Immunology,
Endocrine & Metabolic Agents in Medicinal Chemistry
(Formerly 'Current Medicinal Chemistry - Immunology, Endocrine
and Metabolic Agents')
ISSN: 1871-5222
Immunology, Endocrine &
Metabolic Agents in Medicinal Chemistry
Volume 7, Number 1, February 2007
Contents
Management of Diabetes Mellitus: The Five
Pillars of Wisdom
Guest Editors: C.D.A. Stehouwer, N.C. Schaper and M. Huijberts
Editorial Pp.
1
Lipotoxicity and Mitochondrial Dysfunction in Type
2 Diabetes Pp. 3-17
M.K.C. Hesselink, M. Mensink and P. Schrauwen
[Abstract] [Full
Text Article]
The Surgical Treatment of Diabetic Obesity
Pp. 19-29
J. Nijhuis, W.A. Buurman and J.W.M. Greve
[Abstract] [Full
Text Article]
Fatty Acids: Friends or Foe? Relation Between Dietary
Fat and Insulin Sensitivity Pp. 31-37
E.E. Blaak
[Abstract] [Full
Text Article]
Amino Acids as Pharmaco-Nutrients for the Treatment
of Type 2 Diabetes Pp. 39-48
L.J.C. van Loon
[Abstract] [Full
Text Article]
New Horizons in Diabetes Therapy Pp. 49-55
J.J. Holst and C.F. Deacon
[Abstract] [Full
Text Article]
Therapeutic Interventions in the Glyc(oxid)ation Pathway
Pp. 57-68
C.G. Schalkwijk
[Abstract] [Full
Text Article]
C peptide and Neuropathy in Type 1 Diabetes
Pp. 69-77
J. Wahren, K. Ekberg and H. Jörnvall
[Abstract] [Full
Text Article]
Medical Treatment of Symptomatic Diabetic Neuropathy
Pp. 79-86
A.J.M. Boulton
[Abstract] [Full
Text Article]
New Horizons in Diabetes Therapy: The Angiogenesis
Paradox in Diabetes: Description of the Problem and Presentation
of a Unifying Hypothesis Pp. 87-93
J. Waltenberger
[Abstract] [Full
Text Article]
Treatment of Diabetic Foot Ulcers Pp. 95-104
N.C. Schaper, L.M. Prompers and M.S.P. Huijberts
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Editorial
Management of diabetes is a rapidly expanding area.
A few decades ago diabetes therapy mainly consisted of diet,
sulfonylurea derivatives in type 2 and insulin in type 1 diabetes.
However, at the same time exciting new concepts were discovered
involving the interactions between lipid and glucose metabolism,
on the biochemical and haemodynamic pathways involved in the
development of vascular complications, etc. But the gap between
science and practise was too large. This issue of CMC-IEMA
is dedicated to new insights in the pathophysiology and treatment
of diabetes and its complications. These articles clearly
show that science is reaching practise. Diabetes therapy is
currently based on 5 pillars: stimulation of self-management,
restoration of the metabolic imbalances associated with the
diabetic state, aggressive treatment of cardiovascular risk
factors, measures to prevent microvascular disease and treatment
of diabetic complications.
The development of hyperglycaemia in type 2 diabetes is currently
seen as the consequence of interplay of several cell types
and four major players seem to be involved: adipose tissue,
liver, muscle and pancreas. In summary, during fasting insulin
levels are low and the liver is responsible for maintaining
blood glucose levels at a sufficient level to enable survival.
During fasting, free fatty acids (FFAs), derived from the
breakdown of fat in adipose tissue, are converted to glucose
by the liver. After a meal there is an influx of nutrients,
and glucose levels rise which is accompanied by a rapid increase
in insulin secretion by the pancreas. The elevated insulin
levels inhibit glucose production by the liver and release
of FFAs by adipose tissue; moreover insulin stimulates the
uptake of glucose by insulin sensitive tissues such as muscle,
liver and adipose tissue. In addition, insulin facilitates
the uptake of FFAs. In type 2 diabetes these finely tuned
processes are clearly deranged. Muscle, liver and fat cells
are less sensitive to insulin, resulting in enhanced glucose
and FFA production by the liver and fat cells, respectively.
