obesity, diabetes and bariatric surgerymediquest.in/did2016data/day 2/4 obesity, diabetes and...

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Obesity, Diabetes and Bariatric Surgery

Adrian Vella MD FRCP (Edin.), Mayo Clinic, Rochester, MN

Learning Objectives

• Understand gastrointestinal physiology, gut hormones and glucose metabolism

• Understand the effect of caloric restriction on glucose metabolism

• Understand the physiological differences between different bariatric procedures and the role of GLP-1 in glucose metabolism

• Understand the risks and benefits of bariatric interventions

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Effect of Bariatric Surgery on Diabetes

• A meta-analysis of 136 studies of bariatric surgery which included a total of 22,094 patients

• 1417 of 1846 (76%) patients experienced complete resolution

• Diabetes resolved in 98.9% of patients undergoing DS

• 83.7% for RYGB and 47.9% for AGB

Buchwald et al. JAMA 292, 2004

Why does bariatric surgery benefit carbohydrate metabolism?

• Foregut hypothesis: - the foregut elaborates a diabetogenic factor

• Isolation of the foregut and separation from nutritional input decreases secretion of this factor

• Hindgut hypothesis: - the hindgut secretes a factor that improves handling of a nutritional load

• Increased delivery to the distal intestine increases secretion of this factor

The gut as an endocrine organ • The gut is not a monolithic

organ and comprises multiple cell types (neural, muscle, exocrine, endocrine)

• It is responsible for the integration of multiple peripheral and central signals necessary for the maintenance of body weight

Gut Hormones

Chaudhri et al. Annual Review of Physiology, 2008.

Ghrelin

Amylin

Background: Regulation of Gastric Emptying

+ve -ve

Myenteric plexus

-ve

Mechanoceptors

Myenteric plexusMyenteric plexusChemoreceptors

CCK Gastrin GIP GLP-1 PYY

-ve

Food ingestion Vagus

Delgado-Aros S, et al. AJP Gastrointest Liver Physiol. 2002;282(3):G424-431.

99mTc-SPECT Technique to Measure Gastric Volume

Measurement of Gastric Accommodation

GLP-1 (7,36) GLP-1 (9,36) ACTIVE HORMONE INACTIVE HORMONE

GLP-1 Receptor

Exendin-4 (7,39) Exendin-4 (9,39)

Agonist Antagonist

Differences in function during antagonist administration can be attributed to the actions of GLP-1

Mechanisms

Malabsorption – due to bypass of proximal intestine

Creation of a gastric pouch with decreased volume and compliance

Partial or complete vagotomy

Caloric Restriction • Kelley DE et al: Relative effects of calorie

restriction and weight loss in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 77:1287-1293, 1993

• Wadden TA et al: A multicenter evaluation of a proprietary weight reduction program for the treatment of marked obesity. Arch Intern Med 152:961-966, 1992

Glu

cose

upt

ake

(mg/

min

/m2 )

Weight (kg) 92.7 90.5 77.9 76.2

J Clin Endocrinol Metab 77:1287, 1993

300

200

100

P <0.001

ns

P <0.01

Pre weight loss Post weight loss

Caloric balance Caloric restriction (800 kcal/d x 7d)

Independent Effects of Acute Calorie Restriction and Weight Loss on Insulin Sensitivity in Type 2 DM

Sathananthan. J Nutr 2015;145:2046-51.

Sathananthan. J Nutr 2015;145:2046-51.

Sathananthan. J Nutr 2015;145:2046-51.

Sathananthan. J Nutr 2015;145:2046-51.

Can Bariatric Surgery Provide Mechanistic Insights into Gut-Pancreas Interactions?

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Vella A, Diabetes (2013) 62(9): 3017-3018

4

“Remission” = < 126mg/dL, HbA1c < 6.2%

Dixon JB; JAMA. 299(3):316-23, 2008 Jan 23.

Sleeve Gastrectomy & Duodenal Switch

Abu Dayyeh B et al. Rev Esp Enferm Dig (Madrid Vol. 106, N.º 7, pp. 467-476, 2014

Nguyen NT et al. Journal of the American College of Surgeons 2013 :216(2);252 - 257

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Procedure Pro Cons AGB Simple to place

Can be adjusted No malabsorption Can be effective

Prone to migration Device failure Not effective in the long term

RYGB Established Known efficacy

Malabsorptive Risk of „dumping‟ and post-RYGB hypoglycemia Cost and long-term f/u

SG Simple procedure No malabsorption Less f/u necessary

? Long-term efficacy Not really cheaper or assn. with less complications than RYGB

DS / long-limb RYGB / Scopinaro

Effective for high BMI High morbidity Needs v close f/u Poorer QOL

Karamanakos S. et al. Annals of Surgery. 247(3):401-407, March 2008.

VAS recorded appetite changes after LRYGBP (--[black up pointing small triangle]--) and LSG (--[black small square]--).

Weight Loss, Appetite Suppression, and Changes in Fasting and Postprandial Ghrelin and Peptide-YY Levels After Roux-en-Y Gastric Bypass and Sleeve Gastrectomy: A Prospective, Double Blind Study.

