a-00121

Dr. Robert RUTLEDGE

Title of Paper: BILE ACID DEPLETION WITH GASTRO-

INTESTINAL BYPASS DECREASES HGB-A1C & SERUM

GLUCOSE AND IMPROVES INSULIN SENSITIVITY.

Nationality: United States of America

Position: Director

Department: Surgery

Organization: Center For Laparoscopic Obesity Surgery

Tel: +1-702 714 0011

E-mail: drr@clos.net

BILE ACID DEPLETION

WITH

GASTRO-INTESTINAL BYPASS

DECREASES HGB-A1C &

SERUM GLUCOSE AND

IMPROVES INSULIN SENSITIVITY

Robert RUTLEDGE1

1Director, Surgery, Center For Laparoscopic

Obesity Surgery, United States of America

Introduction

• Long term studies show deterioration of the initial improvement in diabetes after bariatric surgery over time.

• New research shows that Bile Acids (BAs) are signaling molecules, with systemic endocrine functions.

• Decrease in BAs can decrease fat absorption, triglyceride, cholesterol, energy, and

• HORMONALLY ACT improve glucose homeostasis.

Bile Acid Binding

Colesevelam a bile acid sequestrant

Manipulation of the bile acid pool plays a role in glucose homeostasis

Bile acid Sequestrants reduce

glucose levels in patients with

type 2 diabetes mellitus

Farnesoid X receptor (FXR)

• The bile acid receptor (BAR), also known as Farnesoid X receptor (FXR) is a nuclear receptor

• FXR is expressed at high levels in the liver and intestine.

• FXR translocates to the cell nucleus, forms a dimer (in this case a heterodimer with RXR) and binds to hormone response elements on DNA, which up- or down-regulates the expression of certain genes

• The nuclear BA receptor farnesoid X

receptor (FXR) regulates pathways in BA,

lipid, glucose, and energy metabolism,

which become dysregulated in obesity.

Bile Acids & FXR

• Decrease in Bile Acids Decreases FXR attenuates body weight gain and reduces adipose tissue mass in animal and human models.

• Glucose homeostasis is improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity.

• Decreasing elevated plasma BA concentrations in obese mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner,

Bile acids and signal transduction:

Role in glucose homeostasis

• Regulation of glucose metabolism by bile acids

• Regulates Farnesoid X receptor (FXR), which can stimulate the insulin receptor (IR)

Methods:

• Reviewed literature on

• Bile Acids as critical factors in

• Glucose homeostasis and

• Recent publications on

• Bile Acid Pool manipulation in the

• Management of Diabetes.

Methods

• Review of data showing that duodenal bypass as part of

• Combined Gastro-Intestinal Procedures (CGIPs) decrease BA pool (Shorter Bowel)

• decreasing weight, lipids,

• Hormonal Effect: improves insulin sensitivity and glucose homeostasis

• Further support to the importance to the bypass component of durable weight loss procedures.

Results

• Bile acids are known to facilitate digestion and absorption of lipids and regulate cholesterol homeostasis.

• It has now become clear that bile acids are critical hormones involved in activation of various signaling pathways, including triglyceride, cholesterol, glucose, and energy homeostasis.

Results

• Studies show

• Decrease in the bile acid pool

• Results in decreases in

hemoglobin A1c, glucose levels

and

• Improved insulin sensitivity.

Results

• Recent studies from Korea and China have

shown that in comparison to

• Primary Gastric Procedures (PGP) the use

• Combined Gastro-Intestinal Procedures

(CGIP) improve the success in the resolution

of diabetes.

• Combined procedures include duodenal

bypass which leads to decrease in bile acid

pool.

Conclusions:

• Bile acids regulate

triglyceride, cholesterol, glucose, and

energy homeostasis. (OLD)

• Decreased Bile acid pool size decreases

fat absorption, cholesterol and

triglycerides. (OLD)

Conclusions

• Bile Acids are also Gut Hormones

(New)

• Decreaseing Bile Acids (through

modulation of FXR and TGR5)

• Improves Glucose Homeostasis (New)

• Manipulation of Bile Acids Hormonally

can be treatment of Diabetes

(New, Welchol)

Conclusions

• In addition to these lipid effects

• Duodenal bypass in CGIPs decreases BA pool size which leads to improved glucose homeostasis and thus

• Helps explain the improved success and durability of combined bariatric procedures in comparison to primary gastric procedures (band & sleeve)