Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 5, No. 2, 2005
Contents
Guest
Editors: Piero Portincasa and K.J. van Erpecum
New
Insights Into Bile Formation: from Secretion to Therapeutic Implications
Editorial Pp.129-130
Piero Portincasa, KJ
van Erpecum
Lipid Transport into Bile and Role in Bile
Formation Pp.131-135
Albert K. Groen and
Ronald P.J. Oude Elferink
Water Transport into Bile and Role in Bile
Formation Pp.137-142
Giuseppe Calamita,
Domenico Ferri, Patrizia Gena, Giuseppa E. Liquori, Raul A. Marinelli, Giuliano
Meyer, Piero Portincasa and Maria Svelto
Ion Transport Across the Gallbladder
Epithelium Pp.143-151
G. Meyer, F.
Guizzardi, S. Rodighiero, R. Manfredi, S. Saino, C. Sironi, M. L. Garavaglia,
C. Bazzini, G. Botta, P. Portincasa, G. Calamita, M. Paulmichl
Contribution of Canalicular Glutathione
Efflux to Bile Formation. From Cholestasis Associated Alterations to
Pharmacological Intervention to Modify Bile Flow Pp.153-161
Ignazio Grattagliano,
Piero Portincasa, Vincenzo O. Palmieri and Giuseppe Palasciano
The Genetic Background of Cholesterol
Gallstone Formation: An Inventory of Human Lithogenic Genes Pp.163-170
Frank Lammert, and
Siegfried Matern
Effects of Fatty Acid Bile Acid Conjugates (FABACs)
on Biliary Lithogenesis: Potential Consequences for Non-Surgical Treatment of Gallstones Pp.171-175
Fred M. Konikoff, and
Tuvia Gilat
Modulation of Cholesterol Crystallization in
Bile. Implications for Non- Surgical Treatment of Cholesterol Gallstone Disease Pp.177-184
Piero Portincasa,
Antonio Moschetta, Karel J. van Erpecum, Michele Vacca, Michele Petr uzzelli,
Giuseppe Calamita, Giuliano Meyer, Giuseppe Palasciano
Drugs Affecting Biliary Lipid Secretion and
Gallbladder Motility: Their Potential Role in Gallstone Treatment and
Prevention Pp.185-191
Gerard P.
vanBerge-Henegouwen, Niels G. Venneman, Karel J. van Erpecum and Piero
Portincasa
Pharmacological Manipulation of Biliary Water
and Lipids: Potential Consequences for Prevention of Acute Biliary Pancreatitis Pp.193-198
Niels G. Venneman,
Gerard P. vanBerge-Henegouwen and Karel J. van Erpecum
Manipulation of Biliary Lipids by Gene
Therapy: Potential Consequences for Patients with Progressive Familial
Intrahepatic Cholestasis Pp.199-202
Ronald P.J. Oude Elferink
Effects of Leptin on Biliary Lipids:
Potential Consequences for Gallstone Formation and Therapy in Obesity Pp.203-208
Nahum Mendez-Sanchez, Guadalope Ponciano-Rodrigoez, Norberto Chavez-Tapia and Misael Uribe
Assessment of Modes of Action and Efficacy of
Plasma Cholesterol- Lowering Drugs: Measurement of Cholesterol Absorption,
Cholesterol Synthesis and Bile Acid Synthesis and Turnover Using Novel Stable
Isotope Techniques
Pp.209-218
Frans Stellaard and Folkert Kuipers
General Articles
Myocardial Insulin Resistance and Cardiac
Complications of Diabetes
Pp.219-226
E. Dale Abel
Therapeutic Targets for the Prevention of
Type 1 Diabetes Mellitus
Pp.227-236
N. Singh and J.P. Palmer
The Mammalian Innate Immune System: Potential
Targets for Drug Development
Pp.237-247
Thomas T. Wheeler and Kylie A. Hood
Abstracts
[Back
to top] Editorial
Piero Portincasa, KJ
van Erpecum
New Insights Into Bile Formation: from Secretion
to Therapeutic Implications
We are pleased to host so many qualified and
excellent contributions in this special issue of Current Drug Targets – Immune,
Endocrine & Metabolic Disorders edited by Bentham Science Publishers Ltd
and titled: Hot Topic Issue 2005- New Insights Into Bile Formation: from Secretion
to Therapeutic Implications.