After a meal, nutrients are cleared more slowly due the combination
of insulin resistance and impaired insulin secretion by the
pancreas. As discussed by Hesselink et al, the close interaction
between fat and muscle cells could help to explain the development
of insulin resistance (Ref Hesselink). Overflow of
fat from adipose tissue to muscle could be one of the important
mechanisms in the development of insulin resistance in obesity,
“lipotoxicity”. Recent studies indicate that intramyocellular
accumulation of fat results in mitochondrial dysfunction with
impaired fatty acid oxidation and impaired insulin signalling
as a consequence. A drastic reduction in nutrient intake,
as discussed by Nijhuis et al, results in a rapid improvement
in insulin sensitivity in obese type 2 diabetic patients and
bariatric surgery can be a very effective treatment in morbid
obese type diabetic patients (Ref Nijhuis). Blaak
describes in her article the relationship between dietary
fat, FFAs and insulin resistance (Ref Blaak). These
insights could be the basis for new dietary interventions
in which not the absolute amount of fat intake is changed
to reduce caloric intake but in which the type of fat intake
is modulated to improve insulin sensitivity. In the article
of Van Loon another dietary strategy is explored (Ref
van Loon). Specific amino acids/ proteins have been shown
in short term experiments to stimulate insulin secretion and
to reduce muscle proteolysis and/or to stimulate protein synthesis,
which could have beneficial effects on insulin sensitivity.
Supplementation with specific amino acids/ proteins in combination
with an exercise programme seems therefore an attractive intervention
for sedentary type 2 diabetic patients, which remains to be
tested. Insulin secretion is not only influenced by nutrients
but also by several gut hormones (incretins) and several lines
of evidence suggest that one of these incretins, glucagon
like peptide-1 (GLP-1), could be an attractive new therapeutic
modality (Ref Holst). As discussed by Holst GLP-1
has several pancreatic and extra-pancreatic actions, which
might be beneficial for patients with type 2 diabetes.
Aggressive treatment of hyperglycaemia is one of the cornerstones
in the prevention of diabetic complications. Unfortunately,
most patients do not succeed in maintaining a normal glucose
level day after day. As described by Schalkwijk, this chronic
hyperglycaemia results in the formation of advanced glycation
end products (AGEs), which could be one of the pivotal steps
in the development of diabetic micro- and macroangiopathy
(Ref Schalkwijk). Pharmaceutical interventions to
prevent the formation of glycation products, to block of the
effects of AGEs or to increase their breakdown are potential
treatments that could have a major impact on the prevention
of diabetic complications. Another strategy could be treatment
with C-peptide in patients with type 1 diabetes, as described
in the article by Wahren (Ref Wahren). With this
treatment beneficial effects were observed in patients with
diabetic neuropathy. Unfortunately symptomatic treatment is
the only option in most patients with painful neuropathy and
Boulton evaluates in his article the current evidence of the
various medical treatments (Ref Boulton). Vascular
occlusive disease, due to premature atherosclerosis, is the
main cause of death in diabetic patients and as discussed
by Waltenberger, stimulation of angiogenesis could be an attractive
modality to improve tissue perfusion (Ref Waltenberger).
However, this reparative response seems to be impaired in
diabetes and more insight is needed into this rapidly growing
area. This issue ends with a review on the treatment of diabetic
foot ulcers, which is increasingly seen as one of the major
complications of diabetes. Many of the aforementioned abnormalities
affect the lower extremity in diabetic patients with a poorly
healing foot ulcer as result. (Ref Schaper).
C.D.A. Stehouwer
N.C. Schaper
M. Huijberts
Guest Editors
N.C. Schaper
University Hospital Maastricht
PO Box 5800
Internal Medicine, Endocrinology & Diabetes
6202 AZ Maastricht
The Netherlands
E-mail: nsc@sint.azm.nl
[Back to top]
Lipotoxicity and Mitochondrial Dysfunction in Type 2 Diabetes
M.K.C. Hesselink, M. Mensink and P. Schrauwen
[Full
Text Article]
The prevalence of pre-diabetes and type 2 diabetes increases
alarmingly the last few decades and estimates indicate this
rise will continue the forthcoming decades. Transition of
the pre-diabetic to the diabetic state is a slow but inevitable
process. It is therefore of importance to intervene in this
transition period in order to prevent overt type 2 diabetes
to occur.
While the focus of research towards type 2 diabetes has long
been glucocentric, over the last decade the focus has shifted
to a more lipocentric view. Thus, subnormal fat oxidative
capacity, increased mitochondrial damage (lipotoxicity) and
decrease mitochondrial function and biogenesis have been identified
as factors associated with type 2 diabetes.
Within a mitocentric framework, we aim to evaluate the available
literature on lipotoxicity and mitochondrial dysfunction and
its contribution to the development of insulin resistance
and finally type 2 diabetes. In addition, putative targets
of intervention will be identified and the modes of action
of currently available anti-diabetic agents will be reviewed.
