Diabetes Care Volume 38, May 2015 793

C. Christine Lee,1 BruceA.Perkins,2 Peripheral Neuropathy and Nerve Sheena Kayaniyil,1 Stewart B. Harris,3 Ravi Retnakaran,2,4 Hertzel C. Gerstein,5 DysfunctioninIndividualsatHigh Bernard Zinman,2,4 and Risk for Type 2 Diabetes: The Anthony J. Hanley1,2,6 PROMISE Cohort Diabetes Care 2015;38:793–800 | DOI: 10.2337/dc14-2585 PDMOOYHAT EVCSRESEARCH SERVICES EPIDEMIOLOGY/HEALTH

OBJECTIVE Emerging evidence suggests that peripheral neuropathy begins in the early stages of diabetes pathogenesis. Our objective was to describe the prevalence of peripheral neuropathy and nerve dysfunction according to glucose tolerance and metabolic syndrome status and examine how these conditions are associated with neurological changes in individuals at risk for type 2 diabetes.

RESEARCH DESIGN AND METHODS We studied 467 individuals in the longitudinal PROMISE (Prospective Metabolism and Islet Cell Evaluation) cohort. Peripheral neuropathy was defined by Michigan Neuropathy Screening Instrument (MNSI) scores (>2), and the severity of nerve dysfunction was measured objectively by vibration perception thresholds (VPTs) using a neurothesiometer. Metabolic syndrome was defined using the International Diabetes Federation/American Heart Association harmonized criteria.

RESULTS The prevalence of peripheral neuropathy was 29%, 49%, and 50% for normal 1Department of Nutritional Sciences, University glycemia, prediabetes, and new-onset diabetes, respectively (P < 0.001 for trend). of Toronto, Toronto, ON, Canada 2Division of Endocrinology, Department of Medi- The mean VPT was 6.5 V for normal glycemia, 7.9 V for prediabetes, and 7.6 V for cine, University of Toronto, Toronto, ON, Canada new-onset diabetes (P = 0.024 for trend). Prediabetes was associated with higher 3Centre for Studies in Family Medicine, Univer- MNSI scores (P = 0.01) and VPTs (P = 0.004) versus normal glycemia, independent sity of Western Ontario, London, ON, Canada 4 of known risk factors. Additionally, progression of glucose intolerance over 3 years Lunenfeld-Tanenbaum Research Institute, P Mount Sinai Hospital, Toronto, ON, Canada predicted a higher risk of peripheral neuropathy ( = 0.007) and nerve dysfunction 5Division of Endocrinology and Metabolism and (P = 0.002). Metabolic syndrome was not independently associated with MNSI the Population Health Research Institute, De- scores or VPTs. partment of Medicine, McMaster University, Hamilton, ON, Canada 6 CONCLUSIONS Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada In individuals with multiple risk factors for diabetes, prediabetes was associated Corresponding author: Anthony J. Hanley, anthony. with similar risks of peripheral neuropathy and severity of nerve dysfunction as [email protected]. new-onset diabetes. Prediabetes, but not metabolic syndrome, was indepen- Received 31 October 2014 and accepted 5 dently associated with both the presence of peripheral neuropathy and the se- January 2015. verity of nerve dysfunction. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ suppl/doi:10.2337/dc14-2585/-/DC1. Peripheral neuropathy is a serious complication of diabetes. It plays a major contrib- © 2015 by the American Diabetes Association. utory role in the initiation of foot ulceration and the subsequent development of lower- Readers may use this article as long as the work extremity amputation, resulting in severe disability, reduced quality of life, and a is properly cited, the use is educational and not significant economic burden to the health care system (1). Peripheral neuropathy is for profit, and the work is not altered. 794 Neuropathy in Individuals at High Risk for Type 2 Diabetes Diabetes Care Volume 38, May 2015

classically recognized as a complication of peripheral neuropathy in prediabetes study center approved the study protocol, long-standing diabetes, with risk factors are not well documented. Emerging evi- and all participants provided written in- including increased duration of diabetes dence suggests that components of the formed consent. and poor glycemic control (2,3). However, metabolic syndrome, in particular ab- Measurement of Peripheral accumulating evidence suggests that the dominal adiposity and dyslipidemia, are Neuropathy prevalence of peripheral neuropathy is associated with peripheral neuropathy in Peripheral neuropathy was measured markedly elevated at the time of diabetes patients with prediabetes (10,11). In the using the MNSI. The MNSI consisted of diagnosis, with estimates varying from current study, we aimed to describe the two parts: a self-administered question- 11.5 to 48% in population-based observa- prevalence of peripheral neuropathy and naire on clinical signs and symptoms of tional studies (4,5). In contrast, a recent nerve dysfunction and to investigate the neuropathy and a clinical examination study using British