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Current Diabetes Reviews
ISSN: 1573-3998
Current Diabetes Reviews
Volume 3, Number 1, February 2007
Contents
Editorial Pp. 1
Leukocytes in Diabetic Retinopathy Pp. 3-14
Rakesh Chibber, Bahaedin M. Ben-Mahmud, Surina Chibber
and Eva M. Kohner
[Abstract] [Full
Text Article]
Adapting the GLP-1-Signaling System to the Treatment
of Type 2 Diabetes Pp. 15-23
Teresa Salvatore, Ornella Carbonara, Domenico Cozzolino,
Roberto Torella and Ferdinando Carlo Sasso
[Abstract] [Full
Text Article]
Role of Endogenous Androgen Against Insulin Resistance
and Atherosclerosis in Men with Type 2 Diabetes Pp.
25-31
Michiaki Fukui, Yoshihiro Kitagawa, Hiroyuki Ose, Goji
Hasegawa, Toshikazu Yoshikawa and Naoto Nakamura
[Abstract] [Full
Text Article]
Peroxisome Proliferator-Activated Receptor (PPAR)
in Metabolic Syndrome and Type 2 Diabetes Mellitus
Pp. 33-39
Mollie A. Jay and Jun Ren
[Abstract] [Full
Text Article]
Angiotensin I-Converting Enzyme: A Pathogenetic Role
in Diabetic Renal Damage? Pp. 41-52
A. Titia Lely, Peter T. Luik and Gerjan Navis
[Abstract] [Full
Text Article]
Diabetes-Induced Alterations in Renal Medullary Microcirculation
and Metabolism Pp. 53-65
Lina Nordquist and Fredrik Palm
[Abstract] [Full
Text Article]
The Anti-Atherogenic Effects of Thiazolidinediones
Pp. 67-74
Lily Stojanovska, Suzy Y. Honisett and Paul A. Komesaroff
[Abstract] [Full
Text Article]
Cardiac and Metabolic Consequences of Aerobic Exercise
Training in Experimental Diabetes Pp. 75-84
Christine Saraceni and Tom L. Broderick
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Editorial
According to the International Diabetes Federation World Atlas
the frequency of diabetes is increasing at an alarming rate,
with 246 million people worldwide affected, and a projected
figure of 380 million by 2025 if the current situation is
not rectified. More than 90% of this epidemic is of type 2
diabetes, the causes relating in large part to ageing of the
population, diet and obesity, and a sedentary lifestyle. This
gives rise to enormous direct and indirect costs for healthcare
systems, people with diabetes and their families, and society
in general. At no time there has been a greater impetus for
research in to the causes and treatment of diabetes and its
complications.
This issue contains several insightful reviews on aspects
of diabetes and metabolic syndrome, and potential therapeutic
intervention. Jay and Ren, and Stojanovska et al.
examined the role of peroxisome proliferator-activated receptors
(PPARs) in insulin resistance and type 2 diabetes, and review
results of trials with PPAR agonists on diabetes management.
Evidence for reducing the cardiovascular risks of diabetes
is considered, particularly in terms of blood pressure control,
effects on smooth muscle and endothelial function, and the
anti-atherogenic effects of thiazolidinediones. Saraceni and
Broderick review the potential benefits of exercise in diabetes,
with a particular focus on data from animal models. They consider
the actions of exercise to increase myocardial and skeletal
muscle glucose homeostasis, increase insulin sensitivity,
and improve autonomic nervous system control and vascular
endothelium function. The glucagon-like peptide (GLP) signalling
system is of current interest in treatment of type 2 diabetes.
The review by Salvatore et al. give an overview of
the incretin system and examines the therapeutic potential
of GLP-1 and small molecule inhibitors of the enzymes that
degrade this gut peptide. Fukui et al. consider effects
of lowered endogenous androgen levels in men with type 2 diabetes
on insulin resistance and atherosclerosis, and discuss the
potential clinical implications and side effect profile of
androgen replacement therapy in these patients.
The renal complications of diabetes are addressed in two specialist
reviews. Nordquist and Palm review the important effects of
diabetes on renal medulla microcirculation and metabolism.
The research that the normally low medullary oxygen tensions
are further reduced in diabetes is likely to have great significance
for total kidney function. The potential roles of glucose-driven
mechanisms such as oxidative stress, polyol pathway activity,
protein kinase C and advanced glycation are discussed. It
is well established that the angiotensin converting enzyme
(ACE) inhibition is renoprotective in diabetes. The review
by Lely et al. examines evidence for genetic and
environmental factors that increase ACE levels, their role
in the pathogenesis of renal damage, and potential relevance
to treatment of nephropathy.
