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Review Article
Open Access
Prospective Role of β-Cell-Specific IGF-1 for Oxidative Stress in the Pathogenesis
of Diabetic Neuropathy
Seigo Usuki
Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, USA
*Corresponding author:
Seigo Usuki, PhD
Institute of Molecular Medicine and Genetics
Georgia Health Sciences University
Augusta, GA 30912, USA Tel: 706-721-
0499 Fax: 706-721-8685 E-mail: susuki@georgiahealth.edu, agsusuki@yahoo.co.jp
Received May 02, 2012; Accepted May 25, 2012; Published May 28, 2012
Citation: Usuki S (2012) Prospective Role of β-Cell-Specific IGF-1 for Oxidative
Stress in the Pathogenesis of Diabetic Neuropathy. J Diabetes Metab S5:009.
doi:10.4172/2155-6156.S5-009
Diabetic neuropathy is a well-known complication of diabetes mellitus. The mechanism for progression of diabetic
neuropathy is unclear, but many risk factors, such as abnormalities of glucose metabolism and oxidative stress,
have been given much attention for their contributory role in the loss or degeneration of neurons. Homocysteine
is a risk factor of cardiovascular disease and diabetes/metabolic disease. Homocysteine metabolism is dependent
on vitamin B12 the deficiency of which induces peripheral neuropathy. On the other hand, the examination of
generative pathology showed the potential involvement of many growth factors in neuroprotection and regeneration.
This review implicates Insulin-like growth factor-1(IGF-1) as playing a crucial role in pancreatic β-cell functions
and homocysteine-induced oxidative stress. A defense mechanism against diabetic neuropathy via homocysteineinduced
oxidative stress due to a protective effect of β-cell-specific IGF-1 will be discussed.
Neuropathy is the most common complication of diabetes, occurring
in 60% of diabetic patients [1], and it causes significant morbidity
and mortality. Over the past 30 years, diabetic neuropathy has been
shown to involve many biochemical and functional abnormalities, in
both diabetic patients and animal models [2]. While it is known that
oxidative stress is related to the progression of nerve dysfunction and
that growth factors are involved in beneficial protection against functional
nerve failure, the mechanism by which the oxidative stress controls
diabetic neuropathy has not yet been elucidated [3]. Considering
the specific conditions under which peripheral neuropathy occurs in
diabetes mellitus, we believe that pancreatic β-cell function plays a crucial
role in neuroprotection [4]. Insulin-like growth factor-1(IGF-1) is
necessary both for β-cell function [5] and as a protective agent against
neurodegeneration in diabetes [6].
In this review, I will explore the current knowledge of IGF-1 and
homocysteine-induced oxidative stress, introduce our proposed
mechanism of IGF-1-mediated neuroprotection against homocysteineinduced
oxidative stress, and discuss the crucial role of β-cell-specific
IGF-1 in diabetic neuropathy.
Homocysteine-Induced Oxidative Stress
Reactive Oxygen Species (ROS) are formed as natural toxic byproducts
of the normal metabolism of oxygen. Cells typically defend
themselves against ROS damage using enzymes such as superoxide
dismutases, catalases, lactoperoxidases, and glutathione peroxidases
[7]. However, environmental stress, such as exposure to UV, ionizing
radiation and heat, causes drastic increases in ROS levels [8]. This effect
is known as oxidative stress. ROS interfere with the function of Nitric
Oxide (NO), which is a key mediator of cell signaling and is critical to
many important vascular and nervous functions [9].
