Fisiología molecular gastrointestinal en el control del hambre y la saciedadcontrol del hambre y la saciedad

RAUL A. BASTARRACHEA, M.D.RAUL A. BASTARRACHEA, M.D.Staff Scientist

Auxology & Metabolism Working GroupDepartment of GeneticsDepartment of Genetics

Southwest Foundation for Biomedical ResearchSan Antonio, Texas, USA

E-mail: raulbs@sfbrgenetics orgE-mail: raulbs@sfbrgenetics.orgWebsite: www.sfbr.org

Glucagon-like Peptide 1 (GLP-1)

and

l d li hi

and

Glucose-Dependent Insulinotrophic Polypeptide (GIP)Polypeptide (GIP)

Account for ~90% of the i ti ff tincretin effect

El GLP-1 postprandial está disiminuído en intolerantes y DMT2

J Clin Endocrinol 2001; 86: 3717

EXPERIMENTAL DESIGNBYETTA

336 metformin treated type 2 diabetics336 metformin-treated type 2 diabeticsAge = 53±10y BMI = 34 2±5 9 kg/m2

SUBJECTS:

BMI = 34.2±5.9 kg/mHbA1c = 8.2±1.1%

● 4 week run with placebo● 4 weeks of exenatide (5 ug bid)

PROTOCOL:● 4 weeks of exenatide (5 ug bid)

or placebo● 26 weeks exenatide (10 ug bid)26 weeks exenatide (10 ug bid)

or placebo● metformin dose kept constant

EFFECT OF BYETTA ON EFFECT OF BYETTA ON HbAHbA1c1c

Time (wk)

0 10 20 30 40 50 60 70 80 900.5

Pl b BID (N 128) 8 3%Baseline A1C

0 5

0.0Placebo BID (N = 128)BYETTA 5 mcg BID (N = 128)BYETTA 10 mcg BID (N = 137)

c(%

) 8.3%

8.3%8.3%

-1.0

-0.5

HbA

1c

-1.5

1.0

Δ

-2.0 Open-Label ExtensionPlacebo-Controlled Trials

EFFECT OF BYETTA ON EFFECT OF BYETTA ON

Time (wk)

BODY WEIGHT BODY WEIGHT

Baseline Weight

0 10 20 30 40 50 60 70 80 90

0

2

Pl b BID (N 128))

220 lbs215 lbs

220 lbs-2

0 Placebo BID (N = 128)BYETTA 5 mcg BID (N = 128)BYETTA 10 mcg BID (N = 137)

t (lb

s

-6

-4

Wie

gh

10

-8Δ W

-12

-10

Open-Label ExtensionPlacebo-Controlled Trials

Hipotálamo

LEP ( r ) ( + )Complejo Dorso Vagal (NTS)

Cuerpos neuronales delPeptido analogo del Glucagon

(GLP 1)(GLP-1)

Axones de GLP-1

Núcleo Paraventricular ( P V N )Inhibicion del apetito despues de la ingesta de comida

(factor de saciedad intracerebral)

Proglucagon Gen

Drucker, Diabetes 1998; 47: 159

Oxyntomodulin (OXM)

• 37-aa peptide that arises from posttranslational processing• 37-aa peptide that arises from posttranslational processing of proglucagon from endocrine L cells in the distal gut

• Inhibits gastric acid secretion - originally named after its inhibitory action on the oxyntic glands of the stomach andinhibitory action on the oxyntic glands of the stomach - and gastric emptying

• Circulating levels of OXM rise within 30 min of a meal (in proportion to meal calorie content) and remain elevated forproportion to meal calorie content) and remain elevated for several hours

ICV Administration of OXM Decreases Daily Food Intake and Body Weight Gain

Dakin, C. L. et al. Am J Physiol Endocrinol Metab 283: E1173-E1177 2002

Subcutaneous OXM reduces body weight in overweight and obese subjects

Wynne et al, 2005, Diabetes 54:2390

Exenatide

OXM

DPP-IV Inhibitor

TCF7L2

Wnt signaling pathway

B-CATENIN

TCF7L2

Bone Marrow Cell

Wnt

FrzzR Dkk1

Dsh

GSK3b b CATENINGSK3b b-CATENIN

(-)PPARg

( )

INHIBITION OF ADIPOGENESIS – OSTEOBLAST DIFFERENTIATION

( ) (+)(-) (+)

Osteoporosis, the obesity of the boneOsteoporosis and obesity, two disorders of body composition, are growing in prevalence.

I t ti l th di h l f t i l di tiInterestingly, these diseases share several features including a genetic predisposition and a common progenitor cell.

