Abstract
OBJECTIVE
The clinical presentation, symptoms, and signs of neuropathy vary substantially. We determined whether painful neuropathic symptoms and distal symmetrical polyneuropathy (DSPN) were associated with different risk factors in a longitudinal study of Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS) participants.
RESEARCH DESIGN AND METHODS
We assessed neuropathy in 1,779 DPP/DPPOS participants ∼21 years after DPP randomization. Symptoms were assessed using the Michigan Neuropathy Screening Instrument (MNSI) questionnaire and signs using pinprick, vibration, and monofilament testing. We defined four mutually exclusive neuropathy phenotypes: 1) no symptoms or signs of DSPN, 2) neuropathic pain without signs, 3) other neurologic symptoms without pain or signs, and 4) DSPN (MNSI questionnaire score ≥4 or any signs). We used multinomial logistic regression models to compare nonglycemic and glycemic risk factors among participants to better understand risk factors associated with painful neuropathic symptoms and DSPN.
RESULTS
Among the participants, 501 (28%) had no symptoms or signs, 144 (8%) had painful neuropathic symptoms without signs, and 473 (27%) had DSPN. Compared with participants with neither symptoms nor signs, those with painful neuropathic symptoms were more likely to be women, to have greater weight, and lower estimated glomerular filtration rate. Painful symptoms were not associated with glycemia. In contrast, DSPN, when compared with painful symptoms, was associated with older age, White race, and glycemic exposure.
CONCLUSIONS
In this cohort, risk factors for painful neuropathic symptoms and DSPN differed. Improved recognition of painful neuropathic symptoms and better consensus on diagnostic criteria may facilitate research into their causes, prevention, and treatment.
Graphical Abstract
Introduction
Diabetic distal symmetrical polyneuropathy (DSPN) is defined as symptoms and signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes (1). Prior studies have suggested that in both type 1 and type 2 diabetes, glycemia has a major impact on the development and progression of DSPN (2–4). Less is known about risk factors for painful neuropathic symptoms, which may occur in the absence of objective signs of DSPN. A recent study demonstrated that glycemia was associated with the development of painful neuropathic symptoms in type 1 diabetes (2). Painful neuropathic symptoms occur more frequently in individuals with prediabetes compared with those with normal glucose regulation but less frequently in individuals with prediabetes than in individuals with type 2 diabetes (5–7).
In DSPN, symptoms vary according to the type and caliber of the nerve fibers involved. In general, small fiber symptoms and signs, including burning pain, hyperesthesia (increased touch sensitivity), and allodynia (pain caused by a stimulus that does not ordinarily elicit pain), are associated with small fiber involvement and precede large fiber symptoms and signs (8,9). The subsequent involvement of large fibers may cause numbness, sensory ataxia, and motor weakness (10). On physical examination, small fiber dysfunction is indicated by abnormal pin-pain sensation or reduced temperature sensation (11). Although seemingly straightforward, pin-pain sensation is technically difficult to assess as it may be difficult to distinguish between touch-pressure (a large fiber sign) and pain (a small fiber sign). Both small and large fiber dysfunction occur in DSPN, and both pin-pain and vibration sensation are usually diminished or absent (11). The purpose of this study was to compare and contrast the nonglycemic and glycemic risk factors associated with the occurrence of painful neuropathic symptoms alone and with DSPN in patients with prediabetes and diabetes ∼21 years after randomization into the Diabetes Prevention Program (DPP) to determine whether different approaches to their prevention and treatment might be required.
Research Design and Methods
The DPP was a multicenter, randomized, controlled clinical trial conducted at 27 U.S. centers between 1996 and 2001. It examined whether intensive lifestyle behavior modification or metformin could prevent or delay type 2 diabetes in adults at high risk for developing the disease (12). Eligible participants were ≥25 years of age, had a BMI ≥24 kg/m2 (≥22 kg/m2 for Asian/Pacific Islanders), and had plasma glucose concentrations between 95 and 125 mg/dL in the fasting state and 140–199 mg/dL 2 h after a 75-g oral glucose load. Participants were randomly assigned to receive an intensive lifestyle intervention, metformin (850 mg, twice daily), or a matching placebo (13).
At the end of DPP, participants were unmasked to treatment assignment and all participants were offered a lifestyle intervention provided in a group format (14,15). Participants were then invited to participate in the DPP Outcomes Study (DPPOS) beginning in 2002. Metformin was continued open-label in the metformin group, and the lifestyle intervention group was offered additional lifestyle support. The DPP and DPPOS results have been described in detail elsewhere (13–15).