A starting point is that bile is a complex fluid
containing over 95% water mixed with three classes of lipids (bile salts,
cholesterol, and phospholipids), various proteins, bilirubin, electrolytes and organic
anions. Imbalance in the complex interaction between biliary water and lipid,
i.e. failure to handle cholesterol in solution, leads to formation of
cholesterol crystals and gallstones.
Gallstones represent the most common gastrointestinal disease with an estimated
prevalence of 10-15% in the general population, and enormous health care costs
when considering the aspects of diagnosis, therapy (mainly cholecystectomy),
morbidity and mortality, and postoperative outcomes. Cholesterol-enriched
gallstones (i.e. containing at least 75% crystalline cholesterol) comprise
75-80% of all gallstones in western countries. Apart from specific events
linked to cholesterol gallstone formation, the biliary “enviroment” is the
locus where highly complicated phenomena occurr in physical chemistry.
Advances in both basic pathophysiology and
clinical knowledges over the past few years have certainly helped us to focus
on crucial topics that were integrated in a special issue of this journal.
Each paper is written with a focus on relevant
physiological and pathophysiological aspects of basic and, in several cases,
clinical implications of bile and gallbladder disease. When we first came in
contact with potential authors in this issue, we were impressed by the overall
positive and enthusiastic participation. This allowed us to design a targeted
issue on the state of the art in the field of bile formation, with major
critical topics covered by worldwide leading researchers in lipid, water, and
electrolyte interaction in bile and gallbladder. Their ideas, hypotheses and
articles still contribute to the enormous expansion of this field. We thank all
contributors to join this special project for their committment and fully
motivated work.
Groen and Oude Elferink discuss new developments in research focused on
the elucidation of the molecular mechanism of bile formation. Many novel
transporters including those belonging
to the superfamily of ABC transporters have been shown to play an
important role in bile formation. Current views on the role of such
transporters are reviewed for bile salts, biliary lipids, and transhepatic
cholesterol transport.
Calamita et al. bring novel acquisitions in water transport in the
hepatobiliary epithelia. The recent recognition of the aquaporin water channels
is leading to a rapid reassessment of the molecular mechanisms by which water
is transported and reabsorbed during bile formation and bile flow. The
unexpected involvement of liver aquaporins in the metabolic homeostasis is also
discussed. The emerging pathophysiological significance of hepatobiliary
aquaporins is given.
Meyer et al. review on recent aspects of ion transport mechanisms in gallbladder which ensure both
absorptive and secretive functions. Some of these mechanisms have complementary
and vicarious roles, for instance in relation to the presence/absence of
bicarbonate in the lumen. In gallbladder, just like in all other epithelia, ion
transport is the component that controls all the other transepithelial
transports, particularly of water. Considering this, the role played by the
transport of ions is obviously crucial in relation to both gallbladder
physiology and the onset of associated diseases.
Grattagliano et al. focus on the importance
of hepatic canalicular glutathione secretion. This step represents an
osmotical driven force for bile formation and a major detoxification
system to discharge toxic anionic compounds from hepatocytes
into bile. Impaired hepatic glutathione status and biliary secretory mechanisms
have been associated with bile flow modification and development of
cholestasis. The role of water channels and multidrug resistant proteins
system in glutathione dependent bile flow and their involvement
as possible target to modify bile flow for therapeutic purposes is
discussed.
Lammert and Matern discuss the issue that gallstone disease is, in part,
genetically determined. There is evidence for common genetic determinants of
human gallstone disease in general and provide an inventory of human lithogenic
genes. The precise understanding of such genes and their molecular mechanisms
will establish new targets for rational drug design for this exceptionally
prevalent and economically significant digestive disease.
Konikoff and Gilat review the effect of fatty acid bile acid conjugates
(FABACs), novel synthetic lipid molecules, for the treatment of cholesterol
gallstones. FABACs are indeed cholesterol solubilizers, able to prevent biliary
cholesterol crystallization as well as dissolve preformed crystals in rodents
fed a lithogenic diet. In gallstone susceptible mice, the main constituent,
Aramchol prevented gallstone formation and dissolved gallstones. The potential
use of FABACs as therapeutic agents is discussed.