Capillary occlusion is an early sign of problems in non-proliferative
diabetic retinopathy. Chibber and co workers review the evidence
for leukocyte entrapment as a cause of capillary non-perfusion
in man and experimental models. This is an area of great current
interest. The review examines potential endothelial and leukocyte
mechanisms, and the therapeutic potential of drug therapy
to inhibit leukostasis. A particular novel target identified
by these workers is the leukocyte adhesion molecule core 2
GlcNAc-T.
These states of the art reviews in this issue of CDR were
a pleasure to work with, and I hope readers will find them
stimulating and highly informative.
Prof. Norman E. Cameron, D.Phil.
(Editor-in-Chief)
Diabetic Complications Laboratory
School of Medical Sciences
College of Life Sciences and Medicine
Institute of Medical Sciences
University of Aberdeen
Foresterhill
Aberdeen AB25 2ZD
UK
Tel: +44 1224 555713
Fax: +44 1224 555719
E-mail: n.e.cameron@abdn.ac.uk
[Back to top]
Leukocytes in Diabetic Retinopathy
Rakesh Chibber, Bahaedin M. Ben-Mahmud, Surina Chibber
and Eva M. Kohner
[Full
Text Article]
Diabetic retinopathy is one of the most common diabetic complications,
and is a major cause of new blindness in the working-age population
of developed countries. Progression of vascular abnormalities,
including the selective loss of pericytes, formation of acellular
capillaries, thickening of the basement membrane, and increased
vascular permeability characterizes early nonproliferative
diabetic retinopathy (NPDR). Capillary occlusion, as shown
on fluorescein angiograms, is also one of the earliest clinically
recognizable lesion of NPDR. In response to capillary non-perfusion,
there is dilation of neighbouring capillaries, leading to
early blood-retinal barrier breakdown, capillary non-perfusion,
and endothelial cell injury and death. The resulting ischemia
leads to increased production of growth factors, and the development
of proliferative diabetic retinopathy (PDR), which is characterized
by growth of new vessels and potential severe and irreversible
visual loss. The exact pathogenic mechanism by which capillary
non-perfusion occurs is still unclear but growing evidence
now suggests that increased leukocyte-endothelial cell adhesion
and entrapment (retinal leukostasis) in retinal capillaries
is an early event associated with areas of vascular non-perfusion
and the development of diabetic retinopathy. The leukocytes
in diabetic patients are less deformable more activated, and
demonstrate increased adhesion to the vascular endothelium.
This review summarizes the current literature on the role
of leukocytes in the pathogenesis of capillary occlusion,
and discusses the potential of leukostasis as a new promising
target in the treatment of diabetic retinopathy.
[Back to top]
Adapting the GLP-1-Signaling System to the Treatment
of Type 2 Diabetes
Teresa Salvatore, Ornella Carbonara, Domenico Cozzolino,
Roberto Torella and Ferdinando Carlo Sasso
[Full
Text Article]
Glucagon-like peptide-1 (GLP-1) may contribute to the decreased
incretin effect characterizing type 2 diabetes. Multiple actions
other than insulin secretion stimulation give to GLP-1 a highly
desirable profile for an antidiabetic agent. To overcome the
need for continuous infusion of the native compound, which
is rapidly degraded by dimetyl peptidil peptidase-IV (DPP-IV),
analogues with low affinity for this protease have been developed.
A second major strategy is represented by DPP-IV inhibitors
that act to increase endogenous GLP-1. On the basis of the
promising results in clinical trials, the incretin-based therapy
may offer an useful option for diabetes management.
[Back to top]
Role of Endogenous Androgen Against Insulin Resistance
and Atherosclerosis in Men with Type 2 Diabetes
Michiaki Fukui, Yoshihiro Kitagawa, Hiroyuki Ose, Goji
Hasegawa, Toshikazu Yoshikawa and Naoto Nakamura
[Full
Text Article]
Age-related decline in serum testosterone and dehydroepiandrosterone
sulfate concentrations occur in men. Low concentrations of
these endogenous androgens have been linked with insulin resistance,
which is an important upstream driver for metabolic abnormalities
such as hyperglycemia, hypertension, or hyperlipidemia, and
increased cardiovascular risk. Moreover, men with diabetes
have significantly less circulating androgen than nondiabetic
men. Here, we summarize how androgen affects insulin resistance
and atherosclerosis in men with type 2 diabetes. Low serum
concentrations of endogenous androgens are associated with
visceral fat accumulation. Androgen deprivation by castration
to treat prostate cancer increases insulin resistance, while
testosterone administration in type 2 diabetic men with androgen
deficiency improves glucose homeostasis and decreases visceral
fat, in addition to alleviating symptoms of androgen deficiency
including erectile dysfunction. Androgen correlates inversely
with severity of atherosclerosis and has beneficial effects
upon vascular reactivity, inflammatory cytokine, adhesion
molecules, insulin resistance, serum lipids, and hemostatic
factors. Because men with type 2 diabetes have relative hypogonadism,
testosterone supplementation could decrease both insulin resistance
and atherosclerosis.
