University of PisaUniversity of Pisa

School of MedicineSchool of Medicine

Dipartimento di Medicina Clinica e SperimentaleDipartimento di Medicina Clinica e Sperimentale

UniversitUniversitàà degli Studi di Pisadegli Studi di Pisa

Effetti endocrino-metabolici della chirurgia bariatrica:non solo calo

ponderaleMonica Nannipieri

Rubino F, Nat. Rev. Endocrinol 2010

Sleeve gastrectomy

Bariatric/Metabolic Surgery

Cumulative Incidence of T2DM

Sjostrom L, J Int Med 2012

Cumulative Incidence of type 2 Diabetes over 15 years

Sjoholm K, Diabetes Care 2013

Surgical treatment effect on indicated end-point

Sjostrom L, J Int Med 2012

Buchwald H et al, Am J Med, 2009

Weight and type 2 diabetes after bariatric surgery:systematic review and meta-analysis

Results: weight loss, surgical procedure, and diabetes resolution

Total Gastric Gastroplasty Gastric BPD/DSbanding bypass

% excess bw loss 55.9 46.2 55.5 59.7 63.6

% resolved overall 78.1 56.7 79.7 80.3 95.1

2 <years 80.3 55.0 81.4 81.6 94.0

2 >years 74.6 58.3 77.5 70.9 95.9

BPD/DS = bilio-pancreatic diversion/duodenal switch

Resolution

Remission

2009

Dixon JD, 2008

NMCD 2008

Cure

Buse JB et al. Diab Care 2009

HbA1c < 6.5 %

Glycemia 100-125 mg/dl

HbA1c < 6.0 %

Glycemia < 100 mg/dl

Pournaras DJ et al, BJS 2011

Mingrone G NEJM 2012

Bariatric Surgery versus Conventional Medical Therapy for Type 2

Diabetes

6.5

Metabolic Surgery for type 2 diabetes with BMI<35 kg/m2

Shimizu H, J Obes 2012

Recurrence of Diabetes After Metabolic Surgery

Induced Remission

Lebovitz HE, Obes Surg 2013

Recurrence of Diabetes After Metabolic Surgery

Induced Remission

Sjostrom L, J Int Med 2012

↑ insulin sensitivity

and

↑ β-Cell Function

Cure

remission of the disease

(correction of disease mechanisms)

Metabolic EffectsMetabolic Effects

Insulin sensitivity and/or insulin Insulin sensitivity and/or insulin

secretion?secretion?

From Restrictive to Malabsorbitive From Restrictive to Malabsorbitive

SurgerySurgery

00

1010

2020

3030

4040

5050

6060

7070

8080

1515 2020 2525 3030 3535 4040 4545 5050 5555 60601515 2020 2525 3030 3535 4040 4545 5050 5555 6060

controls

gastric bypass

biliopancreatic diversion

Body mass index (kg.m-2)

Insu

lin s

ensi

tivity

(µm

ol. m

in-1

. kg-

1 )

Muscelli et al. Am J Med 2005;118:51-7

Insulin sensitivity after BPD vs RYGB

ββββ-cell Function in RYGB and DBP

Nannipieri M. Diabetes Care Submitted

Astiarraga B. JCEM 2013

ISR

(p

mo

l. min

-1.m

-2)

Plasma glucose (mmol/L)

0

100

200

300

400

500

600

700

5 7 9 11 13 15 17 19 21 23

Controls

T2D

before2 mos

12 mos

4 5 6 7 8 9 10 11 120

100

200

300

400

500

600

glucose (mM)

secr

etio

n (p

mol

/min

/m2 )

Sleeve Gastrectomy

post

pre

y1

4 5 6 7 8 9 10 11 120

100

200

300

400

500

600

glucose (mM)

secr

etio

n (p

mol

/min

/m2 )

Gastric by-pass

post

pre

y1

Predictive Factors of Type 2 Diabetes Remission 1

Year

After Bariatric Surgery

DIABETES DURATION

Clinical outcomes of diabetes according to duration of

T2DM prior to surgery.

Shimizu H, J Obes 2012

%

BMI AND DIABETES DURATION

How Important Is Weight Loss in the Resolution of Diabetes by

Bariatric Surgery?

Lebovitz HE, Obes Surg 2013

Predictive Factors of Type 2 Diabetes Remission 1

Year

After Bariatric Surgery

Robert M, Ob Surg 2013

Predicting the Glycemic Response to

Gastric Bypass Surgery in Patients

With Type 2 Diabetes

Dixon JB, Diabetes Care 2013

Remission of Type 2 Diabetes

When?

Predictors of successful sustained euglycemia

Retnakaran R, Zinman B, Diabetes, Obesity and Metabolism, 2012.

Baseline 45 days 1 year0

20

40

60

80

100

120

ß-c

ell

glu

cose

se

nsi

tivit

y(p

mo

l. min

-1. m

-2 .m

M-1

)

Insu

lin

se

nsi

tivit

y(m

l. min

-1. m

-2)

Early remitters

Late remitters

Non-remitters

0

100

200

300

400

500

600

Baseline 45 days 1 yearNannipieri M. et al, JCEM 2011

β-Cell Function and Insulin Sensitivity in the Remission

of Type 2 Diabetes after RYGB

p<0.0001

p<0.0005

p<0.02

GLP-1 in remitters and no-remitters

Minutes Minutes

(pg

/ml)

(pg

/ml)

Nannipieri M et al Diabetes Care, Submitted

Proposed mechanism of diabetes resolution after RYGB surgery.