Portincasa et al. describes the most relevant pathways governing cholesterol
crystallization and precipitation in two separate but pathophysiologically
relevant conditions: model biles and native biles. Quantification of lipid
aggregation and interaction are studied within the so-called ternary phase
diagram at equilibrium. Here, three classes of biliary lipids are
dissolved in aqueous systems: cholesterol, bile salts and phospholipids.
Different phases involve the formation of simple micelles, vesicles and
cholesterol crystals either in the anhydrous or monohydrate form.
vanBerge-Henegouwen et al. discuss the issue of impaired
gallbladder motility and the potential therapeutic role of prokinetic agents
for decreasing the recurrence rate of cholesterol gallstones. Whereas bile acid
therapy with UDCA for dissolution or prevention is limited by the high
recurrence rate of gallstones, UDCA therapy may prevent colics or
gallstone-related complications in symptomatic patients with gallbladder stones
with contraindications for surgery or on a waiting list for cholecystectomy.
Venneman et al. argue that particularly patients with fast and extensive
crystallization, due to highly concentrated bile, low biliary phospholipid
contents and gallbladder mucin hypersecretion seem at risk for pancreatitis.
Several therapeutic options are discussed in this group of patients, including
pharmacological manipulation of biliary lipids by the hydrophilic bile salt ursodeoxycholic acid, NSAIDs, N-acetylcystein or even
achieving bile dilution.
Oude Elferink discusses various options involving the manipulation of biliary lipids
by gene therapy. Progresses in gene therapy are reviewed, including liver
repopulation by modified hepatocytes in various models with liver damage. This
approach has enormous therapeutical implications. The exciting topic of liver
repopulation in patients with progressive familial intrahepatic cholestasis, a
severe pediatric disorder, is also
discussed.
Mendez-Sanchez et al. underscores the problem of obesity as the most consistent
and important risk factor for the development of cholesterol gallstones, due to
increased hepatic secretion of the sterol. The hormone leptin appears also to
be involved in biliary cholesterol secretion and cholesterol gallstone
formation in humans. Both these aspects and their potential consequences for
gallstone formation and therapy in the obese subjects are discussed.
Stellaard and Kuipers provide a background on physiological parameters that
determine cholesterol homeostasis, and potential new mechanisms of drug action.
Several approaches are available for plasma-cholesterol lowering therapies,
particularly aimed at reduction of LDL cholesterol. Currently used therapies
aim to decrease hepatic cholesterol synthesis, to inhibit cholesterol absorption or to stimulate bile acid synthesis.
Techniques to study cholesterol absorption, cholesterol synthesis and bile acid
synthesis and absorption in vivo in human subjects are warranted. In this respect, stable isotopes and mass
spectrometry might provide the answer.
A special thank goes to both Editors in Chief:
Prof Emilio Jirillo from the University of Bari Medical School, Italy and Prof.
Michael J. Quon, from the NIH, Bethesda, USA for strongly encouraging us to
pursue this exiting scientific task.
Last but not least, we would like to thank our
teachers, Prof. Giuseppe Palasciano and Prof. Gerard P. vanBerge-Henegouwen:
over the past few years they have contributed with their examples, advises and
directions, to pursue our career and to strengthen our scientific growth.
[Back
to top] Lipid Transport into Bile and Role in Bile Formation
Albert K. Groen and
Ronald P.J. Oude Elferink
Biliary lipid secretion is driven by bile salts,
the primary metabolites of cholesterol. Transport of bile salts as well as
phospholipids and cholesterol is mediated by ATP Binding Cassette (ABC)
transporters. Expression of these transporters is regulated in a coordinate
fashion by a set of nuclear hormone receptors explaining the old observation of
coupling between bile salt secretion and biliary lipid secretion. Although it
is now clear which proteins are involved, the molecular mechanism of biliary
lipid secretion is still unresolved. In addition, scarce information is
available about the systems responsible for intracellular transport of
cholesterol, phospholipid and bile salt. These issues form the subject of the
review.
[Back
to top] Water Transport into Bile and Role in Bile Formation
Giuseppe
Calamita, Domenico Ferri, Patrizia Gena, Giuseppa E. Liquori, Raul A.
