Farmacologia II

Inflamao, Citocinas e Resistncia

Insulina
Ivana Tothova
Mrio Reis Lima
Simona Blichov
Vnia Maria Santos
Turma L7
Grupo 2
Insulina ela
el p
Hormona sintetizada nas v
o ns dos emia
sp o c
clulas beta dasilhotas de Re ula e gli
d .
Langerhans, reg ores ismo
val organ
dopncreasendcrino. no
A sua biossntese precedida
da formao da Pr-Insulina.
Na clula Aumento da
Glicemia

Uptake de glicose
por GLUT 2

Converso em
glicose -6-fosfato
Gerar ATP

Os canais de K+ so
inibidos e d se o
influxo de Ca 2+

Alterao do
potencial de
membrana
Libertao de
Ao da insulina sobre a glicose

1) A insulina liga-se ao recetor na membrana

2) Abertura da protena de transporte de glicose (glut4)
3) Abertura da protena glut4, possibilita a entrada da glicose na clula3,
4) Armazenamento da glicose na forma de glicognio.
5) Transformao da glicose em Piruvato
6) Transformaoe deposio da glicose nas clulas do tecido adiposo na forma
de cidos gordos.
Aes da Insulina
uptake celular da glicose
sntese de glicognio
transporte de cidos gordos para o
interior da clula
armazenamento de cidos gordos
livres sob a forma de triglicerideos

concentrao plasmtica de glicose,

cidos gordos livres, cetocidos,
aminocidos etc...
beta-oxidao
gliconeogenese
glicogenlise
cetogenese
liplise
protelise
Resistncia insulina
Estado patolgico comum onde as clulas-alvo no
respondem aos nveis normais de insulina
circulante.
Intera
Intera Fatores
Fatores Disfun
Disfun Resistnc
Resistnc
Muta
Muta o
o Obsida
Obsida
inflama
inflama o
o das
das ia
ia

es
es insulina
insulina de
de clulas
trios
trios clulas
Insulina
Insulina
-recetor
-recetor

v i d en c i a-
E
se nas
clulas
e p t i c as,
h
lares
muscu
osas
 Os adipcitos
acumulam
lpidos
(hipertrofia)

Ativao dos
macrfagos

Libertam mais
cidos gordos e
adipocinas pro-
inflamatrias na
corrente
sangunea (TNF-
a, IL-6, IL-8,
resistina
Diminuem a
sntese de
adipocinas anti-
inflamatrias
(adiponectina)
Circulao Portal
e Sistmica
 A Circulao portal faz o seu transporte
para o fgado onde promovem esteatose,
resistncia insulina e inflamao local.

A Circulao sistmica
transporta cidos gordos e molculas
pr-inflamatrias para o msculo
esqueltico onde promovem
acumulao lipdica, resistncia
insulina e inflamao local.
Other Anti-Inflammatory Strategies
to Overcome Insulin Resistance
1876
Ebstein
salicylates high blood glucose
concentrations
1998
NF-B
Yin, Yamamoto, Gaynor
aspirin and salicylates
inhibition of IKK
prevention of activation
NF-B
IB

IKK IKK
IKK

2001
Yuan, Konstantopoulos , Lee
high doses of salicylates
improve hyperglycemia,
hyperinsulinemia, and
dyslipidemia
Fa/fa rat
Ob/ob mouse
IKK
IKK attenuated
attenuated insulin
insulin
signaling
signaling in
in cultured
cultured
cells
cells
salicylates
salicylates &&
heterozygous
heterozygous genegene
deletion
deletion (Ikk
(Ikk beta+/-)
beta+/-)
improve
improve ofof insuline
insuline
2010
Goldfine, Fonseca, age: 18-75
Jablonski higher levels of
efficacy and safety of glycemia & HbA1c
salsalate at different doses treated by diet,
in patients with type 2 exercises and oral
diabetes medication
dosage: 3.0, 3.5, or 4.0 g/d
decrease in HbA1c levels
of 0.5%
Does salsalate
improves also 2012
endothelial Goldfine, Buck,
function in Jablonski
patients with
diabetes mellitus Targeting inflammation
type 2 ??? using Salsalate in
patients with type 2
diabetes: effects on
flow-mediated dilatation
(TINSAL-FMD)
A randomized trial of low-dose aspirin in the
prevention of clinical type 2 diabetes in
women.

??? ASPIRIN = PREVENTION OF DIABETES

TYPE 2 ???
Pradhan AD, Cook NR, Manson JE et al
2009
a 10-year randomized double-blind, placebo-
controlled trial of aspirin and vitamin E

ASPIRI PLACEB
N O
849 847
 Tumor necrosis factor-alpha (TNF-alpha) has been shown
to have certain catabolic effects on fat cells and whole
12animals.
induction of TNF-alpha messenger RNA expression was
observed in adipose tissue from four different rodent
models of obesity and diabetes.

Neutralization of TNF-alpha in obese rats caused a

significant increase in the peripheral uptake of glucose
in response to insulin.
These results indicate a role for TNF-alpha in obesity
and particularly in the insulin resistance and diabetes
that often accompany obesity.
 A high circulating concentration of interleukin
6 is associated with increased risk of coronary
heart disease.
Blockade of the interleukin-6 receptor (IL6R)
with a monoclonal antibody (tocilizumab)
licensed for treatment of rheumatoid arthritis
reduces systemic and articular inflammation.
TNF neutralization in
humans seems to have
no effect on
hyperglycemia thereby
doubting a relevant
role for this cytokine in
metabolic
inammation,
neutralization of IL-1
and/or IL-6 currently
seems more promising
Historically, it has also been known that high doses of salicylates are able to

lower blood glucose concentrations

this positive effect of high-dose aspirin

on insulin is limited by toxicity especially in
gastraintestinal tract
 as atreatment of
insulin resistance
can be use:
salicylates, however
there is arisk in
toxicity to GIT, and
also neutralization
of IL-1/ IL-6 with a
monoclonal antibody
(tocilizumab).
Bibliografia
http://www.sciencemag.org/content/259/5091/87
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316968/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491446/
http://www.ncbi.nlm.nih.gov/pubmed/21419125#
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264591/
http://www.ncbi.nlm.nih.gov/pubmed/14679177/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC296998/
http://genesdev.cshlp.org/content/21/12/1443.full#sec-5
http://cdn2.nursingcrib.com/wp-content/uploads/ASPIRIN-
OVERDOSE.jpg
http://www.heartfailurematters.org/static_file/HeartFailureMatters/I
mages/SiteCollectionImages/Pharmacist.jpg
http://www.diabetes.co.uk/blog/wp-
content/uploads/2015/10/insulin.jpg
Steven E. Shoelson,Jongsoon Lee, andAllison B. Goldfine in
Inammation and insulin resistance J Clin Invest. 2006 Jul 3;
116(7): 1793180
Varman T. Samuel andGerald I. Shulman in Integrating