Impaired glucose tolerance and metabolic syndrome in idiopathic neuropathy

Journal of the Peripheral Nervous System 17(Supplement):15-21 (2012)
REVIEW
Impaired glucose tolerance and metabolic syndrome
in idiopathic neuropathy
A. Gordon Smith
Division of Neuromuscular Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
Abstract Idiopathic neuropathy is one of the most common clinical problems
encountered in general medical and neurological practices, accounting for up to 40%
of all neuropathies in referral series. Several groups have reported an elevated prevalence
of impaired glucose tolerance (IGT) in idiopathic neuropathy subjects, although the only
carefully conducted case-control study suggested hypertriglyceridemia was a more
important risk factor. The nature of the relationship between IGT and neuropathy is a
subject of active debate. An evolving literature suggests metabolic syndrome, particularly
dyslipidemia and obesity, are potent neuropathy risk factors for both idiopathic and diabetic
neuropathy patients. Once established, diabetic neuropathy is likely to be very difficult
to reverse. IGT-associated neuropathy, however, may be more amenable to therapy
and could represent an ideal population in which to examine potential therapies for
diabetes and obesity related neuropathies. Further research is needed to better define
the epidemiological relation between IGT, metabolic syndrome, and neuropathy, its
underlying pathophysiology, and to develop appropriate surrogate measures and clinical
trials strategies.
Key words: diabetes mellitus, idiopathic peripheral neuropathy, impaired glucose tolerance,
metabolic syndrome, obesity
Introduction
amajor cause of patient morbidity due to pain and
gait instability. It is likely that idiopathic neuropathy
Peripheral neuropathy is a common clinical prob-
represents a heterogeneous spectrum of underlying
lem. Over 10% of people over the age of 40 have
causes. However, several groups have observed a
neuropathy, and diabetes is the most common cause
higher than expected prevalence of pre-diabetes in
(Gregg et al., 2004). However, even after extensive
patients with idiopathic neuropathy compared with
evaluation, no cause is found in over one-third of
population normative data. Pre-diabetes is defined
patients in series from referral centers (`idiopathic'
based on either a hemoglobin A1c or an oral glucose
or `cryptogenic' neuropathy) (Dyck et al., 1981). Idio-
tolerance test (OGTT) performed after an overnight
pathic neuropathy represents one of the most com-
fast. Pre-diabetes is further defined as impaired fast-
mon causes of peripheral neuropathy in referral-based
ing glucose (IFG) or impaired glucose tolerance (IGT)
series (Dyck et al., 1981). Idiopathic neuropathy is
(Table 1). Pre-diabetes is a known risk factor for overt
diabetes and its macrovascular complications (Single-
ton et al., 2003). However, the relationship between
Address correspondence to: Prof. A. Gordon Smith, MD, Division of
pre-diabetes and neuropathy is a source of debate.
Neuromuscular Medicine, University of Utah School of Medicine, 30
This article summarizes the data linking neuropathy
North 1900 East SOM 3R242, Salt Lake City, UT 84132, USA.
and pre-diabetes with a focus on the potential role
Tel: +1 801-585-1737; Fax: +1 801-585-2054; E-mail: Gordon.
smith@hsc.utah.edu
of metabolic syndrome and its component features.
(c) 2012 Peripheral Nerve Society
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Smith
Journal of the Peripheral Nervous System 17(Supplement):15-21 (2012)
Table 1. Diagnostic criteria for diabetes and pre-diabetes.
Diagnosis
Fasting plasma glucose
2-hour OGTT
Hemoglobin A1C
Normal
<100 mg/dl (5.6 mmol/l)
<140 mg/dl (7.8 mmol/l)
<5.7%
Pre-diabetes
100-125 mg/dl (5.6-6.9 mmol/l)
140-199 mg/dl (7.8-11.0 mmol/l)
5.7-6.4%
Diabetes
126 mg/dl (7.0 mmol/l)
200 mg/dl (11.1 mmol/l)
6.5%
The potential underlying pathophysiology, treatment
a significantly higher serum triglyceride concentration
options, and future lines of research are discussed.
in patients compared with control subjects. A logistic
regression analysis also suggested exposure to
environmental toxin's increased the risk (Hughes et al.,
Idiopathic Neuropathy and IGT
2004). While these results suggest pre-diabetes may
not be a significant risk for neuropathy, they do
The recognition of a potential link between pre-
implicate hyperinsulinemia in painful neuropathy and
diabetes and neuropathy has its origin in the clinical
hypertrigylceridemia in neuropathy risk in general.
observation that many idiopathic neuropathy patients
If pre-diabetes has a risk or causal relationship
share phenotypic characteristics of diabetes, such
to neuropathy, one would expect subjects with pre-
as obesity, hypertension, and dyslipidemia, without
diabetes to have a higher risk of neuropathy. Several
having overt diabetes. This led several groups to
studies have attempted to examine this question.
examine the prevalence of pre-diabetes using OGTT.