Marinelli, Giuliano Meyer, Piero Portincasa and Maria Svelto
Formation of bile and generation of bile flow are
driven by the active secretion of bile salts (BS), lipids and electrolytes into
the canalicular and bile duct lumens followed by the osmotic movement of water.
Although the transporting proteins involved in solute secretion have been
cloned and their coordinated interplay defined both in health and disease,
boosted by the discovery of the aquaporin water channels, only recently has
considerable attention been addressed to the mechanism by which water, the
major component of bile (>95%), moves across the hepatobiliary epithelia.
This review summarizes the novel acquisitions in
liver membrane water transport and functional participation of aquaporin water
channels in multiple aspects of hepatobiliary fluid balance. Emerging evidences
suggesting involvement of aquaporins in the metabolic homeostasis of the
hepatobiliary tract are also discussed.
[Back
to top] Ion Transport Across the Gallbladder Epithelium
G. Meyer, F.
Guizzardi, S. Rodighiero, R. Manfredi, S. Saino, C. Sironi, M. L. Garavaglia,
C. Bazzini, G. Botta, P. Portincasa, G. Calamita, M. Paulmichl
The function of the gallbladder is not only to
store bile, but also to concentrate it during the interdigestive phase by means
of salt-dependent water reabsorption. On the contrary, secretions of water and
salt take place during the digestive phase. Dysregulation of ion absorption or
secretion are common in many gallbladder diseases, such as colelithiasis.
Transepithelial absorptions are determined by the Na+/K+
pump on the basolateral membrane, and by several apical membrane Na+-coupled
transporters. Among these, some isoforms of Na+/H+ and Cl-/HCO3-
exchangers have been studied. The presence of a Na+-Cl-
simport has been molecularly and functionally characterized in some animal
species. The ion transepithelial secretion is mainly dependent on an apical
chloride transport attributable to a CFTR-like cAMP-activated channel with high
permeability to HCO3-. The apical membrane electrical
potential is one of the factors influencing anion secretion and is maintained
by the activity of cAMP-dependent K+ channels. The regulation of the
activity of these channels is complex, because of their sensitivity to voltage,
and to intracellular calcium and pH. The coordinated interplay underlying the
regulation of transporters and channels needs to be clarified yet, as well as
the interactions between transporters, channels and aquaporins.
[Back
to top] Contribution of Canalicular Glutathione Efflux to Bile Formation. From
Cholestasis Associated Alterations to Pharmacological Intervention to Modify
Bile Flow
Ignazio Grattagliano,
Piero Portincasa, Vincenzo O. Palmieri and Giuseppe Palasciano
At least one third of the bile flow is driven
osmotically by the amount of hepatic glutathione excreted into canalicular
spaces. Beyond the importance of this secretory mechanism for bile formation,
the excretion of glutathione is an important way to discharge toxic anionic
compounds deriving from liver metabolism of exogenous and endogenous
substances. Thus, biliary secretion of glutathione and its conjugates really
works as a major detoxification system for the hepatocytes. Derangement of
hepatic and/or biliary glutathione status can occur in several experimental
animal models of liver injury and in human diseases.
In the present review, we will focus on
mechanisms of bile glutathione efflux and changes associated with cholestatic
conditions. Novel findings on the role of water channels and of the multidrug
resistant proteins in bile salt-independent bile formation, will also be
discussed. New routes of intervention to modify bile flow for therapeutic
purposes are considered.
[Back
to top] The Genetic Background of Cholesterol Gallstone Formation: An Inventory
of Human Lithogenic Genes
Frank Lammert, and Siegfried Matern
Family and twin studies as well as animal studies
indicate that gallstone disease is, in part, genetically determined. Recently
new single gene defects have been identified in specific patients with
cholesterol and pigment gallstones. Examples include low
phospholipid-associated cholelithiasis due to mutations of the gene encoding
the hepatocanalicular phosphatidylcholine transporter, and pigment stones in
association with mutations of the ileal bile salt transporter gene. Here we
summarize the evidence for common genetic determinants of human gallstone
disease in general and provide an inventory of human lithogenic genes. The
precise understanding of such genes and their molecular mechanisms will
establish new targets for rational drug design for this exceptionally prevalent
and economically significant digestive disease.
