Caroline Bulcão Souza
CONTRIBUIÇÃO DA METFORMINA E SINVASTATINA PARA O ENTENDIMENTO DA RELAÇÃO DA
RESISTÊNCIA À INSULINA COM A INFLAMAÇÃO
Tese apresentada à Universidade Federal de São Paulo - Escola Paulista de Medicina para obtenção de título de Doutor em Ciências
Caroline Bulcão Souza
CONTRIBUIÇÃO DA METFORMINA E SINVASTATINA PARA O ENTENDIMENTO DA RELAÇÃO DA
RESISTÊNCIA À INSULINA À INFLAMAÇÃO
Tese apresentada à Universidade Federal de São Paulo - Escola Paulista de Medicina para obtenção de título de Doutor em Ciências Área de concentração: Endocrinologia
Orientadora: Profa. Dra. Sandra Roberta G. Ferreira Coordenador: Prof. Dr. Sérgio Atala Dib
Bulcao-Souza, C.
Contribuição da metformina e sinvastatina para o entendimento da relação da resistência à insulina e inflamação. Caroline Bulcão Souza. São Paulo, 2006. p.1-79
Tese (Doutorado) - Universidade Federal de São Paulo, Escola Paulista de Medicina.
Programa de Pós-Graduação em Endocrinologia.
Título em inglês: Contribution of metformin and simvastatin for the knowledge of
insulin resistance and inflammation.
1. Insulin resistance 2. Inflammation 3. Metformin
Dedicatória
Dedico esta tese:
a meus pais tão amados, Jorge e Lêda, a quem devo tudo que conquistei até hoje na minha
vida.
a minha orientadora, dra Sandra, o maior e melhor exemplo de mulher, profissional,
pesquisadora, orientadora e amiga.
a meu marido, amigo e companheiro, Fernando, um pedaço de mim, sem o qual tudo seria
Agradecimentos
A Deus, que me dá força, coragem e esperança para seguir em frente nos momentos
difíceis.
Ao dr Fernando Flexa, pela colaboração durante todo o processo.
A todo pessoal do Hospital do Rim e Hipertensão, em especial, Paula, Edinir, Elza, Marta
e Nárcia.
A todo pessoal do Centro de Diabetes, disciplina de endocrinologia e do Ambulatório de
Endocrinologia da UNIFESP.
A todos os professores da Disciplina de Endocrinologia da UNIFESP.
Aos meus colegas de residência e pós-graduação, em especial, Regina, Isabel e Sílvia,
companheiras desde o princípio.
À Escola Paulista de Medicina, que me acolheu quando cheguei em São Paulo há mais
Índice
Página
1. CONSIDERAÇÕES INICIAIS . . . 2
1.a. Resistência à insulina . . . 4
1.b. Inflamação subclínica . . . 6
1.c. Justificativa . . . 9
1.d. Objetivos . . . 9
1.e. Resumo dos Artigos. . . 10
1.f. Referências bibliográficas . . . 12
2.ARTIGO 1: “The New Adipose Tissue and Adipocytokynes” . . . . . . . 14
3. ARTIGO 2: “Effects of Simvastatin and Metformin on Inflammation and Insulin Resistance in Mildly Metabolically Disturbed Individuals” . . . 45
4. ARTIGO 3: “May Beneficial Cardiovascular Effects of Simvastatin Be Also Associated with Hormonal-Dependent Mechanism Improving Insulin Sensitivity?” . . . 63
1.CONSIDERAÇÕES INICIAIS
Neste capítulo serão apenas introduzidos alguns aspectos relevantes do tema
“resistência à insulina e inflamação”, uma vez que o aprofundamento do tema pode ser
encontrado no primeiro dos artigos integrantes desta tese (Artigo 1: “The New Adipose
Tissue and Adipocytokynes.”). Comentar-se-á sobre a sequência de idéias que levou os
autores à elaboração do protocolo de pesquisa, fornecendo o “nexo” que interliga os três
artigos que compõem esta tese.
Espera-se do “doutor em formação” definir o direcionamento inicial das suas
pesquisas que o orientará ao longo da sua vida acadêmica. Para alguns, a opção é pelo
enfoque clínico, embasado em uma série de razões que vão desde o interesse científico,
perfil profissional e potencial de continuidade da linha de trabalho a médio e longo prazo.
Porém, não se pode negar o papel da literatura vigente, que influencia de modo
considerável o rumo do conhecimento.
“Resistência à insulina e inflamação” são processos fisiopatológicos dos mais
relevantes para a saúde do homem atual. Pode-se afirmar que os principais problemas de
saúde pública da atualidade envolvem estes mecanismos, capazes de desencadear
doenças em proporções epidêmicas. Reconhecendo esta situação, a literatura tem
investido amplamente no tema; o presente trabalho procurou dar uma pequena contribuição
a este conhecimento.
O Programa de Pós-Graduação em Endocrinologia da Universidade Federal de São
Paulo oferece um leque de oportunidades para que profissionais atinjam nível de
excelência na produção de ciência básica, experimental e clínica. A opção deste trabalho
foi pela área clínica e, no contexto desta, as doenças mais prevalentes da endocrinologia,
que influenciam de modo significativo à sobrevida das populações. É natural neste perfil
buscar entender mecanismos etiopatogênicos que poderão, um dia, reverter em frutos na
área da prevenção e terapêutica. Tendo isso em mente, gerou-se a idéia da tese, em torno
das condições mórbidas associadas ao excesso de adiposidade corporal – a epidemia do
mundo atual.
Uma vez revisado o tema, o que resultou no Artigo 1, buscou-se recursos junto à
entidade de apoio à pesquisa (FAPESP 02/10010-9), para o desenvolvimento de um projeto
vias escolhidas para se explorar a etiopatogenia de anormalidades que compõem a
síndrome metabólica (SM), ao mesmo tempo procurou-se estudar mais duas medicações –
com benefícios são consagrados no tratamento (ou mesmo na prevenção) de algumas das
doenças da SM – para aprofundar tal conhecimento (Artigo 2: “Effects of Simvastatin and
Metformin on Inflammation and Insulin Resistance in Mildly Metabolically Disturbed
Individuals” e Artigo 3: “May Beneficial Cardiovascular Effects of Simvastatin Be Also
Associated with Hormonal-Dependent Mechanism Improving Insulin Sensitivity?”).
1.A.RESISTÊNCIA À INSULINA
Resistência à insulina (RI) é definida como uma condição, genética ou adquirida, onde ocorre menor utilização de glicose pelos tecidos em resposta ao estímulo insulínico.