[Back to top]
Peroxisome Proliferator-Activated Receptor (PPAR)
in Metabolic Syndrome and Type 2 Diabetes Mellitus
Mollie A. Jay and Jun Ren
[Full
Text Article]
Type 2 diabetes mellitus, a global epidemic, is largely attributed
to metabolic syndrome and its clustering of cardiovascular
risk factors including abdominal obesity, dyslipidemia, hypertension
and hyperglycemia. The two primary approaches to optimally
control risk factors associated with metabolic syndrome are
lifestyle changes and medications. Although many pharmacological
targets have been identified, clinical management of cardiovascular
risk factors associated with metabolic syndrome and type 2
diabetes is still dismal. Recent evidence suggests premises
of the peroxisome proliferator-activated receptor (PPAR) ligands
in the combat against type 2 diabetes and metabolic syndrome
including obesity and insulin resistance. Three subtypes of
the PPAR nuclear fatty acid receptors have been identified:
α,
β/δ
and γ.
PPARα
is believed to participate in fatty acid uptake (β-
and ω-oxidation)
mainly in the liver and heart. PPARβ/δ
is involved in fatty acid oxidation in muscle. PPARγ
is highly expressed in fat to facilitate glucose and lipid
uptake, stimulate glucose oxidation, decrease free fatty acid
level and ameliorate insulin resistance. Synthetic ligands
for PPARα
and γ
such as fibric acid and thiazolidinediones have been used
in patients with type 2 diabetes and pre-diabetic insulin
resistance with significantly improved HbA(1c) and glucose
levels. In addition, nonhypoglycemic effects may be elicited
by PPAR agonists or dual agonists including improved lipid
metabolism, blood pressure control and endothelial function,
as well as suppressed atherosclerotic plaque formation and
coagulation. However, issues of safety and clinical indication
remain undetermined for use of PPAR agonists for the incidence
of heart disease in metabolic syndrome and type 2 diabetes.
[Back to top]
Angiotensin I-Converting Enzyme: A Pathogenetic Role
in Diabetic Renal Damage?
A. Titia Lely, Peter T. Luik and Gerjan Navis
[Full
Text Article]
The renin-angiotensin aldosterone system (RAAS) is well-established
to be involved in diabetic nephropathy. Several abnormalities
in the RAAS have been described in diabetes mellitus, including
an abnormal aldosterone to renin ratio, elevated angiotensin
I-converting enzyme (ACE) levels, and altered angiotensin
II sensitivity. Whereas the renoprotective properties of ACE-inhibition
in diabetic nephropathy have been demonstrated more than a
decade ago, somewhat surprisingly, the role of ACE-activity
in the pathogenesis of diabetic nephropathy is not well established.
This paper addresses the possible functional impact of genetic
and environmental increased in ACE activity in the pathogenesis
of diabetic renal damage, in the context of the various other
abnormalities in the RAAS in diabetes. Human and experimental
data on circulating and tissue ACE in diabetes are reviewed,
as well as the associations of ACE with angiotensin I conversion,
with pathophysiological responses, and with renal end organ
damage. New data from our laboratory provide evidence for
interaction between genetical regulation of ACE activity by
the ACE (I/D) genotype and diabetes as an environmental factor.
Moreover, for functional effects of the elevated ACE activity
in terms of increased conversion of angiotensin I to angiotensin
II. The effects of enhanced generation of angiotensin II are
modulated by the angiotensin II-subtype I receptor (AT1R).
Altered AT1R sensitivity has been reported in diabetes that
may further modulate the eventual effects of elevated ACE.
Epidemiological data on the association of genetically elevated
ACE activity with diabetic nephropathy provide support for
a pathogenetic role of elevated ACE activity in diabetic nephropathy.
Together, the data suggest that differences in ACE expression
and activity, resulting from both genetic and environmental
factors and their interaction can modulate the pathogenesis
of diabetic nephropathy. Unravelling the nature of this interaction,
with focus on modifiable environmental factors, may help to
ameliorate the risk for nephropathy in diabetes.
