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Diabetes underlies common neurological disorders.

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EDITORIAL
Diabetes Underlies
Common Neurological
Disorders
The diabetes epidemic is probably the greatest health
problem facing developed and developing nations alike.
The current global prevalence of diagnosed diabetes is
165 million and is estimated to increase to 250 million
by 2010 and to 330 million by 2025. These alarming
figures do not include undiagnosed diabetes or prediabetic states. The long-term complications associated
with diabetes carries a heavy burden of increased morbidity and mortality as well as the brunt of diabetes
health care costs.
The most common long-term complication of diabetes affects the peripheral nervous system leading to
limb amputations and sudden cardiac death secondary
to autonomic polyneuropathy. The central nervous system is affected secondarily by diabetic macrovascular
disease with an increased incidence of stroke in the diabetic population. Direct cerebral effects of metabolic
aberrations caused by diabetes result in a diabetes
duration-related cognitive decline, so-called primary diabetic encephalopathy, and may even predispose patients to Alzheimer’s disease.1–3
Despite decades of intensive experimental and clinical research, we still have no effective or specific therapies for somatic and autonomic diabetic polyneuropathies (DPNs). Vigorous hyperglycemic control is the
only advice given to patients, which unfortunately is
not sufficient to fully prevent or control DPN as demonstrated by the Diabetes Control and Complications
Trial.4 The reason for this is most likely the generally
held misconception that hyperglycemia, and hyperglycemia alone, is the culprit underlying long-term complications. This is probably in part founded in the
most commonly used diabetic animal model from
which data, often from acutely diabetic rats, are too
commonly extrapolated to the human disorders. Streptozotocin induction of diabetes in rats causes a partial
␤-cell destruction and hyperglycemia, the latter being
the only attribute it has in common with human diabetes. It is neither insulinopenic (type 1 diabetes) nor
is it insulin resistant (type 2 diabetes). Hence, much
effort has been spent on a suboptimal disease model to
which the human diabetic disorders have been molded.
By using animal models which closely resemble the
pathophysiological bases for the human diabetic disorders, it is becoming increasingly clear that impaired insulin action, be it through insulinopenia in type 1 diabetes or via insulin resistance in type 2 diabetes, plays
probably an equally important initiating pathogenetic
role in the development of the late complications.5 Insulin and C-peptide are now recognized as potent neuroprotective and neurotrophic hormones, with gene
regulatory, antiapoptotic, and posttranslationally modifying effects on functional and structural proteins.5,6
C-peptide is part of proinsulin and is split off from
insulin with which it is secreted in equimolar concentrations. It has insulin-like effects on its own and by
synergizing insulin signaling activities.7 Insulin/Cpeptide have direct regulatory functions on neural
Na⫹/K⫹-ATPase and endothelial nitric oxide (eNOS)
via extracellular signal regulated kinase (ERK) and protein kinase C (PKC)-mediated pathways. Perturbations
of Na⫹/K⫹-ATPase and NO are implicated as major
contributors to the early metabolic and functionally reversible phase of DPN.8 A direct cause and effect relationship has repeatedly been established between Na⫹/
K⫹-ATPase activity and the acute metabolic nerve
conduction defect. Therefore, in addition to the decreased Na⫹/K⫹-ATPase activity caused downstream
by the hyperglycemia-induced activation of the polyol
pathway, insulin/C-peptide deficiencies contribute substantially to this early defect. This is consistent with
the data reported in this issue by Kitano and colleagues,9 who using the threshold tracking technique in
mildly neuropathic diabetic patients showed restoration
of reduced transaxolemmal Na⫹ gradients and improved nerve conduction velocity after 4 weeks of intensive insulin treatment, thereby also improving glycemic control. This finding was supported by increased
strength duration time constant and decreased rheobase. These eloquent human data are consistent with
earlier reported nodal clamp analyses in the acutely diabetic BB/Wor-rat, showing decreased axolemmal Na⫹
equilibrium potentials and decreased Na⫹ permeability
and currents, resulting in decreased nerve conduction
velocity.10,11 The early bioelectrical abnormalities are
perpetuated by increased intraaxonal [Na⫹]i resulting
from impaired neural Na⫹/K⫹-ATPase activity. These
abnormalities were corrected by insulin treatment in
acutely diabetic rats, consistent with the data by Kitano
and colleagues,9 but not in rats with long-standing diabetes.11 The irreversibility in chronically diabetic
nerves is associated with degeneration of the paranodal
ion channel barrier, so-called axoglial dysjunction, and
internodal lateralization of Na⫹ channels resulting in
decreased initial nodal Na⫹ currents as well as increased leak conductances and K⫹ permeabilities, all
consistent with paranodal pathology.12–14 The molecular underpinnings of the breach of the paranodal ionchannel barrier and the dislodging of pore-forming
␣-Na⫹ channels from the nodal axolemma were recently described and were interestingly prevented by