Devido ao distúrbio na captação de glicose, há elevação compensatória da secreção pelas
células beta-pancreáticas que resulta em elevação dos níveis circulantes de insulina
(hiperinsulinemia). A glicemia se mantém estável enquanto as concentrações aumentadas
deste hormônio conseguem vencer a resistência tecidual, determinando captação de
glicose. Quando as células beta tornam-se incapazes de aumentar sua secreção para
superar a resistência, a glicemia se eleva, surgindo graus variados de intolerância à
glicose.
A obesidade se constitui numa das principais condições geradoras de RI e
importante fator de risco para o diabetes mellitus (DM) tipo 2. No momento em que o
diagnóstico de DM é confirmado, dois defeitos básicos desta doença estão presentes – a
resistência à insulina e a deficiência de secreção – que têm como resultado hiperglicemia
de graus variados, mesmo na condição de jejum. Em fase precoce da história natural do
DM a RI parece ser o distúrbio mais proeminente; apenas sob estímulo (teste de
sobrecarga de glicose) a deficiência de insulina torna-se manifesta pela elevação da
glicemia. A prevenção do aparecimento do DM é a melhor opção a ser buscada, uma vez
que, instalada a doença, os esquemas terapêuticos disponíveis não são eficazes em
manter permanentemente a normoglicemia. Estudos de intervenção sobre o estilo de vida
têm mostrado que a prevenção do DM tipo 2 é possível, particularmente por meio de
medidas não-farmacológicas (1,2).
É amplamente conhecido que a tolerância à glicose diminuída (TGD) e o DM tipo 2
diversas técnicas de complexidade variável. O método padrão-ouro de avaliação da
sensibilidade à insulina é o clamp euglicêmico hiperinsulinêmico (3). Devido à
complexidade e custo, o clamp não tem sido usado na prática clínica. Mesmo para fins de
pesquisa, estes limitantes fizeram com que técnicas alternativas para se mensurar a
sensibilidade à insulina fossem desenvolvidas. Entre estas, o cálculo da área sob a curva
glicêmica obtida pelo teste de sobrecarga com glicose, o índice HOMA-RI (4), o índice
ISI0,120 (5) ou a simples dosagem da insulinemia em jejum têm mostrado correlações
aceitáveis com o método de referência (6,7).
A hiperinsulinemia, dentre outras anormalidades, faz parte da síndrome descrita por
Reaven, em 1988 (8). Atualmente, com a incorporação de outras anormalidades
metabólicas (9), é conhecida como Síndrome Metabólica (SM). Engloba distúrbios tais
como obesidade central, resistência à insulina e/ou hiperinsulinemia, intolerância à glicose,
hipertensão arterial, dislipidemia (hipertrigliceridemia e HDL-colesterol baixo), lipemia
pós-prandial, disfunção endotelial (microalbuminúria), hipofibrinólise (aumento de PAI-1),
doença cardiovascular aterosclerótica, hiperandrogenismo (mulheres), hiperuricemia, além
de outros. O risco CV atribuído à distribuição central da adiposidade corporal parece
depender da RI gerada pelo excesso de tecido adiposo visceral (“teoria portal”). Este se
caracteriza por intensa atividade lipolítica, do que resulta grande produção de ácidos
graxos, lançados na circulação portal e sistêmica. Uma série de distúrbios metabólicos
ocorre, especialmente no fígado, pâncreas e musculatura esquelética, que deterioram a
sensibilidade à insulina, podendo gerar hiperinsulinemia. Tendo em mente os efeitos
fisiológicos da insulina sobre a reabsorção renal de sódio, tônus simpático, metabolismo
glico-lipídico, sistema de coagulação e efeitos tróficos sobre a musculatura lisa, é razoável
supor que a exacerbação destes poderia contribuir na gênese da hipertensão e
dislipidemia, que juntos concorrem para ocorrência de doença cardiovascular que
acompanha a SM. Nem todas as manifestações da SM estarão presentes em todos os
indivíduos resistentes à insulina, de modo que a estratégia terapêutica deve ser
individualizada.
Recentemente, o papel do tecido adiposo como órgão endócrino tem sido muito
explorado e são amplas as evidências de que substâncias (hormônios e citocinas) nele
produzidas contribuem para deteriorar a sensibilidade à insulina e elevar o risco
Ao lado dos clássicos fatores de risco cardiovascular (DM, hipertensão arterial,
dislipidemia e tabagismo), o efeito deletério da hiperinsulinemia tem sido reportado.
Demonstrou-se que a hiperinsulinemia per se associa-se independentemente à elevação
do risco cardiovascular (10-13). Os distúrbios do perfil lipídico que classicamente estão
associados à síndrome de resistência à insulina são a hipertrigliceridemia, HDL-colesterol
baixo e elevação das partículas de LDL pequenas e densas. Considerando que
hiperinsulinemia e dislipidemia são fatores de risco independentes, a soma de ambos os
fatores potencializa consideravelmente este risco.
Nas últimas décadas, alterações no sistema de coagulação e fibrinólise,
desencadeantes de eventos trombo-embólicos, têm sido associadas à RI. A hipofibrinólise
observada em pacientes com manifestações da SM pode ser decorrente de níveis elevados
do inibidor da ativação de plasminogênio - PAI-1 (14). Este fator encontra-se aumentado no
plasma de indivíduos com doença cardiovascular, dislipidemia, hipertensão e
hiperinsulinemia. Estes achados fazem supor que a predisposição à doença aterosclerótica
e trombo-embolismo de pacientes com estas condições pode estar também relacionada à
elevação do PAI-1 (15).
A mais recente associação da RI tem sido, no entanto, com marcadores de
processo inflamatório “subclínico” ou “de baixo grau”.
1.B.RESISTÊNCIA À INSULINA E INFLAMAÇÃO
Vários estudos revelam que o aumento de marcadores inflamatórios no plasma é
preditivo de doença cardiovascular (16,17). O fato desta doença e seus fatores de risco
associarem-se com RI, motivou a investigação de uma série de marcadores em diversas
condições clínicas. Existem evidências de que a proteína C reativa (PCR), mesmo
moderadamente elevada, está associada a risco coronariano aumentado. No estudo
prospectivo AFCAPS/TexCAPS, os níveis de PCR basal foram preditivos do primeiro
evento coronariano em indivíduos de risco (18). Mesmo em indivíduos “aparentemente”
normais, alguns estudos sugerem que este marcador inflamatório pode ser um método útil
para se avaliar o risco cardiovascular, particularmente se o perfil lipídico estiver preservado
(19,20). No entanto, não se sabe até que ponto fenômenos inflamatórios estariam
Outros marcadores inflamatórios também relacionados à maior morbidade cardiovascular são a interleucina-6 (IL-6), o Fator de Necrose Tumoral (TNF-α), o fibrinogênio, adiponectina, moléculas de adesão solúveis no plasma entre outros (21). A
literatura, entretanto, carece de estudos de grande porte que definam a inter-relação entre
processo inflamatório e RI, e nenhum estudo prospectivo, envolvendo intervenções
precoces no processo inflamatório, encontra-se disponível.
