Glucose Tolerance Following RYGB in Type 2 Diabetes

Kashyap SR et al. IJO 2010

Proposed Mechanisms• Negative caloric balance and weight loss

• Improvement in insulin sensitivity and “lipotoxicity”; mobilization of ectopic lipids.

• Stimulation of the entero-insular axis and subsequent effects of B-cell function (early weight independent effects)

• Foregut hypothesis

• Hindgut hypothesis

Effect of Duodenal-Jejunal Exclusion in a Non-obese Animal Model of Type 2

Diabetes.Rubino and Marescaux. Ann Surg 2004.

• Can exclusion of duodenum and jejunum control diabetes independent from weight loss?

• GJB 8 rats compared to sham, pair fed, controls

• OGT and ITT performed one week post-op

• No significant difference in food intake are weight gain between groups

Effect of Duodenal-Jejunal Exclusion in a Non-obese Animal Model of Type 2 Diabetes.

Rubino and Marescaux. Ann Surg 2004.

• >40% reduction AUC with glucose tolerance testing in GJB group

• Better insulin sensitivity with GJB

• Exclusion of duodenum and jejunum directly controls DM2 independent of wt loss or treatment of obesity

Insulin Secretion RYGB

Pre-RYGBPost-RYGB

Time (min)

C P

ep

(n

g/m

l)

0 30 60 90 1202

4

6

8

Time (min)

C P

ep

(n

g/m

l)

0 2 10 90 120-1

3

5

9

-10 4 6 8 80 110100

1

7

40% increase

Mixed Meal Tolerance Test Hyperglycemic Clamp - IV

Incretin Effect(Positive)

First Phase Second phase

Baseline labs

Kashyap et al. Int. J Obesity 2010 Mar;34(3):462-71

Glucagon Like Peptide (GLP-1)

Pre-RYGBPost-RYGB

Time (min)

0 30 605

Time (min)

GL

P-1

(p

g/m

l)

5

10

20

30Pre-GRPost-GR

GL

P-1

(p

g/m

l)

15

25

10

20

30

15

25

RYGB Gastric Restriction

0 30 60

P = NS

P = 0.04

Acute Effects of Gastric Bypasson Beta Cell Function

Kashyap SR et al. IJO. 2010, 34; 462-471

GR RYGB

Insu

lin s

ecre

tio

n r

ate

(pm

ol/m

in)

5

Glucose (mmol/l)

0

200

400

600

800

1,000

Pre-surgery4 weeks

6 7 8 9 10

R2=0.638

R2=0.419

5

Glucose (mmol/l)

6 7 8 9 10

R2=0.874

R2=0.675

22Intensive medical

therapy alone

20 Medical therapy + sleeve gastrectomy

Population for 2 Year Analysis17 18 19

62 randomized

STAMPEDE Metabolic Substudy: Flow of Patients

20Medical therapy +

gastric bypass

1 withdrew consentprior to surgery

2 withdrew from substudy2 withdrew consent2 missed 12 month visit

•HbA1c >7.0%•BMI 27- 43 kg/m2

•Age 20-60 years

90 % retention

Population for 1 Year Analysis16 19 19

1 missed12 month visit

1 withdrew consent1 missed 24

month visit1 missed 24 month visit

Clinical Outcomes at 2 yearsClinical Outcomes at 2 years

ParameterMedical Therapy

Bypass Sleeve P Value1 P Value2

HbA1c ≤ 6% (12m) 6.25 44% 26.32% 0.02 0.19

HbA1c ≤ 6% (24m)

5.9% 33.3% 10.5% 0.09 1.00

Change in HbA1c (%) -1.1 -3.1 -2.5 0.001 0.06

Change in BMI (kg/m2) -0.2 -8.7 -8.2 <0.001 <0.001

Change in Total Body Fat (%)

+1.1 -10.6 -7.7 0.001 0.001

Change in Truncal Fat (%) 0.9 -15.9 -10.1 0.001 0.001

Change in Leptin +4864 -11155 -16211 <0.001 <0.001

1 Gastric Bypass vs Medical Therapy; 2 Sleeve vs Medical Therapy

Kashyap SR. et al. Diabetes Care. 2013 Aug;36(8):2175-82

Gastric Bypass Normalizes Post Prandial Glucose Metabolism

Kashyap SR et al. Diabetes Care. 2013 Aug;36(8):2175-82

Glucose Measures During Mixed Meal Tolerance TestBaseline

Insulin Measures During Mixed Meal Tolerance TestBaseline

Glucose Measures During Mixed Meal Tolerance TestMonth 24

Insulin Measures During Mixed Meal Tolerance TestMonth 24

Glu

cose

(m

g/d

l)

0

50

100

150

200

250

300

MedicalRYGBSleeve

Glu

cose

(m

g/d

l)

50

100

150

200

250

300

-10 0 30 60 90 120Minutes

A.

