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Current Diabetes Reviews
ISSN: 1573-3998
Current Diabetes Reviews
Volume 2, Number 4, November 2006
Contents
Metabolic Obesity: The Paradox Between Visceral and
Subcutaneous Fat Pp. 367-373
Osama Hamdy, Sriurai Porramatikul and Ebaa Al-Ozairi
[Abstract]
Impaired Glycogen Synthase Activity and Mitochondrial
Dysfunction in Skeletal Muscle: Markers or Mediators of Insulin
Resistance in Type 2 Diabetes? Pp. 375-395
Kurt Højlund and Henning Beck-Nielsen
[Abstract]
The Role of Adipocytokines and Neuro-hormonal Dysregulation
in Metabolic Syndrome Pp. 397-407
Alice Pik-Shan Kong, Norman N. Chan and Juliana Chung-Ngor
Chan
[Abstract]
Platelet Resistance to the Anti-Aggregating Agents
in the Insulin Resistant States Pp. 409-430
Giovanni Anfossi, Isabella Russo and Mariella Trovati
[Abstract]
Treatment of Diabetic Foot Ulcer: An Overview
Strategies for Clinical Approach Pp. 431-447
Luca D. Paola and Ezio Faglia
[Abstract]
Physiological Significance of Resistin and Resistin-Like
Molecules in the Inflammatory Process and Insulin Resistance
Pp. 449-454
Tomoichiro Asano, Hideyuki Sakosda, Midori Fujishiro,
Motonobu Anai, Akifumi Kushiyama, Nanao Horike, Hideaki Kamata,
Takehide Ogihara, Hiroki Kurihara and Yasunobu Uchijima
[Abstract]
Rheumatological Manifestations in Diabetes Mellitus
Pp. 455-466
Angela Del Rosso, Marco M. Cerinic, Francesca De Giorgio,
Chiara Minari, Carlo M. Rotella and Giuseppe Seghieri
[Abstract]
MTHFR Gene Polymorphism
and Diabetic Retinopathy Pp. 467-476
Makiko Maeda, Yasushi Fujio and Junichi Azuma
[Abstract]
Abstracts
[Back to top]
Metabolic Obesity: The Paradox Between Visceral
and Subcutaneous Fat
Osama Hamdy, Sriurai Porramatikul and Ebaa Al-Ozairi
In contrast to the accumulation of fat in the gluteo-femoral
region, the accumulation of fat around abdominal viscera and
inside intraabdominal solid organs is strongly associated
with obesity-related complications like Type 2 diabetes and
coronary artery disease. The association between visceral
adiposity and accelerated atherosclerosis was shown to be
independent of age, overall obesity or the amount of subcutaneous
fat. Recent evidence revealed several biological and genetic
differences between intraabdominal visceral-fat and peripheral
subcutaneous-fat. Such differences are also reflected in their
contrasting roles in the pathogenesis of obesity-related cardiometabolic
problems, in either lean or obese individuals. The functional
differences between visceral and the subcutaneous adipocytes
may be related to their anatomical location. Visceral adipose
tissue and its adipose-tissue resident macrophages produce
more proinflamatory cytokines like tumor necrosis factor-alpha
(TNF-α)
and interleukin-6 (IL-6) and less adiponectin. These cytokines
changes induce insulin resistance and play a major role in
the pathogenesis of endothelial dysfunction and subsequent
atherosclerosis. The rate of visceral fat accumulation is
also different according to the individual’s gender
and ethnic background; being more prominent in white men,
African American women and Asian Indian and Japanese men and
women. Such differences may explain the variation in the cardiometabolic
risk at different waist measurements between different populations.
However, it is unclear how much visceral fat reduction is
needed to induce favorable metabolic changes. On the other
hand, peripheral fat mass is negatively correlated with atherogenic
metabolic risk factors and its selective reduction by liposuction
does improve cardiovascular risk profile. The increasing knowledge
about body fat distribution and its modifiers may lead to
the development of more effective treatment strategies for
people with/or at high risk for Type 2 diabetes and coronary
artery disease. These accumulating observations also urge
our need for a new definition of obesity based on the anatomical
location of fat rather than on its volume, especially when
cardiometabolic risk is considered. The term “Metabolic
Obesity”, in reference to visceral fat accumulation
in either lean or obese individuals may identify those at
risk for cardiovascular disease better than the currently
used definitions of obesity.