A RI pode ser atenuada através de medidas não-farmacológicas e de
medicamentos. Estudos epidemiológicos, envolvendo indivíduos de alto risco para DM,
demonstraram a eficácia de programas de atividades físicas e dieta (baixo teor de
gorduras, rica em fibras) em prevenir tal desfecho (1). Perda de peso e exercícios possuem
efeitos consagrados sobre sensibilidade à insulina, que certamente participaram da
redução do risco de DM nestes indivíduos. Embora a redução de peso seja uma das mais
importantes medidas no combate a RI, a prática clínica mostra que pode se constituir num
dos maiores desafios a ser alcançado no controle da SM. Estão disponíveis na atualidade
agentes eficazes em melhorar a sensibilidade à insulina, atuando em certos tecidos-alvos,
sem atuar sobre a secreção pancreática de insulina. As biguanidas se constituem numa
das classes mais antigas e mais estudadas. Dentre estas, a metformina atua
preferencialmente no fígado, diminuindo a produção de glicose (gliconeogênese), embora
seu mecanismo de ação não esteja totalmente esclarecido. Este agente está indicado a
pacientes resistentes à insulina, com alterações da tolerância à glicose. O estudo
epidemiológico Diabetes Prevention Program mostrou a eficácia da metformina em reduzir
em 31% a incidência de DM em indivíduos com TGD, acompanhados, em média, por 2,8
anos (2).
O papel da terapia hipolipemiante na prevenção primária e secundária de
manifestações da doença aterosclerótica já está bem estabelecido em estudos
epidemiológicos (22-25). O tratamento da dislipidemia, particularmente com as estatinas –
inibidores da HMG-Co A redutase – diminui os níveis de metaloproteases, a LDL oxidada, o
conteúdo lipídico do core e macrófagos, além de aumentar o conteúdo de colágeno na
matriz da placa, ações estas que contribuem para estabilizá-la, retardando a progressão da
aterogênese (26). Tais agentes têm se mostrado eficazes em reduzir significantemente a
mortalidade cardiovascular em pacientes com SM (18,27-29). No que se refere ao risco de
elementos-chave neste processo, inclusive a redução dos níveis de PAI-1 que estão associados a
estados pró-trombóticos (30).
O interesse pelas estatinas cresceu recentemente com as evidências de que são
capazes de diminuir os níveis de PCR em apenas seis semanas de tratamento,
independentemente da redução na LDL-colesterol (31,32). Este achado levantou a
possibilidade de que estes agentes possam ser dotados de ações anti-inflamatórias com
repercussões desejáveis não apenas sobre a aterogênese, mas também sobre a RI. Além
da redução da PCR, outros investigadores obtiveram diminuição dos níveis plasmáticos de
TNF-α de pacientes hipercolesterolêmicos pelo uso de pravastatina (33). Com base nestes
achados, poder-se-ia especular que parte dos benefícios alcançados por pacientes de risco
com estatinas possa ser decorrente dos seus efeitos sobre o processo inflamatório
subclínico, acarretando, talvez, melhora da RI. Ainda que não tenham sido confirmadas
relações causa-efeito entre processo inflamatório inicial e RI, se a estatina é capaz de
provocar efeitos na direção da normalização dos marcadores inflamatórios, poder-se-ia
especular sobre uma ação cardioprotetora adicional à redução nos níveis plasmáticos de
colesterol.
Nesta linha, alguns estudos em pacientes diabéticos tipo 2 corroboram com a
hipótese de que as estatinas melhoram não só o perfil lipídico do plasma, mas também
exercem efeito positivo na sensibilidade insulínica. Através de clamp euglicêmico
hiperinsulinêmicos ou do índice HOMA, alguns autores, mas não todos, encontraram
diminuição da RI destes indivíduos após o uso de estatinas (34,35). A presença de
hiperglicemia crônica, com seus efeitos deletérios sobre a capacidade secretória das
células beta, pode ser fator limitante na avaliação do efeito da estatina sobre a
sensibilidade tecidual à insulina. Portanto, a ausência de glicotoxicidade representaria a
condição ideal para se avaliar o real papel dos inibidores da HMG-Co A redutase. Seu
conhecido efeito benéfico sobre a função endotelial poderia ser decorrente, pelo menos em
parte, de uma melhora na sensibilidade à insulina. De fato, estudos preliminares in vitro
sugerem que a estatina determina efeitos celulares compatíveis com atenuação da
1.C.JUSTIFICATIVA
Visando à prevenção do DM tipo 2 e, a mais longo prazo, à prevenção de doença
cardiovascular em pacientes de risco, seria de grande interesse a descoberta de agente
terapêutico eficaz em várias das alterações características da SM, tais como a
hiperinsulinemia, intolerância à glicose, dislipidemia, alterações da fibrinólise e processo
inflamatório subclínico. Pelo que se conhece atualmente sobre a metformina e
especialmente sobre as estatinas, é possível que uma ou ambas possam desempenhar
várias destas “funções”. Um medicamento com estas propriedades seria bastante
promissor em prevenir ou pelo menos melhorar o prognóstico de pacientes com SM. As
doenças que compõem esta síndrome são, sem dúvida, os maiores problemas de saúde
pública da atualidade.
1.D.OBJETIVOS
Na presente tese, em linhas gerais, nos propusemos a estudar os efeitos de um
inibidor da HMG-CoA redutase em pacientes pré-diabéticos (com glicemia de jejum
alterada ou TGD) com excesso de peso (supostamente resistentes à insulina), comparando
aos da metformina, no que se refere ao perfil glico-lipídico, hormonal, à sensibilidade à
insulina e resposta de marcadores de inflamação sub-clínica.
Para tanto, foram elaborados três artigos científicos com objetivos específicos
relacionados a seguir.
- Artigo 1:
Discutir a importância da obesidade visceral, possíveis mecanismos que a
relacionam à resistência à insulina, métodos para avaliação da distribuição
do tecido adiposo, bem como descrever as principais substâncias –
adipocitoquinas – expressas e secretadas por este tecido.
- Artigo 2:
Estudar o efeito da sinvastatina e metformina sobre marcadores
- Artigo 3:
Avaliar o efeito da sinvastatina na resistência à insulina, leptina e
adiponectina, comparado aos da metformina, em indivíduos pré-diabéticos
com excesso de peso.