Homocysteine which causes oxidative stress is known to enhance
ROS levels in patients with vascular and neurodegenerative diseases
[10]. Serum homocysteine levels are normally very low in healthy individuals
(around 100 nM) [11], whereas elevated serum homocysteine
levels cause remarkable ROS generation in endothelial cells, leading to vascular injury [12]. In addition to the induction of ROS, homocysteine
is connected to the oxidation defense system through the disulfide
forms of homocysteine. Molecular targeting by homocysteine results
in thiol-disulfide exchange reactions collectively called S-homocysteinylation,
leading to the formation of stable covalent disulfide bonds
with cysteine residues [13]. The non-protein-bound forms of serum
homocysteine (free Hcy) account for 30% of total serum homocysteine;
while protein-bound homocysteine (bound Hcy) accounts for 70% of
total serum homocysteine (Figure 1). The sulfhydryl-reducing action
of Cys34-SH on serum albumin contributes to the defense against oxidative
stress from ROS. In hyper -homocysteinemia, albumin appears as a
carrier of disulfide-bonded homocysteine (Albumin-S-S-Hcy) [14,15].
This finding implies that a decrease of the reduced albumin (Albumin-
SH) in circulation weakens the oxidation defense system. The cysteine
molecule is only one methylene group shorter than homocysteine. Although
serum cysteine levels are 25 times higher than that of homocysteine,
and cysteine generates the disulfide form of albumin (Albumin-
S-S-Cys), cysteine is not toxic and is not considered an oxidative
risk factor. Homocysteine thiolate anion (Hcy-S-), however, is a very
reactive nucleophile that undergoes thiol disulfide exchange with Albumin-
S-S-Cys to form Albumin-S-S-Hcy. This chemical mechanism
is driven by a difference in dissociation constant (pKa) values: cysteine
thiolate anion, with pKa = 8.3; and homocysteine thiolate anion, with
pKa = 10.0. These values are reflective of the fact that Cys-S- is a preferable
leaving group because of its greater stability than Hcy-S- [16].
An excess amount of serum homocysteine generates Hcy-Thiolactone
(HT), which is formed by cyclic thioesterification of homocysteine, as
in methioniyl-tRNA (Met-tRNA) synthesis (Figure 2). HT is toxic, as
it leads to N-homocysteinylation (homocystamide formation) of several serum proteins, including N-Hcy-hemoglobin (75%) and N-Hcyalbumin
(22%). N-homocysteinylation of these proteins causes enzyme inactivation, protein aggregation and eventual precipitation[16]. In
particular, N-homocysteinylation of Low-Density Lipoprotein (LDL) is
suggested to exert oxidative stress, leading to cardiovascular damage in
type 1 diabetes [17]. Paoli P et al. [18] reported that protein N-homocysteinylation
induces the formation of toxic amyloid-like protofibrils.
Figure 1:Influence of homocysteine–induced products on the balance
between oxidation and reduction states Homocysteine (Hcy) and its oxidized products are seen in normal human serum.
Albumin with Cys34-SH (Albumin-SH) contributes to anti-oxidative stress
reactions and is protective against Reactive oxygen species (ROS). This disulfide
adducts of homocysteine control the whole body- balance between
oxidation and reduction.
Figure 2:Homocysteine metabolism
Normally, homocysteine (Hcy) is maintained at very low levels in serum due
to the methionine cycle, which leads to a rapid methyl transfer reaction using
the following enzyme substrates: methionine (Met), S-adenosyl-methionine
(S-Adenosyl-Met), and S-adenosyl-homocysteine (S-Adenosyl-Hcy). The
methionine cycle is controlled by methionine synthase (MS), betaine-Hcy
methyltransferase(BHMT), methionine adenosyltransferase (MAT), methyltransferase
(MT), and S-Adenosyl-Hcy hydrolase (SAHH). Met and Hcy
are also metabolized by methionyl-tRNA synthase (MetRS) to become MettRNA
and Hcy-thiolactone (HT). Under normal conditions, Hcy-thiolactone
is rapidly converted to Hcy by Hcy-thiolactonase (HTase). However, Hcythiolactone
reacts spontaneously with protein ε-lysine residues, leading to
formation of N-Hcy-protein. Alternatively, Hcy can enter the transsulfuration
pathway. It is then converted to cystathionine (Cyst) by cystathionineβ-
synthase (CBS), which is further converted to cysteine (Cys) by cystathionine
γ-lyase (CSE). The transsulfuration pathway ends with sulfate. Additionally,
vitamins, including: B6, B12, betaine (B10), and tetrahydrofolate (THF,
sometimes called B9).