In the majority of this review the organ of interest will
be the skeletal muscle, as this is the major site of insulin
resistance.
[Back to top]
The Surgical Treatment of Diabetic Obesity
J. Nijhuis, W.A. Buurman and J.W.M. Greve
[Full
Text Article]
Morbid obesity is associated with serious co-morbidities as
cardiovascular disease, insulin resistance (IR) and type 2
diabetes (T2DM). Conventional therapy for T2DM consists of
weight loss and pharmacotherapy. Recently, surgery was suggested
to be the best treatment for T2DM in morbid obese patients.
This review will focus on the effects of bariatric surgery
on T2DM. The outcomes of different bariatric techniques will
be discussed. Moreover, the question why weight loss is advantageous
in treating T2DM will be addressed. In this view, the effect
of decreased nutrient intake, decreased intracellular fatty
acid accumulation as well as decreased body fat mass on T2DM
are discussed.
[Back to top]
Fatty Acids: Friends or Foe? Relation Between Dietary
Fat and Insulin Sensitivity
E.E. Blaak
[Full
Text Article]
A high dietary fat intake is associated with an increased
risk for the development of obesity. Obesity, in a particular
abdominal obesity, is one of the major risk factors for the
development of insulin resistance and type 2 diabetes mellitus.
There are indications for a direct relation between dietary
fat and insulin sensitivity, independent of body weight, which
may be mainly mediated by dietary fat quality. Cross sectional
studies in humans show a clear relationship between dietary
fat quality and markers of insulin sensitivity. Also, the
composition of fatty acids in serum lipids and tissues (muscle,
adipose tissue), partly reflecting dietary fatty acid intake,
show that insulin resistance is related to a specific pattern
of fatty acids with a high content of SFAs (mainly palmitic
acid) and a low concentration of PUFAs (mainly n-3 and n-6
PUFAs). There is increased evidence that lipid overflow to
non-adipose tissues (lipotoxicity) may interfer with insulin-mediated
glucose uptake through an accumulaton of intramyocellar lipids.
PUFAs may regulate fuel partitioning within the muscle cell
through effects on membrane phospholipid composition and intramuscular
fat storage mediated by changes in membrane fluidity, intracellular
signaling molecules and gene expression. The relationship
between dietary fat and insulin sensitivity needs additional
confirmation in well-controlled human dietary intervention
trials.
[Back to top]
Amino Acids as Pharmaco-Nutrients for the Treatment
of Type 2 Diabetes
L.J.C. van Loon
[Full
Text Article]
Evidence is accumulating showing amino acids to play a key
regulatory role in numerous metabolic processes. Amino acids,
and leucine in particular, can be applied as potent insulin
secretagogues. These stimulating properties are not restricted
to healthy humans, but are also effective in long-term diagnosed
type 2 diabetes patients. Co-ingestion of amino acid/protein
with carbohydrate substantially augments endogenous insulin
release, accelerates blood glucose disposal, and improves
post-prandial glucose homeostasis. Besides their function
as precursors for protein synthesis, some amino acids are
also able to stimulate protein anabolism in an insulin-independent
manner. Branched chain amino acids (BCAA), and leucine in
particular, are capable of activating the mRNA translational
machinery through the mammalian target of rapamycin (mTOR),
which represents an interesting molecular target for the prevention
or reduction of elevated muscle proteolysis in uncontrolled
type 2 diabetes. Protein and/or specific amino acid supplementation
could help to reduce muscle proteolysis and/or to stimulate
protein synthesis, leading to an improved muscle protein balance,
which augments whole-body blood glucose disposal capacity.
Besides the potential benefits of protein and/or amino acid
supplementation, there is evidence showing hyperaminoacidemia
to impair skeletal muscle insulin signaling. Understanding
the mechanisms by which different amino acids can alter metabolic
signaling will be of great value for the development of effective
nutritional and/or pharmacological interventions to prevent
and/or treat insulin resistance and/or type 2 diabetes. Studies
investigating the benefits of long-term amino acid and/or
protein supplementation in type 2 diabetes patients are warranted.
[Back to top]
New Horizons in Diabetes Therapy
J.J. Holst and C.F. Deacon
[Full
Text Article]
The incretin hormones, GIP and GLP-1, may be responsible for
up to 70% of postprandial insulin secretion. In type 2 diabetes
(2DM) the incretin effect is severely reduced. Secretion of
GIP is normal, but its effect on insulin is lost. GLP-1 secretion
may be impaired, but its actions may restore insulin secretion
to near normal levels. Substitution therapy with GLP-1 might
therefore be possible. GLP-1 actions include: potentiation
of glucose-induced insulin secretion; up-regulation of insulin
and other β-cell
genes; stimulation of β-cell
proliferation and neogenesis and inhibition of β-cell
apoptosis; inhibition of glucagon secretion; inhibition of
gastric emptying; and inhibition of appetite and food intake.