[Back to top]
Impaired Glycogen Synthase Activity and Mitochondrial
Dysfunction in Skeletal Muscle: Markers or Mediators of Insulin
Resistance in Type 2 Diabetes?
Kurt Højlund and Henning Beck-Nielsen
Insulin resistance in skeletal muscle is a major hallmark
of type 2 diabetes and an early detectable abnormality in
the development of this disease. The cellular mechanisms of
insulin resistance include impaired insulin-mediated muscle
glycogen synthesis and increased intramyocellular lipid content,
whereas impaired insulin activation of muscle glycogen synthase
represents a consistent, molecular defect found in both type
2 diabetic and high-risk individuals. Despite several studies
of the insulin signaling pathway believed to mediate dephosphorylation
and hence activation of glycogen synthase, the molecular mechanisms
responsible for this defect remain unknown. Recently, the
use of phospho-specific antibodies in human diabetic muscle
has revealed hyperphosphorylation of glycogen synthase at
sites not regulated by the classical insulin signaling pathway.
In addition, novel approaches such as gene expression analysis
and proteomics have pointed to abnormalities in mitochondrial
oxidative phosphorylation and cellular stress in muscle of
type 2 diabetic subjects, and recent work suggests that impaired
mitochondrial activity is another early defect in the pathogenesis
of type 2 diabetes. This review will discuss the latest advances
in the understanding of the molecular mechanisms underlying
insulin resistance in human skeletal muscle in type 2 diabetes
with focus on possible links between impaired glycogen synthase
activity and mitochondrial dysfunction.
[Back to top]
The Role of Adipocytokines and Neuro-hormonal Dysregulation
in Metabolic Syndrome
Alice Pik-Shan Kong, Norman N. Chan and Juliana Chung-Ngor
Chan
Metabolic syndrome, also known as the insulin resistance syndrome
(IRS), dysmetabolic syndrome or syndrome X, is a burgeoning
global epidemic. This constellation of risk factors, namely
glucose intolerance, hypertension, dyslipidemia (high triglyceride
and low HDL cholesterol), central obesity, pro-inflammatory
and prothrombotic state, culminating to the development of
premature cardiovascular and renal disease, has significant
impact on life expectancy, societal productivity and quality
of life. The underlying mechanism of this complex syndrome
remains to be elucidated. In recent years, light has been
shed on the roles of neuroendocrine system and adipocytokines
on the pathogenesis of IRS. In this review, we summarize the
possible links between insulin and various hormones (growth
hormones (GH), catecholamines, glucocorticoids and sex hormones),
partly mediated through visceral adiposity and adipocytokines
(notably adiponectin, leptin, resistin, visfatin, tumor necrosis
factor α
(TNF-α),
interleukin-6 (IL-6)) in the pathogenesis of this syndrome.
[Back to top]
Platelet Resistance to the Anti-Aggregating Agents
in the Insulin Resistant States
Giovanni Anfossi, Isabella Russo and Mariella Trovati
Insulin resistance is a relevant risk factor for the
major cardiovascular events, caused by severe atherosclerotic
involvement of coronary, cerebral and lower limb blood vessels.
One of the alterations accounting for this increased cardiovascular
risk is the impairment of platelet function, explained, at
least in part, by the reduced sensitivity to the physiological
and pharmacological anti-aggregating agents.
In the first part of this review, we will focus our attention
on the physiological mechanisms involved in the attenuation
of platelet response and on their impairment in insulin resistance,
considering in particular: i) the reduced sensitivity to insulin
and other substances acting via intracellular cyclic
nucleotides; ii) the altered intracellular ionic milieu with
elevated cytosolic Ca2+, iii) the increase of oxidative
stress, which elicits isoprostane production from arachidonic
acid.
