Insulin-Like Growth Factor Replacement Therapy for Diabetic Neuropathy: Experimental Basis
Experimental Diab. Res.
Insulin-Like Growth Factor Replacement Therapy for Diabetic Neuropathy: Experimental Basis
Douglas N. Ishii 0 1
Sean B. Lupien 0 1
0 Department of Biomedical Sciences and Department of Biochemistry and Molecular Biology, Colorado State University , Fort Collins, Colorado , USA
1 Digestive and Kidney Disease grant R01 DK53922 and Centers for Disease Control and Prevention grant R49/CCR811509. SBL was supported in part by a fellowship from the Colorado Institute for Research in Biotechnology. of Biomedical Sciences, Colorado State University , Fort Collins, CO 80523 , USA
CLINICAL DIABETIC NEUROPATHY
There are two types of diabetic patients. Type II diabetes
is previously known as non?insulin-dependent diabetes
mellitus (NIDDM) or adult-onset diabetes. Generally striking late in
adulthood, these patients produce normal or elevated amounts
of insulin, but are resistant to insulin. Type II diabetes has a 5%
to 7% incidence in the general population, and comprises more
than 90% of all diabetic patients, or about 14 million people
in the United States alone. The incidence is rising as a
consequence of the increasing population age, industrialization, and
obesity. Furthermore, Hispanics and African-Americans have a
higher overall incidence than Caucasians, and their proportion
in the general population is increasing. The remaining 10%
have type I diabetes, previously known as insulin-dependent
diabetes mellitus (IDDM) or juvenile-onset diabetes. They are
unable to produce sufficient amounts of insulin due to pancreatic
insufficiency, in most cases believed to arise as an autoimmune
Type I and type II diabetic patients are at risk for diabetic
neuropathy. The major pathological feature is a dying-back
axonopathy that involves both unmyelinated and myelinated
axons. There is a dwindling of axon calibers, reduced axonal
transport, loss of synapses, loss of axons, and, ultimately, loss
of neurons. Daily wear-and-tear on the nervous system requires
ability for nerve regeneration, and the poor nerve
regeneration associated with diabetes may explain the loss of synapses,
dying-back axonopathy, and loss of neurons. There is reduced
conduction velocity in about 90% of patients, but its relationship
to clinically meaningful neuropathy remains uncertain because
a significantly smaller fraction of patients progress to diabetic
neuropathy, and axons can regenerate even when conduction is
blocked by tetrodotoxin. The sensory, sympathetic, and motor
systems may be variably afflicted.
Muscular atrophy and weakness can develop secondary to
motor involvement. Autonomic neuropathy includes
gastroparesis with abdominal bloating and pain, loss of bladder tone
that sometimes requires catheterization, abnormal
cardiovascular function, silent myocardial infarct, and sudden death. Half
of affected males have impotence. The most prevalent form of
this complication is a symmetrical sensory neuropathy.
Burning unremitting pain, such that a patient cannot bear even the
weight of a bed sheet, is sometimes encountered. With
progression, there is loss of sensory function, leading to the inability
to do simple tasks, such as turn the pages of a book. Inability to
perceive pain and touch as well as impaired proprioceptors
results in an increased tendency for injuries. In conjunction with
poor wound healing and increased susceptibility to gangrene,
approximately 100,000 limb amputations are performed on
diabetic patients each year
(Bild et al., 1989; Litzelman et al.,
. For other manifestations of clinical neuropathy, reviews
and monographs on diabetic neuropathy are available
and Tomlinson, 1993; Vinik et al., 1996; American Diabetes
INTENSIVE GLUCOSE THERAPY DOES NOT
PREVENT THE PROGRESSION OF DIABETIC
COMPLICATIONS IN A LARGE FRACTION
The Diabetes Control and Complications Trial (DCCT) has
shown that intensive insulin therapy reduces the incidence of
neuropathy in 60% of highly selected type I diabetic patients
DCCT Research Group, 1993
). This is a very important
clinical finding. Unfortunately, neuropathy continues to progress in
40% of patients, despite the best current method for diabetic
treatment, showing that there is a need for new treatments in
addition to glycemic control. A treatment that could
ameliorate, prevent, and/or reverse diabetic neuropathy would be a
major therapeutic advance, and would help reduce the nearly
$100 billion overall cost of health care for diabetic patients. A
disproportionately high fraction of this amount is expended for
those patients with complications such as neuropathy.
