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2 diabetes as a risk factor for Alzheimer's disease - defective
insulin-degrading enzyme as an etiological link?
DailyUpdates 2nd April 2004: There is growing evidence that type-2 diabetes is a risk factor for Alzheimer disease. In their April American Journal of Pathology article Brigham and Women's Hospital researchers add further evidence to support defects in insulin-degrading enzyme activity as a potential cause of this phenomenon. This and similar data argues for the development of cross-indication treatments of type-2 diabetes and Alzheimer disease and GSK-3 inhibitors may fit the bill. According to WHO, there are some 130 million diagnosed diabetics in the world, a figure that is predicted to increase to 300 million by 2025. The majority of patients suffer from type 2 diabetes. The market for diabetes therapeutics is also rising with global sales reportedly topping $8.1 billion for the 12 months to September 2000, a 19% increase over the previous 12 months.
Diabetes is associated with a
number of other conditions. For example, around 60-65% of diabetics also
have hypertension while diabetes co-exists with dyslipidemia in a third of
patients. Although the treatment of diabetes has traditionally focused
on the disease per se, the concurrent treatment of multiple
co-existing conditions is rapidly gaining attention. Such an approach
will lower the "pill burden" of individual patients and example of
this concept include the development of AGE cross-link breakers for the
treatment of type 2 diabetics with hypertension and dual PPAR agonists for the
treatment of type 2 diabetes with dyslipidemia.
More recently, diabetes has been
proposed to be a risk factor for developing Alzheimer disease. Alzheimer
disease and type 2 diabetes are characterized by increased prevalence with
aging, a genetic predisposition, and comparable pathological features in the
islet and brain (amyloid derived from amyloid beta protein in the brain in
Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in
the pancreas in type 2 diabetes). Evidence is growing to link precursors of
amyloid deposition in the brain and pancreas with the pathogenesis of
Alzheimer disease and type 2 diabetes, respectively and a recent study has
demonstrated that type 2 diabetes is twice as prevalent in Alzheimer disease
versus non-Alzheimer disease controls.
The reason for diabetes being
a risk fact for Alzheimer disease is unclear however increased beta-amyloid
(Abeta) aggregation through inhibition of
insulin-degrading enzyme is one hypothesis.
Insulin-degrading enzyme (IDE)
has been identified as a principal regulator of Abeta levels in neuronal
and microglial cells and human genetic studies have implicated the
Insulin-degrading enzyme region of chromosome 10 in both Alzheimer disease and
type 2 diabetes. Last year researchers from Brigham and Women's Hospital
reported that mice with homozygous deletions of the insulin-degrading
enzyme gene were characterized by a large decrease in Abeta
degradation in the brain leading to increased cerebral accumulation of
endogenous Abeta as well as hyperinsulinemia and glucose intolerance.
For IDE to remain a valid
candidate gene for late-onset AD on functional grounds, it must be shown that
partial loss of function of IDE can still alter Abeta degradation, but without
causing early, severe elevation of brain Abeta. This has recently been
addressed by the Brigham and Women's Hospital group
In their April American
Journal of Pathology article, Farris et al report that naturally
occurring IDE missense mutations in a well-characterized rat model of type 2
diabetes mellitus result in decreased catalytic efficiency and a 15 to
30% deficit in the degradation of both insulin and Abeta. Endogenously
secreted Abeta(40) and Abeta(42) are significantly elevated in primary
neuronal cultures from animals with the IDE mutations, but there is no
increase in steady-state levels of rodent Abeta in the brain up to age 14
months suggesting that the brain can compensate for the partial deficit
during the life span of the rat.
The aging population will
contribute to an expansion of the already $30 billion neurodegenerative
market. The market for Alzheimer disease therapy is expected to grow from 16
million patients to 21 million by 2010 in the seven major pharmaceutical
markets. Between 2005 and 2010, drugs for treating Alzheimer disease could
achieve sales of well over $2 billion.
The Brigham and Women's
Hospital study adds further weight to the concept that type 2 diabetes may be
a risk factor for Alzheimer disease and offers a mechanism for this
association. The development of diabetes therapeutics which are
additionally able to limit the progression of Alzheimer disease would be of
considerable potential. Of interest the enzyme, glycogen synthase
kinase-3 (GSK-3) has emerged over recent years as a highly promising target
for various condition including both diabetes and Alzheimer disease (for a
state of the art overview of GSK-3 click
here).
GSK-3 negatively regulate several
aspects of insulin signaling, and elevated levels of GSK-3 have been reported
in skeletal muscle from diabetic rodents and humans. GSK-3 inhibition improves
glucose handling in Zucker diabetic fatty rats, lowering fasting
hyperglycemia. Likewise GSK-3 inhibitors also improve glucose handling making
them promising targets for the treatment of diabetes. Researchers at
Chiron, who have developed the field-leading GSK-3 inhibitors CT98014 and
CHIR98023 have recently demonstrated that their molecules enhanced
insulin-stimulated glucose transport in type 1 skeletal muscle from the
insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats.
Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly
lowered blood glucose levels and improved glucose disposal after oral or
intravenous glucose challenges in ZDF rats and db/db mice, without causing
hypoglycemia or markedly elevating insulin.
As in diabetes, GSK-3 is also
elevated in Alzheimer disease brain. Furthermore, GSK-3 inhibitors
prevent tau hyperphosphorylation, and also protect cultured neurons from cell
death triggered by Abeta. GSK-3 not only provides an additional similarity
between Alzheimer disease and diabetes etiology but inhibiting this enzyme may
also be of use in treating the two conditions, more so in light of data such
as that published by Farris et al supporting the hypothesis that type 2
diabetes is a risk factor for Alzheimer disease.
(Source DailyUpdates 2nd April; for a full abstract of the original papers see Am J Pathol. 2004 Apr;164(4):1425-34; for a state of the art overview of GSK-3 click here)
In this edition of DailyUpdates,
LeadDiscovery also highlights ischemic neuroprotection with
selective {kappa}-opioid receptor agonist...data showing that disruption
of neural STAT-3 causes obesity and diabetes...the role that protein
kinase C plays in sildenafil-induced cardioprotection...and much more.
LeadDiscovery Reports - click here |
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