and German adminis- association of glucose tolerance status of both feet involving 1) an inspection trative databases showed that peripheral and metabolic syndrome with these to detect deformities, dry skin, calluses, neuropathy based on diagnostic codes neurological changes using data from infection, fissures, or ulcerations; 2)a was present in only 2.4–5.7% of patients the Prospective Metabolism and Islet grading of ankle reflexes; 3)asemiquan- with newly diagnosed diabetes in primary Cell Evaluation (PROMISE) study, a well- titative assessment of vibration percep- care practices (6). These discrepancies in characterized cohort of individuals at tion at the dorsum of the great toe; and the prevalence of peripheral neuropathy high risk for type 2 diabetes. 4) 10-g monofilament testing. In this in new-onset diabetes could be related to analysis, we used only the clinical exam- differences in the methods used to ascer- RESEARCH DESIGN AND METHODS ination component of the MNSI, with a tain this condition. Study Population maximum possible score of 10. An MNSI The presence of peripheral neuropa- The study population comprised partici- score of .2defined the presence of pe- thy in newly diagnosed diabetes and the pants in PROMISE, a prospective observa- ripheral neuropathy (13). The MNSI has time gap between the onset of diabetes tional study that explores the longitudinal been validated against the Mayo Clinic and clinical diagnosis (7) support the no- relationships of insulin resistance and pan- Neuropathy Disability Score, nerve con- tion that neuropathic changes could be creatic b-cell dysfunction with known and duction measures, quantitative vibra- initiated in the early stages of diabetes emerging risk factors in individuals at high tion threshold tests, and the Michigan pathogenesis. In the Cooperative Health risk for type 2 diabetes. Between May Diabetic Neuropathy Score. In these val- Research in the Region of Augsburg 2004 and December 2006, PROMISE re- idation studies, the maximum possible (KORA) F4 study, the prevalence of pe- cruited 712 participants without diabetes score was 8 because the score at that ripheral neuropathy defined as bilater- from Toronto and London, Ontario, Can- time did not include the 10-g monofila- ally impaired foot vibration perception ada, based on the presence of one or more ment test (14). and/or foot pressure sensation was sim- risk factors for type 2 diabetes, including ilar in patients with known diabetes obesity, hypertension, family history of di- Measurement of Nerve Dysfunction (22%) and in those with impaired fasting abetes, and history of gestational diabetes We used a neurothesiometer to quantify glucose and impaired glucose tolerance or birth of a macrosomic infant (12). the vibration perception threshold (24%) (8). The U.S. National Health and Among these participants, 496 returned (VPT), a measure of the severity of nerve Nutrition Examination Study (1999– for the 3-year follow-up examination, dysfunction. The neurothesiometer is a 2004) reported that the prevalence of pe- when assessments of neuropathy and battery-operated diagnostic instrument ripheral neuropathy, as measured by at nerve dysfunction were conducted. There that assesses sensitivity thresholds at var- least one insensate area on 10-g mono- were no significant differences in BMI or ious sites on the body surface. It has been filament testing, was 11.9% in individuals measures of glucose homeostasis in par- validated against nerve conduction stud- with impaired fasting glucose (9). Using ticipants who attended the follow-up ex- ies (15). On the basis of the method of the Michigan Neuropathy Screening In- amination compared with those who did limits, participants were asked to indicate strument (MNSI), peripheral neuropathy not. After excluding participants in whom when they first perceived vibration sen- was found in 13.0% of subjects with im- diabetes developed after baseline and sation after stimulus was applied to the paired glucose tolerance and 11.3% of before the 3-year follow-up examination distal pulp of their left first toe. The in- those with impaired fasting glucose in (n = 7), those with missing data on glucose tensity of the stimulus was gradually in- the MONICA (Monitoring Trends and De- tolerance status at the 3-year follow-up creased from null to a voltage at which terminants on Cardiovascular Diseases)/ examination (n = 2), and those with miss- vibration was first detected (16). Three KORA Augsburg Surveys (10). However, ingdataonmeasurementsofperipheral separate tests were conducted with par- these studies were limited by the lack of neuropathy and nerve function (n = 20), ticipants’ eyes closed. The average of the oral glucose tolerance testing to ascertain thesamplesizeofthecurrentanalysiswas three VPTs was used for analysis. A null glycemic status in the National