The MONICA/KORA study examined the risk of
These studies revealed a prevalence of IGT in
neuropathic pain in 195 diabetic patients and 198
otherwise idiopathic neuropathy patients of 40-50%
age- and gender-matched controls. IGT was present in
(Novella et al., 2001; Singleton et al., 2001a; 2001b;
23.2% and IFG in 36%. The prevalence of neuropathic
Sumner et al., 2003; Smith and Singleton, 2004). This
pain was 13.3% in diabetics, 8.7% in IGT, 4.2% in
compares to a population prevalence of approximately
IFT, and 1.2% in normal subjects. Aside from IGT,
15% in a similarly aged population (Harris et al., 1987).
age obesity and peripheral artery disease increased
There appears to be a gradient of risk which is lowest
painful neuropathy risk (Ziegler et al., 2009). In the
in control subjects and increases with the transition to
same cohort, overall neuropathy risk was evaluated
IFG to IGT and overt diabetes (Papanas et al., 2011).
using the Michigan Neuropathy Screening Instrument.
While the observation of a high prevalence
Neuropathy was present in 28% of diabetic, 13% of
of IGT in idiopathic neuropathy is nearly uniform,
IGT, 11.3% of IFT, and 7.4% of control subjects (Ziegler
particularly in North American series, these studies
et al., 2008). Small studies evaluating nerve function
have not examined case-controls, but have compared
have described abnormal nerve conduction studies
prevalence to that published in the literature. This leads
(Sahin et al., 2009), sympathetic skin responses (Isak
to several potential problems. There is potential bias in
et al., 2008), and laser Doppler flare (Green et al.,
studies of subjects referred with painful neuropathy
2010) and have demonstrated a higher prevalence
to researchers with a known interest in diabetic
of abnormalities in IGT populations compared with
neuropathy. Another potential pitfall is the growing
controls.
prevalence of obesity. It is likely that the population
A recent case-control study examined subjects
prevalence of IGT in non-neuropathy subjects is
with either IFG or IGT and age- and gender-matched
climbing. These issues have led some investigators
normal and diabetic subjects for neuropathy. Pre-
to question the risk relationship between IGT and
diabetes subjects were identified retrospectively in
neuropathy (Dyck et al., 2007a).
a single county (Olmsted County, MI, USA). Nerve
one carefully controlled neuropathy case-control
conduction studies served as minimal criteria for
study has been performed (Hughes et al., 2004)
neuropathy. Using these criteria 2% of pre-diabetic
comparing 50 consecutive patients with idiopathic
and control subjects had neuropathy compared with
neuropathy to control subjects from the same region.
7.8% of diabetic patients. Using `broad criteria' that
Pre-diabetes was present in 30% of neuropathy
included patients with another diagnosis than diabetes
patients compared with 14% of control subjects. This
(e.g., lumbar disc disease), 12% of pre-diabetic and
difference was not significant when controlled for
control subjects had neuropathy compared with 17.4%
age and gender. However, the mean fasting insulin
of diabetics (Dyck et al., 2012). These findings suggest
levels remained significantly higher among neuropathy
there may not be an elevated risk of neuropathy
patients who had pain (p < 0.0001). After controlling
among pre-diabetic subjects. However, this study
for body mass index (BMI), age, and gender, there was
has a number of limitations. Neuropathy associated
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Smith
Journal of the Peripheral Nervous System 17(Supplement):15-21 (2012)
with IGT may involve small axons preferentially and
risk factors. Among 28,700 diabetic patients, serum
many patients have normal nerve conduction studies
triglyceride level was an independent stepwise risk
(Smith et al., 2006). It is likely that IGT carries a
factor for lower extremity amputation (Callaghan et al.,
higher neuropathy risk than IFG (Singleton et al.,
2011). Among 1172 T1D subjects without baseline
2003), and 18% of IFG subjects refused OGTT. Lastly,
neuropathy followed in the Eurodiab study, hyper-
the prevalence of neuropathy in this population was
tension, smoking, obesity, and serum triglycerides
surprisingly low (2%), suggesting the cohort may not
were independent risk factors for neuropathy (Tes-
be representative of the larger population. Despite
faye et al., 2005). A series of studies have examined
these limiations, this study emphasizes the need
neuropathy risk factors among subjects who under-
for additional, larger, carefully designed case-control
went sequential sural nerve biopsies as part of aldose
studies examining the risk relationship between
reductase inhibitor clinical trials. Subjects were divided
pre-diabetes, metabolic syndrome, and peripheral
into those who had progressive neuropathy and those
neuropathy.
who did not. Progressors had significantly higher base-
The clinical phenotype of pre-diabetes-associated
line triglycerides controlling for other relevant variables
neuropathy is similar to painful idiopathic sensory
(Wiggin et al., 2009). More recently, this same group
predominant
neuropathy.