With aging the composition of bone marrow shifts to favor theWith aging, the composition of bone marrow shifts to favor the presence of adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis.

Both diseases can be traced to dysregulation of a common precursor llcell

7L2 Gene - LINKING OSTEOPOROSIS – OBESITY AND DIABETES

R l ti f th l i d t l f BRegulation of the proglucagon gene is under control of B-catenins

B-Catenin Proglucagon

Drucker, Diabetes 1998; 47: 159

RYGB: Effect on appetite/satietyRYGB: Effect on appetite/satiety

Gastric BandingGastric BandingGastric BandingGastric BandingEarly satiety → ↓ meal size

RYGB RYGB ↓ Hunger between meals

1. Restriction1. Restriction

–↓ Hunger between meals –↓ Meal frequency; ↓ snacking –↓ Intake of calorie-dense foods

2. Malabsorption2. Malabsorption

Total Ghrelin

700Lean

0Lean RYGBP Matched

600 MatchedRYGBP

-10

0

400

500

30

-20*

%

0 30 60 90 120 150 180300 -40

-30

Minutes

% decrease

PYY (3-36) is increased following gastric bypass

Korner J et al., 2004 JCEM After Roux-en-Y Gastric Bypass there is an Acute and Exaggerated Post-Prandial PYY Response

Rates of Remission of Diabetes

Adjustable Roux-en-Y BiliopancreaticAdjustable Gastric Banding

Roux-en-Y Gastric Bypass

Biliopancreatic Diversion

>95%48% 84% >95% (Immediate)

48% (Slow)

84% (Immediate)

Hypothesis

Rubino and Gagner.Rubino and Gagner. Ann Surg 2002Ann Surg 2002

Hypothesis

Rubino and Gagner.Rubino and Gagner. Ann Surg 2002Ann Surg 2002

Conclusions

EExclusion of the proximal small intestinexclusion of the proximal small intestineEExclusion of the proximal small intestine xclusion of the proximal small intestine plays a major role in the beneficial effect of plays a major role in the beneficial effect of gastrointestinal bypass surgery on type 2 gastrointestinal bypass surgery on type 2 diabetesdiabetes

These findings suggest that GI factors These findings suggest that GI factors from the proximall small intestine mayfrom the proximall small intestine mayfrom the proximall small intestine may from the proximall small intestine may contribute to the pathophysiology of the contribute to the pathophysiology of the diseasediseasedisease disease

RouxRoux--enen--Y Gastric BypassY Gastric Bypass (RYGB)(RYGB)

Hormonal effects Ghrelin

XXX

PYY

X

XX XXX

PYY

X XX XXX XX X

XX

X XX

XXXX

X

PYY (3-36) is increased following gastric bypass

Korner J et al., 2004 JCEM After Roux-en-Y Gastric Bypass there is an Acute and Exaggerated Post-Prandial PYY Response

Clinical StudyClinical Study

4 Days after RYGB: 4 Days after RYGB:

PYY (++ PostPYY (++ Post--prandial response) prandial response)

Insulin; HOMAInsulin; HOMA--IR; GIP; LeptinIR; GIP; LeptinInsulin; HOMAInsulin; HOMA--IR; GIP; Leptin IR; GIP; Leptin

Rubino and GagnerRubino and Gagner

RouxRoux--enen--Y Gastric BypassY Gastric Bypass (RYGB)(RYGB)

11 R t i ti ?R t i ti ?1. 1. Restriction?Restriction?

2. Malabsorption ?2. Malabsorption ?pp3-Hormonal effects

Amylin and Insulin Are Co-Secreted in Response to Meals

30

Meal Meal Meal

Plasma Amylin

Plasma Insulin (pM)

25600

(pM)

20

15

400

10200

57 am Midnight5 pm12 noon

Time (24 h)

0

Mean from 6 healthy male adults

Time (24 h)

35Mean from 6 healthy male adults Adapted from Kruger D, et al. Diabetes Educ. 1999; 25: 389-398

Vehicle

Amylin-Mediated Weight Loss is Attributable to Food Intake Reduction, and is Fat-Specific

114% of Baseline Body Weight Body Weight

Vehicle Pair-Fed

Amylin

10Body Composition

Δ

108110112114

-100

10Δ in Body Fat (g)

100102104106

-11.2%

-40-30-20 *

* #

949698

100

123

Δ in Protein (g)

0 7 14 2192

Days-2-101

*

DIO (Levin) Prone rats; 32% fat diet (6 wk) Ad-lib food except for Pair-fed Controls Continuous SC Vehicle, amylin 300 mcg/kg/day

Body composition; Echo MRI *P <0.05 compared to Vehicle; #P <0.05 compared to Pair-Fed

-2

36

Data on file, Amylin Pharmaceuticals, Inc.

