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Current Diabetes Reviews
ISSN: 1573-3998
Current Diabetes Reviews
Volume 2, Number 1, February 2006
Contents
Editorial Pp. 1
Beta Cell Regeneration Pp. 3-9
Luc Bouwens
[Abstract]
Transcriptional Regulation of Glucose Sensors in Pancreatic
β Cells and Liver Pp. 11-18
Seung-Soon Im, So-Youn Kim, Ha-il Kim and Yong-Ho Ahn
[Abstract]
The New Adipose Tissue and Adipocytokines Pp.
19-28
Caroline Bulcão, Sandra Roberta G. Ferreira,
Fernando M.A. Giuffrida and Fernando Flexa Ribeiro-Filho
[Abstract]
Chronic Inflammation: Role of Adipose Tissue and Modulation
by Weight Loss Pp. 29-37
Tongjian You and Barbara J. Nicklas
[Abstract]
Hyperandrogenism, Insulin Resistance and Hyperinsulinemia
as Cardiovascular Risk Factors in Diabetes Mellitus Pp.
39-49
Gema García-Romero and Héctor
F. Escobar-Morreale
[Abstract]
Insulin and Endothelial Function: Physiological Environment
Defines Effect on Atherosclerotic Risk Pp. 51-60
Edward Duncan, Vivienne Ezzat and Mark Kearney
[Abstract]
Factors Influencing the Hemodynamic and Metabolic
Effects of Insulin in Muscle Pp. 61-70
Stephen Rattigan, Lei Zhang, Hema Mahajan,
Cathryn M. Kolka, Stephen M. Richards and Michael G. Clark
[Abstract]
Angiogenic and Antiangiogenic Factors in Proliferative
Diabetic Retinopathy Pp. 71-98
Rafael Simó, Esther Carrasco, Marta García-Ramírez
and Cristina Hernández
[Abstract]
Intravitreal Triamcinolone for the Treatment of Diabetic
Macular Edema Pp. 99-112
Francisco Gómez-Ulla, Joaquín Marticorena, D.
Virgil Alfaro III, Maribel Fernández, Elizabeth Rodríguez
Méndez and Michelle Rothen
[Abstract]
Current Concepts in Gastric Motility in Diabetes Mellitus
Pp. 113-130
Christophe E.M. De Block, Ivo H. De Leeuw, Paul A. Pelckmans
and Luc F. Van Gaal
[Abstract]
Abstracts
[Back to top]
Editorial
This issue of CDR contains a range of interesting, well-crafted
and insightful reviews on diabetes mellitus and its complications
by highly respected groups of investigators. At the level
of the pancreatic acinar cells, Bouwens examines the ability
of beta cells to regenerate, and considers recent data such
as the use of combinations of growth factors to promote regeneration
or replacement by precursor cell neogenesis, which may eventually
contribute to a therapeutic approach to insulin-dependent
diabetes. Kim et al. reviews research on the transcriptional
regulation of glucose sensors (GLUT2 and glucokinase) in beta
cells and liver and the potential role for these mechanisms
in the development of insulin resistance in type 2 diabetes.
Two papers examine the links between obesity, insulin resistance,
pro-inflammatory changes and cardiovascular disease in type
2 diabetes. Bulcao et al. review patterns of cytokine
production by adipose tissue, including adiponectin and leptin,
which promote insulin sensitivity and other cytokines such
as tumor necrosis factor alpha that promote to pro-inflammatory
changes and insulin resistance. You and Nicklas focus on the
beneficial consequences of lifestyle modifications to cause
weight loss and their effects on inflammatory changes and
adipose tissue pro- and anti-inflammatory cytokine production.