Subjects
complain
of
has taken advantage of the banked tissue to examine
burning or tingling foot pain. Weakness is rarely
gene expression profiles in those whose neuropathy
present. The diagnostic evaluation often reveals
progressed compared to those whose neuropathy did
normal nerve conduction studies, and diagnostic
not. A total of 532 genes were differentially expressed.
confirmation requires use of validated measures of
These genes were clustered in pathways relevant for
small fiber function, most frequently skin biopsy with
inflammation and lipid metabolism. In particular, net-
assessment of intraepidermal nerve fiber density,
works involving apolipoprotein E, jun, leptin, serpin
which is abnormal in the majority of patients (Smith
peptidase inhibitor E type 1, and peroxisome prolifera-
et al., 2001).
tor activated receptor gamma appeared most relevant
(Hur et al., 2011). Together these studies and others
suggest toxic adiposity and dyslipidemia may be much
Metabolic Syndrome as a Neuropathy
more important contributors to diabetic neuropathy
Risk Factor
risk than has previously been recognized.
There is an evolving literature linking obesity
The literature linking obesity and its complications
and its complications to neuropathy risk in patients
to diabetic neuropathy are mirrored by a growing
with and without diabetes. There is clear evidence
consensus that they also play a potential role in
from the Diabetes Control and Complications Trial
idiopathic neuropathy. Obesity is a core feature of
(DCCT) that intensive glycemic control reduces risk
the metabolic syndrome, which also consists of
of neuropathy in patients with type 1 diabetes (T1D).
elevated triglycerides, low high-density lipoprotein
While it is generally accepted that poor glycemic
(HDL) cholesterol, insulin resistance, and hypertension
control increases neuropathy risk in type 2 diabetes,
(the
presence
of
3/5
defines
the
syndrome).
there is minimal data to support a reduced neuropathy
Metabolic syndrome is associated with elevated risk
risk in those receiving intensive versus conventional
of macrovascular outcomes including stroke and
glucose lowering therapy. While the United Kingdom
myocardial infarction. Data from studies examining
Prospective Diabetes Study (UKPDS) demonstrated a
the relationship between pre-diabetes and neuropathy
reduced risk of reduced vibration sensation assessed
support a risk relationship between aspects of
with a biothesiometer (Stratton et al., 2000), there
metabolic
syndrome,
including
dyslipidemia
and
was minimal data suggesting a reduced risk of
obesity, and neuropathy (Ziegler et al., 2008; 2009).
clinical neuropathy. The largest studies to address this
The only carefully performed neuropathy case-control
question include the Action to Control Cardiovascular
study identified hypertriglyceridemia as a neuropathy
Risk in Diabetes (ACCORD) and Veterans Affairs
risk factor (Hughes et al., 2004). Metabolic syndrome
Diabetes Study studies. Neither demonstrated a
may prove an important neuropathy risk factor
significant reduction in clinically defined neuropathy
even in the absence of glucose intolerance. Among
with intensive versus conventional glycemic control
219 sequential subjects with idiopathic neuropathy
(Duckworth et al., 2009; Ismail-Beigi et al., 2010).
who underwent a complete neuropathy evaluation,
These studies suggest there are important risk factors
metabolic syndrome was present in 86% of those
aside from hyperglycemia that predict neuropathy risk
with IGT and 54% of those with normal glucose
in diabetes.
tolerance. Over 80% of the normal glucose tolerance
Obesity related complications, including dyslipi-
group had lipid abnormalities (elevated triglycerides,
demia, might be particularly important neuropathy
reduced HDL, or a history of dyslipidemia requiring
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Smith
Journal of the Peripheral Nervous System 17(Supplement):15-21 (2012)
medical therapy) (Smith et al., 2008). Given that
et al., 2003). Insulin resistance and dyslipidemia are
those with normal glucose tolerance are expected
intertwined, self-reinforcing processes that are inti-
to have a lower risk of metabolic syndrome and
mately associated with obesity (Lewis et al., 2002).