Pramlintide: Synthetic Amylin Analog

• Synthetic analog of human amylin l bl– soluble

– equipotent

Ad i i t d b SC i j ti i t l• Administered by SC injection prior to meals

37Weyer C, et al. Current Pharm Design. 2001; 7(14):1353-1373

16-Week Pramlintide Dose-Ranging Study:Mean Change in Weight and Waist CircumferenceMean Change in Weight and Waist Circumference

Placebo (n = 36) 120 mcg TID (n = 38)360 mcg BID (n = 39)

0

Body Weight

g ( )

0

Waist Circumference

∆

-2

-1-2

-1∆ Waist

-4

-3

-5

-4

-3(cm)

-6

-5** (360 mcg BID)

*** (120 mcg TID) -7

-6

5

* (120 mcg TID)

0 4 8 12 16-7

Time (wk)% ∆ Body Weight

0 4 8 12 16-8

TID)

38Evaluable; *P <0.05, **P <0.05, ***P <0.001 based on comparisons of LS means vs placeboData from Wadden T, et al. Obes Rev. 2006; 7:112-113

Amylin and Leptin Synergistically Reduced Food Intake and Body Weight in DIO-Prone Rats

Amylin+Leptin

VehicleLeptin 500 mcg/kg/d

Amylin 100 mcg/kg/d

250Food IntakeCum

ulative

Amylin+Leptin

0

2Body Weight

% ∆ Bod

150

200Food Intak -2

0y Weight (Vehi

100 * *e (grams) -6

-4(Vehicle-Correcte

0 7 140

50

0 7 14-10

-8

* * *

d)

0 7 14Time (d)

0 7 14Time (d)

39Diet-induced obesity prone rats (CRL; N = 6/group); *P <0.05 compared to all groupsRoth J, et al. 66th Annual Sessions of the American Diabetes Association, late-breaking Poster # 52-LB

Body Composition: Weight Loss With Amylin+Leptin Is Fat-Specific and Lean-Sparing

VehicleLeptin 500 mcg/kg/d

Amylin 100 mcg/kg/d(Pairfed Amylin)+Leptin

Fat Mass Lean Mass

Amylin+Leptin(Pairfed-Amylin)+Leptin

6

8 * *

15

20Fat Mass Lean Mass

4

6

10

15*

25

00

% Body Fat % Body Protein

40Diet-induced obesity prone rats (CRL; N = 7/group); *P <0.05 compared to vehicle control groupsRoth J, et al. 66th Annual Sessions of the American Diabetes Association, late-breaking Poster # 52-LB

Co-administration of Amylin, PYY(3-36), and Leptin: Marked Reduction in Body Weight and Adiposity

VehicleLeptin 500 mcg/kg/dAmylin 300 mcg/kg/d

PYY(3-36) 1000 mcg/kg/dA+P+L (1/2)

PYY(3-36) 1000 mcg/kg/d

Body Weight% ∆ B d 0

4

A+P+L: At 50% of the single-agent doses,

Body Weight -8

-4

0

g gweight was decreased by 16%, and body fat

d d t 4%

Fen/phen(Vehicle-Corr

t-16

-12 *

# was reduced to 4%Roux-en--Y

ected)

0 4 8 12 16 20 24 28-24

-20#

Time (d)

Means of Achieving Greater Weight Loss: Integrated Therapy With Three Neurohormones in DIO Rats

41DIO rat (CRL; n = 5/group); minipump infusion; *P <0.05 vs vehicle, *P <0.05 vs all groupsSources: Fen/phen - historical in-house data, Roux-en-Y – Stylopoulos, et al. 2005, Surg Endosc; 19:942-946 Roth, et al. Submitted to NAASO 2006 (accepted)

Three Neurohormones in DIO Rats

Multi-Hormonal Control of Body Weight:Role of Fat-, Gut-, and Islet-Derived Signalso e o at , Gut , a d s et e ed S g a s

Vagal afferents

GI tractAdipose tissue

Hypothalamus

HindbrainGhrelin

CCK

Insulin

Leptin

PYY3-36Insulin

Amylin

OXM

GLP-1

3 36

ResistinVisfatin

Pancreatic islets

Adiponectin OXM

GIPPP

42Adapted from Badman MK and Flier JS. Science. 2005; 307:1909-1914