Health and 467 participants without known diabetes stimulus test was added randomly to en- Nutrition Examination Survey (9) and at the time of the 3-year examination who sure participant adherence and under- the relatively small sample size in the had peripheral neuropathy and nerve standing of the test requirements. Each MONICA/KORA Augsburg Surveys (10). function measurements. The study proce- center followed standardized procedures Age, sex, ethnicity, height, duration of dures detailed in this article were per- for the measurement of peripheral neu- diabetes, and glycemic control are estab- formed at the 3-year examination, and ropathy and nerve dysfunction using iden- lished risk factors for diabetic neuropa- the data were analyzed cross-sectionally. tical sets of equipment. To ensure that the thy (2,3). However, the risk factors for The institutional review boards at each outcomes were measured consistently, care.diabetesjournals.org Lee and Associates 795

research assistants were trained centrally status on the prevalence of neuropathy 2-h postload blood glucose for predia- with annual review sessions. using two separate approaches: 1)Wecat- betes to determine their specificcontri- egorized glucose tolerance status using butions to neuropathic outcomes. In Clinical Measurements and Procedure data from the 3-year follow-up examina- addition, we defined peripheral neurop- Glycemic status (i.e., normal glucose tol- tion (i.e., normal glucose tolerance, predi- athy by VPT .12 V (21) and .15 V (22) erance, prediabetes, diabetes) was cat- abetes, and diabetes were categorized and estimated its prevalence. Statistical egorized using 1999 World Health using glucose concentrations at the analyses were performed using Stata Organization criteria (17). Prediabetes 3-year examination only), and 2)wecate- 12.0 software (StataCorp, College Sta- was defined as impaired glucose toler- gorized participants into four groups tion, TX). ance and/or impaired fasting glucose. according to progression of glucose intol- Plasma glucose, HDL cholesterol, and erance between the baseline and 3-year RESULTS triglyceride levels were measured in examinations (i.e., sustained normal Of the 467 participants with data on pe- fasting blood samples by standard labo- glucose tolerance at both baseline and ripheral neuropathy and nerve dysfunc- ratory methods. We defined metabolic 3-year examination, progression to predia- tion at the 3-year examination, 344 had syndrome and its components using the betes, sustained prediabetes, progression normal glycemic control (74%), 101 had International Diabetes Federation/ to diabetes). Because of the small number prediabetes (21%), and 22 had new- American Heart Association harmonized of participants who regressed from predi- onset diabetes (5%) ascertained by 75-g criteria (18). abetes at baseline to normal glucose tol- oral glucose tolerance test at that exam- Anthropometric measurements, includ- erance at 3-year examination (n =1),this ination. Among these 467 participants, ing height, weight, and waist circumfer- data point was included in the sustained 73% were women and 63% reported ence, were taken in duplicate according normal glucose tolerance group. having a family history of diabetes. The to standardized procedures, and the aver- We investigated the impact of the met- average age of the study population was ages of these measurements were used in abolic syndrome on the prevalence of 53 years (interquartile range 46–60 the analyses. BMI was calculated as neuropathy using three approaches: 1) years), and the ethnic distribution for weight in kilograms divided by height in we analyzed the metabolic syndrome Caucasians, South Asians, Hispanics, square meters. Resting systolic and dia- as a dichotomous variable (i.e., presence and other races was 71%, 12%, 10%, stolic blood pressures were recorded vs. absence); 2) we analyzed the number and 7%, respectively. Approximately twice using an automated sphygmoma- of metabolic syndrome disorders (0–5); 34% of the participants had evidence of nometer after a 5-min rest. Information and 3) we calculated the mean of the z peripheral neuropathy as defined by an on demographics (age, sex, ethnicity), life- scores of metabolic disorders, which was MNSI score .2. The prevalence of pe- style factors (smoking, alcohol consump- analyzed as a continuous variable (20). ripheral neuropathy according to in- tion), and family history of diabetes were Because the distribution of VPTs was creasing MNSI score was 65.7% for a collected in standardized questionnaires skewed, we log -transformed this vari- score #2, 19.2% for a score .2–3, by self-report (12). Ethnicity was catego- e able to achieve normality before sub- 11.8% for a score .3–4, 2.6% for a score rized into four groups for the analysis: sequent analyses. In the subset of .4–5, and 0.7% for