Mecanismos De Resistencia A La Insulina

674
© 2005 Diabetes UK.
Diabetic Medicine
,
22
, 674–682
Correspondence to
: Dr Andreas Barthel, Klinik für Endokrinologie, Diabetologie und Rheumatologie, Heinrich-Heine-Universität, Moorenstr. 5, D-40225 Düsseldorf,
Germany. E-mail: Andreas.Barthel@uni-duesseldorf.de
Abstract
Currently, we observe an epidemic expansion of diabetes mellitus. In subjects with
Type 2 diabetes theresistance of fat, muscle and liver to insulin is the central
pathophysiological event in the development of this disease. Genetic and environmental
factors play a major role in this process, although the precise pathogenesis
of insulin resistance and Type 2 diabetes is still largely unknown. However, recent
studies have contributed to a deeper understanding of the molecular mechanisms
underlyingthis process. In this review we therefore summarize the current
developments in understanding the pathophysiological process of insulin resistance
and Type 2 diabetes. Among the many molecules involved in the intracellular
processing of the signal provided by insulin, insulin receptor substrate (IRS)-2,
the protein kinase B (PKB)-
β
isoform and the forkhead transcription factor
Foxo1a (FKHR)are of particular interest in this context as recent data have provided
strong evidence that dysfunction of these proteins results in insulin resistance
in-vivo
. Furthermore, we have now increasing evidence that the adipose
tissue not only produces free fatty acids that contribute to insulin resistance, but
also acts as a relevant endocrine organ producing mediators (adipokines) that
canmodulate insulin signalling. The identification of the molecular pathophysiological
mechanisms of insulin resistance and Type 2 diabetes is essential for the
development of novel and more effective therapies to better treat our patients
with insulin resistance and Type 2 diabetes.
Diabet. Med. 22, 674–682 (2005)
Keywords
adipokines, diabetes mellitus Type 2, insulin resistance, PI 3-kinase,protein kinase B
Abbreviations
CAP, Cbl associated protein; Cbl, casitas B-lineage lymphoma;
G6Pase, glucose-6-phosphatase catalytic subunit; GLUT-4, glucose transporter
4; GS, glycogen synthase; GSK-3, glykogen synthase kinase-3; FFA, free fatty
acids; FKHR, forkhead in rhabdomyosarcoma; Foxo, forkhead box protein;
HK, hexokinase II; HNF, hepatocyte nuclear factor; IR, insulin receptor;IRS,
insulin receptor substrate; MODY, maturity onset of diabetes in the young; PDH,
pyruvate dehydroxygenase; PDK, phosphoinositide-dependent protein kinase;
PEPCK, phosphoenolpyruvate carboxykinase; PFK, phosphofructokinase;
PGC-1, peroxysome-proliferator activated-receptor
γ
coactivator-1; PIP2,
phosphatidylinositol-3,4-bisphosphate; PIP3, phosphatidylinositol-3,4,5-
trisphosphate; PI 3-K,phospho-inositide 3-kinase; PKB, protein kinase B; PKC,
protein kinase C; PPAR
γ
, peroxysome-proliferator activated-receptor
γ
; PTEN,
phosphatase and tensin homologue; PTP, protein tyrosine phosphatase; SH, Src
homology; SHIP2, SH2-containing inositol phosphatase; src; sarcoma; TNF
α
,
tumour necrosis factor-
α
; TZD, thiazolidinediones
02BRDOM17leixMoa4vfclb2oiEekee-rcw3wdtui0,cle Aa7aU lMrlr1rt K tPimeiccudlelebiecclhiisnaheniinsgm, s2L o0tdf0 .4insulin resistance S. Schinner et al.
Molecular mechanisms of insulin resistance
S. Schinner*, W. A. Scherbaum*†, S. R. Bornstein‡ and A. Barthel*
*Klinik für Endokrinologie, Diabetologie und
Rheumatologie, Universitäts Klinikum Düsseldorf,
Düsseldorf †Deutsches Diabetesforschungsinstitut,
Heinrich-Heine-Universität,Düsseldorf and
‡Medizinische Klinik III, Universitäts Klinikum Carl
Gustav Carus, Dresden, Germany
Accepted 24 September 2004
Review article
675
© 2005 Diabetes UK.
Diabetic Medicine
,
22
, 674–682
Introduction
Diabetes mellitus is the most common endocrine disorder,
currently affecting over 170 million people world-wide and
prospectively over 365 million in the year 2030 [1]. More than...