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Current
Diabetes Reviews
ISSN: 1573-3998
Current Diabetes Reviews
Volume 4, Number 2, May 2008
Contents
Role of Islet-, Gut-, and Adipocyte-Derived Hormones
in the Central Control of Food Intake and Body Weight: Implications
for an Integrated Neurohormonal Approach to Obesity Pharmacotherapy
Pp. 79-91
Hubert C. Chen, Jonathan D. Roth, Brock E. Schroeder and
Christian Weyer
[Abstract]
Advanced Glycation End Products and Cardiovascular
Disease Pp. 92-100
Melpomeni Peppa and Sotirios A. Raptis
[Abstract]
Emerging Incretin Based Therapies for Type 2 Diabetes:
Incretin Mimetics and DPP-4 Inhibitors Pp. 101-109
Anthony Stonehouse, Ted Okerson, David Kendall and David
Maggs
[Abstract]
Candidate Genes Implicated in Type 1 Diabetes
Susceptibility Pp. 110-121
Mourad Aribi
[Abstract]
Metabolic Syndrome - Risk Factors for Atherosclerosis
and Diabetes Pp. 122-128
Marko Mihic and Pankaj Modi
[Abstract]
Clinical Measures of Islet Function: Usefulness
to Characterize Defects in Diabetes Pp. 129-145
Bo Ahrén, Richard E. Pratley, Mazin Soubt, Beth E.
Dunning and James E. Foley
[Abstract]
Dietary Toxins, Endoplasmic Reticulum (ER) Stress
and Diabetes Pp. 146-156
Kalindi D. Hettiarachchi, Paul Z. Zimmet and Mark
A. Myers
[Abstract]
Abstracts
[Back to top]
Role of Islet-, Gut-, and Adipocyte-Derived Hormones
in the Central Control of Food Intake and Body Weight: Implications
for an Integrated Neurohormonal Approach to Obesity Pharmacotherapy
Hubert C. Chen, Jonathan D. Roth, Brock E. Schroeder and
Christian Weyer
Contrary to its historical epithet as a lifestyle disorder,
obesity is now widely recognized as having a neurobiological
basis. This progress is due to our knowledge not only about
energy homoeostatic pathways within the central nervous system
(CNS), but also about the role of peripheral peptide hormones
acting upon the CNS. These hormones include long-term adiposity
signals, such as leptin, that inform the CNS primarily of
changes in the body’s overall fat and energy reserves,
and short-term signals such as amylin, peptide YY (PYY) and
ghrelin, that primarily reflect changes in the immediate nutritive
state (energy intake). The limited weight loss effects achieved
with current monotherapy approaches to obesity have been attributed,
at least in part, to the redundancies and potent counter-regulatory
responses within the neurohormonal feedback loop governing
energy balance. Recently, we reported that combinations of
amylin, leptin and PYY3-36
resulted in additive and/or synergistic interactions and caused
marked weight loss in the diet-induced obese rat model, which
to date has reasonably predicted the clinical effects of several
hormones in obese humans. If confirmed in ongoing translational
clinical research studies, these findings may provide a physiological
rationale for a novel, integrated neurohormonal approach to
pharmacotherapy for obesity.
[Back to top]
Advanced Glycation End Products and Cardiovascular
Disease
Melpomeni Peppa and Sotirios A. Raptis
Cardiovascular disease (CVD) is the leading cause of
mortality worldwide. Advanced glycation end products [AGEs]
seem to play an important role for the development and/or
progression of CVD mainly through induction of oxidative stress
and inflammation. AGEs are a heterogenous group of molecules
formed by the nonenzymatic reaction of reducing sugars with
amino acids of proteins, lipids and nucleic acids. Recent
studies suggest that in addition to those endogenously formed,
diet constitutes an important exogenous source of AGEs. Diet-derived
AGEs contribute to the whole body AGE pool and the AGE-related
pathology. Recent in vitro and in vivo studies
revealed significant correlations between diet-derived AGEs
and several risk factors and/or markers of CVD, suggesting
the dietary AGEs restriction as a promising therapeutic intervention.
[Back to top]
Emerging Incretin Based Therapies for Type 2 Diabetes:
Incretin Mimetics and DPP-4 Inhibitors
Anthony Stonehouse, Ted Okerson, David Kendall and David
Maggs
Type 2 diabetes is a chronic disease characterized by
impaired insulin action, progressive β-cell
dysfunction as well as abnormalities in pancreatic α-cell
function and postprandial substrate delivery. These pathophysiologic
defects result in both persistent and progressive hyperglycemia,
resulting in increased risk of both microvascular and cardiovascular
complications.
Traditional treatments for type 2 diabetes have focused on
impaired insulin secretion and insulin resistance. These strategies
are typically used in a stepwise manner: employing oral glucose
lowering agents, followed by insulin therapy. This traditional
approach fails to address the progressive decline in β-cell
function. Moreover, these therapies are often associated with
weight gain in overweight or obese patients with type 2 diabetes.
Both exogenous insulin and insulin secretagogues are associated
with an increased risk of hypoglycemia.
Recently, new treatments that leverage the glucoregulatory
effects of incretin hormones, such as glucagon like peptide
1 have been introduced. Both incretin mimetics and DPP-4 inhibitors
address both the underlying pathophysiology and overcome several
of the limitations of established therapies by providing improvements
in glycemia, and control of body weight with minimal risk
of hypoglycemia.