The study protocols for DPP and DPPOS are publicly available at https://dppos.bsc.gwu.edu/web/dppos/about. The study was conducted according to the guidelines set out in the Declaration of Helsinki. Prior to initiating the study protocol, each participant provided written informed consent and each study center obtained approval from its respective institutional review board. The trials are registered at ClinicalTrials.gov (Diabetes Prevention Program: NCT00004992; Diabetes Prevention Program Outcomes Study: NCT00038727; Diabetes Prevention Program Outcomes Study Alzheimer's Disease [AD] and Alzheimer's Disease Related Dementias [ADRD]: NCT05704309).
During DPPOS year 17, ∼21 years after DPP randomization and 18 years after the end of the randomized interventions, symptoms of neuropathy were assessed using the Michigan Neuropathy Screening Instrument (MNSI) questionnaire, and signs were assessed using pinprick, vibration, and monofilament testing. The MNSI is a self-administered questionnaire with 15 questions. It was not designed to separately assess small fiber and large fiber symptoms but to assess the presence of DSPN. Symptoms of pain were assessed as a positive response to question 2 (Q2) (burning pain in your legs and/or feet), Q3 (feet too sensitive to touch), or Q6 (hurts when the bed covers touch your skin) (Supplementary Table 1). Other neuropathic symptoms without pain were classified as a positive response to Q1 (legs and/or feet numb), Q4 (muscle cramps in your legs and/or feet), or Q5 (prickling feelings in your legs or feet), or a negative response to Q7 (able to tell hot water from cold water in the bath or shower) or Q13 (able to sense your feet when you walk) with a total MNSI score <4 representing insufficient symptoms to diagnose DSPN (Supplementary Table 1). DSPN was defined as a total MNSI questionnaire score ≥4 of 15 potential abnormal responses or any sign among pinprick, vibration, and monofilament testing. Using data from Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC), we previously demonstrated that an MNSI questionnaire score of ≥4 was 40% sensitive and 92% specific in predicting neurologist-assessed and nerve conduction study–confirmed clinical neuropathy in patients with type 1 diabetes (16).
Pinprick sensation was examined using two Owen Mumford Neuropens. One Neuropen had a semisharp Neurotip examination pin exposed (sharp) and the second had a blunt Neurotip examination pin exposed (dull). Each tip was applied four times with 40g of pressure in a random sequence to the dorsal aspects of the great toes bilaterally, and participants were asked to indicate whether they felt a sharp or dull sensation. Each incorrect response to the sharp Neurotip was given 1 point. A cumulative score of ≥5 of a maximum score of 8 was considered abnormal (17). Vibration sensation was tested using a Rydel-Seiffer 128-Hz graduated tuning fork applied twice over the dorsal aspects of the distal interphalangeal joints of each of the great toes bilaterally. Each test was scored as 2 if the participant could not feel any vibration, 1 if vibration sensation was lost when the tuning fork indicator was ≤4, and 0 if the vibration sensation was lost when the tuning fork indicator was >4 (18). A cumulative score of ≥5 of a maximum score of 8 was considered abnormal vibration (17) (Supplementary Table 2). Protective sensation was assessed using a 10-g Owen Mumford Neuropen monofilament applied 10 times to the dorsal aspect of each of the great toes bilaterally. Abnormal protective sensation was considered present when fewer than eight applications were detected on both great toes. Supplementary Table 2 shows the symptoms and signs of the DPP/DPPOS population at the neuropathy assessment overall and by neuropathy phenotype.
Nonglycemic risk factors assessed included age, sex, race and ethnicity, lifetime cigarette smoking, alcohol consumption, history of thyroid disease, history of systemic (nonskin) cancer, height, weight, BMI, waist circumference, triglycerides, estimated glomerular filtration rate (eGFR), and vitamin B12 status at the time of the neuropathy assessment. Glycemic risk factors assessed included randomized DPP treatment group (lifestyle, metformin, or placebo), diabetes status at the time of the neuropathy assessment, diabetes duration in years for those with diabetes at the time of the neuropathy assessment, years of metformin exposure, and time-weighted mean updated HbA1c. We also assessed history of any retinopathy, defined on the basis of fundus photography performed at DPPOS visits 1, 5, 11, or 16, and history of nephropathy, defined by eGFR <45 mL/min/1.73 m2, albumin-to-creatinine ratio ≥30 mg/g, or dialysis recorded at any visit at or before DPPOS visit 17.