1.E.RESUMO DOS ARTIGOS
- Artigo 1: The New Adipose Tissue and Adipocytokines
A obesidade é fator determinante de resistência à insulina que está
envolvida na fisiopatogênese de um conjunto de anormalidades tais como o
diabetes mellitus tipo 2, dislipidemia, hipertensão arterial e a doença
cardiovascular. Mais que a quantidade total de gordura corporal, a
distribuição central do tecido adiposo (obesidade visceral) é relevante na
gênese destas anormalidades, conhecida como síndrome metabólica. O
tecido adiposo, antes reconhecido como um órgão de estoque de energia,
hoje é reconhecido como o maior órgão endócrino do organismo. Esse
tecido secreta numerosas substâncias – as adipocitocinas – com múltiplas
funções em processos metabólicos e imunológicos. O excesso de tecido
adiposo desencadeia inflamação, distúrbios metabólicos e hemostáticos e
aumenta risco de doenças cardiovasculares. As adipocitocinas podem agir
localmente ou à distância, como sinalizadores inflamatórios, imunes ou
hormonais. Nesta revisão, discutem-se os mecanismos pelos quais a
obesidade visceral determina resistência à insulina nos diferentes tecidos,
métodos para sua avaliação e ações das principais adipocitocinas expressas
e secretadas pelo tecido adiposo.
- Artigo 2: Effects of Simvastatin and Metformin on Inflammation and Insulin Resistance in Mildly Metabolically Disturbed Individuals
Além de suas ações hipolipemiantes e sensibilizadoras da ação da insulina,
as estatinas e metformina podem apresentar efeitos pleitrópicos. Este estudo
metformina sobre marcadores inflamatórios e a sensibilidade à insulina de
pacientes pré-diabéticos com excesso de peso. Quarenta e um indivíduos
com IMC >25 kg/m2 e glicemia de jejum alterada ou tolerância à glicose
diminuída foram randomizados para usar sinvastatina ou metformina por 16
semanas. Amostras de sangue foram obtidas para medida de parâmetros
metabólicos e inflamatórios antes e ao final de cada tratamento. Após
tratamento com metformina, houve redução significante nas médias de IMC,
circunferência da cintura e HOMA-IR. Com sinvastatina, observou-se
redução significante dos níveis de LDL-colesterol, triglicérides e
apolipoproteína B. As concentrações de PCR e IL-6 diminuíram de forma
semelhante com as2 medicações. Não houve mudança nos níveis de TNF-α.
Detectou-se correlação entre os valores basais de PCR e IL-6 e seus
percentuais de declínio (r = 0,71 e r = 0,67, respectivamente, p <0,001). No
grupo tratado com sinvastatina, não foi encontrada correlação entre a queda
de PCR e IL-6 com a queda nos lipídios séricos; do mesmo modo, no grupo
metformina, os percentuais de queda destes marcadores inflamatórios não
se correlacionaram com os do IMC e do HOMA-IR. Conclui-se que
atenuação da inflamação é obtida após tratamento com sinvastatina em
indivíduos pré-diabéticos com níveis de LDL normal ou pouco elevados. Os
achados também sugerem efeito benéfico da metformina sobre os níveis de
PCR e IL-6 em humanos. A ausência de correlação descrita acima sugere
efeito anti-inflamatório independente destes agentes. Reforça-se a
importância de se tratar indivíduos de risco cardiovascular antes do quadro
de diabetes ou da síndrome metabólica completa.
- Artigo 3: May beneficial cardiovascular effects of sinvastatin and metformin be also associated with hormonal-dependent mechanism improving insulin sensitivity?
Além de suas ações hipolipemiantes e cardioprotetoras, é possível que
estatinas possuam efeitos benéficos na sensibilidade à insulina. O objetivo
deste estudo foi avaliar os efeitos da sinvastatina sobre a resistência à níveis
de insulina, leptina e adiponectina e PCR, comparando-os aos da
um indivíduos com IMC >25 kg/m2 e glicemia de jejum alterada ou tolerância
à glicose diminuída foram randomizados para tratamento com sinvastatina,
20 mg ao dia (n = 20), ou metformina, 1,7 mg ao dia (n=21), por 16
semanas. Amostras de sangue foram obtidas para determinação de
parâmetros metabólicos, inflamatórios e hormonais, antes e após cada
medicação. Após tratamento com metformina, houve redução significante no
IMC e circunferência da cintura. Com a sinvastatina, houve redução
significante dos níveis séricos de LDL e triglicérides. O HOMA-IR caiu
apenas após o uso de metformina. As concentrações de PCR diminuíram de
forma semelhante com as 2 medicações. Não houve mudança nos níveis de
leptina e adiponectina com nenhuma medicação. Detectou-se correlação
entre os níveis basais de leptina e IMC (r = 0,314; p = 0,046) e entre os
níveis adiponectina e HDL (r = 0,466; p < 0,002). Nossos dados revelam que
a sinvastatina em doses baixas não apresenta efeito na resistência à insulina
e não altera os níveis de adiponectina ou leptina em indivíduos
pré-diabéticos com excesso de peso. Estudos envolvendo maior número de
indivíduos e com doses mais elevadas de estatinas são necessários para
confirmar tais achados.
1.F.REFERÊNCIAS BIBLIOGRÁFICAS
1. Tuomilehto J, Uusitupa M, Valle TT et al. Prevention of type 2 diabetes
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2.ARTIGO 1
THE NEW ADIPOSE TISSUE AND ADIPOCYTOKINES
*Caroline Bulcão1, MD; Sandra Roberta G. Ferreira2, PhD; Fernando M. A. Giuffrida1, MD; Fernando Flexa Ribeiro-Filho1, PhD
1 Division of Endocrinology, Department of Internal Medicine, Federal University of
Sao Paulo, Brazil
2 Department of Preventive Medicine, Federal University of Sao Paulo, Brazil
Correspondence Caroline Bulcão
Disciplina de Endocrinologia – UNIFESP
Rua Botucatu, 740 - 2o andar
Caixa postal 20266
CEP 04034-970 - São Paulo, SP, Brasil
Phone: 55 11 8149-4745 Fax: 55 11 5572-0889
E-mail: cbulcao@uol.com.br
ABSTRACT
Obesity is a well-known risk factor for the development of insulin resistance, type 2
diabetes, dyslipidemia, hypertension, and cardiovascular disease. Rather than the total
amount of fat, central distribution of adipose tissue is very important in the pathophysiology
of this constellation of abnormalities termed metabolic syndrome. Adipose tissue, regarded
only as an energy storage organ until the last decade, is now known as the biggest
endocrine organ of the human body. This tissue secretes a number of substances –
adipocytokines – with multiple functions in metabolic profile and immunological process.
Therefore, excessive fat mass may trigger metabolic and hemostatic disturbances as well
as CVD. Adipocytokines may act locally or distally as inflammatory, immune or hormonal
signalers. In this review we discuss visceral obesity, the potential mechanisms by which it
would be related to insulin resistance, methods for its assessment and focus on the main
adipocytokines expressed and secreted by the adipose tissue.
Particularly, we review the role of adiponectin, leptin, resistin, angiotensinogen, TNF-α, and PAI-1, describing their impact on insulin resistance and cardiovascular risk, based on more recent findings in this area.
