Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 3, No. 4, 2003
Contents
Diabetes
Guest
Editor: Alex M. DePaoli
Dual Roles of Adiponectin/Acrp30 In Vivo as
an Anti-Diabetic and Anti-Atherogenic Adipokine Pp. 243-253
Toshimasa
Yamauchi, Kazuo Hara, Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Philippe
Froguel, Ryozo Nagai and Takashi
Kadowaki
Tissue-Specific Glucocorticoid Reactivating
Enzyme, 11β-Hydroxysteoid Dehydrogenase Type 1 (11β-HSD1) - A
Promising Drug Target for the Treatment of Metabolic Syndrome Pp. 255-262
Hiroaki
Masuzaki and Jeffrey S. Flier
DGAT: Novel Therapeutic Target for Obesity
and Type 2 Diabetes Mellitus
Pp. 263-270
Angela
Subauste and Charles F. Burant
Stearoyl-CoA Desaturase-1 and the Metabolic
Syndrome Pp. 271-280
Paul
Cohen, James M. Ntambi and Jeffrey M.
Friedman
Physiological Roles of Glycogen Synthase
Kinase-3: Potential as a Therapeutic Target for Diabetes and Other Disorders Pp. 281-290
J.R.
Woodgett
SHIP2: An Emerging Target for the Treatment
of Type 2 Diabetes Mellitus
Pp. 291-298
James
W. Baumgartener
Protein-Tyrosine Phosphatase 1B as a
Potential Drug Target for Obesity Pp. 299-304
Shrikrishna
Dadke and Jonathan Chernoff
Abstracts
[Back to top] Dual Roles of Adiponectin/Acrp30 In Vivo as
an Anti-Diabetic and Anti-Atherogenic Adipokine
Toshimasa
Yamauchi, Kazuo Hara, Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Philippe
Froguel, Ryozo Nagai and Takashi Kadowaki
Genome-wide scanning
is a powerful tool to identify susceptible chromosome loci, however, individual
chromosomal regions still have many candidate genes. Although cDNA microarray
analysis provides valuable information for identifying genes involved in
pathogenesis, expression levels of many genes are changed.
A novel approach for
identification of therapeutic targets is the combination of genome-wide
scanning and the use of DNA chips, as shown in Fig. (1). Using DNA chips, we
screened for secreted molecules, the expressions of which were changed in
adipose tissues from mice rendered insulin resistance. Decreased expression of
one of these molecules, adiponectin/Acrp30, correlates strongly with insulin
resistance. Interestingly, recent genomewide scans have mapped a susceptibility
locus for type 2 diabetes and metabolic syndrome to chromosome 3q27, where
adiponectin gene is located.
Decreasing serum
adiponectin levels are associated with increased risk for type 2 diabetes.
Interestingly, adiponectin was decreased in insulin resistant rodent models
both of obesity and lipoatrophy, and replenishment of adiponectin ameliorated
their insulin resistance. Moreover, adiponectin transgenic mice ameliorated
insulin resistance and diabetes Adiponectin knockout mice showed insulin
resistance and glucose intolerance. In muscle and liver, adiponectin activated
AMP kinase and PPARα pathways thereby increasing β- oxidation of
lipids, leading to decreased TG content, which ameliorated insulin resistance
under a high-fat diet.
Despite similar plasma
glucose and lipid levels on an apoE deficient background, adiponectin
transgenic apoE deficient mice showed amelioration of atherosclerosis, which
was associated with decreased expressions of class A scavenger receptor and tumor
necrosis factor α.
Finally, cDNA encoding
adiponectin receptors (AdipoR1 and R2) have been identified by expression
cloning, which facilitates the understanding of molecular mechanisms of adiponectin
actions and obesity-linked diseases such as diabetes and atherosclerosis and
the designing of novel antidiabetic and anti-atherogenic drugs with AdipoR1 and
R2 as molecular targets.
