Transcript Polyglucosamine - Obesity Conferences

Dr. Prof. Umberto Cornelli MD PhD Dr Sci Hc
Loyola University Medical School Chicago
Dept Molecular Pharmacology and Therapeutics
The three main aspects
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Caloric intake and liposaccharides (LPS)
Lipids -oxidized lipids
Polyglucosamine
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The caloric excess causes an inflammatory condition in the gut and
sistemically.
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The reason is due to the bacterial liposaccharides (LPS) increase
Variable
LPS plasma levels (U/mL)
P
trend
<9
9-39
> 39
[kcal/day]
2307
2518
2617
0.02
Carbohydrates
[g/day
233
251
263
0.07
Proteins
[g/day]
96
101
102
0.24
Lipids
[g/day]
92
103
110
0.009
Alcohol
[g/day]
26
28
25
0.82
Energy total
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The increase of LPS is due to the immune reaction against
the bacterial overgrowth
Aggressed bacteria release DNA, RNA and membrane
lipoproteins
These events stimulate macrophages TLRs (Toll-like
receptors), particularly TLR2, TLR4 y TLR9, that activate
NF-Kb, TNFα e IL-1
Lipids accumulation end up with an inflammatory condition
Other Effects Due to Lipids
Lipids intake increases the production of
chylomicrons and bile
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Other Effects Due to Lipids
Chylomicrons bind LPS and bring them to the
lymphatic system and to the liver to be
metabolized.
Normally this process does not activate
macrophages of the lymphatic system
However, in case lipoproteins are oxidized a
strong reaction takes place
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Oxidized Lipids
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The permanence of meat under the light
generates oxidized lipids
The increase of oxidized lipids is common
during food cooking.
Oxidized lipids generate oxidized
chylomicrons and follow with the production
of oxidized lipoproteins in the liver
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The Effect of Bile
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Fats intake increases bile production
Bile has some bacteriostatic activity over the
colon bacteria
Bacteria resistant to bile (Bacterioides spp) can
produce lithocholic acid and desoxycholic acid
(secondary bile) that are considered as one of
the causes of colorectal carcinoma
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One Important Cofactor

The oxidative stress generated by excessive
caloric intake has an impact over another
important variable:
The insulin receptors
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Insulin Receptors
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Receptor and normal menbrane
Receptor ptosis following membrane oxidation that transfers oxidation to
the insuline α and β subunits
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One Important Cofactor
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In case of membranes oxidation insulin receptors are
not in the condition to interact with substrate, due to
«receptor ptosis» and subunits binding
[α subunit and 2β subunits are bound by a disulfide bonds
compromizing the tirosine kinase activity]
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This causes insulin and glucose resistance
Glycogen synthase is also compromised by oxidation
[Abdul-Ghani M et al. J Biomed Biotech 2010;doi:10.1155/2010/476279]
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The Combination of Events
Caloric increase
 Omental lipidic burden
 LPS increase
 Oxidized lipids intake
 Overproduction of bile
a quintet causing an inflammatory condition
and a strong endothelial reaction
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37 F; 56 M, (aged 24-64), overweight and at risk of Metabolic
Syndrome
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52 weeks with 30% of caloric restriction
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(MJ/day for Females and 7 MJ/day Man)
Two Different Diets
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BC/AG [low carbohydrates (5%); high fats (58%); proteins (35%)
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HC/BG (high carbohydrates (46%); low fats (28%); proteins (24%)
[Brinkworth GD et al BJN 2009;101:1493-1502]
[Brinkworth GD et alAm J Clin Nutr 2009;90:23-32]
Variable
LC/
HF
Bifidobacteria spp (A)
↓
Feces weight
↓
Acetate
↓
Propionate
↓
Butirrate
↓
Weight (kg)
HC/
LF
↓(7.6)
↓ (6.3)
Waist circumference
↓
↓
Glucose
↓
↓
Triglycerides
↓
↓
HDL
↑
↑
LDL
↑
LDL/HDL
↓
↓
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The diet low in carbohydrates causes a reduction of
saccharolytic bacteria and a reduction of SCFA in feces
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The diet low in lipids does not modify microbiota
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In both cases the variables related to body weight and
Metabolic Syndrome are significantly reduced due to
the caloric restriction
The Possible Solution
(Physiological Modulation)
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A natural polyanionic fiber aimed at:
a) bind lipids with very high affinity for
oxidized lipids (direct and indirect antioxidant
activity)
b) bring lipids to the colon allowing bacteria to