dyslipidemia than the general population, these figures
In obesity, as skeletal muscle loses insulin sensitiv-
are striking. By comparison, the risk of dyslipidemia in
ity, more glucose is taken up by adipocytes, stim-
the normal glucose tolerant population in the Finnish
ulating production and release of free fatty acids
Diabetes Prevention Study was 33% (Ilanne-Parikka
and triglycerides, and increasing adiposity. Triglyc-
et al., 2004).
erides and free fatty acids, when accumulated out-
Several small studies link obesity and idiopathic
side of adipocytes (for instance in muscle or liver)
neuropathy. Among 58 morbidly obese subjects,
are considered `ectopic'. Intracellular muscle and
there was evidence of small fiber axonal dysfunction
liver steatosis potently decrease insulin sensitivity in
irrespective of the presence of diabetes (and despite
these tissues (Samocha-Bonet et al., 2010), in part
the fact that all but four subjects were asymptomatic)
by increasing protein kinase C-mediated phosphory-
(Herman et al., 2007). Another small study of 20
lation of insulin receptor substrate-1 (Morino et al.,
obese non-diabetic subjects demonstrated abnormal
2006). Elevated circulating free fatty acids promote
compound muscle and sensory nerve action potential
hyperglycemia by stimulating hepatic gluconeogenesis
amplitudes as well as abnormal sensory thresholds
and potently inhibit endothelial nitric oxide synthe-
compared with 20 age-matched control subjects.
sis and vasodilation (Pleiner et al., 2002; Esenabhalu
et al., 2003). Tumor necrosis factor- is also released
from enlarged adipocytes, where it increases oxida-
Animal Models Support a Relationship
tive stress, reduces insulin receptor expression, and
Between Metabolic Syndrome and
promotes endothelial injury (Boyanovsky et al., 2003).
Conversely, enlarged adipocytes reduce expression
Neuropathy
of the vasoprotective agent adiponectin, accelerat-
Animal models of diet-induced obesity, including
ing endothelial cell proliferation, and macrophage-
various transgenic mice, Zucker fatty rats, and fat-
mediated atherosclerotic injury (Ukkola and San-
fed Harlan Sprague Dawley rats, have demonstrated
taniemi, 2002). Ectopic adipose accumulation results
both microvascular and neural dysfunction in non-
in lipotoxic injury to multiple organs via several addi-
hyperglycemic animals (Oltman et al., 2005; Obrosova
tional mechanisms including direct effects of elevated
et al., 2007; Davidson et al., 2010). These studies
plasma free fatty acids to generate diacylglycerols and
show decreased vascular relaxation and impaired
toxic lipid metabolites such as long-chain fatty acyl
nerve conduction velocity, endoneurial blood flow, and
CoAs, acyl carnitine products of incomplete fatty acid
thermal nociception. C57Bl6/J mice fed a high-fat diet
oxidation, ceramides, and lipid peroxides. Lipid peroxi-
develop obesity, moderate non-fasting hyperglycemia
dation is a commonly used marker for oxidative stress
and neuropathy (Obrosova et al., 2007). Non-diabetic
that may be assessed by measuring the level of thio-
mice fed a high-fat diet develop increased levels of
barbituric acid reactive substance (TBARS). TBARS is
oxidized low-density lipoprotiens, free fatty acids, and
elevated in serum from diabetic patients (Celiker et al.,
triglycerides, as well as evidence of increased systemic
2002). Data from a dorsal root ganglion culture model
and nerve oxidative stress. These mice develop nerve
of diabetes demonstrated that hyperglycemia results
conduction velocity and sensory deficits before IGT
in elevated TBARS and 8-isoprostane leading to neu-
(Vincent et al., 2009). These findings are highly relevant
ronal apoptosis that can be prevented by application of
to neuropathy seen in human subjects with insulin
the antioxidant alpha lipoic acid (Vincent et al., 2005).
resistance, obesity, and dyslipidemia. Rodent models
Diabetic patients exhibit evidence of lipid peroxidation
of obesity will be useful to investigate dietary and
of erythrocyte membranes, which in turn are more
pharmacological approaches to halt progression and
susceptible to exogenously generated oxidative stress
reverse diabetic neuropathy, ideally at the earliest
(Ahmed et al., 2006). It is possible that lipid peroxi-
stages of the disease (Oltman et al., 2009).
dation and oxidative stress directly injure peripheral
nerves even in the absence of diabetes.
