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COMMENT
By Aaron I. Vinik
MD, PhD, FCP, MACP, FACE
T
he explosion in the epidemic of obesity
in the US and globally is closely being
followed by an epidemic in diabetes.
Somewhat disconcerting is the 44% increase
in type 2 diabetes in children, many of whom
will not live beyond 30 years of age because
of the early development of diabetes and its
complications, including neuropathy. There
is also a growing consensus that obesity
and dyslipidemia are critical contributors to
neuropathy in diabetes. Among a cohort of
217 patients participating in the Utah Dia-
betic Neuropathy Study without neuropathy
symptoms, or with symptoms for fewer than 5
years, obesity andmetabolic syndromewere
potent neuropathy risk factors. The relative
risk of diabetic peripheral neuropathy (DPN)
was 4.0 (95% CI, 1.1–14.4) for those with met-
abolic syndrome and 4.1 (95% CI, 1.1–15.0) for
obese participants (P < 0.02).
Metabolic syndrome is associated with
neuropathy risk in human disease and ani-
mal models.
The type of neuropathy is frequently a sen-
sory/motor neuropathy as occurs in DPN.
More frequently, cryptogenic sensory
polyneuropathy (CSPN) is found to co-segre-
gatewithmetabolic syndromeor prediabetes
in up to 70%of cases. Multiple animal models
of diet-induced obesity demonstrate neurop-
athy with loss of intraepidermal nerve fibers
(IENF), which is reversible with a program
of exercise and nutritional restriction. Exer-
cise-based lifestyle interventions improve
metabolism and result in nerve regeneration
in prediabetic and diabetic neuropathy. Exer-
cise increases insulin production, reverses or
prevents diabetes, and reduces neuropathic
pain, inflammatory cytokine production, and
nerve conduction study (NCS) features of
neuropathy in animal models.
Studies, including the Diabetes Preven-
tion Program (DPP), demonstrate that
exercise and diet counseling may normal-
ize metabolic syndrome features (obesity,
hypertriglyceridemia) and reduce diabetes
risk. The Impaired Glucose Tolerance Neu-
ropathy trial, led by the University of Utah,
provided a DPP-based intervention to 32
impaired glucose tolerance (IGT) patients
with neuropathy. After 1 year, there was sig-
nificant improvement in weight, glucose
tolerance, and lipid parameters, and signif-
icant improvement in intraepidermal nerve
fiber density (IENFD) and neuropathic pain.
Similarly, in a 4-year randomized trial, type 2
diabetic participants without baseline DPN
assigned to 4 hours of observed treadmill
walkingweekly improved vibration detection
and NCS, and were significantly less likely to
develop neuropathy symptoms than controls.
The Look AHEAD study began in 2001 with
5145 overweight or obese people with
type 2 diabetes aged 45 to 76 years old
randomized to intensive life style interven-
tion (ILI; n= 2570) or a diabetes support and
education group (DSE; n= 2575), and the
interventions were terminated in Septem-
ber 2012, 9 to 11 years after randomization.
Patients completed annually the Michigan
Neuropathy Screening Instrument (MNSI),
a compendium of 15 questions related to
symptoms of neuropathy, and an examina-
tion and measurement of touch perception
with a 10-g monofilament. The MNSI has
15 questions, 13 of which are positive and
2 are negative, with a maximal total score
of 15. The NMSI physical exam scores
1 point for each of deformities, dryness and
cracking of skin, loss of sensory percep-
tion, absence of ankle reflexes, and loss
of vibration perception. Scores above 2.5
Effects of a long-term
lifestyle modification
program on peripheral
neuropathy in obese adults
with type 2 diabetes
Diabetologia
Take-home message
•
The authors of this randomized study investigated the effect of a long-term, inten-
sive lifestyle intervention (ILI) on diabetic peripheral neuropathy in overweight and
obese individuals with type 2 diabetes. A total of 2570 patients were assigned to
ILI, and 2575 were assigned to a control group who received diabetes support
and education. Interventions continued for 9 to 11 years after randomization. The ILI
group experienced more weight loss and achieved better scores on a neuropathy
screening tool than the control group 1 year after the interventions began. After
the interventions were terminated, there was no difference between the groups
in physical exam measures for peripheral neuropathy except for better light touch
sensation in the ILI group. Changes in neuropathy screening tool score were
strongly correlated with changes in HbA1c, lipid profiles, and body weight in both
treatment groups.
•
Intensive lifestyle intervention resulted in significant weight loss and some modest
improvements in measures of peripheral neuropathy in overweight and obese
individuals with type 2 diabetes.
Abstract
AIMS/HYPOTHESIS
The aim of this study was to
evaluate the effects on diabetic peripheral
neuropathy (DPN) of a long-term intensive life-
style intervention (ILI) programme designed to
achieve and maintain weight loss.
METHODS
Beginning in 2001, a total of 5145 over-
weight or obese people with type 2 diabetes,
aged 45-76 years, participating in the multicentre
Look AHEAD (Action for Health in Diabetes) study
were randomised to ILI (n = 2570) or to a diabe-
tes support and education (DSE) control group (n
= 2575) using a web-based management system
at the study coordinating centre at Wake Forest
School of Medicine (Winston-Salem, NC, USA).
Randomisationwas stratified by clinical centre and
was not revealed to the clinical staff responsible
for obtaining data on study outcomes. Because of
the nature of the study, patients and the local cen-
tre interventionists were not blinded to the study
group assignments. In addition, the coordinating
centre staff members responsible for data man-
agement and statistical analyses were not blinded
to the study group assignments. The interventions
were terminated in September 2012, 9–11 years
after randomisation, but both groups continued
to be followed for both primary and secondary
The Holy Grail for
neuropathy is an agent that
addresses the underlying
biology of the disease, and
there are many in the wings
including gene therapy.
MICROVASCULAR COMPLICATIONS
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