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Connections between diabetes and Alzheimer's
disease explored
In a special issue of the Journal of
Alzheimer's Disease (April 2009), nineteen
contributions examine the possible
connections between AD and T2D.
Modern societies face the increasing burden
of age-related diseases, in particular
Alzheimer's disease (AD) and type 2 diabetes
(T2D).
There is some evidence that the causes
underlying both diseases are linked.
Do AD and T2D represent the endpoint of
aged, exhausted, and dysfunctional cells
having reached their maximal life expectancy
or are AD and T2D the consequences of living
in superabundance including excessive food
supply, work demands, psychosocial stress,
and an excessive sedentary life style?
Numerous epidemiological studies have
described the incidence of both AD and T2D
in the Western world and extensively defined
common environmental risk factors. Guest
Editors Angelika Bierhaus and Peter P.
Nawroth, both of the University of
Heidelberg, have assembled a group of
prominent investigators to explore the
connections between AD and T2D pathologies
using literature reviews of current human
studies, overviews of animal models, reviews
of basic pathophysiology findings, and
biochemical analyses.
In the introduction Bierhaus and Nawroth
note that several pathological features have
been identified as common denominators of AD
and T2D including impaired glucose/energy
metabolism, altered insulin-signaling
pathways, mitochondrial dysfunction,
oxidative stress, and inflammation.
Daniel Kopf and Lutz Frölich report a
systematic review of fourteen studies that
examined the risk of incident Alzheimer's
disease in diabetic patients. All studies
reported risk ratios greater than one with
four studies showing statistically
significant excess risk.
Pablo Toro, Peter Schönknecht, and Johannes
Schröder follow with the results of a study
of almost 200 subjects born between 1930 and
1932. For those with either mild cognitive
impairment (MCI) or with AD, there was an
increased tendency for T2D.
José A. Luchsinger and Deborah R. Gustafson
present a comprehensive review of the
epidemiologic evidence linking the continuum
of adiposity and T2D with AD. The mechanisms
relating adiposity and T2D to AD may include
hyperinsulinemia, advanced products of
glycosylation, cerebrovascular disease, and
products of adipose tissue metabolism.
The implication of these associations is
that a large proportion of the world
population may be at increased risk of AD
given the trends for increasing prevalence
of overweight, obesity, hyperinsulinemia,
and T2D.
However these associations may also present
a unique opportunity for prevention and
treatment of AD.
Ceramides are a type of lipid molecule that
are both neurotoxic and causes insulin
resistance. Ming Tong and Suzanne M. de la
Monte report on their investigation of the
role of ceramides as mediators of
neurodegeneration using an in vitro culture
model.
Exposure to two different ceramides impaired
energy metabolism, viability, and insulin
and insulin-like growth factor signaling
mechanisms, and resulted in increased levels
of AβPP-Aβ and pTau, while an inactive
ceramide analogue had no significant effect
on these parameters.
Following this line of investigation,
Lascelles E. Lyn-Cook, Jr., Margot Lawton,
Ming Tong, Elizabeth Silbermann, Lisa
Longato, Ping Jiao, Princess Mark, Jack R.
Wands, Haiyan Xu and Suzanne M. de la Monte
used pairs of mice fed a high-fat diet (HFD)
or a normal diet and found that mild
neurodegeneration and brain insulin
resistance resulted from the high-fat diet.
They found that ceramide production
increased in the HFD mice and that obesity,
T2D and nonalcoholic steatohepatitis (NASH)
might all be mediated by the excess
ceramides.
In the area of possible therapies for AD,
Nikolaos Tezapsidis, Jane M. Johnston, Mark
A. Smith, J. Wesson Ashford, Gemma Casadesus,
Nikolaos K. Robakis, Benjamin Wolozin,
George Perry, Xiongwei Zhu, Steven J. Greco,
and Sraboni Sarkar write about a possible
use of leptin to reduce the affects of AD.
They speculate that a deficiency in leptin
levels or function may contribute to
systemic and central nervous system
abnormalities leading to AD.
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