[Back to top]
Candidate Genes Implicated in Type 1 Diabetes Susceptibility
Mourad Aribi
Type 1 diabetes (T1D) is an autoimmune disease resulting
from pancreatic beta-cells destruction, often appearing on
a genetic ground susceptibility under the influence of one
or more environmental factors. Multiplex families studies,
using genetic markers allowed the identification of various
genes, including HLA, insulin, SUMO-4 and CTLA-4 all being
linked with different degrees to disease risk. The MIF gene
was also suggested, although its role has yet to be established
on family or twin studies. The difference in susceptibility
among T1D patients suggest the development of the disease
as resulting from the interaction between genetic and environmental
factors. This review emphasizes the importance of identifying
the genes that have a direct impact on the autoimmune process,
while recalling the different strategies that are followed.
The style of writing should appeal to those with strong interests
in molecular biology with an equal balance of immunology and
molecular epidemiology.
[Back to top]
Metabolic Syndrome - Risk Factors for Atherosclerosis
and Diabetes
Marko Mihic and Pankaj Modi
Objective: To evaluate the lipoprotein profiles, triglycerides
and glycemia along with the abdominal fat to explore the risk
factors associated with non-diabetic state to IGF, IGT and
Type-2 diabetes in Canadian population.
Methods: We examined 780 subjects using the ADA and
WHO criteria to classify them into groups based on (1) normal
glucose tolerance with FBS <6.0 and 2hBS <7.0 mmol/l),
(2) IFG; FPG >6.1 mmol/l but 2hBS >7.8-11.1
mmol/l; (3) combined IFG/IGT (FPG >7.0 mmol/l and
2hBS >11.1 mmol/l). We compared the three groups for glycemia,
insulin secretion and insulin sensitivity based on their WHR,
abdominal and visceral fat measurements.
Results: The subjects with higher 2 hrs glucose levels
5.2 for NGT vs. 9.1 for IGT and 13.4 mmol/l for NIDDM,
p<0.001, apo C-III level (12.8 (DM) vs. 8.9 mg/dl
(normal), p<0.001), waist to hip ratio (0.91 (IGT) vs.
0.89 (Normal), p<0.01) and abdominal fat and were found
to be highly insulin resistant.
Conclusions: The higher apolipoproteins levels, BMI
and abdominal and visceral fat accompanied by poor glycemia
were shown to be associated strongly with the metabolic abnormalities.
These factors led to the worsening of insulin secretory dysfunction
and insulin resistance and were strong predictors of diabetes.
Abbreviations: 2hBS, 2-hour blood sugar, •
FBS, fasting blood glucose, • NGT, normal glucose tolerance,
• IFG, impaired fasting glucose, • IGT, impaired
glucose tolerance, • MS, metabolic syndrome, •
IR, insulin resistance • ISI, insulin sensitivity index
• OGTT, oral glucose tolerance test • WHR, waist-to-hip
ratio, • BMI, body mass index, • VFA, visceral
fat area, • SFA, subcutaneous fat area, • WHO,
World Health Organization.
[Back to top]
Clinical Measures of Islet Function: Usefulness to
Characterize Defects in Diabetes
Bo Ahrén, Richard E. Pratley, Mazin Soubt, Beth E.
Dunning and James E. Foley
In healthy individuals, the ability of the pancreatic
islets to sense and respond appropriately to changes in plasma
glucose levels maintains plasma glucose levels within a narrow
range despite broad fluctuations in nutrient intake and variable
“demand” for insulin imposed by changes in insulin
sensitivity. This ability of the pancreatic islets is lost
in type 2 diabetes (T2DM). For studies on the pathophysiology
of T2DM, methods for analyzing islet function are therefore
required. Many methods of varying degrees of complexity have
been developed and used to measure pancreatic β-cell
function in humans and to characterize the defects existing
in patients with T2DM or precursors thereof (impaired fasting
glucose [IFG] and impaired glucose tolerance [IGT]). Significant,
although perhaps less progress has been made toward development
of methods to characterize α-cell
function. This work presents an overview of clinical measures
of islet function, from simple static measures such as HOMA-β
to the more complex dynamic measures such as those utilizing
stepped hyperglycemic clamps and acute administration of arginine
to obtain more detailed information regarding the interaction
of glucose and non-glucose secretagogues. We emphazise the
need for accurate measures of α-cell
function, and we discuss the strengths and limitations of
the various methods, highlighting the many aspects of both
α-
and β-cell
function that become impaired during development of T2DM.
[Back to top]
Dietary Toxins, Endoplasmic Reticulum (ER) Stress
and Diabetes
Kalindi D. Hettiarachchi, Paul Z. Zimmet and Mark
A. Myers
The incidence of Type 1 diabetes has been increasing
at a rate too rapid to be due to changes in genetic risk.
Instead changes in environmental factors are the likely culprit.
The endoplasmic reticulum (ER) plays an important role in
the production of newly synthesized proteins and interference
with these processes leads to ER stress. The insulinproducing
beta cells are particularly prone to ER stress as a result
of their heavy engagement in insulin production. Increasing
evidence suggests ER stress is central to initiation and progression
of Type 1 diabetes. An early environmental exposure, such
as toxins and viral infections, can impart a significant physiological
load on beta cells to initiate abnormal processing of proinsulin,
ER stress and insulin secretory defects. Release of altered
proinsulin from the beta cells early in life may trigger autoimmunity
in those with genetic susceptibility leading to cytokine-induced
nitric oxide production and so exacerbating ER stress in beta
cells, ultimately leading to apoptosis of beta cells and diabetes.
Here we suggest that ER stress is an inherent cause of beta
cell dysfunction and environmental factors, in particular
dietary toxins derived from Streptomyces in infected root
vegetables, can impart additional stress that aggravates beta
cell death and progression to diabetes. Furthermore, we propose
that the increasing incidence of Type 1 diabetes may be accounted
for by increased dietary exposure to ER-stress-inducing Streptomyces
toxins.
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