Pathophysiology
Peripheral Neuropathy Associated with
Cellular and molecular consequences of obesity
Pre-diabetes is Potentially Treatable
closely reflect recognized pathogenic mechanisms in
diabetic neuropathy, especially nitric oxide inhibition,
Once neuropathy becomes established it is diffi-
vascular dysregulation, and oxidative injury (Singleton
cult if not impossible to reverse. Data from pancreatic
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Smith
Journal of the Peripheral Nervous System 17(Supplement):15-21 (2012)
transplantation studies indicate neuropathy stabilizes
may be a causal relationship. There are two avenues
but does not improve following transplant (Navarro
of human subject investigation that have potential to
et al., 1997). There is broad consensus that therapeutic
answer the questions of `if' and `why' pre-diabetes is
trials in diabetic neuropathy should focus on subjects
associated with neuropathy. An epidemiological study
with early neuropathy. However, multiple treatment
comparing neuropathy risk in a diverse population-
trials in early diabetic neuropathy have failed, and data
based sample of pre-diabetic subjects to age- and
from natural history studies and the placebo arms of
gender-matched controls or a large case-control study
controlled studies indicate early diabetic neuropathy
of neuropathy subjects examining metabolic features
changes slowly (Dyck et al., 2007b). This leads to a
compared with matched controls without neuropathy
`therapeutic paradox' where one is unable to measure
would be illustrative. Either approach must examine
progression at the disease stage when therapy is most
the relationship between neuropathy risk and other
likely to succeed. There are several approaches to this
features of metabolic syndrome, particularly obesity
problem. Development of validated surrogate mea-
and dyslipidemia and should include subjects with
sures of early diabetic neuropathy that are sensitive to
small fiber predominant neuropathy using established
a potential therapeutic effect might be used to demon-
diagnostic criteria. These studies would of necessity be
strate efficacy. Such surrogate measures could be
very large and expensive and neither seems likely in the
used in prevention studies involving high risk diabetic
foreseeable future. Another approach is to indirectly
patients (e.g., those with obesity and dyslipidemia).
prove a causal relationship by showing a therapeutic
Another approach is to focus therapeutic efforts
intervention results in slowed progression or even
on neuropathy patients with pre-diabetes, before the
improvement in pre-diabetes-associated neuropathy.
onset of frank diabetes. The impaired glucose tol-
Several potential therapies might be tested including
erance neuropathy (IGTN) Study was a multicenter
lipid lowering and aggressive glycemic control. The
NIH funded pilot project designed to characterize the
IGTN study suggests a randomized trial of lifestyle
neuropathy associated with IGT and develop small
intervention may be appropriate. There is support for
fiber-specific clinical instruments for its evaluation. All
this approach in the diabetic neuropathy literature.
IGTN subjects received individualized diet and exercise
The potential efficacy of treating metabolic syndrome
counseling based on that used in the Diabetes Preven-
features among diabetic subjects was tested in the
tion Program (Tuomilehto et al., 2001), with goals of
Steno-2 study which showed subjects randomized
reducing weight by 7% and achieving 150 min of aer-
to receive aggressive multifactorial treatment of
obic exercise weekly. In this uncontrolled study, 65
hypertension and lipid abnormalities were significantly
subjects were counseled for at least 1 year. Following
less likely to develop autonomic neuropathy as well
1 year of counseling, there was significant improve-
as coronary or cerebral vascular disease than those
ment in multiple features of metabolic syndrome
who underwent standard of care therapy (Gaede
including BMI, OGTT, cholesterol, and triglycerides.
et al., 2003). A similar trial in subjects with pre-
This metabolic improvement was associated with sig-
diabetes and neuropathy would be feasible, although
nificant improvement in measures of small fiber func-
highly complex. A lifestyle intervention would have a
tion including intraepidermal nerve fiber density and
similar effect (weight loss, improved insulin sensitivity,
quantitative sudomotor axon reflex testing. The change
improved lipid measures) but would be much easier
in fiber density correlated with several other neuropa-
from a logistical perspective. Such a proof of concept
thy measures including improvement in pain assessed
study is achievable and represents the logical next step
using the visual analog scale (p < 0.05). These find-
in the effort to better understand how pre-diabetes
ings suggest lifestyle intervention improves metabolic
and metabolic syndrome influence neuropathy risk and
parameters resulting in recovery of small fiber function
progression.
(Smith et al., 2006). This neuropathy improvement is
significant given that the natural history of intraepider-
Disclosure
mal nerve fiber density in IGT neuropathy is of slow
progression.
The author received funding for this study from
NIH (R01DK064814) and the American Diabetes
Association (ADA7-08-CR-52).
Future Directions
While the data supporting a relationship between
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