Trakia Journal of Sciences, Vol. 7, No. 4, pp 84-92, 2009
Copyright © 2009 Trakia University
Available online at:
http://www.uni-sz.bg
ISSN 1313-7050 (print)
ISSN 1313-3551 (online)
Mini-Review
NATURE AND MECHANISMS OF INSULIN RESISTANCE – ROLE OF
ADIPOKINES IN ETIOLOGY AND PATHOGENESIS
E. Slavov*
Faculty of Veterinary Medicine, Trakia University – Stara Zagora, Bulgaria
ABSTRACT
Insulin resistance is the main link between obesity and a number of metabolic and cardiovascular disorders.
Still mechanisms, by which white adipose tissue impairs insulin sensitivity, are not well understood. White
adipose tissue produces hormones, such as leptin, resistin and adiponectin, and a great number of protein
signals known as adipokines. These include proteins, playing role in energy balance, lipid and glucose
metabolism, angiogenesis and blood pressure regulation. Visceral obesity is associated with a state of low
grade inflammation, which has a direct impact on development of diabetes type 2 and atherosclerosis.
Intraabdominal adipose depots produce a number of cytokines (TNF-α, IL-1, IL-6, IL-8), which together
with some adipokines (leptin, resistin, adiponectin) take part in pathogenesis of inflammation and acute
phase response. The aim of the present overview is to summarize the existing scientific data, concerning the
role of white adipose tissue secretory products in etiology and pathogenesis of obesity - associated insulin
resistance.
Key words: leptin, adiponectin, resistin, tumor necrosis factor- α, interleukin-6
INTRODUCTION
Insulin resistance is an impaired biological
response to the action of exogenous or
endogenous insulin. It is characterized by
inability of insulin to induce its biological
effects in concentrations that are effective in
healthy individuals. Insulin resistance is a state
in which main target tissues – muscles, liver
and adipose tissue, become less sensitive to
insulin. Thus storage of glycogen in muscles
and liver, clearance of glucose in blood, and
use of glucose for production of energy and
synthesis of fats in adipose tissue are being
reduced (1). Insulin available in circulation can
not suppress release by liver of endogenous
glucose (2). These conditions force pancreas to
secret more insulin to maintain glucose blood
levels in the normal range. Insulin resistance is
directly linked to a number of syndromes,
diseases and metabolic disorders, including
impaired glucose tolerance, hyperinsulinemia,
dyslipidemia, hypertension, increased blood
___________________________
* Correspondence to: Dr E. Slavov, Faculty of
Veterinary Medicine – Stara Zagora 6000,
Bulgaria, E-mail: [email protected]
84
coagulation (3), polycystic ovary syndrome,
metabolic syndrome (known also as syndrome
X), cancer, acute and chronic infections,
trauma and mostly obesity and diabetes
mellitus type 2 (1). These and some other
conditions and diseases (acanthosis nigricans,
Cushing`s
syndrome,
acromegalia,
osteoporosis, some autoimmune diseases), also
being linked to insulin resistance, make it
become a phenomenon of extreme interest. At
this point a number of questions, concerning its
etiology, arise for scientists to study. Far more
are questions concerning pathogenesis of
insulin resistance and its role in the
development of so many various pathological
processes. Defining the primary pathogenetic
event is the base for understanding the origin
and nature of insulin resistance and far more it
is the essence of a successful radical therapy.
Suspected reasons leading to development of
insulin resistance are many. This supposes not
well understood etiology and pathogenesis.
Different concepts exist: influence of genetic
factors (2, 4, 5); hormonal disorders – more
exactly
disorders
in
hormone-receptor
interactions of growth hormone (GH),
glucocorticiods, sex hormones, hormones of
Trakia Journal of Sciences, Vol. 7, No. 4, 2009
thyroid gland (6, 7, 8, 9, 10, 11); increased
levels of non-esterified fatty acids (NEFA) in
circulation (12, 13, 14, 15); liver parasympatic
innervation disorders linked to secretion of
hepatic insulin sensitizing substance (HISS)(16, 17, 18, 19). Acute and especially chronic
infectious processes – viral and bacterial, posttraumatic inflammatory processes, fractures,
autoimmune diseases having distinctive
inflammatory symptoms – chronic juvenile
arthritis, polymyalgia rheumatica and many
others are accompanied by a continuous and
sometimes chronic insulin resistance (20, 21,
22, 23, 24).