Homocysteine-Thiolactonase
Homocysteine is produced by the intracellular demethylation of
methionine, which then enters the transsulfuration pathway or the remethylation
cycle, as shown in Figure 2. Fifty percent of homocysteine
enters the transsulfuration pathway, where it is irreversibly combined
with serine to form cystathionine via the B6-dependent enzyme, Cystathionine
β-Synthase (CBS) [15,19]. This cystathionine is then metabolized
to cysteine via another B6-dependent enzyme cystathionine
γ-lyase (CSE) and ultimately to sulfate, which is excreted in the urine.
The other 50% of homocysteine enters the remethylation pathway and
is recycled to methionine. Homocysteine is converted back to methionine
by two different reactions, either catalyzed by Betaine-Hcy Methyltransferase
(BHMT) or Methionine Synthase (MS), the latter reaction
requiring 5-methyltetrahydofolate as methyl donor and vitamin B12
as a cofactor. Thus, these two pathways for intracellular homocysteine
metabolism can be impaired either by genetic defects in the enzymes
needed for homocysteine metabolism or by the nutritional deficiency
of the necessary vitamin cofactors such as folate, B12, and B6 [15]. Such
metabolic deterioration of the remethylation cycle and transsulfuration
pathway induces formation of either disulfide adduct or Hcy-thiolactone
[20]. Hcy-thiolactone then causes protein N-homocysteinylation
and subsequent protein damage [21]. In particular, homocysteinylated
LDL becomes more susceptible to lipid peroxidation [22]. On the other
hand, High-Density Lipoprotein (HDL) is resistant to N-homocysteinylation
because of an associated Hcy-thiolactonase (HTase), hydrolyzing
enzyme of Hcy-thiolactone; this hydrolysis prevents subsequent
HDL peroxidation. Hcy-thiolactone is reported to produce oxidative
stress in rat hippocampal neurons by inhibiting Na+/K+-ATPase activity
[23,24]. Further, Vignini et al. [25] reported that HT-modified LDL
(HT-LDL) attenuates Na+/K+-ATPase activity in cultured human aortic
endothelial cells.
Hcy-thiolactone is thought to be an endogenous substrate for the
serum arylesterases/paraoxonase-1 (PON1) [26]. PON1 has been implicated
in the detoxification of various organophosphatases, such as
nerve gases, dietary neurotoxins, or toxic lipids produced during oxidative
stress [27]. Serum PON1 activity is decreased in type 2 diabetic
patients with atherosclerosis [28] as well as in type 1 diabetic rats [29].
Decreased PON1 activity is also observed in patients with type 1 and
type 2 diabetic peripheral neuropathy, suggesting that diabetic neuropathy
may also arise, in part, due to the increased susceptibility of the
nervous system to neurotoxic damage resulting from the diabetic’s lack
of protection by PON1 [30]. The influence of PON1 activity on HDL
in diabetes has become another important concern [31,32]. We believe
HTase activity can be an important biomarker for evaluating diabetic
neuropathy, especially when estimation of this enzyme activity requires
Hcy-thiolactone to be a natural substrate.