The development of supplemental treatments for diabetic
complications is particularly desirable, because intensive
insulin therapy is not benign, and is associated with a threefold
increased risk of life-threatening hypoglycemia. Extreme caution
is warranted because 43% of severe hypoglycemic episodes are
found to occur during sleep. Diabetic patients with neuropathy
may be particularly susceptible to severe hypoglycemia
under intensive insulin therapy
(Hoeldtke et al., 1982; Santiago
et al., 1984)
. These patients may have impaired autonomic
function and, thereby, a diminished counterregulatory system to
oppose hypoglycemia. Mortality can be increased (Teutsch et al.,
Oral monotherapies have been unable to achieve the goal
of intensive therapy in type II diabetic patients, but a
combination of insulin, oral agents, and diet can partially reduce
(UK Prospective Diabetes Study Group,
. Intensive therapy reduced hemoglobin (Hb)A1C levels
by approximately 1% below results achieved with conventional
therapy, resulting in a 35% reduction in the risk of
complications. Therefore, complications continue to progress in a large
fraction of patients in spite of the best current methods of
glucose control. The incidence of major hypoglycemic adverse
events is 2.3% of patients per year. Thus, it is very important
for both type I and type II diabetic patients to manage blood
glucose as close to normal as possible, and therapies to supplement
glycemic control to specifically treat diabetic complications are
SUPPLEMENTAL THERAPIES THAT DO NOT
TARGET GLYCEMIC CONTROL ARE
CLINICALLY EFFECTIVE IN PREVENTING
High blood pressure and microalbuminuria are risk factors
for the progression of nephropathy in diabetic patients. Like
other diabetic complications, it has long been believed that
nephropathy is due mainly to hyperglycemia. However, recent
data challenge this belief. There is a 50% reduction in
endstage renal disease and mortality in patients with type I diabetes
treated with angiotensin-converting enzyme inhibitors
et al., 1993)
. Moreover, there is a 70% reduction in the
progression to nephropathy in type II diabetic patients with
microalbuminuria when treated with angiotensin-II receptor blockers
(Parving et al., 2001)
. Control of hypertension is important
as well. The IGF data are consistent with these observations
that diabetic complications can be prevented independently of
OVERVIEW OF THE IGF SYSTEM
The IGF genes are quite large and each is unique in
vertebrates. Alternative exon usage, splicing, and multiple poly(A)
termination sites produce multiple IGF-I and IGF-II transcripts.
Because all IGF transcripts encode the complete prepro-IGF
molecule, it is believed that the multiple transcripts facilitate
complex, tissue-selective regulation of gene expression. The
IGF-I gene is under growth-hormone control in certain tissues
such as liver, but is also responsive to developmental signals,
nutritional status, diabetes, aging, and neural activity. The
IGFII gene is likewise responsive to developmental signals,
nutritional status, diabetes, aging, and neural activity. However, it is
not responsive to growth hormone. In the adult rat, the highest
levels of IGF-II gene expression are found in brain, spinal cord,
and peripheral nerves. It is expressed in liver in humans, but not
rats, due to absence of the hepatic promoter. Hence, circulating
IGF-II is abundant in humans but essentially absent in adult
rodents. The IGF-I gene is likewise expressed in adult brain,
spinal cord, peripheral nerves, and liver, but its expression is
more widespread among other tissues as well. IGF-II is by far
the predominant IGF in brain.
IGF-I and IGF-II are protein hormones (molecular weight
7.5 kDa) comprised of a single polypeptide chain held together
by three intrachain disulfide bonds. IGFs are members of the
insulin gene family; they are endocrine, autocrine, and paracrine
factors. Both IGF-I and IGF-II bind to the type I IGF
receptor, and it is believed that most actions of IGFs are through
this receptor. The type I receptor is a plasma membrane?bound
heterodimer homologous to the insulin receptor where the
extracellular ? subunits contain the IGF-binding domain, and an
intracellular domain of the ? subunit is a tyrosine kinase. The
type I receptor is present on all or virtually all neurons, and
is localized to the cell body, axons, and nerve terminals. This
receptor on brain neurons is smaller than those on peripheral
tissues due to decreased glycosylation of the ? subunits, and does
not appear to gate glucose uptake. In addition, IGF-II binds the
type II receptor that is comprised of a single polypeptide located
in the plasma membrane and devoid of tyrosine kinase activity.
It appears to be involved in IGF-II degradation and lysosomal
targeting, and may also signal possibly through a G-protein
mechanism. Because their three-dimensional structures
resemble that of insulin, IGFs can cross-occupy insulin receptors, but
this occurs only at supraphysiological concentrations.
There are six members of an IGF-binding protein (IGFBP-1
through -6) family that sequester IGFs. Circulating IGFs form
a trimeric complex, predominantly with IGFBP-3, and the acid
labile subunit. IGFs in the extracellular fluid, on the other hand,
are generally in the form of dimers together with one of the
IGFBPs. It is believed that tissue proteases may act on these
dimers to regulate the availability of free IGFs.
It is instructive to consider the major additive sources of
IGFs for the nervous system. Neurons have access to IGFs
produced in brain, spinal cord, and peripheral nerve. In
addition to these autocrine/paracrine sources of IGFs, circulating
endocrine sources of IGFs, primarily from liver, can provide
further support for peripheral neurons. Because the signaling
type I IGF receptor binds to both IGF-I and IGF-II, these
two neurotrophic ligands form a redundant back-up system
for one another. The onset of neuropathy may be slower in
humans because hepatic IGF-II production provides back-up
neurotrophic support to partially offset the loss of circulating
IGF-I in younger diabetic patients, whereas the onset may be
more rapid in adult diabetic rats due to the absence of
circulating IGF-II. It will be seen that in diabetes there is a progressive
loss of autocrine, paracrine, endocrine, and redundant IGF
neurotrophic support. Such loss is proposed to increase the risk of
NEUROBIOLOGY OF IGFs
A brief review of the neurobiology of IGFs helps to explain
how IGFs are implicated in diabetic neuropathy. The strength
of this model is that diabetic neurological disturbances can be
rationally understood from the biochemistry and physiology of
IGF action in the nervous system.