INDRODUCTION
Obesity has been seen from different points of view according to current cultural and
scientific values. When access to food was possible only by means of hunting and
gathering, obesity was not an issue; evolutionary mechanisms selected those individuals
with more efficient energy storage systems. Modern societies, characterized by easy access
to food and reduced physical activity, brought about obesity. Urbanization, industrialization
and automation processes still play a major role in the growing global epidemics of obesity.
Increasing interest on obesity has been noticed in the last decades since it was shown to be
strongly related to morbidity and mortality. Once, body fat was considered only as a
protective tissue against trauma and an energy storage organ, and obesity seen as a sign of
beauty, richness and health. Nowadays, obesity is a serious disease that predisposes to
insulin resistance, diabetes, essential hypertension and dyslipidemia. Some tumors,
gallstones, respiratory, reproductive, and locomotory diseases are also obesity-related
disorders (1,2).
Body mass index (BMI) is the main parameter used to quantify body adiposity, but
other anthropometric and imaging methods are more reliable to reflect body composition
and fat distribution. The importance of body fat distribution has been stressed since studies
by Vague in the beginning of last century (3). Central obesity is indicative of visceral fat
deposition, which is closely associated with metabolic disorders and cardiovascular risk.
Epidemiological data show that an indirect estimate of visceral fat such as waist
circumference is able to predict a number of diseases. This measurement should be a part
of routine clinical examination, since it improves prediction of cardiovascular complications
when combined with BMI (4-6).
Obesity became an important public health issue even in developing countries (7).
The number of obese individuals in the world is estimated to be around 100 million, and
marked growth is expected for the next decades (8). Almost 50% of the U.S. adult
population has BMI over 25 kg/m² and 25% are over 30 kg/m² (9). If this trend is not
reversed, 100% of the American population will be obese by 2230 (10).
VISCERAL OBESITY
Visceral accumulation of fat is a particularly important trigger of insulin resistance
and metabolic syndrome. Hyperinsulinemia may occur as a consequence of reduced insulin
intolerance, hypertension, dyslipidemia and cardiovascular disease (CVD) was first
described by Reaven, who coined the term syndrome X (11). Several metabolic factors,
including adipocytokines, have been included in the spectrum of the syndrome, which is
now known as metabolic syndrome. The simplest diagnostic criterion was proposed by the
National Cholesterol Education Program (12) and a broader one by the American
Association of Clinical Endocrinologists/American College of Endocrinology (13),
considering cytokine involvement in the pathophysiology of the syndrome. Such diagnosis is
of great relevance since it is closely related to CVD (14).
The impact of central distribution of fat on the deterioration of insulin sensitivity and
cardiovascular risk has been extensively shown in prospective studies (15-17). Due to
intense lipolytic activity of the visceral adipose tissue, large amounts of free fatty acids
(FFA) are released into portal circulation, leading to hepatic synthesis of triglycerides.
Mechanisms for the lipidic effect on hepatic glucose output include β-oxidation of fatty acids
and increased availability of glycerol. Oxidation of fatty acids provides ATP, the energy
needed to drive gluconeogenesis, as well as acetylCoA, which activates pyruvate
carboxylase, the first key enzyme in the gluconeolitic pathway. Glycerol, in turn, is an
excellent substrate for gluconeogenesis. This determines elevation of plasma glucose and
insulin secretion, which may cause hyperinsulinemia, worsened by the diminished hepatic
insulin clearance (18). Peripheral glucose uptake is reduced due to downregulation of
insulin receptors and the large amount of circulating FFA, competing with glucose in
oxidative metabolism and insulin signaling (19,20). In addition, FFA may deteriorate insulin
secretion, accelerating the development of type 2 diabetes (21). Elevated VLDL-cholesterol
production is a determinant of the typical atherogenic profile, characterized by small dense
LDL-cholesterol particles and low HDL-cholesterol (22).
ASSESSMENT OF VISCERAL FAT
Body fat distribution is usually assessed by anthropometry and imaging techniques.
Direct or indirect methods for the assessment of visceral fat are mandatory when the goal is
to estimate cardiovascular risk. Computed tomography (CT) is considered the gold standard
for quantification of visceral adipose tissue but some anthropometric measurements, like
waist circumference, waist-to-hip circumference ratio (WHR) and abdominal sagittal
diameter provide good estimates and have been used in epidemiological studies. Waist
factors, events and deaths (24-26). Despite significant correlation between WHR and
visceral fat area measured by CT or magnetic resonance imaging (MRI) (26), most authors
reported waist circumference to have a better correlations with reference methods than
WHR (25,26) and BMI (27), as well as a stronger association with metabolic syndrome.
Imaging techniques – CT, MRI, and ultrasonography (US) – are better predictors of
visceral adipose tissue than anthropometry. CT scan, obtained at the L4-L5 level, has high
reproducibility (28), but with the disadvantages of cost and exposure to ionizing radiation.
MRI has accuracy and reproducibility for total and visceral fat evaluation similar to CT (29).
The linear distance of intra-abdominal fat determined by US shows a strong correlation to
visceral fat area measured by CT (27,30). Therefore, US-determined visceral fat is an
alternative for quantification and follow-up of patients with central obesity, due to its low cost
and absence of radiation (27).
DEXA (dual energy x-ray absorptiometry) is a method for evaluation of fat and lean
mass (31). The exam takes only 10 to 20 minutes, with low irradiation rates and reasonable
reproducibility. Although body sections can be evaluated separately, the method does not
distinguish between visceral and SC fat. Its cost is high when compared to US, but it is less
expensive than CT or MRI.
ADIPOSE TISSUE AS AN ENDOCRINE ORGAN
Adipose tissue has a fundamental role in metabolism and homeostasis regulation
through secretion of several factors – the adipocytokines. Those implicated in insulin
resistance and atherogenesis will be discussed in this article. In general, adipocytokine
production is proportional to fat mass and its secretion is distinctive according to adipose
tissue location, i.e. subcutaneous or visceral.
According to this new concept, adipose tissue is an endocrine organ, capable of
secreting hormones and cytokines which, in abnormal amounts, can induce metabolic,
hemodynamic and hemostatic disturbances (32). The immunological term “cytokine”, which
designates a large group of molecules involved in immune cell signaling, has been
increasingly used in clinical sciences. Cytokines are produced during innate and specific
immune activation to mediate inflammatory and immune responses. The main groups of
cytokines are interferons, interleukins, colony stimulating factors and tumor necrosis factors
(33,34). Hormones – secretion products of endocrine glands - once in the bloodstream
responses (35). Therefore, adipose tissue could be regarded as the largest endocrine organ
in the human body, whose products – cytokines and hormones – are called
“adipocytokines”. They have autocrine, paracrine or endocrine actions and are involved in
inflammatory responses (36). Inflammatory properties of adipocytokines, along with their
possible role in insulin resistance, have been widely studied in recent years. In this article
the following will be emphasized: tumor necrosis factor alfa (TNF-α), interleukin 6 (IL-6),
resistin, adiponectin, leptin, angiotensinogen, and plasminogen activator inhibitor 1 (PAI-1).