[Back to top] Tissue-Specific Glucocorticoid Reactivating
Enzyme, 11β-Hydroxysteoid Dehydrogenase Type 1 (11β-HSD1) - A
Promising Drug Target for the Treatment of Metabolic Syndrome
Hiroaki
Masuzaki and Jeffrey S. Flier
Obesity is closely
associated with the Metabolic Syndrome, which includes insulin resistance,
glucose intolerance, dyslipidemia and hypertension. The best predictor of these
morbidities is not the total body fat mass but the quantity of visceral (e.g.
omental, mesenteric) fat. Glucocorticoids play a pivotal role in regulating fat
metabolism, function and distribution. Indeed, patients with Cushing’s syndrome
(a rare disease characterized by systemic glucocorticoid excess originating
from the adrenal or pituitary tumors) or receiving glucocorticoid therapy
develop reversible visceral fat obesity. The role of glucocorticoids in
prevalent forms of human obesity, however, has remained obscure, because
circulating glucocorticoid concentrations are not elevated in the majority of
obese subjects. Glucocorticoid action on target tissue depends not only on
circulating levels but also on intracellular concentration. Locally enhanced
action of gluccorticoids in adipose tissue and skeletal muscle has been
demonstrated in the Metabolic Syndrome. Evidence has accumulated that enzyme activity
of 11β-hydroxysteoid dehydrogenase type 1 (11β-HSD1), which
regenerates active glucocorticoids from inactive forms and plays a central role
in regulating intracellular glucocorticoid concentration, is commonly elevated
in fat depots from obese individuals. This suggests a role for local
glucocorticoid reactivation in obesity and the Metabolic Syndrome.
11β-HSD1 knockout mice resist visceral fat accumulation and insulin
resistance even on a high-fat diet. Furthermore, fat-specific 11β-HSD1
transgenic mice, those have increased enzyme activity to a similar extent seen
in obese humans, develop visceral obesity with insulin and leptin resistance,
dyslipidemia and hypertension. In adipocytes, both antidiabetic PPARγ
agonists and LXRα agonists significantly reduce 11β-HSD1 mRNA and
enzyme activity, suggesting that suppression of 11β-HSD1 in adipose tissue
may be one of the mechanisms by which these drugs exert beneficial metabolic
effects. Recently reported selective inhibitors of 11β-HSD1 can ameliorate
severe hyperglycemia in the genetically diabetic obese mice. In summary,
11β-HSD1 is a promising pharmaceutical target for the treatment of the
Metabolic Syndrome.
[Back to top] DGAT: Novel Therapeutic Target for Obesity
and Type 2 Diabetes Mellitus
Angela
Subauste and Charles F. Burant
Obesity is currently
an exceptionally common problem in humans. The last several years have produced
a significant number of breakthroughs in obesity related areas of
investigation. Triglycerides are considered the main form of storage of excess
calories in fat. A key enzyme in the synthesis of triglycerides is acylCoA:
diacylglycerol acyltransferase (DGAT). Recent studies have shown that mice
deficient in this enzyme are resistant to diet induced obesity and have
increased insulin and leptin sensitivity. These effects suggest that inhibition
of DGAT in vivo may be a novel therapeutic target not only for obesity but also
for diabetes.
[Back to top] Stearoyl-CoA Desaturase-1 and the Metabolic
Syndrome
Paul
Cohen, James M. Ntambi and Jeffrey M.
Friedman
The incidence of
obesity has increased dramatically in recent years, making it one of the most pressing
public health concerns worldwide. Obesity is commonly associated with comorbid
conditions, most notably diabetes, coronary artery disease, and hypertension,
and the coexistence of these diseases has been termed the Metabolic Syndrome.
The identification of the hormone leptin provided a molecular link to obesity.
Leptin is recognized as the central mediator in an endocrine circuit regulating
energy homeostasis. Leptin administration leads to hypophagia, increased energy
expenditure, and weight loss, while leptin deficiency enacts an adaptive
response to starvation manifested by hyperphagia, decreased energy expenditure,
and suppression of the neuroendocrine axis. While elucidation of leptin’s role
has permitted a more detailed view of the biology underlying energy
homeostasis, most obese individuals are leptin resistant. A more complete
understanding of the molecular components of the leptin pathway is necessary to
develop effective treatment for obesity and the Metabolic Syndrome. The
identification and role of one such component, stearoyl-CoA desaturase-1
(SCD-1), is reviewed here.
Leptin’s actions are
not due to its anorectic effects alone. Leptin also mediates specific metabolic
effects, including the potent depletion of triglyceride from liver and other
peripheral tissues. To explore the molecular basis by which leptin depletes
hepatic lipid, we used oligonucleotide arrays to identify genes in liver whose
expression was modulated by leptin treatment. An algorithm was created that
identified and ranked genes specifically repressed by leptin. The gene ranking
at the top of this list was SCD-1, the rate limiting enzyme in the biosynthesis
of monounsaturated fats. SCD-1 was specifically repressed during
leptin-mediated weight loss, and mice lacking SCD-1 showed markedly reduced
adiposity on both a lean and ob/ob background (abJ/abJ;
ob/ob), despite higher food intake. abJ/abJ; ob/ob
mice also showed a complete correction of the hypometabolic phenotype and
hepatic steatosis of ob/ob mice, suggesting that fatty acid oxidation is
enhanced in the absence of SCD-1. These findings indicate that pharmacologic
manipulation of SCD-1 may be of benefit in the treatment of obesity, diabetes,
hepatic steatosis, and other components of the Metabolic Syndrome.