OBESITY AND INSULIN RESISTANCE
In people and animal models it has been
proved that high correlation between obesity
and development of insulin resistance exists. It
has been determined that intraabdominal
(visceral) adipose depots play more important
role (25, 26, 27). In a number of studies in the
recent years it was established that adipose
tissue is not only a depot of triacylglycerols,
but to great extent it possesses typical features
of an endocrine organ secreting various
hormones, cytokines and other biologically
active substances: estrogens, factors of blood
coagulation
and
fibrinolysis
/PAI-1/,
interleukin 6 /IL-6/, interleukin 1 /IL-1/,
interleukin 8 /IL-8/, tumor necrosis factor α
/TNF- α/, prostaglandin E2 /PG-E/, and of
course leptin, adiponectin and resistin, which
are specific for adipose tissue. Also highly
positive correlation was found between
amounts of adipose depots, insulin resistance
and a number of disorders – hypertension,
hyperlipemia, dyslipidemia, impaired glucose
tolerance, diabetes type 2, endothelial
dysfunction, increased blood coagulation,
atherosclerotic lesions in blood vessels and
others (26, 28, 29). Insulin resistance and proinflammatory cytokines (IL-1, IL-6, TNF- α)
produced by adipose tissue play leading role in
mechanism of these disorders. Increased levels
of these cytokines in circulation during
obesity, lead to a chronic, low-grade, systemic
inflammatory process (30, 31, 32).
ROLE
OF
INSULIN
RECEPTOR
DYSFUNCTION AND IMPAIRED POSTRECEPTOR SIGNALING PATHWAYS IN
INSULIN RESISTANCE ORIGIN
Glucose enters the cell through facilitated
diffusion, but in muscles, adipose tissue and
SLAVOV E.
some other tissues insulin contributes to
utilizing of glucose by means of increasing the
number of glucose transport proteins in cell
membranes. Action of insulin on target tissues
and realization of its biological effects is due to
activation of specific insulin receptors on
surface of cell membranes. First studies
proving the existence of such receptors were
conducted in 1971 (33, 34). Following studies
in this sphere revealed direct link between
disorders in synthesis, structure and affinity of
insulin receptors and insulin resistance (35, 36,
37). Mutations of gene encoding the insulin
receptor have been described to cause
disorders in receptor synthesis and impaired
structure and function of the receptor in
patients with syndromes linked to insulin
resistance (38). Caro et al. (39) found that
insignificant decrease in the number of insulin
receptors in tissues and cells in patients having
diabetes type 2, leads to a reduced response to
hyperinsulinemia. Normal structure and
functional activity of insulin receptor and
normal function of post-receptor signaling
mechanisms and pathways are of decisive
importance for an adequate cell response to
insulin stimulation. Activation of insulin
receptor
tyrosine
kinase
results
in
autophosphorylation and phosphorylation of
intracellular substrates, which plays a major
role in the complicated and multi-component
post-receptor signaling cascade mediating the
complex of cell reactions (40, 41, 42).
Autophosphorylation
and
substrate
phosphorylation can be affected by the priority
of phosphorylation of amino-acid residues of
insulin receptor (IR) and substrates of insulin
receptor (IRS) – tyrosine or serine. Decreased
tyrosine phosphorylation of IR and IRS is the
molecular basis for inhibition of insulin action
(43, 44, 45) and impaired intracellular
translocation of glucose transport systems,
called glucose transporters (GT) (46).
Variations in size of adipocytes, which are due
to reduction or increase in the amount of fat
accumulated, lead to modulation and changes
in their endocrine and metabolic functions.
Studies confirm that adipose tissue produces
leptin (47, 48), adiponectin (49, 50), resistin
and some similar molecules (51, 52), which are
linked to insulin resistance and are being
intensively investigated. It was also proved
that adipose tissue cells in obese individuals
(and especially cells of stromal vascular
fraction) produce greater amounts of
proinflammatory cytokines - IL-1, IL-6, TNFα and others (53, 54), as compared to
Trakia Journal of Sciences, Vol. 7, No. 4, 2009
85
individuals with normal body weight. Besides
these
proinflammatory
cytokines,
and
especially TNF- α, take an active part in
etiology and pathogenesis of insulin resistance
and disorders linked to it.
ADIPOKINES AND INSULIN
RESISTANCE
Tumor necrosis factor- α
TNF-α is secreted mainly by phagocytic cells
of immune system, but it is produced also by
adipose tissue, especially in visceral obesity.
Production of small amounts of TNF-α has
been found in skeletal muscles and heart. This
cytokine is a factor having multiple effects on
different tissues, taking part in immune and
inflammatory reactions, and is one of the main
mediators of insulin resistance (55, 56, 57).
TNF-α regulates sensitivity of target cells to
insulin by affecting signaling pathways and
expression of genes encoding structure of
glucose transporters. Spiegelman et al. (58)
present data showing that exposing of
adipocytes to action of TNF-α leads to
increased phosphrylation of serine residues of
IRS-1, resulting in inhibition of insulin
induced phosphorilation of tyrosine residues.
IRS-mediated inhibition of insulin receptor
tyrosine kinase activity may be due both to a
direct or indirect interaction between IR and
IRS-1 (56, 59, 60). Experiments involving
lines of genetically obese mice have studied
four potential mechanisms by means of which
TNF-α can provoke insulin resistance in this
animal species. Four potential mechanisms
include – regulation of levels of non-esterified
fatty acids, production of leptin, number of
glucose transporters and activity of insulin
receptors (61, 62, 63).