IGFs are neurotrophic factors that can support and prevent
damage to neurons. The neurotrophic properties of IGF-I and
IGF-II were initially discovered in the 1980s. IGF-I and -II
were found to induce neurite outgrowth and support survival
in cultured sensory, sympathetic, and human neuroblastoma
(Recio-Pinto and Ishii, 1984; Ishii et al., 1985;
RecioPinto et al., 1986)
. These studies were soon extended to show
that IGFs can support a wide variety of central nervous system
(CNS) as well as peripheral nervous system (PNS) neurons.
The cloning and sequencing of the rat IGF-I
(Soares et al., 1985, 1986)
permitted examination of their tissue-specific and
developmental expression. The IGF-II gene is selectively expressed at the
highest levels in the brain, spinal cord, and peripheral nerves
among tissues of the adult rat. The IGF receptors are found on
neurons as well as glial cells. The expression of the IGF-II gene
is closely correlated with the development of synapses
. IGFs can increase neurite (axon and dendrite) growth
in cultured neurons
(Recio-Pinto and Ishii, 1984; Recio-Pinto
et al., 1986)
, by increasing the expression of the genes that
encode structural proteins of axons, such as tubulins and
(Mill et al., 1985; Wang et al., 1992)
purified recombinant human IGF-I and IGF-II can increase axon
growth and support survival of neurons cultured from various
parts of the central (brain and spinal cord) and peripheral
nervous systems. Overexpression of IGF-I in brain of transgenic
mice results in brains 55% larger than normal (Mathews et al.,
1988), and mouse strains with reduced IGF-I levels have
(Noguchi et al., 1986; Beck et al., 1995)
IGFs appear to be able to act on all or virtually all neurons in the
Various data suggest that the normal role of IGFs is to
help maintain the nervous system in adult mammals,
including humans. IGF treatment can help repair damaged nervous
systems. Administration of recombinant human IGF-I
et al., 1989)
(Glazner et al., 1993)
was found to
significantly increase the rate of sensory nerve regeneration in
adult rats. IGF-II administration increases motor nerve
regeneration as well (Near et al., 1992). IGFs are normally produced
in nerves, and IGF genes are turned on to help damaged nerves
(Glazner et al., 1994)
. Following sciatic nerve
transection in neonatal rats, IGF-II administration can prevent loss
(Pu et al., 1999a)
. These results demonstrate
that IGF treatment can help repair damaged peripheral nerves
in a mammal.
Although the central effects of IGFs are not discussed here,
what has emerged is the concept that IGFs are circulating and
CSF neurotrophic factors that provide general support to
virtually all neurons within the PNS and CNS. Other neurotrophic
factors, such as neurotrophins (nerve growth factor [NGF],
brain-derived nerve factor [BDNF], neurotropin-3 [NT-3])
provide additional support for select populations of neurons.
Review articles may be consulted on the neurobiological actions
(Recio-Pinto and Ishii, 1988; de Pablo and de la Rosa,
1995; D?Ercole et al., 1996; Ishii and Pu, 1999)
. These data
show the broad potential that IGFs have to treat the many
different types of cells of the central and peripheral nervous systems.
LOSS OF IGF CAUSES NEUROLOGICAL DISTURBANCES THAT MIMIC THOSE OBSERVED IN DIABETES
Blocking of IGF activity in normal, nondiabetic animals will
produce neuropathy with characteristics similar to that observed
in diabetes. For example, anti-IGF antibodies can block sensory
and motor nerve regeneration in normal rats
(Kanje et al., 1989;
Near et al., 1992; Glazner et al., 1993)
, and nerve regeneration
is impaired in diabetes. Neuron loss may occur in clinical
diabetes in both the peripheral and central nervous systems, and
this is observed in rats treated with an anti-IGF antiserum
et al., 1999a)
and in IGF-I?null mice
(Beck et al., 1995)
Conduction velocity (rate at which electrical signals travel down
nerves) and axonal diameters are reduced in diabetic patients,
and also in IGF-I?knockout mice
(Rabinovsky et al., 1996; Gao
et al., 1999)
. IGF-I administration can reverse the low motor
and sensory nerve conduction velocity in these mice. These
data show the loss of IGF activity is a risk factor for neuropathy
independently of hyperglycemia.
IGFs can increase ?-tubulin, ?-tubulin, 68-kDa
neurofilament, and 170-kDa neurofilament gene expression
(Mill et al.,
1985; Wang et al., 1992)
. Consequently, a decline in IGF gene
expression in diabetes is conjectured to cause diabetic
biochemical disturbances, including reduced neurofilament and tubulin
production in nerves, and tubulins are needed for assembly of
microtubules. Neurofilaments regulate axonal diameters, and
axonal diameters are reduced in diabetes. The absence of
adequate amounts of these major cytoskeletal proteins may result
in loss of synapses and axons. Tubulins further provide tracks
on which axonal transport depends, and axonal transport is
disrupted in diabetes. The metabolic need would be greatest for
the longest axons, and this may underlie the length-dependent
axonopathy in diabetes.