C.

B.

D.

Insu

lin

(u

U/d

mL

)0

20

40

60

80

100

-10 0 30 60 90 120Minutes

Insu

lin

(u

U/d

mL

)

0

20

40

60

80

100

Absolute Change in Insulin Sensitivity During the Mixed Meal Tolerance Test

*[(AUC ISR//AUC Glucose) x Matsuda Index]

A.Increase in Pancreatic -cell Function

B.Increase in Insulin Sensitivity

Incr

ease

in

Ora

l D

isp

osi

tio

n In

dex

Medical Sleeve Gastric Bypass0.0

0.1

0.2

0.3

0.4

0.5

p=0.001

p=0.30 p=0.34

Incr

ease

in

Mat

sud

a In

dex

Medical Sleeve Gastric Bypass0.0

1.0

2.0

3.0

5.0

6.0

p=0.001

p=0.05 p=0.024.0

Change in GLP-1 and GIP Response to Mixed Meal Tolerance Test

A. Change in GIP Response to Mixed MealTolerance Test

Baseline to Month 24

B.

Ch

ang

e in

GIP

Res

po

nse

(p

g/m

l)

Medical Sleeve Gastric Bypass-30

-20

-10

0

10

20p=0.001

p=0.59p=0.05

Medical Sleeve Gastric Bypass-5

0

5

10

15p<0.001

p<0.001 p=0.07

Ch

ang

e in

GL

P R

esp

on

se (

pm

ol/L

)

Change in GLP-1 Response to Mixed MealTolerance Test

Baseline to Month 24

Physiologic effects of Gastric Bypass on Classical Pathways of Glucose Metabolism.

Goldfine A B , and Patti M E Diabetes 2014;63:1454-1456

Non-remission of DM• Result of impaired incretin stimulation of

residual beta cell function

• OR

• Weight/fat related effects of insulin sensitivity

• Does weight regain following surgery impact recurrence of DM?

Non‐remitters showed blunted response to bariatric surgery

Results: Adiponectin

Malin , Kashyap et al. Diabetes, Obesity And Metabolism. 2014 Dec;16(12):1230-8

Malin  et al. Diabetes, Obesity And Metabolism. 2014 Dec;16(12):1230-8

Summary Points• Diabetes remission characteristic of bariatric

surgery (RYGB>Sleeve Gastrectomy) and linked to improvements in post prandial glucose metabolism.

• Weight independent effects related to GLP-1 specific effects to increase insulin secretion

• For those who initially achieved remission but relapse subsequently, consider targeting additional weight/fat loss and adiponectin raising interventions. (diet/exercise/metformin/?SGLT2)

• Continuous surveillance for micro- and macro-vascular complications post-surgery is Key!!

EVOLUTION IN MEDICINE 2015: DIABETES MEDICINE AND DIABETES/METABOLIC SURGERY

• Funding– Ethicon endo-surgery (EESIIS 19900; PRS) – RO1 DK089547 (PRS, SRK, JPK)– ADA clinical translational award 1-11-26 CT

(SRK)– 1UL1RR024989 – T32 DK007319 (SKM)

• CRU & Subjects

AcknowledgementsSTAMPEDE TeamSangeeta R. Kashyap, MDPhilip R. Schauer, MDJohn P. Kirwan, PhDStacy A. Brethauer, MDJulianne Filion, RN, BSNBeth Abood, RNClaire E. Pothier, MPHDeepak L. Bhatt, MD, MPHSteven Nissen, MD

StatisticsKathy Wolski, MPHJames Bena, M.S.

Biochemical AnalysisSarah Neale, BScHazel Huang, MS