Holst J J Diabetes 2011;60:2203-2205

Copyright © 2011 American Diabetes Association, Inc.

Intestinal

Gluconeogenesis

Hepato-portal

sensing

Intestinal

Gluconeogenesis

Hepato-portal

sensing

Ileal Brake

Gut Hormones

Ileal Brake

Gut Hormones

Fat metabolism

Adipokines

Fat metabolism

Adipokines

Bile

metabolism

Bile

metabolism

Gut microbiota

modulation

Gut microbiota

modulation

Metabolite shift

(systemic/local)

Metabolite shift

(systemic/local)

Nerve-mediated

effects

Nerve-mediated

effects

Starvation,

caloric restriction,

Weight loss

Starvation,

caloric restriction,

Weight loss

Mechanisms Facilitating T2DM Improvement/Resolution

Metabolic effects-Pancreas (enteroinsular

axis)

-Liver (hepatic glucose

production)

-Adipose tissue (Lipolysis)

-Muscle (insulin resistance)

Metabolic effects-Pancreas (enteroinsular

axis)

-Liver (hepatic glucose

production)

-Adipose tissue (Lipolysis)

-Muscle (insulin resistance)

Foregut Exclusion

Gut Hormones

Foregut Exclusion

Gut Hormones

GhrelinGhrelin

Starvation,

Caloric restriction,

Weight loss

Starvation,

Caloric restriction,

Weight loss

Effect of Weight Loss by Gastric Bypass Surgery Versus Hypocaloric Diet (10

days) on Glucose and Incretin Levels in Patients with Type 2 Diabetes

Laferrere B, JCEM 2008

OGTT 50 g

Isbell JM. et al Diabetes Care 2010

Laferrere B, JCEM 2008

Effect of Weight Loss by Gastric Bypass Surgery Versus Hypocaloric Diet on

Glucose and Incretin Levels in Patients with Type 2 Diabetes

Evans S, Surg Endosc 2012

Caloric Restriction in the Early Improvements in Insulin Sensitivity After Roux-en-Y

Gastric Bypass Surgery

Isbell JM. et al Diabetes Care 2010

Foregut Exclusion

Gut Hormones

Foregut Exclusion

Gut Hormones

Ileal Brake

Gut Hormones

Ileal Brake

Gut Hormones

GhrelinGhrelin

Diniz MS et al, Nutrition 2010

Bariatric surgery and the gut-brain

communication: a review

Gut microbiota

modulation

Gut microbiota

modulation

Diamant M Ob Rev 2011 (modified)

Do nutrient–gut–microbiota interactions play a role in human obesity, insulin

resistance and type 2 diabetes?

Short-Chain FAShort-Chain FA

Bariatric SurgeryBariatric Surgery

Bile

metabolism

Bile

metabolism

conjugationsecretionsecretion

UPPER GI

Fecal lossFecal loss

12 g/day12 g/day

0.5 g/day0.5 g/day

reabsorptionreabsorption

LOWER GI

12 cycles/day12 cycles/day

flora

LIVER

synthesis

deconjug

cholesterol

tau/gly

secondary bile acidssecondary bile acids

Bile acids turnoverBile acids turnover

TGR5 (and PPAR?) TGR5 (and PPAR?) activationactivation by bile acids leads to:by bile acids leads to:

•• Increase in the conversion from TIncrease in the conversion from T44 into Tinto T33 (through DIO2) (through DIO2)

•• Increase in energy expenditureIncrease in energy expenditure

•• Improvement of insulin sensitivityImprovement of insulin sensitivity

•• Increase in release of GLPIncrease in release of GLP--1 and GIP (via c1 and GIP (via c--AMP)AMP)

B= Serum Bile Acids

B= Serum Bile Acids:

Potential contribution to improve glucose metabolism

Patti ME. et al Obesity 2009

SUMMARY

�The effects of bariatric surgery on diabetes are related to improvement or

restoration of:

a.insulin sensitivity (weight loss in restrictive or mixed surgery);

b.insulin secretion (possibly due to modification of GI transit and neuro-

endocrine factors and reduction of glucotoxicity and lipotoxicity).

�Rate of success of bariatric surgery in terms of diabetes remission may

depend on the extent of β-cell dysfunction/loss at time of operation and, hence,

could be lower for:

a.longer diabetes duration;

b.less severe degrees of obesity.

•Bariatric surgery is associated with a significant rate of short term and long

term complications

Role of the foregut in the early improvement in glucose tolerance and insulin

sensitivity following Roux-en-Y gastric bypass surgery

Hansen EN et al Am J Physiol 2011

Hansen EN et al Am J Physiol 2011

Role of the foregut in the early improvement in glucose tolerance and insulin sensitivity

following RYGBP

Cumulative Incidence and Remission of T2DM

Sjostrom L, J Int Med 2012

Metabolic Surgery for type 2 diabetes with BMI<35 kg/m2

Randomized trials

ASMBS Clinical Issue Committee, Surg Obes Rel Dis 2013