Statistical Analyses
Data are expressed as frequency (%), mean (SD), or median (interquartile range). To assess differences in nonglycemic and glycemic risk factors among phenotypes, we used ANOVA or Kruskal-Wallis tests for numerical variables whose distributions were not approximately normal and Pearson χ2 tests for categorical variables. We then constructed single-predictor multinomial logistic regression models to assess bivariate associations between phenotypes and nonglycemic and glycemic risk factors by calculating odds ratios and their corresponding 95% CIs. Finally, we constructed a multivariable multinomial logistic regression model that selected variables using backward stepwise selection based on Akaike information criteria. From this model, we estimated adjusted odds ratios, 95% CIs, and P values. We only used observations with complete data on all variables in the final model (n = 1,662). Analyses were performed using the R Language and Environment for Statistical Computing (19).
Data and Resource Availability
In accordance with the National Institutes of Health Public Access Policy, we continue to provide all manuscripts to PubMed Central, including this manuscript. DPP/DPPOS has provided the protocols and lifestyle and medication intervention manuals to the public through its public website (https://www.dppos.org). The DPPOS abides by the National Institute of Diabetes and Digestive and Kidney Diseases data sharing policy and implementation guidance as required by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (https://repository.niddk.nih.gov/studies/dppos/).
Results
Of the 3,234 participants at DPP baseline, 2,779 consented to continue participation in the DPPOS. Of them, 348 had died and 53 had withdrawn from the study by DPPOS study visit 17, which occurred 20 to 23 years after enrollment in the DPP (mean 21 years). There were 1,792 participants who had DPPOS year 17 visits, and 1,779 (99%) had data from which we could determine a neuropathy phenotype.
Participants were classified into one of four mutually exclusive neuropathy phenotypes. Phenotype 1 included 501 participants (28%) with neither symptoms nor signs of neuropathy (normal). Phenotype 2 included 144 participants (8%) with painful neuropathic symptoms only but an MNSI score <4 and no signs. Phenotype 3 included 661 participants (37%) with neuropathic symptoms other than pain, an MNSI questionnaire score <4, and no signs. Phenotype 4 (defined as DSPN) included 473 participants (27%) with a MNSI score ≥4 or signs (Supplementary Table 2).
Among participants with painful symptoms (phenotype 2), the most frequently reported symptom was burning pain in the legs and/or feet (79%) (Supplementary Table 2). Of participants with painful symptoms, 76% also reported other neurologic symptoms (55% muscle cramps in the legs and/or feet and 36% prickling feelings in the legs or feet), but only 6% reported that their legs and/or feet were numb and none had an MNSI score ≥4 or signs (Supplementary Table 2). Among participants with DSPN (phenotype 4), 57% reported painful symptoms, including 49% who reported burning pain in the legs and/or feet (Supplementary Table 2). Other neurologic symptoms were reported by 88% of participants with DSPN, including 72% who reported muscle cramps in the legs and/or feet, 62% who reported prickling feelings, and 37% who reported that their legs and/or feet were numb (Supplementary Table 2). Of participants with DSPN, 66% had MNSI scores ≥4, 26% had abnormal pinprick, 26% had abnormal vibration, and 20% had abnormal protective sensation (Supplementary Table 2).
Table 1 shows the characteristics of the study population overall and the distribution of variables across the four phenotypes. The 1,779 participants were equally divided among the three DPP treatment groups. The mean age at the time of the neuropathy assessment was 70.4 years. Among the participants, 71% were women, 51% White, 21% Black, 17% Hispanic, 5% Asian, and 7% American Indian. Thirty-eight percent were ever smokers; however, only 3% reported currently smoking at DPPOS year 17. Alcohol consumption, assessed as median grams per week, was generally low. Ten percent of participants had histories of thyroid disease, and 14% had histories of cancer (excluding skin cancer). The mean height was 164 cm, the mean weight was 88.3 kg, the mean BMI was 32.1 kg/m2, and the mean waist circumference was 107 cm. Triglyceride levels and renal function were generally normal. Among the participants, 9% had histories of low vitamin B12 levels or reported having ever used vitamin B12 supplements. By the time of the neuropathy assessment, diabetes had developed in 66% of participants. Among those with diabetes, median duration of diabetes was 15 years. The median exposure to metformin was 4.5 years. The mean time-weighted HbA1c was 6.1%. Twenty percent of participants had histories of any retinopathy, and 21% had histories of nephropathy. Age, sex, race and ethnicity, smoking status, history of thyroid disease, height, weight, BMI, waist circumference, eGFR, duration of diabetes among those with diabetes, time-weighted HbA1c, and history of nephropathy all differed significantly across the phenotypes (Table 1).
Table 1.