a score .5–6. The Caucasian, South Asian, Hispanic, and participants without diabetes at the 3- median VPT was 5.7 V in all participants other. An identical protocol for these year follow-up examination, we used (interquartile range 4.0–8.3 V). clinical measurements and procedures multiple regression analyses to investi- Characteristics of the study popula- was used at both the baseline and the gate the association of glucose tolerance tion stratified by the presence of 3-year follow-up examinations. status and metabolic syndrome with MNSI-defined peripheral neuropathy Statistical Analysis MNSI scores and VPTs. The regression co- are shown in Table 1. Participants with We summarized the participant charac- efficients (b) for linear regression were peripheral neuropathy were more likely teristics stratified by the presence or ab- presented along with their 95% CIs. We to be older. They also had a higher level sence of peripheral neuropathy defined included covariates in the analyses if of fasting blood glucose and 2-h post- by an MNSI score of .2 out of a total of they were of a priori clinical relevance or load blood glucose as well as higher 10, using medians with interquartile if they were associated with both the VPTs. No substantial ethnic or sex dif- ranges for continuous variables and per- exposure and the outcome. Covariates ferences existed between those with centages for categorical variables. We included age, sex, ethnicity, and height. and without MNSI-defined peripheral used ANOVA, Kruskal-Wallis, and x2 In sensitivity analyses, we used the neuropathy. tests to determine whether continuous original MNSI definition (.2 out of total The prevalence of peripheral neurop- and categorical variables differed by the scoreof8)todefine peripheral neurop- athy was 29% for participants with nor- presence of peripheral neuropathy. We athy in prevalence estimates and regres- mal glucose tolerance, 49% for those plotted the prevalence of peripheral sion models to assess the consistency of with prediabetes, and 50% for those neuropathy and the means and SEs of the findings across the different defini- with newly diagnosed type 2 diabetes VPTs by glucose tolerance status and tions of MNSI. We also conducted a at the 3-year examination (P , 0.001) metabolic syndrome. stepwise backward regression analysis (Fig. 1A).Thereweresignificant differ- In light of the well-recognized variabil- with covariates being removed from ences in the prevalence of neuropathy ity in 2-h glucose concentrations after the multivariable-adjusted model if across categories of glucose tolerance oral glucose tolerance test (19), we inves- P . 0.05. In the stepwise models, we status progression between baseline tigated the impact of glucose tolerance substituted fasting blood glucose and and the 3-year examination. Specifically, 796 Neuropathy in Individuals at High Risk for Type 2 Diabetes Diabetes Care Volume 38, May 2015

Table 1—Baseline characteristics of participants stratified by the presence of regression models materially (data not peripheral neuropathy in the PROMISE cohort shown). In backward stepwise multiple Neuropathy 2 Neuropathy +* P value regression models, age, height, and pre- diabetes were all significant, independent n (%) 307 (65.7) 160 (34.3) d positive correlates of MNSI scores and Age (years) 51 (45–58) 57 (48–64) 0.0001 VPTs (all P , 0.05). Female sex 75.6 67.5 0.06 When prediabetes was replaced Ethnicity 0.08 by fasting blood glucose and 2-h post- Caucasian 70.4 71.9 South Asian 5.54 8.75 load blood glucose in the stepwise Hispanic 14.7 7.50 regression model of neuropathic out- Other 9.45 11.9 comes, only 2-h postload blood glucose Current smoker 4.6 5.6 0.3 reached a significance level of 0.05 and Heavy drinker 11.8 13.1 0.7 wasretainedinthefinal model (data Family history of diabetes 60.1 67.5 0.1 not shown). We evaluated an alterna- fi BMI (kg/m2)30.4(26.6–34.4) 30.7 (27.8–35.1) 0.3 tive de nition of peripheral neuropa- Height (cm) 164 (159–171) 166 (160–174) 0.07 thy using neurothesiometer cut points . . Waist circumference (cm) 98.2 (88.3–108) 101 (91.0–110) 0.04 of VPT 12 V and 15 V as reported previously (21,22). In the entire study Systolic blood pressure (mmHg) 125 (115–135) 125 (117–136) 0.3 sample, neuropathy prevalence was Plasma triglycerides (mmol/L) 1.23 (0.95–1.65) 1.27 (1.00–1.81) 0.3 9.7% for VPT .12 V and 5.1% for VPT HDL cholesterol (mmol/L) 1.3 (1.1–1.6) 1.3 (1.0–1.5) 0.4 .15 V, although there were no signifi- Fasting blood glucose (mmol/L) 5.1 (4.8–5.6) 5.3 (4.9–5.7) 0.03 cant differences in prevalence under – – 2-h postload blood glucose (mmol/L) 5.9 (4.8 7.3) 6.7 (5.4 8.5) 0.0001 these definitions according to glycemic – – VPT (V) 5.2 (3.8 7.2) 6.5 (5.1 9.9) 0.0001 or metabolic syndrome status (data not Data are median (interquartile range) or % unless otherwise indicated. *The