Homocysteine and LDL/HDL Cholesterol Transportation
Cholesterol synthesis occurs mainly in the liver, although the Central
Nervous System (CNS) synthesizes its own considerable supply
[33]. Other extra hepatic organs synthesize cholesterol de novo after
uptake of the necessary components from circulating LDL, with cholesterol
esterification occurring in the liver. The flow of cholesterol metabolism in the Peripheral Nervous System (PNS) is not well understood,
but it seems to involve a homeostatic mechanism for regulating
cholesterol, similar to that demonstrated in the CNS. Turnover of PNS
cholesterol is also regulated by this balanced system whereby the liver
coordinates cholesterol synthesis and metabolism with all other organs
via LDL-cholesterol and HDL-cholesterol in the blood circulation (Figure
3). LDL cholesterol is transported across the Blood Nerve Barrier
(BNB) into PNS neurons via a LDL-receptor. LDL can homocysteinylate
its proteins via Hcy-thiolactone to become oxidized LDL, which is
a toxic substance causing a great deal of oxidative stress [34]. HTase,
found in HDL, is an enzyme that protects against Cardiovascular Disease
(CVD) by detoxifying Hcy-thiolactone and preventing the formation
of oxidized LDL [31]. As illustrated in Figure3, our hypothesis
regarding diabetic neuropathy is based on the homocystamide-related
mechanism for elevating serum homocysteine.
Figure 3:Effect of homocysteine on the HDL/LDL cholesterol transport
and the peripheral nervous system Under normal conditions, most, but not all, of homocysteine (Hcy) is converted
into methionine. Excessive amounts of Hcy-thiolactone (HT) are eliminated
from the circulation immediately, and are metabolized by HTase, which detoxifies
the HT.
Under diabetic conditions, however, excessive Hcy is produced and converted
to HT, which appears in the circulation. Decreasing HDL-cholesterol (HDLC)
levels reflect an equivalent lessening of the HDL-related enzyme, HTase.
The decreased amount of HTase allows LDL proteins to undergo N-homocysteinylation.
HT-modified LDL in circulation attacks the microvasculature and
invades the peripheral nervous system through the blood nerve barrier (BNB).
Eventually, the circulating HT-modified LDL shows neurotoxicity through suppression
of Na, K-ATPase activity in myelin-making Schwann cells. Thus diabetic
neuropathy develops with a reduction of normal membrane potential.
Keen arrows indicate direction of flow of cholesterol transport system.
Line arrows indicate stimulation of enzyme activity, metabolite production, or
oxidized modification. Dotted line arrows indicate suppressions of enzyme
activity, metabolite production, or oxidized modification.
IGF-1 and Oxidative Stress
Studies on the pathology of diabetic neuropathy have encouraged
further investigation of the influence of various growth factors on PNSdegenerative
processes such as demyelination and axonal injury. In particular,
there has been extensive research on the role of neurotrophins,
insulin-like growth factors, Ciliary Neurotrophic Factor (CNTF), and
Glia-Derived Neurotrophic Factor (GDNF) [35].
Serum IGF-1 is known to be decreased in rats and humans with diabetic neuropathy [36,37]. The observation of low serum IGF-1 levels
in human patients and animal models of different types of neurodegenerative
diseases led to therapeutic use of IGF-1 to restore normal serum
levels [38]. In addition, IGF-1 is a glucose-dependent growth factor and
is closely associated with diabetes mellitus. Glucose is implicated as a
regulatory molecule for inducing β-cells to secrete insulin and IGF-1. It
is known that this glucose-dependent IGF-1 activation system is closely
coupled to glucose metabolism via such mechanisms as the glycolytic
pathway and the pentose phosphate pathway [5,39,40]. For example,
activation of the glucose-dependent IGF-1 system subsequently enhances
the glycolytic pathway for cell proliferation [5]. There are also
well- known specific inhibitors for each of these pathways: 6-aminonicotinamide
(6-AN) for the pentose phosphate pathway, and 2-deoxyglucose
(2-DG) for the glycolytic pathway [41,42].
Islet β-cell dysfunction also occurs from the oxidative stress of elevated
ROS levels, which are misregulated by the defense system in diabetic
islet β-cells suffering diabetes mellitus. Streptozotocin (STZ) is a
toxic chemical that induces type 1 diabetes mellitus when injected into
rats; these STZ-diabetic rats have provided a useful etiological model
for studying diabetic neuropathy caused by oxidative stress. It has been
suggested that STZ may generate ROS such as NO and O2-, thereby inducing
apoptosis of pancreatic β-cells [43-45]. It is reported that homocysteine also impairs β-cell functions such as insulin secretion through
alterations in β-cell glucose metabolism [46,47].