Characteristics of the DPP/DPPOS population at neuropathy assessment overall and by neuropathy phenotype
| Phenotypes | ||||||
|---|---|---|---|---|---|---|
| Overall | Normal (phenotype 1) | Neuropathic pain without DSPN (phenotype 2) | Other neuropathic symptoms without DPSN (phenotype 3) | DSPN (phenotype 4) | P value | |
| N (%) | 1,779 | 501 (28) | 144 (8) | 661 (37) | 473 (27) | |
| Treatment group, n (%) | 0.216a | |||||
| Placebo | 593 (33) | 155 (31) | 52 (36) | 223 (34) | 163 (35) | |
| Lifestyle | 575 (32) | 186 (37) | 46 (32) | 199 (30) | 144 (30) | |
| Metformin | 611 (34) | 160 (32) | 46 (32) | 239 (36) | 166 (35) | |
| Age (years), mean (SD) | 70.4 (9.1) | 69.2 (8.9) | 69.5 (8.2) | 69.8 (8.7) | 72.7 (9.6) | <0.001b |
| Female sex, n (%) | 1254 (71) | 337 (67) | 106 (74) | 501 (76) | 310 (66) | 0.001a |
| Race and ethnicity, n (%) | <0.001a | |||||
| White | 904 (51) | 239 (48) | 64 (44) | 320 (48) | 281 (59) | |
| Black | 364 (21) | 108 (22) | 33 (23) | 145 (22) | 78 (17) | |
| Hispanic | 295 (17) | 88 (18) | 28 (19) | 98 (15) | 81 (17) | |
| Asian | 90 (5) | 35 (7) | 7 (5) | 38 (6) | 10 (2) | |
| American Indian | 126 (7) | 31 (6) | 12 (8) | 60 (9) | 23 (5) | |
| Ever smoker, n (%) | 677 (38) | 194 (39) | 49 (34) | 231 (35) | 203 (43) | 0.036a |
| Alcohol (g/week) | 0.5 | 0.5 | 0.0 | 0.5 | 0.7 | 0.066c |
| Median (IQR) | (0.0, 12.1) | (0.0, 11.1) | (0.0, 4.8) | (0.0, 14.8) | (0.0, 14.6) | |
| History of | ||||||
| Thyroid disease, n (%) | 179 (10) | 31 (6) | 12 (8) | 75 (11) | 61 (13) | 0.003a |
| Cancer, n (%) | 253 (14) | 69 (14) | 21 (15) | 87 (13) | 76 (16) | 0.567a |
| Height (cm), mean (SD) | 164 (9) | 164 (8) | 164 (8) | 163 (8) | 165 (10) | 0.001b |
| Weight (kg), mean (SD) | 88.3 (19.5) | 86.0 (18.6) | 91.2 (19.3) | 87.6 (19.2) | 90.7 (20.7) | <0.001a |
| BMI (kg/m2), mean (SD) | 32.1 (6.7) | 31.4 (6.3) | 33.1 (6.9) | 32.1 (6.6) | 32.4 (7.1) | 0.019b |
| Waist at exam (cm), mean (SD) | 107 (14) | 105 (14) | 108 (12) | 106 (14) | 110 (15) | <0.001b |
| Triglyceride (mg/dL) | 113 | 111 | 117 | 113 | 114 | 0.406c |
| Median (IQR) | (84, 156) | (83, 151) | (93, 153) | (84, 154) | (85, 159) | |
| eGFR (mL/min/1.73 m2), mean (SD) | 78 (19) | 80 (18) | 76 (19) | 79 (19) | 74 (20) | <0.001b |
| Low B12 or B12 supplement, n (%) | 146 (9) | 37 (8) | 11 (8) | 47 (7) | 51 (11) | 0.129a |
| Diabetes at exam, n (%) | 1,171 (66) | 325 (65) | 97 (67) | 424 (64) | 325 (69) | 0.402a |
| If yes, diabetes years | 15.0 | 14.1 | 13.5 | 14.0 | 16.5 | <0.001c |
| Median (IQR) | (9.6, 18.1) | (9.0, 17.9) | (8.0, 18.4) | (8.9, 18.1) | (11.9, 19.0) | |
| Metformin (years) | 4.5 | 3.5 | 4.8 | 4.0 | 6.5 | 0.075c |
| Median (IQR) | (0.0, 13.0) | (0.0, 12.50 | (0.0, 13.0) | (0.0, 13.0) | (0.0, 13.5) | |
| Time-weighted HbA1c (%), mean (SD) | 6.1 (0.7) | 6.1 (0.6) | 6.1 (0.8) | 6.1 (0.7) | 6.2 (0.9) | <0.001b |
| Retinopathy, n (%) | 361 (20) | 97 (20) | 28 (20) | 122 (19) | 114 (25) | 0.117a |
| Nephropathy, n (%) | 369 (21) | 96 (19) | 32 (22) | 116 (18) | 125 (26) | 0.002a |
IQR, interquartile range.