presence of shown). neuropathy was defined as .2 out of a total MNSI score of 10. CONCLUSIONS prevalence was ;29% for those with different between those with and with- In a cohort at high risk for type 2 diabe- sustained normal glucose tolerance, out metabolic syndrome (33% vs. 37%, tes, we observed that participants with 48% among those who progressed respectively; P = 0.4), the average VPT prediabetes had a similar neuropathy from normal glucose tolerance to pre- was higher, specifically, 7.6 V for partic- prevalence as those with new-onset di- diabetes, 42% in those with sustained ipants with and 6.5 V for those without abetes. In addition, the severity of nerve prediabetes, and 83% among those metabolic syndrome (P = 0.01) (Fig. 2C). dysfunction, as measured objectively who progressed from prediabetes to di- The average VPT was greater with the by a neurothesiometer, was directly abetes (P , 0.001) (Fig. 1B). Results presence of a higher number of compo- proportional to the burden of metabolic were similar when we defined neuropa- nents of the metabolic syndrome, from syndrome disorders. In individuals with- thy using the original MNSI definition 5.5 V with one component to 8.8 V with out diagnosed diabetes, we observed (.2 out of total score of 8). four or more components (P = 0.0005) that age, height, and prediabetes, par- The average VPT was 6.5, 7.9, and (Fig. 2D). ticularly impaired glucose tolerance, 7.6 V for participants with normal glu- Compared with those with normal were independently associated with cose tolerance, prediabetes, and newly glycemia, participants with prediabetes both peripheral neuropathy and nerve diagnosed type 2 diabetes, respectively had significantly higher MNSI scores and dysfunction. The findings extend the (P = 0.02) (Fig. 2A). The average VPT was VPTs (Table 2). In addition, progression current literature by documenting that 6.5 V for participants who had sustained of glucose intolerance compared with the prevalence of peripheral neuropa- normal glucose tolerance between sustained normal glucose control was thy in individuals with prediabetes is as baseline and the 3-year examination, significantly associated with a higher high as among those with new-onset di- 7.9 V among those who progressed risk of peripheral neuropathy and nerve abetes and by providing additional evi- from normal glucose tolerance to pre- dysfunction (Table 2). There was no as- dence from a large, well-characterized diabetes, 6.6 V in those who had sus- sociation between metabolic syndrome cohort that prediabetes is an indepen- tained prediabetes, and 11.4 V among and MNSI scores (Supplementary Table dent risk factor for neuropathy and those who progressed from prediabetes 1). Initial associations of metabolic syn- nerve dysfunction. to diabetes (P =0.006)(Fig.2B). drome with VPTs were attenuated to The prevalence of peripheral neurop- On the basis of International Diabetes nonsignificance after adjusting for age, athy observed in individuals with predi- Federation/American Heart Association sex, ethnicity, and height (Supplemen- abetes was higher than previously harmonized criteria, approximately tary Table 1). reported (9,10). This could be related one-third of the study population had In sensitivity analyses, using the origi- to differences among study populations metabolic syndrome, as defined by the nal MNSI definition (.2 out of total score because PROMISE participants were re- presence of three or more disorders. of 8) to define peripheral neuropathy did cruited based on their risk for type 2 di- Although the prevalence of peripheral not change the prevalence estimates abetes, and thus, potential risk factors neuropathy was not significantly (Fig. 1) and magnitude of association in for peripheral neuropathy (including care.diabetesjournals.org Lee and Associates 797

peripheral neuropathy, with prevalence ranging from 20.8% in patients with di- abetes for ,5yearsto36.8%inthose with diabetes for .10 years (23). In ad- dition, poor glycemic control increases the risk and progression of diabetic neu- ropathy (2,3). The PROMISE cohort com- prised participants at risk for type 2 diabetes. The alarmingly high preva- lence of peripheral neuropathy in indi- viduals with prediabetes suggests that the duration and degree of dysglycemia before the clinical diagnosis of diabetes may be a crucial factor in the early initi- ation of neurological changes. Despite well-established evidence re- garding the risk factors for diabetic neuropathy, a literature gap exists for normal glucose tolerant and predia- betic populations. Nonglycemic pa- rameters of the metabolic syndrome, including abdominal adiposity and dys- lipidemia, have been shown to be asso- ciated with peripheral neuropathy in patients with prediabetes (10,11). In contrast, we did not observe indepen- dent associations of metabolic