Tumor Necrosis Factor Alpha – TNF-α
This adipocytokine, primarily known for its role in inflammatory responses, has
additional effects on glucose transport, lipid metabolism and insulin action, which have been extensively investigated, especially in rodents. TNF-α stimulates production of other cytokines involved in the inflammatory response such as IL-8 and IL-6, both related to
obesity and insulin resistance in animals and humans (37,38). It has been shown that TNF-α
has direct (independent of insulin), and indirect lipolytic activity. Activation of a TNF-α
-responsive serine kinase causes serine-phosphorilation of insulin receptor substrate 1
(IRS-1), resulting in a reduction of insulin signaling. Serine-phosphorilated IRS-1 is less effective
in activating phosphoinositide 3-kinase (PI3K), involved in insulin-determined lipolysis suppression (39). It has been previously suggested that TNF-α may also have paracrine actions, affecting insulin-stimulated glucose uptake at the skeletal muscle (39). Since this
adipocytokine production is proportional to body adiposity, these effects on glucose
metabolism are expected to be exacerbated in obesity.
A body of evidence has reinforced the impact of increased TNF-α levels on the
deterioration of insulin sensitivity despite some contradictory data. In the study by Tsigos et al, including 26 obese women, TNF-α was significantly correlated to WHR and insulin levels, but not to BMI (40). Similar findings were reported by others (41-43). The higher levels of
this adipocytokine in obese as compared to lean individual decreases following weight loss (42). These data are in accordance with the observation of increased TNF-α mRNA expression in human adipocytes from obese subjects with the highest circulating levels of
such adipocytokine (38). Moreover, thiazolidinediones were able to reverse the TNF-α
inhibitory effect on insulin action, supporting a pathogenic role in insulin resistance (44,45).
Nevertheless, Bruun et al did not find a difference in TNF-α levels between obese and lean
TNF-α with insulin resistance and type 2 diabetes was not confirmed in other studies (46-48); in an euglycemic hyperinsulinemic clamp study, TNF-α was not associated with hyperinsulinemia or obesity, and normal mRNA expression in obese and diabetic men was
observed (49).
A role for TNF-α has been raised in the pathogenesis of ovarian hyperandrogenism, included in the spectrum of the metabolic syndrome. In female rats, TNF-α stimulates
proliferation and steroidogenesis of theca cells in vitro and could be involved in anovulation
(50,51). Polycystic ovary syndrome is accompanied by increase in this cytokine, suggesting
that TNF-α could be related to hyperandrogenism, independent of obesity and insulin
resistance (43,52).
TNF-α seems to have a close relation to leptin in obese individuals, leading to the hypothesis that TNF-α hyperactivity could represent a common pathway in pathophysiology
of insulin resistance and hyperleptinemia in obesity (53,54).
Interleukin-6 – IL-6
Approximately one third of total circulating IL-6 in humans originate from adipose
tissue (55). Besides adipocytes, other cells produce IL-6: immune cells, endothelial cells,
skeletal muscle, and fibroblasts (36). Its secretion is distinctive according to adipose tissue
distribution; visceral adipose tissue releases 2 to 3 times more IL-6 than subcutaneous fat
(56).
This cytokine, essentially implied in inflammatory responses, has also plenty of
pleiotropic effects (57). Epidemiologic and genetic studies show an association between
IL-6 and insulin resistance. High IL-IL-6 levels are not only related to obesity and
hyperinsulinemia, but also predictive of type 2 diabetes (58) and myocardial infarction (59).
IL-6 is increased in obese subjects and decreases with weight loss (42,60,61); a study with
120 obese women confirmed positive correlations of IL-6 with BMI and WHR, as well as with
FFA, fasting insulin, and HOMA-IR; and showed a great reduction of IL-6 and FFA levels
with weight loss (60).
Several findings have linked IL-6 to insulin resistance. IL-6 increases fat oxidation
and circulating FFA in humans (62), which are known to deteriorate insulin sensitivity (63).
Additionally, IL-6 causes reduction in the secretion of adiponectin (60,64), a cytokine
positively related to insulin sensitivity. Moreover, deleterious actions on fibrinolysis and
hepatic secretion of fibrinogen, and in pro-coagulant platelet activity (65,66). Evidences that
IL-6 increases insulin resistance, has pro-coagulant effects, and induces increase in
C-reactive protein levels (65-67) suggest a role in the pathogenesis of metabolic syndrome
and in cardiovascular risk.
Finally, the systemic action of IL-6 in stimulating the hypothalamus-pituitary-adrenal
axis should be stressed. IL-6 increases hypothalamic corticotropin secretion, which
stimulates secretion of ACTH and cortisol (68). Subcutaneous administration of IL-6 to
healthy volunteers resulted in a raise in ACTH and cortisol levels (69). Cortisol, in turn,
suppresses IL-6 production by adipose tissue, acting through negative feedback (70).
Considering the complexity of mechanisms, current knowledge supports that IL-6
works essentially as a hormone, acting locally or systemically, with immune as well as
inflammatory actions, modulating insulin sensitivity, and participating in feedback loops.
Adiponectin
Adiponectin is specifically produced and secreted by adipose tissue (71,72). This
protein is similar to collagen and exists in large amounts in the circulation, i.e. 0.01% of total
plasma proteins (73). Interest in adiponectin grows because of its important role in energy
homeostasis and insulin sensitivity (36). In contrast to other cytokines, adiponectin is
diminished in obesity (73), type 2 diabetes, in other conditions of insulin resistance (74),
dyslipidemia (75) and CVD (76,77); concordantly with the latter effects, its levels increase
with weight loss (60,78,79).
Studies conducted in Caucasians and Pima Indians confirmed the association of
hypoadiponectinemia with obesity and type 2 diabetes, and adiponectin concentration was
more closely related to insulin sensitivity and fasting insulinemia than to adiposity and
glycemia (74). Several studies have shown that hypoadiponectinemia is an independent risk
factor for the development of diabetes (80-82). Low adiponectin levels in obese individuals
with diabetes may be largely attributable to insulin resistance and a role for
hypoadiponectinemia in the development of metabolic syndrome is reinforced.