insulinomimetic C-peptide, suggesting an insulinrelated defect.6 The expression of the main molecular
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
459
constituents of paranodal tight junctions such as caspr,
contactin, and receptor protein tyrosine phosphatase ␤
are progressively downregulated in diabetic nerve. In
addition, their posttranslational modifications by p85
adducts and phosphorylation, regulating protein–protein interactions, become severely perturbed. Simultaneously nodal ankyrinG and associated cell-adhesive
␤-Na⫹ channels become progressively downregulated
and posttranslationally compromised resulting in detachment of otherwise normally expressed ␣-Na⫹
channels allowing them to diffuse away from the node
through the now breached ion-channel barrier.6
Taken together these data reflect complex, progressive, and dynamic metabolic, molecular, and structural
changes with effects on the intricate interplay between
ion permeabilities at the node ultimately resulting in
impaired nerve conduction velocities. The different expressions of molecular, functional, and structural abnormalities in type 1 and type 2 DPN are reflective of
the relative contributions by hyperglycemia vis à vis
impaired insulin action.15,16
A generally less well-known complication of diabetes
is primary diabetic encephalopathy. This is increasingly
being recognized clinically and experimentally as a diabetes-duration–related cognitive dysfunction. Impairments in learning, memory, problem solving, and intellectual development have been documented in type
1 diabetic patients in a duration-related manner and
independent of hypoglycemic episodes.17,18 In type 2
diabetic patients, cognitive dysfunctions and impaired
performances in abstract reasoning and psychomotor
functioning have been known for some time.2,19,20
In diabetic rodents, impaired spatial memory has
been associated with impaired long-term potentiation
in hippocampus indicative of pre- and postsynaptic
deficits.21 Insulin substitution of streptozotocin diabetic rats prevents impaired cognitive performances
and the electrophysiological abnormalities.22 In the
BB/Wor-rat, a duration-related apoptotic neuronal loss
occurs in CA1 and CA2 of hippocampus and prefrontal
cortex associated with progressive impairments of Morris water maze performances.23 These abnormalities
have been linked to suppression of tyrosine kinase–activated receptors and their ligands. Downstream signaling deficits result in perturbations of the PI-3 kinase
pathway and the bidirectional regulation of p38 and
JNK and promotion of Bcl2 expression and caspase-3
activation.23,24 Note that recent data have implicated
additional caspase-dependent and independent pathways in central nervous system neuronal apoptosis associated with diabetes.25 This cascade of events is likely
to be related to impaired insulin action, because it can
be partially prevented by insulinomimetic proinsulin
C-peptide, which together with insulin has gene regulatory effects on the insulin growth factor (IGF) system
and the insulin receptor itself.24,26 Additional proapop-
460
Annals of Neurology
Vol 56
No 4
October 2004
totic influences include mitochondrial and endoplasmic
reticulum dysfunction resulting in increased cytosolic
Ca⫹⫹ and oxidative stress as well as activation of the
Fas/TNF-R death receptor complex.25 The study of
cognitive defects in diabetes is a rapidly evolving research area, adding another until recently largely unrecognized neurological entity to the late complications
of diabetes.
Interestingly, data are rapidly accumulating implicating abnormal function of the insulin/IGF axis in the
early pathogenesis of Alzheimer’s disease.27,28 Insulin/
IGF-1 are likely to regulate ␤-amyloid levels27 and
phosphorylation of the tau protein.29 Hence, it is plausible that pathogenetic commonalties exist between two
so diverse disorders as diabetes and Alzheimer’s disease.
The Rotterdam study2 and that by Arvanitakis and colleagues3 showing a twofold higher incidence of Alzheimer’s disease in the diabetic population does not contradict this notion. Could it be that the increasing
incidences of diabetes and Alzheimer’s disease are
mechanistically interrelated?
So what do we do to curb the onslaught of diabetes?
It will definitely take serious and effective concerted
efforts by governments, multinational and national
health organizations, and patient advocacy groups to
inform and educate the public at large, because the
most common type 2 diabetes is largely a preventable
disorder, and for granting agencies to expand and facilitate coordinated and targeted research efforts into
the complications of diabetes. Only by knowing the
beast can it be defeated.
Anders A. F. Sima, MD, PhD, FRCP(C)
Departments of Pathology and Neurology
Wayne State University
Detroit, MI
References
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J Pharmacol 2004;490:187–197.
2. Olt A, Stalk RP, van Harskamp F, et al. Diabetes mellitus and
the risk of dementia. Rotterdam Study. Neurology 1999;53:
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3. Arvanitakis Z, Wilson RS, Bienias JL, et al. Diabetes mellitus
and risk of Alzheimer disease and decline in cognitive function.
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4. The DCCT Research Group. The effect of intensive treatment
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DOI: 10.1002/ana.20249
Sima: Diabetes and Neurology
461
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