A broadly related review by Garcia-Romero and Escobar-Morreale
considers the relation between polycystic ovary syndrome,
insulin resistance and compensatory hyperinsulinemia, and
hyperandrogen disorders in women with type 2 diabetes. They
also examine the notion that insulin resistance and hyperinsulinemia
resulting from insulin injection are important in the development
of hyperandrogenism in type 1 diabetes. For these women, the
combination of hyperandrogenism and insulin resistance exacerbates
cardiovascular risk.
The important vascular actions of insulin, and their potential
consequences for diabetic complications, are considered. Duncan
et al., review the effects of insulin on vascular
endothelium, with particular regard to insulin signaling and
the endothelial nitric oxide (NO) system. For macrovascular
function, insulin-stimulated NO production has an antiatherogenic
effect, however, insulin resistance reveals adverse effects;
NO production is reduced and the proatherogenic effects may
be apparent, possibly stimulated by activation of MAPkinase
cascades, endothelin production and reactive oxygen species.
Rattigan et al address the hemodynamic and metabolic
effects of insulin in skeletal muscle, particularly in terms
of microvascular effects, capillary recruitment and the role
of the NO and endothelin systems. The potentially important
causative relationship between vascular factors and insulin
resistance is reviewed.
This issue contains two papers on diabetic retinopathy. Simo
et al. critically review the changes in angiogenic and
antiangiogenic factors that are important in the etiology
and control of proliferative retinopathy. The former include
vascular endothelial growth factor, insulin-like growth factor,
and the latter, which may have therapeutic implications, include
pigment epithelium derived factor and somatostatin. Gomez-Ulla
et al. examine the problem of diabetic macular edema,
with particular regard to therapeutic application by intravital
injection of the anti-inflammatory glucocorticosteroid, triamcinolone,
emphasizing safety and efficacy data.
Finally, De Block et al. consider the important
problem of diabetic gastroporesis, which has a 30-50% prevalence
in patients with type 1 or type 2 diabetes. They review current
understanding of gastroporesis, including epidemiology, diagnosis,
clinical consequences, the roles of potential mechanisms such
as autonomic neuropathy, hyperglycemia, and altered gastrointestinal
neuropeptides, as well as current therapeutic approaches.
I hope readers find these reviews as stimulating, informative
and enjoyable as I did.
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]
Beta Cell Regeneration
Luc Bouwens
Beta cell replacement and regeneration therapies seem promising
approaches to the treatment of insulin-dependent diabetes.
The short supply in beta cells from cadaveric organ donors
and the very low replication capacity of human beta cells
have spurred efforts to find robust ways of (re-)generating
beta cells in vitro and in vivo. In the
pancreas, both the capacity of regeneration and the mechanism
involved can differ significantly depending on the experimental
model, as it has also been found in other organs like the
liver. Robust expansion of the beta cell mass in adult rodent
pancreas doesn’t normally occur after partial (50-70%)
pancreatectomy nor after beta cell destruction by streptozotocin
or alloxan. However, extensive tissue injury and treatment
with certain gastrointestinal hormones, like gastrin and growth
factors from the EGF-family can stimulate beta cell regeneration.
Whereas a slow rate of beta cell mass expansion can result
from beta cell replication, more robust regeneration depends
largely on neogenesis from precursor cells. Precursor cells
can be derived from stem cells or from pancreatic exocrine
cells which are known to retain phenotypic plasticity and
can transdifferentiate into, amongst others, endocrine cells.
Identifying the conditions involved in the regulation of cellular
plasticity and regenerative growth may lead to new pharmacological
strategies for the treatment of diabetes.