THEORY FOR IGF INVOLVEMENT IN THE
PATHOGENESIS OF DIABETIC NEUROPATHY
IGFs support the types of neurons afflicted in diabetes,
namely sensory, sympathetic, and motor. The theory is
proposed that both insulin and IGFs are required to maintain the
proper functioning of the nervous system, and that there is a
decline in insulin and IGF activity in diabetes that predisposes to
. In brief, insulin, IGF-I, and IGF-II are
proposed to provide redundant neurotrophic support for
neurons. This theory predicts that (i) IGF activity is reduced in
diabetes; (ii) neuropathy can be prevented by administration of
IGFs; (iii) central and peripheral neurological disturbances may
share a common etiology involving IGFs; (iv) neuropathy might
be treatable irrespective of hyperglycemia; (v) differences in the
manner in which rats and humans develop neuropathy can be
explained at least in part by a species-specific difference in the
pattern of IGF gene expression; and (vi) an age-dependent loss
of IGF may explain the age-dependent risk of neuropathy.
Multifactorial risk is inherent in this formulation, and the total IGF
activity in an individual would depend, for example, on
regulation of IGF gene expression, IGF transcript processing, IGF
protein synthesis and turnover rates, IGF BP levels, proteases
that may govern availability of IGF sequestered to binding
proteins, IGF receptors, postreceptor signaling, and other factors.
Predictions and tests of the theory are discussed below.
IGF Levels are Reduced in Animal and Human Diabetes
Humans and Rhesus Monkeys
IGF levels are reduced in diabetic patients. Early clinical
studies did not control for age, and failed to find a decline in IGF
activity in diabetes. However, later studies, using age-matched
patient groups, found that IGF-I level is significantly reduced
by 40% to 50% in type I as well as type II diabetes
Baxter, 1986; Arner et al., 1989; Ekman et al., 2000)
circulating levels are elevated, and this is expected to sequester
and reduce the activity of IGFs
(Crosby et al., 1992)
patients with neuropathy have lower serum IGF-I levels versus
diabetic patients without neuropathy or nondiabetic patients
(Migdalis et al., 1995; Guo et al., 1999)
. Reduced numbers of
IGF-I receptors are found on red blood cells of diabetic patients
(Haruta et al., 1989; Migdalis et al., 1995)
. Serum IGF-I levels
are not correlated with glycemic control, measured as HbA1C
levels, in type I diabetic patients treated with insulin
et al., 2000)
. This observation may explain why neuropathy is
not better controlled in insulin-treated patients.
It is critical to recognize that there is an age-dependent
decline of IGFs in humans in the later decades of life
. This may explain the age-dependence of clinical
neuropathy (Pirart, 1978), and the increased incidence of
neuropathy after the fourth decade of life. Thus, neurons suffer the
loss of IGF neurotrophic activity as a consequence of diabetes,
and IGF levels decline further with advancing age slowly over
Neuropathy may be less prevalent in type I juvenile diabetics
who are adolescents or young adults, because IGF-I and IGF-II
activities remain relatively high in these age groups. However,
in ketotic episodes IGF-I levels transiently decline, and there is
(Rieu and Binoux, 1985)
Young rhesus monkeys are lean and have normal glucose
tolerance. As animals age, they become obese and develop
impaired glucose tolerance, but have normal or slightly elevated
insulin levels. Later, they become overtly type II diabetic. It
is fascinating that there is a decline in IGF-I activity with
every stage in the progression towards diabetes
(Bodkin et al.,
. IGF-I levels are observed to decline in the prediabetic
state prior to overt hyperglycemia. Thus, IGF-I levels are not
correlated with glucose levels in neither monkeys nor humans.
Neuropathy is known to develop
(Cornblath et al., 1989)
rhesus monkey provides important support for the theory in
animals genetically close to humans, and shows further the
relationship between age-dependent decline in IGF activity and
age-dependent risk of diabetic neuropathy.
Type I Diabetic Rats
IGF-I gene expression is profoundly reduced in liver, adrenal
glands, and spinal cords of streptozotocin (STZ)-diabetic rats, a
model of type I diabetes
(Ishii et al., 1994)
. IGF-II gene
expression is reduced in diabetic rat brain (Wuarin et al., 1996). The
significant decrease in poly(A)+RNA content per milligram
(Wuarin et al., 1996)
may be related to the
progressive cerebral atrophy in the brains of diabetic patients
et al., 1994)
. IGF-I and IGF-II mRNA content is reduced in
sciatic nerves early after the induction of diabetes
(Wuarin et al.,
, most likely in Schwann cells
(Pu et al., 1995)
mRNA and its receptor mRNA levels are reduced in spinal cord,
superior cervical ganglia
(Bitar et al., 1997; Bitar and Pilcher,
, and dorsal root ganglia (Craner et al., 2002). Rats quickly
develop neuropathy because of a profound loss of neurotrophic
activity involving insulin, IGF-I, and IGF-II. IGF-II activity is
(Soares et al., 1985; 1986)
insulin activity is reduced experimentally, and IGF-I activity
falls secondary to diabetes.