It may also have cardio- and neuroprotective actions. These
actions make GLP-1 particularly attractive as a therapeutic
agent for 2DM but GLP-1 is rapidly destroyed in the body by
the enzyme, DPP-IV. Clinical strategies therefore include:
1) the development of metabolically stable activators of the
GLP-1 receptor; and 2) inhibition of DPP-IV. Orally active
DPP-IV inhibitors are currently undergoing clinical trials
and recent clinical studies have provided long term proof
of concept. Metabolically stable analogues/activators include
the structurally related lizard peptide, exendin-4, or analogues
thereof, as well as GLP-1 derived molecules that bind to albumin
and thereby assume the pharmacokinetics of albumin. These
molecules are effective in animal experimental models of type
2 diabetes, and have been employed successfully in clinical
studies of up to 82 weeks’ duration, and exendin-4 has
just been approved for add-on therapy of 2DM.
[Back to top]
Therapeutic Interventions in the Glyc(oxid)ation Pathway
C.G. Schalkwijk
[Full
Text Article]
It is now well established that the non-enzymatic glycation
can have direct and indirect biological effects leading to
micro- and macrovascular complications in diabetes. Accumulation
of AGEs in the extracellular matrix can cause aberrant cross-linking,
resulting in vascular stiffness. AGEs can also bind to AGE-receptors,
including RAGE, on different cell types resulting in cell
activation. In addition, cellular formation of AGEs may be
an important contributor to diabetic vascular complications
by modification of growth factors. Because of these deleterious
effects, a number of natural or synthetic inhibitors are currently
being advanced to reduce the clinical impact of AGEs. These
specific inhibitors exhibit three possible modes of action:
1. inhibition of the formation of AGEs, 2. cleavage of existing
AGE cross-links, and 3. interference of the binding of AGEs
to RAGE or suppression of AGE-RAGE induced signalling pathways.
Aminoguanidine was the first compound designed to inhibit
AGE formation and has undergone clinical trials. Due to safety
concerns and lack of efficacy, aminoguanidine is unlikely
to be used for therapeutic purpose. In vitro experiments
and animal models have shown the potential of other agents
designed to reduce the formation of AGEs such as pyridoxamine.
In addition, AGE cross-link breakers such the stable derivative
ALT-711 were also reported to be effective in in vitro
experiments and in several diabetic animal models. Pyridoxamine
and ALT-711 are now in clinical trials. The soluble form of
RAGE (sRAGE) was reported to reduce deleterious effects of
AGEs. Therefore, blockage of RAGE by sRAGE may be a new target
for therapeutic intervention in diabetic disorders.
These agents interfering in the glycation pathway offer new
potential treatments for glucose-derived vascular complications
of diabetes.
[Back to top]
C peptide and Neuropathy in Type 1 Diabetes
J. Wahren, K. Ekberg and H. Jörnvall
[Full
Text Article]
New data indicate that proinsulin C peptide, contrary to previous
views, exerts important physiological effects and shows the
characteristics of a bioactive peptide. Studies in animal
models and in type 1 diabetes patients have demonstrated multifaceted
effects. Peripheral nerve function, as evaluated by determination
of sensory nerve conduction velocity and quantitative sensory
testing, is improved by C peptide replacement in diabetes
type 1 patients with early stage neuropathy. Similarly, autonomic
nerve dysfunction is ameliorated following administration
of C peptide for up to 3 months. C peptide given to type 1
diabetic animals results in improved nerve conduction velocity
and reversal or prevention of nerve structural changes. C
peptide corrects diabetes-induced reductions in endoneurial
blood flow and in Na+,K+ ATPase activity.
In vitro studies demonstrate that C peptide binds
specifically to cell membranes, activating a G protein coupled
receptor as well as Ca2+-, PKC- and MAPK-dependent
signaling pathways, resulting in stimulation of Na+,K+
ATPase and endothelial nitric oxide synthase (eNOS). In addition,
C peptide activates transcription factors resulting in augmented
eNOS mRNA and protein content of endothelial cells and modulation
of neurotrophic factors as well as apoptotic phenomena in
neuroblastoma cells. Combined, the results demonstrate that
C peptide is a bioactive peptide, possibly of importance in
the treatment of neuropathy in type 1 diabetes.