parame- ters with peripheral neuropathy or nerve dysfunction, which may be re- lated to the high prevalence of these risk factors in the current study popula- tion. However, the findings confirm pre- vious observations that prediabetes, in particular impaired glucose tolerance, is independently associated with both pe- ripheral neuropathy and nerve dysfunc- tion (25,26). Hyperglycemia may lead to neurological pathology in part through increasing oxidative stress and activa- tion of the protein kinase C and polyol pathways, both of which exert neuro- toxic effects (27,28). Besides hypergly- Figure 1—Prevalence of peripheral neuropathy by glucose tolerance status comparing different definitions of MNSI at 3-year follow-up (A) and by progression of glucose intolerance between cemia, dyslipidemia, microvascular baseline and 3-year follow-up (B). The P value refers to the overall comparison across subgroups. dysfunction, and metabolic syndrome DM, diabetes mellitus; NFG, normal fasting glucose; NGT, normal glucose tolerance. have all been shown to initiate neurop- athy in prediabetes through a common mechanism of oxidative stress (29). In clinical practice, the neurothesiom- glycemia, a family history of diabetes, also observed in those with normal glu- eter has been used to monitor the pro- and metabolic syndrome disorders) cose tolerance, an observation that may gression of peripheral neuropathy were highly prevalent. In addition, vari- be explained by the substantial burden rather than as a tool for diagnosing pe- ous diagnostic criteria could account for of diabetes risk factors in this group. ripheral neuropathy. To this point, ele- the difference in the prevalence of neu- Previous studies consistently demon- vated VPTs have been shown to be ropathy in the various subgroups of glu- strated an association of age and height associated with an increased risk of sub- cose abnormalities. For example, the with diabetic neuropathy (2,23,24). In sequent foot ulceration (21,22). The KORA F4 study used bilaterally impaired the current study, we observed that neurothesiometer, being minimally in- foot vibration perception and foot pres- these nonmodifiable risk factors were vasive and returning results in ,3min, sure sensation to detect more severe also associated with peripheral neurop- may be more sensitive for the diagnosis peripheral neuropathy (8). A high prev- athy in prediabetes. Duration of diabe- of peripheral neuropathy, particularly in alence of peripheral neuropathy was tes has been shown to be a risk factor of patients with mild neuropathy, such as 798 Neuropathy in Individuals at High Risk for Type 2 Diabetes Diabetes Care Volume 38, May 2015

Figure 2—Severity of nerve dysfunction by glucose tolerance status at 3-year follow-up (A), by progression of glucose intolerance between baseline and 3-year follow-up (B), by the presence of the metabolic syndrome (C), and by the number of metabolic disorders (D). The P value refers to the overall comparison across subgroups. DM, diabetes mellitus; MetS, metabolic syndrome; NFG, normal fasting glucose; NGT, normal glucose tolerance.

those with prediabetes (21). However, neuropathy. This risk is further exacer- examinations and inadequate preventive no standardized VPT cutoff value to de- bated by the presence of impaired glu- education on foot care (30). These obser- fine the presence of peripheral neurop- cose tolerance or new-onset diabetes. vations coupled with the high prevalence athy has been published to date. These findings emphasize the need to of peripheral neuropathy and nerve dys- The findings of this study have impor- determine etiological factors for neurop- function stress the urgent need for early tant research and clinical implications. athy onset independent of glucose me- detection and intervention not only in From a research perspective, although tabolism and to determine the threshold populations with established diabetes the documentation of impaired glucose of glucose exposure below that of a di- but also in those with risk factors such tolerance in patients with idiopathic agnosis of impaired glucose intolerance as prediabetes or metabolic syndrome. neuropathy (11) has raised the concern that may promote nerve injury. From a The strengths of the PROMISE study that clinically significant nerve dysfunc- clinical perspective, previous evidence include a well-characterized multiethnic tion may be present before diabetes on- has suggested that older patients with cohort as well as detailed measurement set, the current study adds that the diabetes or prediabetes are often un- of peripheral neuropathy and nerve dys- presence of risk factors for diabetes aware of their peripheral neuropathy function. However, several potential onset alone conveys a high risk for and that they receive infrequent foot limitations should also be considered.