[Back to top] Physiological Roles of Glycogen Synthase
Kinase-3: Potential as a Therapeutic Target for Diabetes and Other Disorders
J.R.
Woodgett
Glycogen synthase
kinase-3 (GSK-3) has perplexed signal transduction researchers since its
detection in skeletal muscle 25 years ago. The enzyme confounds most of the
rules normally associated with protein kinases in that it exhibits significant
activity, even in resting, unstimulated cells. However, the protein is highly
regulated and potently inactivated in response to signals such as insulin and
polypeptide growth factors. The enzyme also displays a distinct and unusual
preference for substrates that have been previously phosphorylated by other
protein kinases which provides obvious opportunities for cross-talk. It’s
substrates are diverse and are predominantly regulatory molecules. The
molecular cloning of the kinase revealed it to be encoded by two related but
distinct genes. Moreover, the mammalian proteins showed remarkable similarity
to a fruitfly protein isolated on the basis of its role in cell fate
determination. From these humble beginnings, study of the enzyme has accrued
further surprises such as its inhibition by lithium, its regulation by serine
and tyrosine phosphorylation and its implication in several human disorders
including Alzheimer's disease, bipolar disorder, cancer and diabetes. Most
recently, small molecule inhibitors of GSK-3 have been developed and assessed
for therapeutic potential in several of models of pathophysiology. The question
is whether modulation of such an “involved” enzyme could lead to selective
restoration of defects without multiple unwanted side effects. This review
summarizes current knowledge of GSK-3 with respect to its known functions,
together with an assessment of its real-life potential as a drug target for
chronic conditions such as type 2 diabetes.
[Back to top] SHIP2: An Emerging Target for the Treatment
of Type 2 Diabetes Mellitus
James W. Baumgartener
With the rapid
increase in the number of patients developing type 2 diabetes mellitus and the
lack of optimal therapies, much focus has been placed on the insulin-signaling
pathway in the discovery of novel drug targets. Phosphatidyl Inositol 3-Kinase
(PI3K) is central to mediating insulin’s metabolic effects. PI3K catalyzes the
generation of phosphatidyl inositol (3,4,5) triphosphate (PIP3).
Inhibition of PI3K activity results in a blockade of insulin signaling
including glucose uptake and glyocogen synthesis. Thus, PIP3 is a
critical mediator of insulin action. A family of phosphatidyl inositol
phosphatases have been identified that counter-regulate PI3K activity by
hydrolyzing PIP3 to phosphatidyl inositol bisphosphate at either the 3’ or 5’
position of the inositol ring. Mice lacking one of these enzymes, Src-Homology
Inositol Phosphatase-2 (SHIP2), demonstrate increased insulin sensitivity,
suggesting that pharmacological inhibition of SHIP2 could alleviate insulin
resistance. Recent studies demonstrate elevated SHIP2 expression is associated
with insulin resistance in human patients. Comparing the studies on SHIP2 and
other phosphatases suggests how inhibition of SHIP2 leads to increased insulin
sensitivity without deleterious effects. This review focuses on the emergence
of SHIP2 as a target in the insulin-signaling pathway for the treatment of type
2 diabetes.
[Back to top] Protein-Tyrosine Phosphatase 1B as a
Potential Drug Target for Obesity
Shrikrishna
Dadke and Jonathan Chernoff
Obesity is increasing
at an alarming rate and is considered by the World Health Organization as one
of the top 10 epidemics worldwide. Resistance to leptin and insulin are likely
to play a central role in obesity; thus, blocking inhibitors of these signaling
pathways could prove useful in treating this disorder. Several lines of
evidence have converged on protein tyrosine-phosphatase 1B (PTP1B) as one of
the most important negative regulators of leptin as well as insulin signaling.
Therefore, PTP1B appears to be a promising therapeutic candidate for the
treatment of obesity. In this review, we discuss the role of PTP1B in leptin
and insulin signaling, as well as its potential as a drug target in the
treatment of obesity.