fisiología molecular gastrointestinal en el control del...
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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: [email protected]: www.sfbr.org
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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
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El GLP-1 postprandial está disiminuído en intolerantes y DMT2
J Clin Endocrinol 2001; 86: 3717
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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
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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
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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
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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)
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Proglucagon Gen
Drucker, Diabetes 1998; 47: 159
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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
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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
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Subcutaneous OXM reduces body weight in overweight and obese subjects
Wynne et al, 2005, Diabetes 54:2390
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Exenatide
OXM
DPP-IV Inhibitor
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TCF7L2
Wnt signaling pathway
B-CATENIN
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TCF7L2
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Bone Marrow Cell
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Wnt
FrzzR Dkk1
Dsh
GSK3b b CATENINGSK3b b-CATENIN
(-)PPARg
( )
INHIBITION OF ADIPOGENESIS – OSTEOBLAST DIFFERENTIATION
( ) (+)(-) (+)
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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
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R l ti f th l i d t l f BRegulation of the proglucagon gene is under control of B-catenins
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B-Catenin Proglucagon
Drucker, Diabetes 1998; 47: 159
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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
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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
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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
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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)
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Hypothesis
Rubino and Gagner.Rubino and Gagner. Ann Surg 2002Ann Surg 2002
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Hypothesis
Rubino and Gagner.Rubino and Gagner. Ann Surg 2002Ann Surg 2002
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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