[Back to top]
Medical Treatment of Symptomatic Diabetic Neuropathy
A.J.M. Boulton
[Full
Text Article]
Diabetic peripheral neuropathy affects up to 50% of older
type 2 diabetic patients: at any time, up to 50% of patients
will experience painful or uncomfortable symptoms, some of
whom will require symptomatic therapy. The first step in management
is to exclude other causes of neuropathy and assess the level
of glycaemic control. Recent research suggests that neuropathic
pain may be exacerbated by erratic blood glucose control:
thus the first aim in management should be to optimize and
stabilize glycaemic control. A number of symptomatic therapies
have been proven to be efficacious in randomized controlled
trials. Whereas the tricyclic drugs are still commonly prescribed,
their use is limited by troublesome and predictable side effects.
The anticonvulsants Gabapentin and Pregabalin are now widely
used in the management of neuropathic pain: the adverse events
appear to be superior to the tricyclics. Other promising therapies
include Duloxetine and Tramadol. There is also increasing
evidence that opioids may be efficacious in some severe cases
unresponsive to traditional treatments.
[Back to top]
New Horizons in Diabetes Therapy: The Angiogenesis
Paradox in Diabetes: Description of the Problem and Presentation
of a Unifying Hypothesis
J. Waltenberger
[Full
Text Article]
Diabetes mellitus is associated with a significant and complex
pathology involving a large number of secondary cellular and
subcellular changes. Most organ functions are impaired resulting
in clinical manifestations such as retinopathy, impaired wound
healing, and accelerated atherosclerosis, nephropathy and
neuropathy. With regard to vascular changes, the situation
seems paradox: There is enhanced angiogenesis, such as in
the context of proliferative retinopathy or atherosclerotic
plaque angiogenesis. On the other hand, arteriogenesis and
collateral artery growth is reduced in diabetes mellitus,
which is associated with reduced regional organ perfusion.
Likewise, wound healing is impaired in diabetes on the basis
of reduced angiogenesis. This coexistence of enhanced and
impaired neovascularization in diabetes mellitus is defined
as the angiogenic paradox.
This review is focusing on the different vascular complications
of diabetes mellitus, and presents a unifying hypothesis for
explaining the angiogenic paradox: The response to vascular
growth factors (lead example: VEGF) is impaired in diabetic
conditions, secondary to an impaired responsiveness of their
receptor systems. The molecular defect is likely to be located
within the signal transduction system either downstream of
the receptor (“signal transduction defect”) or
at the level of the receptor itself. Under specific pathological
circumstances that allow the prolonged accumulation of the
ligand (VEGF), such as in the eye or within an atherosclerotic
plaque, pathological angiogenesis may be induced.
[Back to top]
Treatment of Diabetic Foot Ulcers
N.C. Schaper, L.M. Prompers and M.S.P. Huijberts
[Full
Text Article]
The development of diabetic foot ulcers is a well-known complication
of diabetes. The pathophysiological mechanism is complex,
and different clinical presentations are possible, depending
on the specific underlying pathology. Diabetic foot ulcers
are usually caused by several factors acting in concert, with
polyneuropathy, altered biomechanics, inadequate shoes and
peripheral arterial disease (PAD) as major factors. Neuropathy
is present in most patients with diabetic foot ulcers, while
PAD is present in 30 – 50 %; infection can be diagnosed
in up to 50% of patients presenting with a foot ulcer. Therefore
careful examination of the patient and identification of these
specific pathologies is needed before the start of any treatment.
Because most patients have lost the natural protective mechanism
to relieve pressure from the wound, off-loading of these ulcers
is extremely important. For plantar foot ulcers total contact
casting is the current stan-dard: with this technique up to
90% of neuropathic ulcers can be healed within two months.
The recognition and treatment of infection is equally important.
Diagnosing infection is a challenge in these patients because
signs and symptoms can be absent. The choice of the initial
antimicrobial therapy is usually empiric and based on the
severity of the infection, prior antibiotic use and local
resistance to most common pathogens. Evaluation of the severity
of PAD is indicated in many patients. Patients with critical
limb ischemia should undergo revascularisation as soon as
possible, and both endovascular treatment and bypass surgery
are suitable interventions to improve tissue perfusion. Most
other strategies to improve wound healing, such as local application
of growth factors, have failed to show significant clinical
benefits. Recently, negative pressure wound therapy was shown
to improve wound healing in patients with a partial foot amputation
in a large randomised trial. Many patients not only have foot
problems but also other health problems such as cardiovascular
and renal disease and self care problems. Therefore an integrated
management programme is needed, in which optimal regulation
of diabetes and associated co-morbidity, and regular communication
and instruction of the patient and his or her caregivers are
taken care of.
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