Another research line contributes to understand the underlying mechanisms between
hypoadiponectinemia and insulin resistance. Growth hormone lowering therapies (such as
somatostatin analog or surgery) were shown to reverse the low levels of adiponectin found
in acromegalic patients (83). It is possible that hypoadiponectinemia contributes to generate
Data from animals corroborated humans’ findings. Leptin deficient ob/ob mice
crossed with globular adiponectin transgenic mice (gAd Tg ob/ob mice) resulted in
improvement of insulin sensitivity (84). In addition, gAd Tg ob/ob mice exhibited increase in
plasma insulin levels during glucose tolerance test, which was associated with increased
insulin content, suggesting a direct protective effect on beta cells (84). Lipoatrophic mice
with leptin deficiency and hypoadiponectinemia showed partial reversion of
hyperinsulinemia and insulin resistance-induced hyperglycemia with administration of
adiponectin; these disturbances were almost abolished by concomitant administration of
leptin and adiponectin (85). Similarly, another diabetic rodent model had reversion of insulin
resistance with adiponectin administration (85). These studies open a new therapeutic
perspective for metabolic syndrome and type 2 diabetes. Indeed, adiponectin seems to be,
at least in part, responsible for anti-inflammatory and insulin-sensitizing properties of
thiazolidinediones in humans, once its clinical use significantly increases adiponectin
circulating levels (86,87).
The mechanisms by which adiponectin acts on insulin sensitivity are not fully
understood. In human skeletal muscle it increases FFA oxidation, lowering FFA plasma
levels and hepatic influx, which ameliorates insulin sensitivity in these tissues (84,88).
Additionally, adiponectin stimulates glucose uptake via AMP-activated-protein-kinase in
adipocytes and skeletal muscle (85,89).
Recently, 2 receptors for adiponectin (ADIPOR1 and ADIPOR2) were identified in
human tissues (90). They share 67% homology with the mouse gene and show marked
conservation of the transmembrane domains from yeast to mammals. ADIPOR1 is
universally expressed, while ADIPOR2 seems to be more expressed in liver (90). Both exist
in large amounts in rat and human pancreatic beta cells (91). A recent finding of reduction of
mRNA ADIPOR1 in transformed lymphocytes of Afro-Americans with type 2 diabetes
compared with control cell lineages, suggests a possible role for this receptor in the
pathophysiology of metabolic syndrome (92).
Adiponectin is also involved in lipid metabolism. Elevated adiponectin is associated
with higher HDL-cholesterol and lower triglyceride levels, independently of insulin sensitivity
and obesity (76,79,93). The negative association with CRP and fibrinogen concentrations
(93-98) may indicate that adiponectin has anti-inflammatory and anti-atherogenic properties.
Moreover, inhibitory effects on monocyte adhesion to the endothelium, in macrophage
change to foam cell (99), and in TNF-α production (100-102) were reported. Adiponectin
metabolism (102) and in animal models of atherosclerosis (apoE-deficient mice) with high
expression of globular adiponectin, such adipocytokine inhibited the progression of
atherosclerosis in vivo, independently of conventional risk factors as plasma glucose and
lipid profile; it was also found to supress expression of class A scavenger receptor and
TNFα, both closely related to atherogenesis (84). In human aortic endothelial cells,
adiponectin inhibited TNFα-induced monocyte adhesion and suppressed expression of
vascular cell adhesion molecule (VCAM)-1 mRNA (103,104). Low plasma adiponectin levels
are associated with impaired endothelium-dependent vasodilation, which suggests this
hormone may act as a link between adipose tissue and the vasculature (105). These
findings are in accordance with evidences of hypoadiponectinemia in individuals with CVD
(76,100).
In summary, adiponectin is an adipocytokine with insulin sensitizing,
anti-inflammatory, and antiatherogenic properties; this may be also a cardio-protective
substance, what may provide a novel modality of treatment for metabolic syndrome.
Plasminogen activator inhibitor-1 – PAI-1
This glycoprotein is a serine protease inhibitor that circulates as a complex with
vitronectin, which stabilizes its active conformation and increases biological half-life (106).
The fibrinolytic system is controlled mostly by PAI-1 activity, through inhibition of the
endogenous fibrinolysis modulators: tissue plasminogen activator (tPA) and urokinase
plasminogen activator (uTPA) (106). The major sources of PAI-1 are the liver and
endothelial cells, but fibroblasts, mononuclear cells, platelets, and adipocytes participate in
its secretion (107,108).
PAI-1 activity is strongly related to BMI, triglyceride and insulin levels as well as
abdominal fat accumulation. Several studies suggested that visceral fat is an important
determinant of PAI-1 increase in insulin resistance (109-111). It is expressed in animal and
human adipose tissue (112), being more expressed in visceral adipose tissue of obese,
insulin resistant subjects (113). PAI-1 was more closely related to WHR than to BMI, and
clamp techniques indicated positive correlation with fasting glucose and insulin levels, and
negative correlation with the degree of insulin sensitivity (114). This altogether suggests that
fibrinolytic disturbances in individuals with central obesity and insulin resistance are likely
Insulin sensitizers as troglitazone (115,116) or metformin (117-119), physical activity
and weight loss (120-122) were shown to reduce circulating PAI-1, suggesting that
metabolic improvement can be the main determinant of PAI-1 reduction in metabolic
syndrome. Other evidences pointed out the importance of PAI-1 in reduction of 15 to 30% in
myocardial infarction occurrence (111,123,124). Similarly, high levels of PAI-1 increase the
risk of cardiovascular events in insulin resistant subjects, despite the presence of type 2
diabetes (125).
PAI-1 activity is regulated by several substances involved in the metabolic
syndrome. Cytokines like TNF-α (126,127), insulin and insulin-like growth factors (128-130),
triglycerides (131,132), unsaturated fatty acids (133) and angiotensin II (134,135) stimulate
PAI-1 release by endothelial cells. Administration of TNFα and insulin to animals led to
higher expression of PAI-1 in adipose tissue (126,127,136) and, in humans, angiotensin II
administration increased circulating PAI-1 levels (137).
The role of PAI-1 in the metabolic syndrome pathophysiology is not yet fully
understood, but certainly different cells and metabolic stimuli are involved.
Angiotensinogen
Angiotensinogen is a substrate for renin, yielding angiotensin I, which is in turn
transformed into active angiotensin II (AII), through the action of angiotensin-converting
enzyme (ACE). The main source of angiotensinogen is the liver, followed by adipose tissue,
which expresses ACE, renin (138,139), and angiotensin II type I and type II receptors
(138,140,141). A number of substances are able to stimulate angiotensinogen secretion in
hepatocytes but in adipocytes its secretion is stimulated only by FFA and glucocorticoids,
which, in rats, are implicated in white adipose tissue hypertrophy (142,143).
Many evidences link central obesity to the renin-angiotensin system.