[Back to top]
Transcriptional Regulation of Glucose Sensors in Pancreatic
β Cells and Liver
Seung-Soon Im, So-Youn Kim, Ha-il Kim and Yong-Ho Ahn
Derangement of glucose metabolism is a key feature of T2DM,
with the liver and pancreatic β-cells
playing a key role in glucose homeostasis. In the postprandial
state, glucose is transported into hepatocytes and either
metabolized to fatty acids or CO2, or stored as
glycogen. Glucose also acts as a key signal in pancreatic
β-cells
for regulating insulin secretion. Because GLUT2 and GK expressed
in liver and β-cells
are responsible for sensing glucose levels in the blood, studies
on the regulation of these biomolecules are important in understanding
glucose homeostasis in vivo. These molecules are
known to be regulated either transcriptionally or post-transcriptionally,
and recent studies on the structure and function of promoters
of these genes have revealed the involvement of various transcriptional
factors in their regulation. Here, we review recent progress
in elucidating the transcriptional regulation of glucose sensors
in the liver and pancreatic β-cells
and the relevance to T2DM.
[Back to top]
The New Adipose Tissue and Adipocytokines
Caroline Bulcão, Sandra Roberta G. Ferreira,
Fernando M.A. Giuffrida and Fernando Flexa Ribeiro-Filho
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.
[Back to top]
Chronic Inflammation: Role of Adipose Tissue and Modulation
by Weight Loss
Tongjian You and Barbara J. Nicklas
Chronic inflammation has been linked with an increased risk
of type 2 diabetes and cardiovascular disease. As an endocrine
and inflammatory organ, adipose tissue is an important source
of circulating pro-inflammatory cytokines. Current evidence
strongly supports that chronic inflammation is associated
with enlarged body fat mass. Moreover, inflammation is independently
linked with abdominal, especially visceral fat mass, possibly
due to the regional variation in adipose tissue cytokine production.
In addition to pharmacological approaches, lifestyle modifications
have been advocated for the treatment of chronic inflammation.
A number of studies have indicated that either weight loss
via energy restriction, or energy restriction plus
other strategies (aerobic exercise, behavioral counseling,
and liposuction), could reduce chronic inflammation. While
the amount of weight loss tends to be important, exercise
and other strategies may have additional effects. A few studies
have reported weight loss effects on adipose tissue cytokine
production. Weight loss reduces subcutaneous adipose tissue
production of pro-inflammatory cytokines (i.e. interleukin
6, tumor necrosis factor alpha) and increases adipose expression
of anti-inflammatory cytokines (i.e. interleukin 10, interleukin
1 receptor antagonist). More studies are needed to investigate
the role of regional adipose tissue cytokine production in
regulation of inflammation and the modulating effects of weight
loss.
[Back to top]
Hyperandrogenism, Insulin Resistance and Hyperinsulinemia
as Cardiovascular Risk Factors in Diabetes Mellitus
Gema García-Romero and Héctor
F. Escobar-Morreale
The polycystic ovary syndrome (PCOS) and hyperandrogenism
are some of the most common endocrine disorders in women of
fertile age. Insulin resistance is present in a significant
proportion of hyperandrogenic patients, yet also, impaired
ß-cell function, even in absence of clinically evident
glucose intolerance, is a frequent finding, especially in
patients with familial history of type 2 diabetes mellitus.
Therefore, it is not surprising that hyperandrogenism, PCOS,
and disorders of carbohydrate metabolism are associated frequently.
This association was first reported 75 years ago and, although
the mechanisms responsible are not precisely understood, insulin
resistance plays an important role in the development of both
disorders. PCOS patients develop type 2 diabetes mellitus
more frequently than non-hyperandrogenic women and, conversely,
women with type 2 diabetes have a greater risk of having PCOS
compared with the normal population.
Although type 1 diabetes mellitus is a disease characterized
by complete abolition of endogenous insulin secretion, a certain
degree of hyperinsulinism may exist, resulting from the relatively
excessive insulin doses needed to maintain a strict metabolic
control. This exogenous hyperinsulinism may increase ovarian
androgen secretion, and it has been reported that there is
an increased prevalence of hyperandrogenic disorders in type
1 diabetic women.
Considering that insulin resistance, hyperinsulinemia and
androgen excess may collaborate in increasing the risk for
CVD in these women, the identification of hyperandrogenic
symptoms in diabetic women, and the identification of disorders
of glucose tolerance in hyperandrogenic patients, may have
important consequences for the correct management of these
women.