[Back
to top] Effects of Fatty Acid Bile Acid Conjugates (FABACs) on Biliary
Lithogenesis: Potential Consequences for Non-Surgical Treatment of Gallstones
Fred M. Konikoff, and
Tuvia Gilat
Fatty acid bile acid conjugates (FABACs) are
novel synthetic lipid molecules, which were designed for the treatment of
cholesterol gallstones. The rationale was to combine a cholesterol solubilizing
moiety (a saturated fatty acid) with a bile acid (cholic acid) as a vehicle to
enable secretion into bile and entry into the enterohepatic circulation. An
amide bond was used to provide stability against intestinal degradation.
Initial in vitro studies showed that FABACs are indeed cholesterol
solubilizers, able to prevent biliary cholesterol crystallization.
Arachidyl-amido-cholanoic acid (Aramchol) was found to be the most potent FABAC
in these studies.
Animal studies revealed that Aramchol was
absorbed after oral administration and could prevent cholesterol
crystallization as well as dissolve preformed crystals in rodents fed a
lithogenic diet. In gallstone susceptible mice, Aramchol prevented gallstone
formation and dissolved gallstones. FABACs were found to be metabolically
active substances, also able to decrease blood cholesterol, atherosclerotic
plaques and fat accumulation in the liver in several animal species.
The underlying mechanisms of action are under
active investigation, and several effects, e.g. on cholesterol and bile salt
metabolizing enzymes as well as cholesterol efflux from cells have been
discovered. These findings are, however, only the beginning of our
understanding of the metabolic actions as well as the potential of use of
FABACs as therapeutic agents.
[Back
to top] Modulation of Cholesterol Crystallization in Bile. Implications for
Non- Surgical Treatment of Cholesterol Gallstone Disease
Piero
Portincasa, Antonio Moschetta, Karel J. van Erpecum, Michele Vacca, Michele
Petruzzelli, Giuseppe Calamita, Giuliano Meyer, Giuseppe Palasciano
The first step in cholesterol gallstone disease
is precipitation of cholesterol crystals in bile. In gallbladder bile,
cholesterol is normally solubilized together with bile salts and phospholipids
to form mixed micellar structures. When cholesterol in bile is in excess,
vesicles (i.e. phospholipid-cholesterol globular structures: liquid
crystals) form which become supersaturated in cholesterol. Early aggregation
and precipitation of cholesterol molecules into submicroscopic nuclei occurs
from these supersaturated vesicles. This crucial step is followed by
precipitation and agglomeration of cholesterol crystals which then become
visible at light microscopy. Here we describe the mechanism of cholesterol
crystallization and its modulation in vivo and in vitro. Recent
advances on the role of ursodeoxycholate as an agent preventing the
precipitation of cholesterol crystals in bile will be highligthed.
[Back
to top] Drugs
Affecting Biliary Lipid Secretion and Gallbladder Motility: Their Potential
Role in Gallstone Treatment and Prevention
Gerard P.
vanBerge-Henegouwen, Niels G. Venneman, Karel J. van Erpecum and Piero Portincasa
Gallstone disease in the Western world has an
estimated prevalence of 10-15% and more than 75% are cholesterol-enriched
gallstones. Defective gallbladder motility has been identified as an important
pathogenic factor for cholesterol gallstone disease. Various agents may enhance
or impair postprandial gallbladder motility, and their effects on
interdigestive gallbladder and intestinal motility should also be taken into
account. Patients in high-risk situations for gallstone disease, and those
chronically treated with drugs inhibiting gallbladder motility (e.g.
somatostatin analogues) may benefit from improving gallbladder motility with
prokinetic agents. Whether such a strategy can really prevent gallstone
formation is still unknown, long-term studies are lacking so far. The efficacy
of bile acid therapy with UDCA for gallstone dissolution or for prevention in
high risk patients is limited and hampered by high recurrence rates. The
efficacy of UDCA in prevention of colics or gallstone related complications in
symptomatic patients with gallbladder stones with contraindications for
operation or on the waiting list should be explored further, since several
retrospective studies showed favourable outcomes with this strategy.