Type II Diabetic Rats
The ZDF (fa/fa) rats provide a genetic model of type II
diabetes. These rats are obese and become spontaneously
hyperinsulinemic and diabetic at about 5 to 6 weeks of age. IGF-II
gene expression is reduced in brain, spinal cord, and peripheral
nerves in adult diabetic (fa/fa) versus nondiabetic (+/+)
(Zhuang et al., 1997; Wuarin et al., 1996)
. The brains
of (fa/fa) rats are smaller. IGF-I gene expression is reduced in
liver, but not in spinal cord or nerves. IGF-I, rather than IGF-II,
is responsible for regulating the rate of axon elongation during
(Pu et al., 1999)
. Because nerve IGF-I gene
expression is not reduced, nerve regeneration does not appear
to be impaired in type II diabetic rats. This is in contrast to
the type I diabetic rat where nerve IGF-I gene expression is
reduced and regeneration is impaired. These findings in rats is in
accordance with clinical data showing that nerve injury is more
extensive in type I than type II disease.
These data show that the IGF genes are under complex
regulation, and largely independent of hyperglycemia. IGF
levels are reduced in the prediabetic state prior to hyperglycemia,
and reduced further as a consequence of aging. It is
instructive that IGF-I and IGF-II gene expression are increased in
cultured hepatocytes directly in response to insulin
et al., 1991; Goya et al., 2001)
. Consequently, IGF gene
expression may decline in diabetes partially as a consequence
of the reduction in insulin activity rather than in response to
hyperglycemia. Because IGF-I treatment can normalize brain
IGF-II gene expression in diabetic rats independently of
hyperglycemia (Armstrong et al., 2000), there may be a cascade in
which a reduction of insulin activity leads to a decline in IGF-I
and a secondary decline in IGF-II. Because of complex
regulation, insulin may be able only to partially restore IGF levels in
Replacement IGF Doses Prevent or Reverse
Neuropathy in Diabetic Rats
Biochemical and electrophysiological measurements,
although interesting, are often difficult to relate directly to
symptomatic clinical disturbances. For example, conduction velocity
is reduced in virtually all diabetic patients, whereas clinical
neuropathy is observed in a much smaller fraction of patients. The
relationship of reduced conduction velocity to hyperalgesia or
impaired nerve regeneration is unknown. Concerning the latter,
nerves are known to regenerate normally even when conduction
is blocked with tetrodotoxin. Because the nexus between
biochemical and electrophysiology disturbances and symptomatic
disturbances are unclear, our studies have focused mainly on
functional end points.
IGF-I and IGF-II Treatments Prevent the Progression of Hyperalgesia
Supersensitivity to stimuli, or hyperalgesia, is a difficult
management problem in diabetic patients. Hyperalgesia is
observed in diabetic animals. Mechanical compression elicits paw
withdrawal when rats feel uncomfortable, and the threshold
force for withdrawal is gradually reduced with the onset of
hyperalgesia in STZ-diabetic rats. Osmotic minipumps were
implanted under the skin that released either vehicle or solvent
in diabetic rats. Infusion of either IGF-I or IGF-II arrested the
progression of hyperalgesia
(Zhuang et al., 1996)
Hyperalgesia also develops in the ZDF (fa/fa) obese and spontaneously
diabetic rat. IGF administration can reverse the hyperalgesia in
this model of type II diabetes
(Zhuang et al., 1997)
IGF-I and IGF-II Treatments Prevent or Reverse Impaired
There is daily wear-and-tear on the nervous system, and a
need to regenerate nerve terminals. Nerve regeneration is shown
to be impaired in diabetes
(Longo et al., 1986; Ekstrom and
, and this may directly contribute to the loss
of synapses and the dying back of axons.
Because it is known that IGFs normally regulate nerve
(Kanje et al., 1989; Near et al., 1992; Glazner et al.,
, and that IGF gene expression is reduced in diabetic
nerves (Wuarin et al., 1995), the IGF theory
predicts that replacement IGF therapy should prevent impaired
nerve regeneration in diabetes. Localized infusion of IGF-I
alongside a crush-injured nerve was shown to prevent the
impairment of sciatic nerve regeneration in STZ-diabetic rats
and Lupien, 1995)
. Additional studies now reveal that systemic
infusion of IGF-I or IGF-II can prevent or reverse impaired
(Ishii and Lupien, 1995; Zhuang et al., 1996;
. Single daily subcutaneous injections are effective as
well. These studies show that systemically administered IGFs
can act on nerve cells, and the blood-nerve barrier is not an
impediment. Systemically administered IGFs can reach ganglion
cells via fenestrated capillaries, have access to nerve terminals,
and can probably reach axons at nodes of Ranvier as well.
IGF-I Treatment Reverses Neuraxonal Dystrophy
Daily subcutaneous injections of IGF-I can reverse
ultrastructural damage to the sympathetic nervous system. This
treatment reverses by 86% the neuroaxonal dystrophy in the superior
mesenteric ganglion and ileal mesenteric nerves in rats diabetic
for 6 months
(Schmidt et al., 1999)
. Neuroaxonal dystrophy is
the hallmark of diabetic autonomic neuropathy, characterized
by swollen preterminal axons and synapses, and shown in
tissues obtained at autopsy from diabetic human subjects (Schmi
et al., 1993
IGF-I Treatment Prevents Impaired Wound Healing
Wounds heal poorly in diabetic patients, often progressing
to gangrene and limb amputations. The poor healing is closely
associated with development of neuropathy in diabetes. This
is not unexpected, because nerve injuries in themselves can
produce tissue atrophy, and the health of limbs is dependent
on an adequate nerve supply. IGF-I mRNA levels are reduced
in the gut mucosa, and gastric lesions heal poorly in diabetic
(Korolkiewicz et al., 2000)
. These investigators showed
that subcutaneous administration of IGF-I normalizes wound
healing in diabetic rats.