[Back to top]
Insulin and Endothelial Function: Physiological Environment
Defines Effect on Atherosclerotic Risk
Edward Duncan, Vivienne Ezzat and Mark Kearney
A number of population studies have suggested that hyperinsulinaemia
is an independent risk factor for the development of cardiovascular
atherosclerosis. Furthermore, there is an emerging body of
evidence supporting a role for insulin as both a vasoregulatory
and glucoregulatory peptide. Principal amongst insulin’s
putative vascular effects is to stimulate release of the anti-atherosclerotic
signalling molecule nitric oxide (NO) from endothelial cells.
Moreover, there is data demonstrating that in parallel to
insulin mediated glucose uptake, stimulation of NO release
by insulin is blunted in insulin resistant conditions.
A number of in-vitro studies have begun to dissect
and define the pathway by which insulin stimulates release
of NO from endothelial cells and complimentary studies in
gene-modified murine models of abnormal insulin signalling
and/or hyperinsulinaemia have begun to elucidate the role
of hyperinsulinaemia in NO release in-vivo.
It is emerging that the effects of insulin on endothelial
function are complex and in part dependent on the physiological/pathophysiological
environment present when insulin binds to its receptor on
the endothelial cell surface. The present article reviews
the evidence for insulin being a pro-atherosclerotic and anti-atherosclerotic
peptide with particular reference to endothelial cell derived
NO bioavailability. In the present review we attempt to clarify
the complex relationship between insulin, endothelial function
and the risk of atherosclerosis by using data from in-vivo
and ex-vivo models.
[Back to top]
Factors Influencing the Hemodynamic and Metabolic
Effects of Insulin in Muscle
Stephen Rattigan, Lei Zhang, Hema Mahajan,
Cathryn M. Kolka, Stephen M. Richards and Michael G. Clark
Insulin mediates its own access and that of glucose to muscle
by capillary recruitment and an increase in bulk blood flow.
In addition, insulin resistance of muscle may result in part
from an impaired hemodynamic action of insulin. The present
review examines some of the factors that influence the effects
of insulin both at the level of hemodynamics and metabolism
in muscle. Factors include fatty acids, the inflammatory cytokine
TNFα,
vasodilators that relax the blood vessels and increase bulk
flow, and elevated blood pressure that may be mediated by
endothelin, a potent locally released vasoconstrictor, or
other vasoconstrictor influences.
[Back to top]
Angiogenic and Antiangiogenic Factors in Proliferative
Diabetic Retinopathy
Rafael Simó, Esther Carrasco, Marta García-Ramírez
and Cristina Hernández
Diabetic retinopathy continues to be the leading cause of
legal blindness among working-age individuals. The earliest
histological features of diabetic retinopathy include neuroretinal
damage, capillary basement membrane thickening, loss of pericytes
and loss of endothelial cells. At advanced stages, neovascularization,
the hallmark of proliferative diabetic retinopathy (PDR) occurs,
and blindness can result from relentless abnormal fibrovascular
proliferation with subsequent bleeding and retinal detachment.
Macular oedema is another retinal complication of diabetes
that is responsible for a major part of vision loss, particularly
in type 2 diabetes. The breakdown of the blood retinal barrier
and the consequent vascular leakage and thickening of retina
are the main events involved in its pathogenesis. Although
a tight control of both blood glucose levels and hypertension
are essential to prevent or arrest progression of the disease,
the recommended goals are difficult to achieve in many patients.
Laser photocoagulation treatment soon after the onset of PDR
significantly reduces the incidence of severe vision loss.
However, the optimal timing for laser treatment is frequently
passed and, in addition, it is not uniformly successful in
halting visual decline. For all these reasons, new pharmacological
treatments based on the understanding of the pathophysiological
mechanisms of diabetic retinopathy have been developed in
recent years.