[Back
to top] Pharmacological
Manipulation of Biliary Water and Lipids: Potential Consequences for Prevention
of Acute Biliary Pancreatitis
Niels G. Venneman,
Gerard P. vanBerge-Henegouwen and Karel J. van Erpecum
Acute biliary pancreatitis, caused by macroscopic
cholesterol gallstones or microlithiasis, is often a severe disease with
considerable morbidity and mortality. Formation of cholesterol gallstones and
microlithiasis is caused by cholesterol crystallization from cholesterol
supersaturated gallbladder bile. Particularly patients with fast and extensive
crystallization, due to highly concentrated bile, low biliary phospholipid
contents and gallbladder mucin hypersecretion seem at risk for pancreatitis.
Patients who suffered from acute biliary
pancreatitis should undergo cholecystectomy as secondary prevention strategy.
For patients at high surgical risk, endoscopic sphincterotomy may be an
appropriate alternative. Pharmacological manipulation of biliary lipids by the
hydrophilic bile salt ursodeoxycholic acid is reserved for patients with
recurrent pancreatitis despite previous cholecystectomy or sphincterotomy, or
with contraindications to surgical and endoscopic treatment. Maintenance
therapy with ursodeoxycholic acid is however a very effective secondary
prevention strategy. Potentially, secondary prevention of acute biliary
pancreatitis could also be achieved through decreasing biliary mucin contents
by UDCA, NSAIDs or N-acetylcystein, or through achieving bile dilution
(currently not feasible).
[Back
to top] Manipulation of
Biliary Lipids by Gene Therapy: Potential Consequences for Patients with
Progressive Familial Intrahepatic Cholestasis
Ronald P.J. Oude Elferink
Gene therapy constitutes a great promise for the
treatment of inherited diseases as well as cancer. Although the principle is
extremely elegant, reality proves that several important problems remain to be
solved before gene therapy becomes a standard application for these conditions.
Meanwhile, and because of these problems alternatives are being considered as
well. For the treatment of hepatic inherited disorders, hepatocyte
transplantation has proven to be an attractive alternative, although this form
of therapy also remains experimental at this moment. Problems and possibilities
are discussed with the inherited disease, Progressive Familial Intrahepatic
Cholestasis, as an example.
[Back
to top] Effects of Leptin on
Biliary Lipids: Potential Consequences for Gallstone Formation and Therapy in
Obesity
Nahum Mendez-Sanchez, Guadalope Ponciano-Rodrigoez, Norberto Chavez-Tapia and Misael Uribe
Gallstone disease is exceptionally common,
occurring especially in Western populations, with cholesterol gallstones
predominating. Currently, it is believed that obesity is the most consistent
and important risk factor for the development of cholesterol gallstones.
Obesity has been shown to be associated with the supersaturation of bile with cholesterol
because of increased hepatic secretion of the sterol. In accord with current
information from experimental studies, leptin appears to be involved in biliary
cholesterol secretion and cholesterol gallstone formation in humans. This
review summarizes the current information on the role of obesity in biliary
lipid secretion as well as the effect of leptin and its potential consequences
for gallstone formation and therapy in the obese.
[Back
to top] Assessment of Modes
of Action and Efficacy of Plasma Cholesterol- Lowering Drugs: Measurement of
Cholesterol Absorption, Cholesterol Synthesis and Bile Acid Synthesis and
Turnover Using Novel Stable Isotope Techniques
Frans Stellaard and Folkert Kuipers
Several processes are involved in control of
plasma cholesterol levels, e.g., intestinal cholesterol absorption, endogenous
cholesterol synthesis and transport and bile acid synthesis. Adaptation of
either of these processes allows the body to adapt to changes in dietary cholesterol
intake. Disturbances herein may lead to hypercholesterolemia and increase the
risk for atherosclerosis. Several approaches are available for
plasma-cholesterol lowering therapies, particularly aimed at reduction of
low-density lipoprotein (LDL) cholesterol. Currently used therapies aim to
decrease (hepatic) cholesterol synthesis, to inhibit cholesterol absorption or
to stimulate bile acid synthesis. The latter can be achieved by reducing bile
acid absorption to alleviate the negative feedback control exerted by bile
acids circulating in the body. Approaches to directly stimulate bile acid
synthesis may become available. Novel drugs should be tested on the efficiency
to influence their actual targets. Several techniques are available to measure
cholesterol absorption, cholesterol synthesis and bile acid synthesis and
absorption in vivo in human subjects. The most reliable techniques are
based on the use of stable isotopes and mass spectrometry. This paper provides
a condensed background on physiological parameters that determine cholesterol
homeostasis, and potential new mechanisms of drug action and focuses,
especially, on new techniques to monitor the effects of drugs in humans.