Interleukin-6
Together with TNF- α, adipose tissue produces
another multifunctional cytokine – IL-6,
having an important role for the development
of insulin resistance (53). Investigations show
that one third of circulating IL-6 descends
from adipose tissue. Omental adipose tissue
produces three times more IL-6 than does
subcutaneous adipose tissue. Like other
proinflammatory cytokines (TNF-α, IL-1, IFNγ) local and circulating levels of IL-6 strongly
correlatively increase during cancer, cachexia,
and most infections, which are almost always
accompanied by insulin resistance. IL-6 is the
one of proinflammatory cytokines to have
highest correlation with insulin resistance and
86
SLAVOV E.
diabetes type 2 (64, 65, 66). Effects of IL-6 on
regulation of glucose metabolism are mainly
due to his action in the liver. IL-6 increases
glucose blood levels by stimulating glucose
production in hepatocytes (64). Increased
levels of IL-6 are linked to inhibition of
hepatic glycogen synthase, activation of
glycogen phosphorylase and lipase and
increased production of triglycerides (68, 67).
Leptin
Hormone leptin is one of the many products
secreted by adipose tissue. In humans its
structure is encoded in ob-gene and its
molecular weight is 16 kDa. Leptin is the key
regulator of energy expenditure and energy
intake, so it regulates energy balance of
organism. Leptin is secreted mainly by
subcutaneous adipose tissue, and its production
is proportional to amount of adipose depots.
Data prove that leptin is increased in all
experimental models of obesity. In obese
humans leptin levels are four times higher as
compared to normal levels. Effects of leptin
are due to its influence on some structures of
hypothalamus (arcuate nucleus), which are
responsible for regulation of appetite and
thermogenesis. Signaling pathways of leptin
action are being intensively investigated. These
include influence on melanocortin and
inhibiting synthesis of neuropeptide Y –
powerful stimulator of appetite (70, 71). Leptin
reaches hypothalamus by means of specific
transport systems that transfer it through
blood-brain barrier and disorders in these
transport systems lead to leptin resistance even
during hyperleptinemia (72). Etiology of leptin
resistance is still not well understood, but it is
clear that both leptin resistance and leptin
deficiency are linked to development of insulin
resistance. This is probably due to the ability
of leptin to stimulate oxidation of fatty acids
and to prevent ectopic fat accumulation in
tissues outside typical fat depots, by means of
which it increases insulin sensitivity (73).
Resistin
Resistin is one of the lately found adipokines
and has its name from its ability to induce
insulin resistance (52). Resistin expression is
increased both on mRNA (74) and protein
level (75, 76) in intraabdominal adipose
depots, which links visceral obesity to insulin
resistance and its metabolic disorders. In mice
plasma levels of resistin are high both in diet
induced obesity and genetic forms of obesity
(52). Application of recombinant resistin in
Trakia Journal of Sciences, Vol. 7, No. 4, 2009
mice leads to a systemic insulin resistance and
decrease in insulin stimulated glucose transport
in adipose tissue. Infusion of resistin in rats
leads to increased production and release in
circulation of glucose by liver, as a result of
hepatic insulin resistance (77, 74). On the
contrary, data concerning humans are
controversial and the significance of resistin in
development of insulin resistance has not been
proved statistically yet (78).
Adiponectin
Adiponectin is a collagenlike protein, whose
encoding gene is highly expressed in
adipocytes.
Unlike
most
adipokines,
expression of adiponectin and its overall
concentration do not increase, but on the
contrary decrease in many cases of insulin
resistance and obesity (79), more over in
experimental animal models this tendencies
have been proved to have strong correlation
(80). Multivariable analyses in humans have
determined that hypoadiponectinemia is more
closely linked to insulin resistance and
hyperinsulinemia, than are degree of obesity
and impaired glucose tolerance (81). Basic
mechanisms of these interactions are unknown,
but some data reveal that TNF-α reduces
expression and secretion of adiponectin by
adipocytes (82, 83, 84).
Pharmacological effects of adiponectin,
together with reduction of insulin resistance,
include decrease in plasma levels of fatty acids
and decrease of triacylglycerols in muscles and
liver in obese mice (85, 86). Data show that
these effects of adiponectin are due to its
ability to increase expression of genes
concerning
β-oxidation
and
energy
expenditure. Adiponectin also increases insulin
stimulated phsphorylation of IR and IRS-1 in
skeletal muscles, phosphorylation of acetylCoA carboxylase and reduction of molecules
taking part in gluconeogenesis in liver (87).
CONCLUSION
Adipokines produced by adipose tissue play
central role in a number of physiological
processes taking part in control of energy
balance, regulation of lipid and carbohydrate
metabolism, insulin secretion and action, blood
pressure control and changes in cardiovascular
system. Production of these proteins by
adipose tissue and its stromal vascular fraction,
which is rich in macrophages, is being
increased in obesity, diabetes type 2 and some
other disorders linked to insulin resistance. In
SLAVOV E.
spite of the intensive studies in this sphere in
the recent years, role of adipokines for the
development of insulin resistance is still not
well understood. Future attempts for detailed
clarifying of the role and place of each factor
in etiology and pathogenesis of insulin
resistance will be the key for a successful
therapy of diseases linked to insulin resistance.
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