[Back to top]
Diabetes-Induced Alterations in Renal Medullary Microcirculation
and Metabolism
Lina Nordquist and Fredrik Palm
[Full
Text Article]
Diabetes-induced renal complications, i.e. diabetes nephropathy,
are a major cause of morbidity and mortality. The exact mechanisms
mediating the negative influence of hyperglycemia on renal
function are unclear, although several hypotheses have been
postulated. Cellular mechanisms include glucose-induced excessive
formation of reactive oxygen species, increased glucose flux
through polyol pathway and pentose phosphate shunt, formation
of advanced glycation end-products and activation of protein
kinase C and NADPH oxidase. However, the renal effects in
vivo of each and every one of these mechanisms are less
clear, although recent studies have shown several major alterations
predominantly in the renal medulla as a result of sustained
hyperglycemia.
Already during normal conditions, the renal medulla has a
remarkably low oxygen tension (PO2) and a high
degree of non-oxygen dependent energy metabolism. Alterations
in either blood perfusion or oxygen delivery to the medullary
region will have significant effects on both regional metabolism
and total kidney function. Recently, sustained hyperglycemia
has been shown to induce a pronounced reduction in preferentially
renal medullary PO2.
This review will present the current knowledge of diabetes-induced
alterations in renal medullary metabolism and function, but
also discuss future targets for prevention of diabetic nephropathy.
[Back to top]
The Anti-Atherogenic Effects of Thiazolidinediones
Lily Stojanovska, Suzy Y. Honisett and Paul A. Komesaroff
[Full
Text Article]
The thiazolidinediones (TZDs) rosiglitazone (ROS) and pioglitazone
(PIO) are insulin-sensitising agents widely used to treat
patients with type 2 diabetes mellitus (T2DM). Thiazolidinediones
significantly improve glycaemic control in diabetics by reduced
fasting glucose, insulin and glycated haemoglobin and they
delay the progression of insulin resistance/impaired glucose
tolerance into T2DM. It is well recognized that adequate glycaemic
control and subsequent amelioration of hyperinsulinaemia and
hyperglycaemia can delay the onset of vascular complications.
TZDs, however, also have a number of anti-atherogenic effects
independent of their influences on glucose and insulin metabolism.
They improve lipid profiles, lower blood pressure, have anti-inflammatory
properties, improve endothelial function and increase large
artery compliance in patients with type 2 diabetes mellitus.
When compared to rosiglitazone, pioglitazone has more favourable
effects on the lipid profiles of patients with T2DM. The disease
preventive actions of TZDs may be the result of their agonistic
effects on peroxisome proliferator-activated receptors (PPARs),
ligand-activated transcription factors that regulate the expression
of numerous genes and affect metabolism and vascular parameters.
Thiazolidinediones, provide an effective treatment for populations
with insulin resistance which is at high risk of developing
cardiovascular disease. This paper discusses the differences
between ROS and PIO and explores their anti-atherogenic effects
with particular focus on post-menopausal women with type 2
diabetes mellitus.
[Back to top]
Cardiac and Metabolic Consequences of Aerobic Exercise
Training in Experimental Diabetes
Christine Saraceni and Tom L. Broderick
[Full
Text Article]
The experimental literature of the foregoing decade has furnished
an assemblage of mechanisms explaining the metabolic perturbations
and overall decline in cardiac performance implicated in the
pathogenesis of diabetes mellitus. Particularly, the experimentally-induced
diabetic rat model has been indispensable in the examination
of diabetic cardiomyopathy, an entity distinctly separable
from atherosclerosis, hypertension, coronary artery disease
and valvular dysfunction, yet convincingly attributable to
the increase in cardiac-associated mortality commonly observed
in the diabetic patient. The widespread epidemic of diabetes
mellitus in developed societies has elicited considerable
attention and the role of exercise as an adjuvant therapy
in diabetes management has been increasingly emphasized. However,
the evidence endorsing the beneficial attributes of exercise
in the diabetic state is indeterminate despite markedly observed
increases in myocardial and skeletal muscle glucose homeostasis,
endothelial and autonomic function, insulin sensitivity and
amelioration of diabetes pathogenesis. As evidenced by review
of the experimental literature, a mild to moderately intense
exercise regime may be a reliably implicated insulin-sensitizing
therapy for the experimentally-diabetic rat model as well
as the human diabetic patient. Notably, the cardio-protective
and metabolic benefits of aerobic exercise are seemingly more
pronounced in those individuals most susceptible to diabetes
progression.
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