RYGB

SG

STAMPEDE

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Shauer PR, NEJM 2012; 366:1567-1576

2 years after STAMPEDE

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RYGB SG IMT n 18 19 17

Female (%) 44 84 47

HbA1c (%) 6.7 ± 1.2 7.1 ± 0.8 8.4 ± 2.3

% Body Fat -16 -10

Insulin Action 2.7 x

DI 5.8 x

Kashyap SR, Diabetes Care 2013; 36:2175-2182

Bariatric Surgery versus Intensive Medical Therapy for Diabetes — 3-Year Outcomes

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Schauer PR, NEJM (2014) Mar 31

Mechanisms

Malabsorption – due to bypass of proximal intestine

Creation of a gastric pouch with decreased volume and compliance

Partial or complete vagotomy

[6,6-2H2] Glucose Infusion

-180 360

Meal at 0 mins labeled with [1-13C] Glucose and 111In

0

[6-3H] Glucose infusion

-30 300

Gamma Camera

111In in egg meal

+ / - Exendin-9,39 @ 300pmol/kg/min

Post-RYGB Controls

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Shah M, Diabetes (2014) 63(2): 483-493

Post-RYGB Controls

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Shah M, Diabetes (2014) 63(2): 483-493

Post-RYGB Controls

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Shah M, Diabetes (2014) 63(2): 483-493

Post-RYGB Controls

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* *

Shah M, Diabetes (2014) 63(2): 483-493

Post-RYGB Controls

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*

Shah M, Diabetes (2014) 63(2): 483-493

Post-RYGB Controls

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Shah M, Diabetes (2014) 63(2): 483-493

• Jimenez A et al: GLP-1 Action and Glucose Tolerance in Subjects With Remission of Type 2 Diabetes After Gastric Bypass Surgery. Diabetes Care 2013;36:2062-2069

• 750pmol/kg/min – 18% change in glucose

• Jorgensen NB et al: The exaggerated glucagon-like peptide-1 response is important for the improved beta-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes. Diabetes 2013;62(9):3044-52

• 900pmol/kg/min – 25% change in glucose

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Diabetes Surgery Study

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Ikramuddin S, JAMA 2013; 309(21) :2240-2249

Preoperative prediction of type 2 diabetes remission after Roux-en-Y gastric bypass surgery

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Still et al. Lancet Diabetes Endocrinol. 2014 Jan; 2(1): 38–45

Beta-Cell mass does not change after RYGB

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Dirksen C et al. Diabetologia. 2013 Dec;56(12):2679-87.

Mechanisms

Malabsorption – due to bypass of proximal intestine

Creation of a gastric pouch with decreased volume and compliance

Partial or complete vagotomy

Blockade of the Vagal Nerve by Overdrive Electrical Stimulation

Camilleri M et al. Surgery 2008:143:6 :723 -731

Blockade of the Vagal Nerve by Overdrive Electrical Stimulation

0

500

1000

1500

2000

2500

Pre-Implant (n=10) Week 4 (n=10) Week 12 (n=8) Week 26 (n=9)

kcal

Fat Carbohydrates Protein

Camilleri M et al. Surgery 2008:143:6 :723 -731

Sathananthan, M., et al. (2014). Diabetes, metabolic syndrome and

obesity : targets and therapy 7: 305-312.

Sathananthan, M., et al. (2014). Diabetes, metabolic syndrome and

obesity : targets and therapy 7: 305-312.

Sathananthan, M., et al. (2014). Diabetes, metabolic syndrome and

obesity : targets and therapy 7: 305-312.

Conclusions • Gastric emptying integrates with insulin

secretion and action to regulate postprandial carbohydrate metabolism

• Gastric emptying affects postprandial glucose directly only when other parameters do not change

• Bariatric surgery provides insights into the interaction between the gut and the pancreas

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Acknowledgments

University of Padua • Francesca Piccinini • Francesco Micheletto • Chiara Dalla Man • Claudio Cobelli

Vella Laboratory • Matheni Sathanthan • Meera Shah • Paula Giesler • Jeannette Laugen • Gail DeFoster

Robert Rizza Michael Camilleri Alan Zinsmeister Michael Jensen Michael Sarr Jim Swain Todd Kellogg

CTSA Study Subjects

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Case Presentation • 54 year old female presenting with painful 1st

meta-tarso phalangeal joint.

• H/O DM 2 • diagnosed 8 years ago

• No evidence for microvascular complications

• Pertinent PMH • Hypothyroidism • GERD

Medications • Levothyroxine 137mcg once daily

• Omeprazole 20mg bid

• Metformin 1000mg bid

• Glimepiride 1mg daily

• Simvastatin 20mg daily

• Indomethacin 50mg 1-2 tablets q8hr PRN

Physical Examination • Weight 115kg

• BMI 40.3 kg/M2

• HR 80 min, BP 130 / 76 mmHg

• No respiratory distress

• Cardiorespiratory exam is unremarkable

• Inflamed, swollen left 1st MTP joint. Exquisitely tender to touch

Laboratory evaluation • Fasting glucose 138 mg/dL

• HbA1c 8.0%

• Uric acid 6.5 mg/dL (2.3 – 6.0)

• Lipids • Total Chol 204 mg/dL • TG 310 mg/dL • HDL 38 mg/dL • Calc LDL 104 mg/dL

Question 1 • Is the patient a candidate for bariatric surgery?

a)Yes – she meets clinical criteria

b)Yes – she will likely experience diabetes remission

c)No – it is unlikely that her diabetes will benefit from surgery

d)No – any consideration for surgery should come after detailed psychological assessment and completion of a lifestyle intervention program

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Question 2 • What factors DO NOT affect diabetes remission

after bariatric surgery?

a)Prior duration of diabetes

b)Baseline weight

c)Prior therapy with insulin

d)Type of surgery

e)Number of medications prior to surgery

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Question 3 • Which of the following is INCORRECT?

a)Gastric banding has good long-term outcomes

b)Duodenal sleeve is associated with hepatic abscess

c)Differences between sleeve gastrectomy and RYGB become apparent over time

d)After RYGB close follow up to ensure compliance with vitamin replacement therapy is required

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