[Back
to top] Myocardial Insulin
Resistance and Cardiac Complications of Diabetes
E. Dale Abel
Cardiovascular disease is a major cause of
mortality and morbidity in individuals with obesity, type 2 diabetes and the
metabolic syndrome. The mechanisms for this are partially understood, but
include increased atherosclerosis, hypercoagulability and increased
hypertension. Epidemiological data suggests however, that a component of the
excess cardiovascular mortality occurs independently of underlying coronary
artery disease. Indeed, diabetes is an independent risk factor for the
development of heart failure and the mechanisms responsible remain to be
clarified. Insulin resistance in skeletal muscle, adipose tissue and the liver
are widely recognized features of obesity and type 2 diabetes, and contribute
to the pathogenesis of impaired glucose homeostasis. Insulin resistance has
also been described in the vasculature, and may contribute to endothelial
dysfunction and atherosclerosis. The heart is an insulin responsive organ and
less is known about whether or not the heart becomes insulin resistant in
diabetes and what the pathogenic consequences of this might be. This review
will discuss the currently available evidence from human and animal studies,
that the heart may become insulin resistant in obesity and type 2 diabetes. The
potential consequences of this on cardiac structure, function and metabolism
will be discussed as well as recent data from transgenic mice with perturbed
cardiac insulin sensitivity that have shed interesting new insight into potential
mechanisms linking cardiac insulin resistance with myocardial dysfunction in
diabetes.
[Back
to top] Therapeutic Targets
for the Prevention of Type 1 Diabetes Mellitus
N. Singh and J.P. Palmer
The pathogenesis of type 1 diabetes is
multifactorial, involving genetic susceptibility, autoimmune mechanisms, and
environmental factors. This article will focus on two main strategies for
altering the underlying disease process in type 1 diabetes. The first strategy
is to identify individuals at risk for the development of diabetes and to halt
the immune process before it leads to overt clinical disease. Promising in
vitro and animal studies with nicotinamide, parenteral insulin, and oral
insulin led to large clinical prevention studies, such as the European
Nicotinamide Diabetes Intervention Trial and the Diabetes Prevention Trial
(DPT-1). These studies failed to show that nicotinamide and insulin prevented
the disease in at risk relatives of patients with type 1 diabetes and left many
questions unanswered. The second strategy focuses on intervention shortly after
diagnosis in order to arrest the destruction of b cells and to preserve residual b-cell function as long as possible. Cyclosporin
was an effective immunosuppressive but was rejected as a potential treatment
for type 1 diabetes because of its renal toxicity. Recently, more attention has
been focused on an anti-CD3 antibody, on DiaPep277, and on glutamic acid
decarboxylase (GAD). Animal studies and small short-term human trials with
these compounds have suggested that they may be effective interventions in
patients recently diagnosed with type 1 diabetes.
[Back
to top] The Mammalian Innate
Immune System: Potential Targets for Drug Development
Thomas T. Wheeler and Kylie A. Hood
The innate immune system is the oldest mammalian
defence against invading micro-organisms and provides the first line of defence
against them, however until recently a detailed understanding of its complexity
has been lacking. This review describes recent advances that have been made in
understanding the components of the innate immune system, including the
pathogen sensing mechanisms, receptor and intracellular signalling pathways,
linkage to the acquired immune system, and effectors of the innate immune
response. These discoveries have created an opportunity for the development of
novel drugs through the identification of targets for rational drug design. The
opportunity for the development of novel anti-inflammatory and antimicrobial
drugs through modulation of pro-inflammatory or antimicrobial signals within
the innate immune system, are discussed. A more detailed understanding of the
effectors of the innate immune system is providing an opportunity for the
design of effector mimetics as novel antimicrobial drugs. The innate immune
system is providing the basis for much-needed alternative approaches to
controlling infection and inflammation in human medicine.