Angiotensinogen is found in higher amounts in visceral than SC adipose tissue of animals
(144). In humans, a homozygous mutation of the ACE gene (D allele at intron 16) was
associated with an age-related greater prevalence of abdominal adiposity and tendency to
develop overweight and hypertension (145). These observations could explain, at least in
part, the higher prevalence of hypertension in subjects with metabolic syndrome. Blockade
of the renin-angiotensin system using ACE inhibitors and AII receptor antagonists led to
Along with its recognized systemic effect in blood pressure, AII has local actions in
the adipose tissue: (a) induces preadipocytes to differentiate into adipocytes by stimulating
prostacyclin production from adipocytes (148,149); (b) acts as a trophic factor involved in
organogenesis of animals and humans (150); and (c) stimulates lipogenesis and triglyceride
accumulation in human adipocytes (151). These effects support a possible role for the
renin-angiotensin system in adipose tissue development and metabolism.
Leptin
The product of the ob gene, expressed essentially in adipocytes (152,153), circulates
bound to a soluble form of its receptor and binds to a transmembrane receptor (36); it acts
as a signaling factor from adipose tissue to the central nervous system – hypothalamus –
regulating energy intake and expenditure, as well as acting in certain neuroendocrine axes
(154,155). The relationships between mRNA leptin expression, serum leptin levels and
amount of body fat are well established (154,156,157). Leptin concentrations are higher in
women than men independently of BMI (158); these differences are attributed to variations
of body fat distribution and the action of sexual hormones in leptin regulation (23).
Interestingly, the expression of mRNA leptin is greater in subcutaneous than in omental fat
and the leptin subcutaneous-to-omental ratio is higher in women than men (159). This could
be attributed to a larger size of subcutaneous as compared to omental adipocytes,
considering that leptin production increase proportionally to adipocyte size (160). Both in
obese and lean subjects, leptin secretion rate was shown to be 2 to 3 times higher in
subcutaneous tissue than in omental fat tissue (161). In addition to the amount of fat,
distribution, and size of adipocytes, nutritional and hormonal factors also regulate leptin
secretion. Its circulating levels increase 40% after a meal (162) and decreases in response
to fasting (163). Therefore, this hormone acts as an energy balance sensor. Likewise, TNF-α modulates leptin secretion by increasing gene expression and circulating levels (53,164,165).
The pathophysiological role of leptin in insulin resistance has been extensively
studied in animal models and humans. Leptin deficient mice (ob/ob) exhibit hyperphagia,
obesity, hypercortisolemia, infertility, and diabetes (166), which are reversed by leptin
replacement independently of body weight (167). Considine et al found positive correlation
between leptin concentrations and percent of body fat in humans (168). In addition, a
serum leptin (169-171). Such findings were discordant with known actions of leptin in
rodents – appetite reduction and increase of energy expenditure with weight loss. Thus, it
was suggested that obese individuals with insulin resistance may have also leptin
resistance, what would explain the lack of benefit from the exogenous administration of
leptin (172,173).
Rare human cases of complete leptin deficiency due to leptin gene mutations were
described. The phenotype is of severe obesity, insulin resistance, and hypogonadotropic
hypogonadism (174), which are reversed with exogenous leptin administration (175). A
similar profile is found in patients with mutations in the leptin receptor, equivalent to db/db
mice, except for an absence of response to leptin therapy in this situation (176). These
mutations are rare causes of obesity in humans.
An additional therapeutic use of leptin is lipodystrophy characterized by the absence
of adipose tissue, insulin resistance, low leptin and high triglyceride levels and hepatic
steatosis. Leptin replacement improved insulin sensitivity dramatically in animals (177,178)
and reduced both glucose and triglyceride levels in humans with this disease (179,180).
Taking all available data together, they strongly suggest that leptin acts as a signaler for
global regulation of insulin sensitivity.
Resistin
This polypeptide – expressed and secreted by adipose tissue – was discovered in
2001 by a cloning strategy designed to search for genes expressed during adipocyte
differentiation when thiazolidinedione-inducible downregulation in mature adipocyte was
being investigated (181). Although little is known about the function of this recently
recognized hormone, one possible effect is to deteriorate insulin sensitivity in animals and
humans.
The resistin gene is expressed in white adipose tissue in mice and rats (182) as well
as in immunocompetent cells (183). Increased circulating levels of this hormone were found
in obese mice and TZDs suppressed its expression (184); in vivo administration of
recombinant resistin to normal mice caused insulin resistance and cultured adipocytes
exposed to resistin showed a reduction of insulin-stimulated glucose uptake (184). However,
the expression of resistin mRNA and protein was found to be strongly suppressed in
adipose tissues in many models of experimental obesity (185,186) and the use of metformin
Resistin is also expressed in human adipose tissue (189) and was more often
detected in those from morbidly obese subjects than in normal controls (183). Its expression
is similar in both abdominal subcutaneous and omental depots, but resistin levels are higher
in abdominal than in thigh fat, what could explain the increased risk of type 2 diabetes
related to central obesity (190). Genetic studies also revealed an increased risk for higher
BMI in carriers of two resistin promoter polymorphisms (191). These findings are in contrast
with other studies that showed no association between insulin resistance and resistin
(183,192); resistin was found to be expressed neither in human muscle nor in most human
isolated fat cells or intact biopsies (193). Similar results were observed by others who did
not detect resistin mRNA in adipocytes from a severely insulin-resistant subject (183). In addition, insulin (194) and TNFα (195), both related to insulin resistance, were shown to inhibit resistin production and gene expression.
Possible additional effects of resistin resulted from in vitro studies, in which
recombinant resistin was shown to directly activate cultured human endothelial cells,
promoting endothelin-1 release and up-regulation of adhesion molecules (196).
In summary, a first report proposed that resistin could be related to insulin
resistance, but a number of others did not support such relation. A possible role for resistin
in metabolic disorders is not excluded. Nevertheless, more studies using resistin knock-out
mice may help to understand pathophysiological resistin variations in humans.
CONCLUSION
Adipocytes were once considered a passive energy storage organ and obesity a
consequence of chronically positive energy balance. Nowadays, adipose tissue is
recognized as an endocrine organ, capable of secreting a variety of adipocytokines which
are essential determinants of energetic metabolism. Several adipocytokines were pointed as
possible links between obesity, inflammation and insulin resistance; they can act
systemically on several sites like liver, vascular endothelium, and the coagulation system,
interacting in the development of atherosclerosis. The mechanisms by which adipocytokines
promote insulin resistance are not yet completely understood. Obesity, especially central
obesity, may increase the levels of TNF-α, IL-6, angiotensinogen, PAI-1, and maybe
resistin, all of them related to insulin resistance. Adiponectin and leptin, in turn, are essential
for insulin sensitivity. An ever growing number of researchers focus on obesity as an
complications. Lifestyle modifications with weight loss result in a beneficial profile of
adipocytokines, but other potentially effective therapeutic interventions are expected as
future studies continue to provide information linking inflammation and metabolism.
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