Figure 4 illustrates the primary defense mechanism against oxidative
stress in β-cells. β-cells bind and take up LDL via cell surface receptors
[48]. Oxidized LDL can damage the β-cells [49]. It is reported that
this detrimental effect is detoxified by PON1/HTase, suggesting the intrinsic
presence of HTase in β-cells, in addition to the presence of HDLassociated
HTase[50]. As shown in Figure 4, the proposed mechanism
for defense against oxidative stress in β-cells is controlled by Superoxide
Dismutase (SOD), Glutathione Peroxidase (GSHPx), and catalase,
all of which act to control the level of ROS produced during oxidative
stress. Maintenance of the redox status in cells is performed by intracellular
regulators, reduced glutathione (GSH), and NADPH. This
mechanism involves two enzymes: Glutathione Reductase (GR) and
Glucose-6-Phosphate Dehydrogenase (G6PD). The overall effect of the
antioxidant system is always to maintain the intracellular balance between
these antioxidant enzymes [51], as a critical balance exists in the
β-cells between endogenous ROS generation and antioxidant defense.
Figure 4:Protective mechanism of β-cell-specific IGF-1 against oxidative
stress in pancreatic β-cells Reactive oxygen species (ROS) generated from STZ exposure are metabolized
and inactivated by superoxide dismutase (SOD) to produce H2O2. An
imbalance in the coordinated expression/activity of glutathione peroxidase
(GSHPx) and glutathione reductase (GR) can cause excessive generation
of ROS, leading to oxidative stress. GSHPx converts H2O2 to water using
glutathione (GSH) and produces oxidized glutathione (GSSG). Cellular maintenance
of a balanced redox state is controlled by intracellular regulators such
as reduced GSH and nicotinamide adenine dinucleotide phosphate (NADPH).
Both GR and glucose-6-phosphate dehydrogenase (G6PD) are enzymes with
expected protective activity against oxidative stress. 2-deoxy-glucose (2-DG,
an inhibitor of the glycolytic pathway) and 6-aminonicotinamide (6-AN, an
inhibitor of the pentose phosphate pathway) both decrease cellular levels of
pyruvate and NADPH. This leads to an accumulation of H2O2, the buildup
of which induces apoptosis. The protective action of β-cell-specific IGF-1 is
exerted via an increase in two targets: increasing methionine synthase activity
(MS), which enhances homocysteine metabolism (Figure 2); and enhancing
the glycolytic pathway, leading to cellular elevation of pyruvate, which inhibitsof
H2O2-induced cell death. Enhancement of the glycolytic pathway also leads to
an intracellular environment favorable to cell growth.
Arrows with (+) and (-) respectively represent stimulation and suppression.
Additionally, IGF-1 can affect normal cellular differentiation and
dedifferentiation via DNA methylation. Methylation reactions, including
DNA methylation and homocysteine methylation, are controlled by
methionine synthase (MS) in the methionine cycle (Figure 2). Therefore,
decreased methylation of homocysteine also implies deficient
DNA methylation, raising the coincidence of interfering withIGF-1
responses. It is reported that IGF-1 functions by altering MS activity
[52,53]. Up-regulation of IGF-1 increases MS activity, which is connected
to amelioration of associated Hcy-oxidative stress.