Therapeutic guidelines recommend a multifactorial prevention
including antiplatelet drugs, even though the protective effect
of antiplatelet therapy in both obese and type 2 diabetic
patients has not been completely clarified so far. Furthermore,
some reports show a decreased sensitivity to the platelet
antiaggregating effect of acetylsalicylic acid in obesity
and type 2 diabetes mellitus. These defects explain why antiplatelet
therapy for both chronic atherosclerotic vascular disease
and acute coronary syndromes should be specifically tailored
in obese, insulin resistant subjects, especially in the presence
of type 2 diabetes mellitus.
Thus, in the second part of this review we performed a critical
overview of the clinical trials on anti-aggregating agents
carried out in subjects with metabolic syndrome and type 2
diabetes mellitus.
[Back to top]
Treatment of Diabetic Foot Ulcer: An Overview
Strategies for Clinical Approach
Luca D. Paola and Ezio Faglia
Diabetic foot disease is a major health problem, which concerns
15% of the 200 million patients with diabetes worldwide. Major
amputation, above or below the knee, is a feared complication
of diabetes. More than 60% of non-traumatic amputations in
the western world are performed in the diabetic population.
Many patients who undergo an amputation, have a history of
ulceration. Major amputations increase morbility and mortality
and reduce the patient’s quality of life. Treatment
of foot complications is one of the main items in the absorption
of economic and health resources addressed to the diabetic
population. It is clear that effective treatment can bring
about a reduction in the number of major amputations.
Over recent years, we have seen a significant increase in
knowledge about the physiopathological pathways of this complication,
together with improvements in diagnostic techniques, but above
all a standardized conservative therapeutic approach, which
allows limb salvage in a high percentage of cases. This target
has been achieved in specialized centers.
An important prelude to diabetic foot treatment is the differing
diagnosis of neuropathic and neuroischemic foot. This differentiation
is essential for effective treatment.
Ulceration in neuropathic foot is due to biomechanical stress
and high pressure, which involves the plantar surface of toes
and metatarsal heads. Treatment of a neuropathic plantar ulcer
must correct pathological plantar pressures through weight
bearing relief. Surgical treatment of deformities, with or
without ulcerations, is effective therapy. A neuropathic ulcer
that is not adequately treated can become a chronic ulcer
that does not heal. An ulcer that does not heal for many months
has a high probability of leading to osteomyelitis, for which
treatment with antibiotics is not useful and which usually
requires a surgical procedure. Charcot neuroarthropathy is
a particular complication of neuropathy which may lead to
fragmentation or destruction of joints and bones. A well-timed
diagnosis of Charcot neuroartropathy is essential to avoid
deformities of chronic evolution.
In the diabetic population peripheral vascular disease (PVD)
is the main risk factor for amputation. If peripheral vascular
disease is ignored, surgical treatment of the lesion cannot
be successful. In diabetic patients, PVD is especially distal,
but often fully involves the femoral, popliteal and tibial
vessels. It can be successfully treated with either open surgical
or endovascular procedures.
Infection is a serious complication of diabetic foot, especially
when neuroischemic: phlegmon or necrotizing fascitis are not
only limb-threatening problems, but also life-threatening
ones. In this case, emergency surgery is needed.
Primary and secondary prevention of foot ulceration is the
main target. Prevention programs must be carried out to highlight
risk factors, lowering amputation incidence.
[Back to top]
Physiological Significance of Resistin and Resistin-Like
Molecules in the Inflammatory Process and Insulin Resistance
Tomoichiro Asano, Hideyuki Sakosda, Midori Fujishiro,
Motonobu Anai, Akifumi Kushiyama, Nanao Horike, Hideaki Kamata,
Takehide Ogihara, Hiroki Kurihara and Yasunobu Uchijima
Resistin was initially identified as a protein, secreted by
adipocytes, which inhibits insulin action and adipose differentiation.
The three proteins homologous to resistin were termed resistin-like
molecules (RELM) α,
β and
γ.
Resistin and RELMα
are abundantly expressed in adipose, but RELMβ
and RELMγ
are secreted mainly from the gut.
Recently, resistin and RELMs were reported to be associated
with inflammation. For example, RELMα,
viewed as an inflammation-related protein, was originally
identified in broncho-alveolar lavage fluid obtained from
animals with experimentally induced pulmonary inflammation.