use them as fuel
c) bind bile salts
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Polyglucosamine PG
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A natural anionic polymer derived from shrimps
chitin, by proteins elimination, deacetylation and
milling
Ascorbic acid and tartaric acid are added
At the end PG consists of a linear chain of the
dimer -glucosamine and glucosamine N-acetylated
Degree of deacetylation > 95%
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The organic acids contained in PG maintain the linearity of
the polymer
polymer
Polymer with organic acids
(ascorbic and tartaric acid)
Physico-Chemistry
1)
MW 125-145 kD
(LMWC or low molecular weight chitosan)
2)
High water affinity
3)
High affinity for lipids, particularly for oxidized lipids
4)
Biliary salt binding
Pharmacology
1)
Body weight reduction
2)
Increase of lipids content in feces (without steathorrhea)
3)
Increase of water in feces
4)
Increase of glucose concentration in feces
5)
Increase of acetic acid concentration in feces
(microbiota modification)
[Bondiolotti et al. EIP 2007;567:155-158]
[Bondiolotti et al. Food Chem 2011;124:978-982]
Other characteristics
1) Chitosan derivatives are used to stop bleeding in wounds
(USA army)
2) Chitosan derivatives have the EFSA (European Agency)
approval for cholesterol reduction
3) In Germany Formoline L112® is a Medical Device approved
for body weight reduction
Polyglucosamine: Clinical Trials
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Overweight vs Placebo
Obesity Vs Orlistat
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115 overweight subjects (36 FG; 79 M), aged 21-75
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Caloric restricition (500 cal/day)
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Physical activity 7 METs/h/week
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Treatment: PG 1.8 g/day (2x2) Vs. Placebo (2x2)
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Double-blind
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Duration: 25 weeks
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Variables: body weight; abdominal circumference (AC)
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Time needed for a 5% body weight reduction
[Pokis K et al. Biomed Cent 2015]
Variable
Placebo
PG
P
Body weight reduction Kg [0-24 weeks]
-4.3
-6.5
< 0.05
AC [0-24 weeks]
-7.4
-9.1
< 0.05
1 week (Number of subjects)
3
6
2 weeks (Number of subjects)
18
30
5R
< 0.05
PG
significantly increases the effect of caloric
restriction and physical activity
The
time needed for a 5% reduction of body weight
gives confidence to the subjects to manage overweight
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64 patients (28 H; 36 M); aged 21-70
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Caloric restriction (500 cal/day)
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Physical activity: 3 METs/h/day
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Treatment: PG 1.8 g/day Vs Orlistat 180 mg/day
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Double blind (dummy): 12 weeks
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Variables: body weight; abdominal circumference (AC)
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Time needed for a 5% body weight reduction
[Stoll H et al. Biomed Cent 2015 in press]
Variable
Orlistat
PG
P
Body weight decrease Kg [0-12 weeks]
-4.8
-6.7
< 0.05
AC cm [0-12 weeks]
-6.1
-8.3
< 0.05
17
[55%]
19
[70%]
NS
5R (number of subjects) [0-12 weeks]
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PG is more active than Orlistat for body weigt and abdominal
circumference reduction
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The number of cases with a 5 % reduction of body weight is
higher with PG but the difference Vs orlistat is not statistically
significant
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PG does not cause steatorrhea
1.Cornelli U, Belcaro G, Cesarone MR, Cornelli M, Ledda A. Polyglucosamine Action on
Oxidised Lipids and Dyslipidemia. La Medicina Biologica 1,2006;25-29.
2.Cornelli U, Milani L, Perra A. The Use of Polyglucosamine in the Metabolic Syndrome
Control. La Medicina Biologica 4,2006;45-54.
3.Cornelli U, Belcaro G, Cesarone MR, Cornelli M. Use of Polyglucosamines and Physical
Activity to Reduce Body Weight and Dyslipidemia in Moderately Overweight Subjects.
Minerva Cardioangiologica 56,1,5,2008;71-78.
4.Bondiolotti G, Bareggi SR, Frega NG, Strabioli S, Cornelli U. Activity of two different
polyglucosamines, L112 and FF45, on body weight in male rats. European Journal of
Pharmacology 567,2007;155-158.
5.Cornelli U. Oxidized Lipids and Poliglucosamine (original “I Lipidi Ossidati e la
Poliglucosamina”). Acsa Magazine 2,1,2008;37-41.
6.Bondiolotti G, Cornelli U, Strabbioli RS, Frega NG, Cornelli M. Effect of a
polyglucosamine on the body weight of male rats: Mechanisms of action. Food
Chemistry 124,2011;978-982.
7. Pokhis K, Roth W, Bitterlich N, Cornelli U, Cassano G. Efficacy of polyglucosamine in a
randomized, double blind, placebo-controlled clinical investigation. Biomed Cent 2015
8. Stoll M, Bitterlich, N, Cornelli U. Randomized , double blind, clinical investigation to
compare two treatments for the management of overweight and obesity. Biomed Cent
2105 in press.