Table 2—Association of glucose tolerance status with peripheral neuropathy and nerve dysfunction in the PROMISE cohort MNSI score** VPT** b (95% CI) P value b (95% CI) P value Prediabetes vs. NFG/NGT (cross-sectional at 3-year follow-up) Unadjusted 0.38 (0.11, 0.65) 0.005 0.20 (0.076, 0.32) 0.001 Multivariable adjusted* 0.34 (0.075, 0.61) 0.01 0.14 (0.044, 0.24) 0.004 Progression of glucose intolerance vs. sustained NFG/NGT Unadjusted 0.40 (0.14, 0.67) 0.003 0.20 (0.085, 0.32) 0.001 Multivariable adjusted* 0.37 (0.10, 0.63) 0.007 0.15 (0.052, 0.25) 0.002 NFG, normal fasting glucose; NGT, normal glucose tolerance. *Adjusted for age, sex, ethnicity, and height. **MNSI scores (with a total score of 10) and VPTs were modeled as continuous variables. care.diabetesjournals.org Lee and Associates 799

Using a single oral glucose tolerance test contributed to the discussion and review and 11. Smith AG. Impaired glucose tolerance and to diagnose prediabetes has been editing of the manuscript. S.B.H., R.R., and B.Z. metabolic syndrome in idiopathic neuropathy. – shown to have low reproducibility (31). researched data and contributed to the discus- J Peripher Nerv Syst 2012;17(Suppl. 2):15 21 sion and review and editing of the manuscript. 12. Hanley AJ, Retnakaran R, Qi Y, et al. Associ- Although the neurothesiometer has A.J.H. researched data and contributed to the ation of hematological parameters with insulin been validated to assess nerve dysfunc- discussion and writing, review, and editing of resistance and b-cell dysfunction in nondiabetic tion, limited evidence supports using the manuscript. A.J.H. is the guarantor of this subjects. J Clin Endocrinol Metab 2009;94: only VPT to assess the severity of periph- work and, as such, had full access to all the data 3824–3832 in the study and takes responsibility for the eral neuropathy. In addition, we did not 13. Moghtaderi A, Bakhshipour A, Rashidi H. integrity of the data and the accuracy of the Validation of Michigan neuropathy screening in- haveinformationonotherknown data analysis. strument for diabetic peripheral neuropathy. causes of peripheral neuropathy or col- Prior Presentation. Parts of this study were Clin Neurol Neurosurg 2006;108:477–481 lect information on whether partici- presented in abstract form at the 74th Scientific 14. Feldman EL, Stevens MJ, Thomas PK, pants were symptomatic. Finally, the Sessions of the American Diabetes Association, Brown MB, Canal N, Greene DA. 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UK Prospective Diabetes Study (UKPDS) Classification of Diabetes Mellitus.Geneva, World Health Organization, 1999 and intervention as a means to reduce Group. Intensive blood-glucose control with sul- phonylureas or insulin compared with conven- 18. Alberti KG, Eckel RH, Grundy SM, et al.; In- the incidence of peripheral neuropathy tional treatment and risk of complications in ternational Diabetes Federation Task Force on and its downstream consequences in patients with type 2 diabetes (UKPDS 33). Lan- Epidemiology and Prevention; National Heart, high-risk populations. cet 1998;352:837–853 Lung, and Blood Institute; American Heart Asso- 5. Spijkerman AM, Dekker JM, Nijpels G, et al. ciation; World Heart Federation; International Microvascular complications at time of diagno- Atherosclerosis Society; International Associa- sis of type 2 diabetes are similar among diabetic tion for the Study of Obesity. Harmonizing the Acknowledgments. The authors thank the patients detected by targeted screening and pa- metabolic syndrome: a joint interim statement study subjects for their ongoing participation tients newly diagnosed in general practice: the of the International Diabetes Federation Task and the research nurses for their expert tech- Hoorn screening study. Diabetes Care 2003;26: Force on Epidemiology and Prevention; Na- nical assistance. 