RELMβ
is also related to bacterial colonization, but RELMβ
injection or hepatic overexpression of RELMβ
induced insulin resistance. RELMγ
isolated from rat nasal respiratory epithelium was found to
be altered by cigarette smoke. Thus, resistin and RELMs could
be useful for assessing the inflammatory condition in
vivo.
On the other hand, whether the serum resistin or RELM concentration
is strongly related to insulin resistance remains unclear.
However, taking recent studies showing a close relationship
between inflammation and insulin resistance in diabetes into
consideration, these proteins may have interactive roles linking
inflammation and insulin resistance, both of which major involvement
in the progression of atherosclerosis. If so, the serum resistin
or RELM concentration may be a good marker of atherosclerotic
risk. In addition, these proteins or unidentified receptors
are potential therapeutic targets for the treatment of diabetes
and prevention of atherosclerosis. These possibilities merit
further study.
[Back to top]
Rheumatological Manifestations in Diabetes Mellitus
Angela Del Rosso, Marco M. Cerinic, Francesca De Giorgio,
Chiara Minari, Carlo M. Rotella and Giuseppe Seghieri
Rheumatological manifestations of Diabetes Mellitus may be
classified in: non articular, articular and bone conditions.
Among non articular conditions,
diabetic cheiroarthropathy, frequent in type I diabetes, the
most important disorder related to limited joint mobility,
results in stiff skin and joint contractures. Adhesive capsulitis
of the shoulder, flexor tenosynovitis, and Duputryen's and
Peyronie's diseases are also linked to limited joint mobility.
Diffuse skeletal hyperostosis, due to calcification at entheses,
is frequent and early, particularly in type 2 diabetes. Neuropathies
cause some non articular conditions, mainly neuropathic arthritis,
a destructive bone and joint condition more common in type
I diabetes. Algodistrophy, shoulder-hand and entrapment syndromes
are also frequent. Mononeuropathy causes diabetic amyotrophy,
characterised by painless muscle weakness. Among muscle conditions,
diabetic muscle infarction is a rare, sometimes severe, condition.
Among articular conditions, osteoarthritis
is frequent and early in diabetes, in which also chondrocalcinosis
and gout occur. Rheumatoid arthritis (RA) and diabetes I have
a common genetic background and the presence of diabetes gives
to RA an unfavourable prognosis. Among bone conditions,
osteopenia and osteoporosis may occur early in type 1 diabetes.
Contrarily, in type 2 diabetes, bone mineral density is similar
or, sometimes, higher than in non diabetic subjects, probably
due to hyperinsulinemia.
[Back to top]
MTHFR Gene Polymorphism
and Diabetic Retinopathy
Makiko Maeda, Yasushi Fujio and Junichi Azuma
Diabetic retinopathy (DR) is the leading cause of catastrophic
loss of vision. Each year, DR darkens the lives of 12,000
to 24,000 diabetic patients in the United States, and more
than 4,000 patients in Japan. Clinically, hyperglycemia induces
proliferative changes in DR synergistically with other risk
factors for vascular diseases. Methyl- enetetrahydrofolate
reductase (MTHFR) is an enzyme involved in remethylation of
homocysteine to methionine. A polymorphic mutation (C677T)
in the MTHFR gene leads to impaired enzyme activity,
resulting in hyper- homocysteinemia as an independent risk
factor for macroangiopathy. Recently, more and more attention
has been paid to the involvement of hyperhomocysteinemia in
the progression of DR, a serious microangiopathic complication
of diabetes. Clinical studies have demonstrated that MTHFR
gene polymorphism can contribute to the progression of DR,
especially in the patients with blood glucose poorly controlled.
Furthermore, accumulating evidence suggests that homocysteine
activates vascular inflammation through inflammatory cytokines,
including VEGF. These data imply that the decrease in plasma
homocysteine could prevent the development and progression
of DR. We also propose the possibility of personalized medicine
for diabetes mellitus based on a better understanding of MTHFR
gene polymorphism and its ramifications, which might cast
new light on diabetic retinopathy.
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