β-Cell-Specific IGF-1 and Diabetic Neuropathy
IGF-1 is expressed in various tissues including brain, bone, muscle,
and liver, but approximately 75% of IGF-1 is expressed in the liver
[54]. Liver-specific IGF-1 knockout (KO) mice showed reduced body
weights and increased life spans [55]. However, these findings did not
suggest something remarkable in neuronal function to be supported by
liver-specific IGF-1. Thus, it has remained unknown whether the beneficial
effects of liver-derived IGF-1 extend to protection of the PNS in
animals with diabetic neuropathy. Because observable pathology, such
as axonal atrophy or neurofilament loss, occurs much later than does
the slowing of nerve conduction velocity in peripheral nerves of diabetes
[4], abnormal glucose metabolism together with oxidative stress
may be importantly related to the early stages of onset of diabetic neuropathy.
After partial pancreatectomy in the dog, pancreatic tissue is
regenerated by remarkably enhanced expression of pancreas-specific
IGF-1 [56]. It is reported that both IGF-1 and its receptor are expressed
in pancreatic islet cells [57,58]. Furthermore, autocrine expression of
β-cell-specific IGF-1has been demonstrated to prevent STZ-induced
oxidative stress and β-cell apoptosis [59]. Rather than the originally
proposed liver-specific IGF-1 or other tissue-specific IGF-1, we now
believe that β-cell-specific IGF-1 may be closely connected to an intrinsic
action in pancreas to resist damage from oxidative stress and prevent
eventual peripheral nerve degeneration.
It has been reported that methylcobalamin is useful for treatment
of diabetic neuropathy, based on an observation that the up-regulation
of peripheral nerve IGF-1 gene expression occurs after intramuscular
injection of methylcobalamin [60]. Clinical studies with L-methylfolate
and methylcobalamin showed restoration of loss of skin sensation in
patients with diabetic neuropathy [61]. These B vitamins are involved in
homocysteine metabolism and may be connected to a defense mechanism
against homocysteine-induced oxidative stress.
β-Cells and Diabetic Autonomic Neuropathy
Histological studies have demonstrated the presence of both cholinergic
and adrenergic nerve fibers in the pancreas. Pancreatic islet
innervations include peptidergic, cholinergic, adrenergic, and GABAergic
fibers [62]. Acetylcholine the major parasympathetic neurotransmitter,
is released by intrapancreatic nerve endings during the
pre-absorptive and absorptive phase of feeding [63]. The overall effect
of this parasympathetic stimulation of β-cells is increased insulin secretion
[64]. On the other hand, the sympathetic innervation of β-cells
provides release of norepinephrine. Catecholamines such as epinephrine
and norepinephrine are known to inhibit insulin secretion in vivo and in vitro [65]. Exocrine pancreatic insufficiency in diabetes mellitus
has been attributed to diabetic neuropathy [66]. Alterations in various
sympathetic autonomic ganglia were observed in autonomic neuropathy
of STZ-induced diabetic rats [67]. In comparison, relatively little
is known concerning the effect of β-cell-specific IGF-1 on autonomic
diabetic neuropathy. Based on the known mechanism for autonomic
dysfunctions in islet cells, we suggest that β-cell-specific IGF-1 may be
a promising growth factor for treatment of autonomic dysfunction together
with diabetic neuropathy.
Conclusion
Homocysteine is known to be a risk factor for diabetic neuropathy;
specifically, homocysteine-induced oxidative stress is involved in the
development of diabetic disease. IGF-1, on the other hand, plays an important
role in protection of peripheral neurons against oxidative stress
and amelioration of neuronal degeneration. Since pancreatic β-cells are
associated with the homocysteine-induced oxidative stress of diabetes,
there is a possibility that β-cell function is involved in a progression
of diabetic neuropathy. As a consequence of these connections, I propose
that β-cell-specific IGF-1 activates a defense mechanism against
homocysteine-induced oxidative stress.
Acknowledgements
The author wishes to thank Ms. Dawn O’Brien for her editorial assistance and
Prof. Robert K. Yu for his support to my research.
References
Feldman EL, Stevens MJ, Russell JW, Greene DA (1999) Diabetic neuropathy. In: Current Review of Diabetes. Taylor S (Ed) Current Medicine, Philadelphia: 71-83.
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