There is mounting evidence to suggest that angiogenic factors
play a crucial role in PDR development, vascular endothelial
growth factor (VEGF) being the most relevant. Other growth
factors or cytokines such as insulin-like growth factor I
(IGF-1), hepatocyte growth factor (HGF), basic fibroblast
growth factor (b-FGF), platelet derived growth factor (PDGF),
pro-inflammatory cytokines and angiopoetins, are also involved
in the pathogenesis of PDR. However, the intraocular synthesis
of angiogenic factors is counterbalanced by the synthesis
of antiangiogenic factors. Therefore, the balance between
the angiogenic and antiangiogenic factors rather than angiogenic
factors themselves will be crucial in determining the progression
of PDR. The main antiangiogenic factor is the pigment epithelium
derived factor (PEDF) but the transforming growth factor beta
(TGF-β),
thrombospondin (TSP) and somatostatin are also among the intraocullary
synthesized antiangiogenic factors.
[Back to top]
Intravitreal Triamcinolone for the Treatment of Diabetic
Macular Edema
Francisco Gómez-Ulla, Joaquín Marticorena, D.
Virgil Alfaro III, Maribel Fernández, Elizabeth Rodríguez
Méndez and Michelle Rothen
Diabetic macular edema is one of the leading causes of visual
loss in first world countries and the first cause in diabetic
retinopathy. The Early Treatment Diabetic Retinopathy Study
showed a significant benefit in using focal laser photocoagulation
for the treatment of macular edema, more specifically defined
as clinically significant macular edema. Nevertheless, progressive
visual loss is found in the 26% of patients with diabetic
macular edema treated with photocoagulation. The failure of
laser treatment and the destructive nature of the therapy
has forced researchers to pursue new alternatives including
vitrectomy with or without internal limiting membrane peels,
the use of proteinkinase C inhibitors, intravitreal injections
of antibodies that inhibit the vascular endothelial growth
factor, somatostatin analog, or the intravitreal injection
with corticosteroids. Triamcinolone acetonide is glucocoticosteroid
with antiangiogenic and antiedematous properties. Publications
evaluating the safety and efficacy of intravitreal injection
of triamcinolone in the treatment of diabetic macular edema
show varying outcomes with respect to the increases of visual
acuity and decreases in foveal thickness. Despite this, intravitreal
triamcinolone is a treatment that has evolved quickly and
is considered increasingly useful.
[Back to top]
Current Concepts in Gastric Motility in Diabetes
Mellitus
Christophe E.M. De Block, Ivo H. De Leeuw, Paul A. Pelckmans
and Luc F. Van Gaal
: This review addresses the current concepts in our understanding
of the epidemiology, mechanisms, symptoms, clinical consequences,
diagnosis and treatment of delayed gastric emptying in patients
with diabetes.
Upper gastrointestinal symptoms, particularly postprandial
fullness, nausea, vomiting and abdominal bloating, occur in
30-50% of patients with diabetes. The use of scintigraphic
techniques, and more recently breath test, has shown that
as many as 50% of diabetic patients have gastroparesis. Diabetic
gastroparesis comprises a decrease in fundic and antral motor
activity, a reduction or a lack of the interdigestive migrating
motor complex, gastric dysrhythmias, and pylorospasms. The
mechanisms involved include: autonomic neuropathy, acute hyperglycaemia,
and abnormalities in gastrointestinal hormones and neuropeptides.
Other possible contributing factors such as hypothyroidism
and H. pylori infection are discussed as well. Because
treatment is possible by means of dietary advise, prokinetics
or surgical procedures, it is important to identify risk factors
for and to diagnose gastroparesis to prevent morbidity by
controlling gastrointestinal symptoms, and to enhance glucoregulation.
Understanding the current advances is key to the development
of novel therapeutic strategies and for making rational choices
in the management of diabetic gastroparesis.
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