Metabolic Surgery Mechanisms of ActionsMetabolic Surgery Mechanisms of ActionsThe Foregut Theory The Foregut Theory

Francesco Rubino, MDFrancesco Rubino, MD

Department of Surgery, Catholic University, Rome, ItalyDepartment of Surgery, Catholic University, Rome, Italy

United States Surgical Metabolic Surgery Panel United States Surgical Metabolic Surgery Panel June 14, 2007June 14, 2007San Diego, CASan Diego, CA

Rates of Remission of Diabetes

AdjustableGastric Banding

Roux-en-YGastric Bypass

BiliopancreaticDiversion

>95%(Immediate)

48%(Slow)

84%(Immediate)

Rehfeld J, 2004

1967 – Gastric Bypass

DISCOVERY OF GASTROINTESTINAL HORMONES

Duodenal-Jejunal Bypass (DJB)Duodenal-Jejunal Bypass (DJB)

January 2004January 2004

DJBDJB

Controls type 2 diabetes in Controls type 2 diabetes in non non obeseobese rats independently on: rats independently on:

weight lossweight loss decreased caloric intakedecreased caloric intake nutrients malabsorptionnutrients malabsorption

Ann Surg 2004Ann Surg 2004Ann Surg November 2006Ann Surg November 2006

Gastrointestinal Bypass Surgery

Direct Antidiabetic EffectDirect Antidiabetic Effect

> Type 2 Diabetes: an operable disease ?> Type 2 Diabetes: an operable disease ?

The Surgeon and the DiabetologistsThe Surgeon and the Diabetologists

Mechanisms of Surgical Treatment of T2DMechanisms of Surgical Treatment of T2D

The exclusion of the duodenal The exclusion of the duodenal nutrient passage may offset an nutrient passage may offset an abnormality of gastrointestinal abnormality of gastrointestinal physiology responsible for physiology responsible for insulin resistance and type 2 insulin resistance and type 2 diabetesdiabetes

« Foregut hypothesis »« Foregut hypothesis »

November 2006November 2006

Goto-Kakizaki Rat (GK)Goto-Kakizaki Rat (GK)

Animal model of type Animal model of type 2 diabetes2 diabetes– The most-widely used The most-widely used

lean model in type 2 lean model in type 2 diabetes research diabetes research

((Nature Genet 1996Nature Genet 1996))

» Non-obeseNon-obese» NormolipidemicNormolipidemic» HyperinsulinismHyperinsulinism» Insulin resistanceInsulin resistance

Gastro-jejunal AnastomosisGastro-jejunal Anastomosis

Early Ileal StimulationEarly Ileal Stimulation

Annals of Surgery Nov 2006Annals of Surgery Nov 2006

(GJA)(GJA) DJBDJB

Sham+

PF to DJB

Annals of Surgery Nov 2006Annals of Surgery Nov 2006

OGTT GK rats

0

100

200

300

400

500

600

0 50 100 150 200

Time (min)

Glu

cose

leve

ls (m

g/dl

)

GK Sham

Oral Glucose Tolerance

Annals of Surgery Nov 2006 Annals of Surgery Nov 2006

OGTT GK rats

0

100

200

300

400

500

600

0 50 100 150 200

Time (min)

Glu

cose

leve

ls (m

g/dl

)

GK DJB

GK Sham

Oral Glucose Tolerance

Annals of Surgery Nov 2006Annals of Surgery Nov 2006

OGTT GK rats

0

100

200

300

400

500

600

0 50 100 150 200

Time (min)

Glu

cose

leve

ls (m

g/dl

)

GK DJB

GK Sham

GK GJ

Oral Glucose Tolerance

Annals of Surgery Nov 2006Annals of Surgery Nov 2006

Duodenal Exclusion

Annals of Surgery Nov 2006Annals of Surgery Nov 2006

OGTT after Doudenal Exlcusion

44000

49000

54000

59000

64000

69000

Duodenal Pass. Duod. Exclus

OGTTAUC

Duodenal Pass.

Duod. Exclus

P<0.05

Annals of Surgery Nov 2006Annals of Surgery Nov 2006

Restoration of Duodenal Passage

AUC OGTT X 2AUC OGTT X 2Annals of Surgery Nov 2006Annals of Surgery Nov 2006

Conclusion

Exclusion of the proximal small bowel from the flow ofExclusion of the proximal small bowel from the flow ofnutrients is the nutrients is the primaryprimary mediator of diabetes resolution mediator of diabetes resolutionafter DJBafter DJB

Annals of Surgery Nov 2006Annals of Surgery Nov 2006

Implication for the Pathophysiology of T2D

Nutrients contact with duodenal mucosa is detrimental Nutrients contact with duodenal mucosa is detrimental in diabetic ratsin diabetic rats

A dysfunctional duodenal response to nutrients passageA dysfunctional duodenal response to nutrients passageplays a role in the pathophysiology of type 2 diabetesplays a role in the pathophysiology of type 2 diabetes

Hypothesis

HypoglycemiaHypoglycemia

Rubino et al; Ann Surg 2002Rubino et al; Ann Surg 2002

Hypothesis

Rubino et al; Ann Surg 2002Rubino et al; Ann Surg 2002

Hypothesis

Rubino et al; Ann Surg 2002Rubino et al; Ann Surg 2002

Hypothesis

Rubino et al; Ann Surg 2002Rubino et al; Ann Surg 2002

GIP and GLP-1GIP and GLP-1

• Stimulated by enteral nutrients

• insulin secretion / action

-cell proliferation

…Anti-Incretin

• Stimulated by enteral nutrients

• insulin secretion / action

-cell proliferation

Anti-incretin

Anti-Incretin

Insulin ResistanceInsulin ResistanceBeta cell depletionBeta cell depletionHyperglycemiaHyperglycemia

Too muchToo much

Dumping SyndromeDumping Syndrome

NesidioblastosisNesidioblastosisHyperinsulinemiaHyperinsulinemiaHypoglycemiaHypoglycemia

Not EnoughNot Enough

TYPE 2 DIABETESTYPE 2 DIABETES

ConclusionsConclusions

Our findings in rats support the hypothesis Our findings in rats support the hypothesis that a dysfunction of the duodenum may that a dysfunction of the duodenum may contribute to the pathophysiology of type 2 contribute to the pathophysiology of type 2 diabetes diabetes