IGF-I Administered Systemically Crosses the Blood-CNS
Barrier and Prevents Impaired Learning/Memory
It is generally regarded that large molecules the size of IGFs
(molecular weight 7.5 kDa) do not cross the blood-CNS
barrier. It would appear, therefore, that to treat the CNS with IGFs,
an access hole would need to be drilled through the skull, a
procedure associated with significant risk of surgical mishap
or infection. However, recent studies show that IGFs can cross
the blood-CNS barrier. In a pioneering study, 8 minutes after
injection of 125I-IGF-I or 125I-IGF-II into the carotid artery,
radioactivity was detected in brain parenchyma by
autoradiography of brain slices
(Reinhardt and Bondy, 1994)
the half-life of free IGF is 5 to 10 minutes, and in 8 minutes,
approximately half of the radioactive IGF would be metabolized.
Because only a small percentage of the radioactivity enters the
brain, it was unclear whether the radioactivity detected in brain
parenchyma represented radioactive free iodine, iodinated IGF
fragments, or intact IGF. This issue was resolved by
withdrawing cerebrospinal fluid (CSF) after injecting 125I-IGF-I into the
carotid artery. The radioactivity in the CSF was subjected to
sodium dodecyl sulfate (SDS) gel electrophoresis, and some of
the radioactivity was observed to migrate together with
authentic IGF, showing that intact IGF molecules did cross the
(Armstrong et al., 2000)
. Further study showed that
the uptake of IGF into CSF was saturable, indicating that there
was an IGF transport molecule at the blood-CNS barrier, and
that the uptake process did not require IGF binding to IGFBP
nor to the type I IGF receptor
(Armstrong et al., 2000; Pulford
and Ishii, 2001)
. Calculations showed that the circulating levels
of endogenous IGF could contribute substantially to the IGF in
CSF, indicating that there is communication between IGF in
blood and brain.
Lesions are present in the central nervous system of diabetic
patients. For example, the brain ventricles are enlarged,
showing brain shrinkage
(Dejgaard et al., 1991; Araki et al., 1994)
Learning and memory are impaired in type I (Ryan et al., 1993)
and elderly type II
(Perlmuter et al., 1984; Tun et al., 1990)
diabetic patients. The incidence of dementia is nearly doubled in
diabetes, even in patients without cerebrovascular disease (Ott
et al., 1999). Like humans, STZ-diabetic rats have reduced brain
(Lupien et al., 2002)
, most likely as a consequence of
reduced size of the brain transcript pool
(Wuarin et al., 1996)
(Biessels et al., 1996)
. IGFs can
support hippocampal neurons
(Cheng and Mattson, 1992)
, and the
hippocampus plays a role in several forms of learning/memory.
IGF is essential for learning/memory, because infusion of an
anti-IGF antibody into the lateral ventricles of the brain can
block the acquisition of learning/memory
(Lupien et al., 2002)
IGF gene expression is reduced in the brain and spinal cord
in diabetes as discussed above. As in the case of the PNS,
these neurobiological observations, based on the IGF theory
, led to the prediction that IGF replacement would
prevent cognitive disturbances in diabetes. In fact it is found
that IGF-I administered by subcutaneous infusion can cross the
blood-CNS barrier and prevent impaired learning/memory in
(Lupien et al., 2002)
. IGF treatment may prevent
learning/memory disturbances and progression to dementia in
IGF Replacement Therapy Prevents Neuropathy During Ongoing Hyperglycemia
Many patients are unable to institute or maintain tight
glucose control, and many even with excellent glucose control
develop neuropathy. A treatment to prevent diabetic
neuropathy that is effective independently of glycemic state would
be welcome. Systemic as well as local infusion of IGF-I or
IGF-II prevents or reverses hyperalgesia
(Zhuang et al., 1996,
, impaired nerve regeneration
(Ishii and Lupien, 1995;
Zhuang et al., 1996)
, impaired wound healing (Korolkiewicz
et al., 2000), and disturbances in learning/memory
et al., 2002)
independently of ongoing hyperglycemia and
hypoinsulinemia in type I diabetic rats. In the latter study, rats
had ongoing hyperglycemia for 11.5 weeks. A sensitive index
of metabolic disturbance is weight loss, and the IGF treatment
did not prevent weight loss in these investigations. The doses
of IGF in these studies were small physiological replacement
doses (5 to 20 ? g/rat/day). Because IGF-I administration can
reduce amyloid-beta, which is implicated in the pathogenesis of
Alzheimer?s disease (Carro et al., 2002), this form of treatment
may prevent memory disturbances in Alzheimer?s disease as
In studies reversing neuraxonal dystrophy, a higher dose of
IGF-I was injected, subcutaneously, such that glucose levels
were transiently significantly reduced for 1 to 2 hours from
427 mg/dL to 418 mg/dL
(Schmidt et al., 1999)
. A control
group was treated with a low dose of insulin to replicate the
transient IGF effect on glucose, and insulin, unlike IGF, did
not reverse neuraxonal dystrophy. Consequently, neuraxonal
dystrophy most likely is specifically reversed by IGF rather
than the transient partial reduction in hyperglycemia.