2604–2608 tional Heart, Lung, and Blood Institute; Ameri- Funding. R.R. is supported by a Heart and Stroke 6. Kostev K, Jockwig A, Hallwachs A, Rathmann can Heart Association; World Heart Federation; Foundation of Ontario Mid-Career Investigator W. Prevalence and risk factors of neuropathy in International Atherosclerosis Society; and Inter- Award. A.J.H. holds a Tier II Canada Research newly diagnosed type 2 diabetes in primary care national Association for the Study of Obesity. Chair in Diabetes Epidemiology. PROMISE is practices: a retrospective database analysis in Circulation 2009;120:1640–1645 supportedbygrantsfromtheCanadianDiabetes Germany and U.K. Prim Care Diabetes 2014;8: 19. Sacks DB. A1C versus glucose testing: a com- Association, the Connaught Fund from the Uni- 250–255 parison. Diabetes Care 2011;34:518–523 versity of Toronto, and the Canadian Institutes of 7. Harris MI, Klein R, Welborn TA, Knuiman 20. Kelly AS, Steinberger J, Jacobs DR, Hong CP, Health Research. MW. Onset of NIDDM occurs at least 4-7 yr Moran A, Sinaiko AR. Predicting cardiovascular Duality of Interest. B.A.P. participated on an before clinical diagnosis. Diabetes Care 1992; risk in young adulthood from the metabolic syn- advisory board for Neurometrix, Inc. S.B.H. has 15:815–819 drome, its component risk factors, and a cluster received consultation fees from or participated on 8. Bongaerts BW, Rathmann W, Kowall B, score in childhood. Int J Pediatr Obes 2011;6: advisory boards for Merck, Novo Nordisk, Sanofi, et al. Postchallenge hyperglycemia is posi- e283–e289 Boehringer Ingelheim, Lilly, AstraZeneca, Janssen, tively associated with diabetic polyneuropathy: 21. Bril V, Perkins BA. Comparison of vibration Takeda, and Abbott and received funding from the KORA F4 study. Diabetes Care 2012;35: perception thresholds obtained with the Neuro- Sanofi, Novo Nordisk, and AstraZeneca. H.C.G. 1891–1893 thesiometer and the CASE IV and relationship to has received consulting fees from Sanofi,Novo 9. Gregg EW, Gu Q, Williams D, et al. Preva- nerve conduction studies. Diabet Med 2002;19: Nordisk, Lilly, Bristol-Myers Squibb, Roche, lence of lower extremity diseases associated 661–666 AstraZeneca, Abbot, GlaxoSmithKline, and with normal glucose levels, impaired fasting 22. Young MJ, Breddy JL, Veves A, Boulton AJ. The Bayer; lecture fees from Sanofi and Bayer; glucose, and diabetes among U.S. adults aged prediction of diabetic neuropathic foot ulceration and support for research or continuing educa- 40 or older. Diabetes Res Clin Pract 2007;77: using vibration perception thresholds. A prospec- tion through his institution from Sanofi, Lilly, 485–488 tive study. Diabetes Care 1994;17:557–560 Merck, Novo Nordisk, Boehringer Ingelheim, 10. Ziegler D, Rathmann W, Dickhaus T, 23. Young MJ, Boulton AJ, MacLeod AF, Bristol-Myers Squibb, and AstraZeneca. No other Meisinger C, Mielck A; KORA Study Group. Prev- Williams DR, Sonksen PH. A multicentre study potential conflicts of interest relevant to this alence of polyneuropathy in pre-diabetes and of the prevalence of diabetic peripheral neurop- article were reported. diabetes is associated with abdominal obesity athy in the United Kingdom hospital clinic pop- Author Contributions. C.C.L. contributed to and macroangiopathy: the MONICA/KORA ulation. Diabetologia 1993;36:150–154 the discussion and writing, review, and editing Augsburg Surveys S2 and S3. Diabetes Care 24. Cheng YJ, Gregg EW, Kahn HS, Williams DE, of the manuscript. B.A.P., S.K., and H.C.G. 2008;31:464–469 De Rekeneire N, Narayan KM. Peripheral 800 Neuropathy in Individuals at High Risk for Type 2 Diabetes Diabetes Care Volume 38, May 2015

insensate neuropathyda tall problem for in diabetes and impaired glucose tolerance. ticking early? Nat Rev Endocrinol 2011;7: US adults? Am J Epidemiol 2006;164:873– Neurology 2003;60:108–111 682–690 880 27. Yagihashi S, Mizukami H, Sugimoto K. 30. Bongaerts BW, Rathmann W, Heier M, 25.DyckPJ,DyckPJ,KleinCJ,WeigandSD. Mechanism of diabetic neuropathy: where are et al. Older subjects with diabetes and pre- Does impaired glucose metabolism cause we now and where to go? J Diabetes Investig diabetes are frequently unaware of having polyneuropathy? Review of previous stud- 2011;2:18–32 distal sensorimotor polyneuropathy: the ies and design of a prospective controlled 28. Dobretsov M, Romanovsky D, Stimers JR. KORA F4 study. Diabetes Care 2013;36: population-based study. Muscle Nerve 2007; Early diabetic neuropathy: triggers and mecha- 1141–1146 36:536–541 nisms. World J Gastroenterol 2007;13:175–191 31. American Diabetes Association. Standards 26. Sumner CJ, Sheth S, Griffin JW, Cornblath 29. Papanas N, Vinik AI, Ziegler D. Neurop- of medical care in diabetesd2014. Diabetes DR, Polydefkis M. The spectrum of neuropathy athy in prediabetes: does the clock start Care 2014;37(Suppl. 1):S14–S80