IGF treatment reversed hyperalgesia in the ZDF (fa/fa)
model of type II diabetes independently of hyperglycemia,
hyperinsulinemia, and weight gain
(Zhuang et al., 1997)
Therefore, IGF treatment can prevent neuropathy in type I or type II
diabetes irrespective of hyperglycemia or direction of weight
change. Taken together, the data show that diabetic
neurological disorders as well as nephropathy can be treated
independently of hyperglycemia. It is clear that extensive biochemical
pathways involved in the etiology of neuropathy and
nephropathy are not blocked by the consequences of hyperglycemia,
and manipulation of growth factor levels can prevent diabetic
PHARMACOKINETICS OF IGFs
The pharmacokinetics of IGFs in man has been reviewed
(Ishii and Pu, 1999)
. The half-life of IGF-I is 8 to 20 hours
due to the formation of complexes with IGFBPs. The daily
production is about 40 to 50 ? g per kg per day, and the volume of
distribution is about 0.18 L/kg. Clinically efficacious levels can
be maintained for at least 16 hours by the subcutaneous route of
administration. The pharmacokinetics of IGF-II appears similar
from studies in a few patients, but additional study is needed in
larger numbers of subjects. These pharmacokinetic parameters
indicate that clinical trials may be conducted using a single daily
subcutaneous injection of IGFs. Formulation to enhance the
stability and extend the duration of IGFs would not be needed.
The daily production rate indicates that the most
appropriate IGF dose would be in the range of 15 to 40 ? g/kg/day. This
is a replacement dose, and replacement doses are effective in
diabetic rats. There are many successful examples of
replacement therapy. For example, insulin is replacement therapy for
diabetes in type I diabetic patients, glucocorticoids (cortisol,
prednisone, dexamethasone) are replacement therapy for
Addison?s disease, and mineralocorticoids are replacement therapy
for adrenal insufficiency.
Many diabetic patients are trained in self-administration of
insulin, and could easily adapt to IGF. There is a 50% failure
rate within 5 years of initiating use of oral hypoglycemic agents
in type II diabetes, and many of these patients convert to insulin
use. Thus, 40% of the total diabetic population (types I and II)
self-inject insulin, and daily IGF subcutaneous administration
would require a minimum of patient education.
SAFETY OF IGF ADMINISTRATION
Humans normally have high levels of IGF-I and IGF-II in the
circulation. Because the goal of replacement therapy is to return
the depleted levels of IGF in diabetic patients back to normal,
side effects are not anticipated. The safety and pharmacology of
IGFs have been reviewed
(Ishii and Pu, 1999)
. A good deal has
been learned about the safety of IGF products. No significant
side effects were encountered in diabetic patients treated for
24 weeks with 20 and 40 ? g/kg/day IGF-I
(Acerini et al., 1997)
Both retinopathy and nephropathy were monitored, and IGF-I
did not cause progression. IGF-I is approved for the treatment
of Laron dwarfs in Japan. These patients have growth hormone
deficiency and an extreme form of insulin resistance; high IGF
doses are administered.
Vascular endothelial growth factor (VEGF) is believed to
contribute to diabetic proliferative retinopathy, but conclusive
evidence of IGF-1 involvement in diabetic retinopathy is
lacking. In a careful study,
Simo et al. (2002)
as well as VEGF levels in the vitreous fluid from diabetic
patients with retinopathy and corrected for increased
leakiness of retinal blood vessels. After correcting for serum
proteins, it was found that VEGF levels are significantly higher,
whereas free active IGF-I levels are lower in the vitreous of
patients with proliferative diabetic retinopathy versus
nondiabetic subjects. Moreover, IGF-I mRNA levels are lower in
diabetic versus nondiabetic retinas in humans
et al., 2001)
(Lowe et al., 1995)
. Consequently, free
IGF-I levels are not correlated with VEGF levels or
proliferative retinopathy. These data are consistent with the observation
that an increased incidence of retinopathy is not observed in
acromegaly patients with or without diabetes
(Ballintine et al,
1981; Sonken et al., 1993; Cogessal and Root, 1940)
hormone increases IGF-I and GH is increased in acromegaly.
In a 2-year prospective study in type II diabetic patients, the
level of IGF-I was progressively reduced during insulin
treatment, whereas retinopathy progressively worsened; no
relationship was established between level of IGF-I and progression of
(Henricsson et al., 1999)
. In a 6-year study,
et al. (1995)
came to the same conclusion. Intraocular IGF-I
levels are mainly derived from the circulation because IGF-I
as well as serum albumin together leak into the eye in
(Spranger et al., 2000)
. Early treatment with
an IGF-I analog can prevent early predegenerative changes in
(Kummer et al., 2003)
. A somatostatin analog,
ocreotide, was reported to prevent the progression of
proliferative diabetic retinopathy
(Grant et al., 2000)
however, pointed out the problems in the experimental design,
including that the baseline retinopathy scores of the control and
treated groups were not compared, the treated group had lower
HbA1C levels, and treated patients may have managed
themselves better because there was an open label design. Hence,
these results were not interpretable. Further studies would be
Unnaturally high, or supraphysiological, doses of IGF-I can
cause side effects
(reviewed in Ishii and Pu, 1999)
. High doses
of IGF-I (60 to 220 ? g/kg/day, subcutaneous) intended to
prevent hyperglycemia in type II diabetic patients may cause side
effects, including hypoglycemia, arthalgia, myalgia, edema,
bilateral jaw tenderness, tachycardia, papilledema, orthostatic
hypotension, nausea, facial pallor or flushing, hand tremors,
headaches, dyspnea, and hand erythema. These untoward
effects were all reversible following withdrawal of IGF treatment.
IGF-I doses below 50 ? g/kg/day are well tolerated.
IGF-II is not, but IGF-I is, associated with prostate cancer
(Chan et al., 1998)
. IGF-I is also associated with breast cancer.
IGF-I levels may be elevated because tumors produce IGF-I.
Similarly, insulin is a mitogen and is produced by some tumors.
The safety issues for IGFs and insulin have many similarities.
For example, normal humans have approximately 150 ng/mL
IGF-I and 400 ng/mL IGF-II in their circulation, but normal
humans do not have an abnormal risk of cancer. Generally
cancer risk increases with aging when IGF-I levels are reduced
(Tan and Baxter, 1986)
. In diabetic neuropathy, patients have
50% reduced levels of IGF-I, and replacement therapy intended
to normalize IGF levels is not expected to increase cancer risk.
Returning IGF levels to normal in diabetic patients seems likely
to be associated with normal, not excessive, risk. Interestingly,
diabetic patients have been treated for decades with insulin,
and the high doses of insulin at the subcutaneous injection site
would cross-occupy type I IGF receptors, but this is not known
to increase cancer risk.
Growth hormone is used clinically and can elevate IGF-I
Cohen et al. (2000)
have reviewed the risks and
concluded that causality has not been established between cancer
risk and IGF-I levels, and that growth hormone?treated patients
in which IGF-I levels are brought up to normal levels should not
have cancer risk increased above the normal population.
Circulating IGF-I appears to have less effect on tissue growth than
IGF-I produced within tissues. This is clear because
inactivation of the IGF-I gene exclusively in liver, which results in 70%
reduction of circulating IGF-I, has no effect on body weight
or length in mice
(Yakar et al., 1999)
. This result suggests that
the administration of IGF to increase circulating levels is much
less likely to cause cancer risk than experimental procedures in
which the IGF gene is overexpressed in tissues of transgenic
Nevertheless, there is the important issue of whether IGF
may cause progression of existing tumors. Colon
adenocarcinomas developed more rapidly when transplanted to mice with
higher IGF-I levels (Wu et al., 2002). As in other forms of
hormone replacement therapy, it would seem prudent that IGF-I
be contraindicated in existing tumors.
A decline in IGF activity is proposed to contribute to
the pathogenesis of diabetic neurological complications
. This theory provides a rational basis both for the design
of testable hypotheses and therapeutic treatment. The theory
predicts with a high success rate that IGF treatment, intended
to replace the IGF levels diminished in diabetes, can prevent or
reverse diabetic neurological disturbances, particularly those
neural functions normally governed by IGFs. The observation
that IGF replacement therapy can prevent or reverse
neurological disturbances in both the central and peripheral nervous
systems in diabetes is a powerful indication that these
neurological disturbances share a common etiology, namely loss of
IGF activity. Heretofore, the literature on central and peripheral
neurological diabetic disturbances have been separate, and the
new data may help merge these fields of investigation.
The theory further predicts and finds that IGF may
prevent neurological disturbances independently of ongoing
hyperglycemia. Clinical trial shows that the progression of renal
disease likewise can be prevented in diabetic patients by
treatments that do not target glycemic control. These data together
show that a large number of complex biochemical pathways
involving pathogenetic processes in peripheral nerve, brain, and
kidneys are not blocked by the consequences of hyperglycemia.
Disturbances to these pathways can be prevented and/or
reversed by increasing or inhibiting growth factor responses
independently of ongoing hyperglycemia. This realization may
help fuel the development of new therapeutic approaches to
treat diabetic complications.
The pharmacokinetic and safety profiles of IGFs are
satisfactory for consideration of clinical trials for IGF treatment of
diabetic neuropathy. A major challenge is to find support for
clinical trials. For example, there is no mechanism by which
the National Institutes of Neurological Disorders and Stroke
or National Institute of Diabetes, Digestive and Kidney
Disorders can fund the acquisition of clinical grade IGFs for
trials. The cost of drug acquisition can exceed the other costs
of a clinical trial. A change in Institute policy is needed to
permit basic research developed under National Institutes of
Health (NIH)-funded research to be rapidly moved into the
clinics. The National Cancer Institute provides a model by which
manufacturing might be accomplished. It supports a center that
synthesizes promising small drug candidates under
manufacturing guidelines set by the Food and Drug Administration (FDA).
A similar center is needed for the synthesis of promising
therapeutic proteins. The successful human genome project is likely
to uncover many additional promising therapeutic proteins, and
the efficient testing of new therapies will be greatly aided by
the availability of an NIH-supported center for the production
of clinical grade therapeutic proteins.
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