P value from Pearson χ2 test. bP value from ANOVA test. cP value from Kruskal-Wallis test.
We then compared nonglycemic and glycemic risk factors in participants with painful symptoms alone (phenotype 2) and in those with DSPN (phenotype 4) with the risk factors in participants without symptoms or signs of neuropathy (phenotype 1) using single-predictor multinomial logistic regression models to estimate odds ratios and 95% CIs (Table 2). Compared with having no symptoms or signs, having painful symptoms without DSPN (phenotype 2) was significantly associated with greater weight, greater BMI, larger waist circumference, and lower eGFR (Table 2). Painful symptoms were not, however, associated with diabetes status, HbA1c, retinopathy, or nephropathy. Compared with having no symptoms or signs, DSPN (phenotype 4) was significantly associated with older age, White versus Black and Asian race, history of thyroid disease, greater height, weight, BMI, and waist circumference, lower eGFR, longer duration of diabetes, higher HbA1c, and history of nephropathy (Table 2). Compared with participants with painful symptoms alone (phenotype 2), those with DSPN (phenotype 4) were older, more likely to be White relative to other race categories, and to have a longer duration of diabetes (Table 2).
Table 2.
Bivariate associations between neuropathy phenotypes and nonglycemic and glycemic risk factors (odds ratios and 95% CIs)
| Painful symptoms vs. normal (2 vs. 1) | Other neuropathic symptoms vs. normal (3 vs. 1) | DSPN vs. normal (4 vs. 1) | DSPN vs. pain (4 vs. 2) | P value* | |
|---|---|---|---|---|---|
| Treatment group | 0.22 | ||||
| Lifestyle vs. placebo | 0.74 | 0.74 | 0.74 | 1.00 | |
| (0.47, 1.16) | (0.56, 0.99) | (0.54, 1.00) | (0.63, 1.58) | ||
| Metformin vs. placebo | 0.86 | 1.04 | 0.99 | 1.15 | |
| (0.54, 1.35) | (0.78, 1.38) | (0.72, 1.34) | (0.73, 1.81) | ||
| Age (5 years) | 1.02 | 1.04 | 1.24 | 1.22 | <0.01 |
| (0.92, 1.14) | (0.98, 1.11) | (1.16, 1.34) | (1.10, 1.35) | ||
| Sex (female vs. male) | 1.36 | 1.52 | 0.93 | 0.68 | <0.01 |
| (0.90, 2.06) | (1.18, 1.97) | (0.71, 1.21) | (0.45, 1.03) | ||
| Race and ethnicity | <0.01 | ||||
| Black vs. White | 1.14 | 1.00 | 0.61 | 0.54 | |
| (0.71, 1.84) | (0.74, 1.35) | (0.44, 0.86) | (0.33, 0.88) | ||
| Hispanic vs. White | 1.19 | 0.83 | 0.78 | 0.66 | |
| (0.72, 1.97) | (0.60, 1.16) | (0.55, 1.11) | (0.40, 1.10) | ||
| Asian vs. White | 0.75 | 0.81 | 0.24 | 0.33 | |
| (0.32, 1.76) | (0.50, 1.32) | (0.12, 0.50) | (0.12, 0.89) | ||
| American Indian vs. White | 1.45 | 1.45 | 0.63 | 0.44 | |
| (0.70, 2.97) | (0.91, 2.30) | (0.36, 1.11) | (0.21, 0.92) | ||
| Ever smoker vs. never smoker | 0.82 | 0.85 | 1.19 | 1.46 | 0.04 |
| (0.55, 1.20) | (0.67, 1.08) | (0.92, 1.54) | (0.99, 2.15) | ||
| Alcohol (g/week) | 1.00 | 1.00 | 1.00 | 1.01 | 0.11 |
| (0.99, 1.00) | (1.00, 1.01) | (1.00, 1.01) | (1.00, 1.01) | ||
| Ever thyroid disease | 1.38 | 1.94 | 2.24 | 1.63 | <0.01 |
| (0.69, 2.76) | (1.26, 3.00) | (1.43, 3.53) | (0.85, 3.12) | ||
| Height (1-cm increase) | 1.00 | 0.99 | 1.02 | 1.01 | <0.01 |
| (0.98, 1.02) | (0.98, 1.00) | (1.00, 1.03) | (0.99, 1.03) | ||
| Weight (5-kg increase) | 1.07 | 1.02 | 1.06 | 0.99 | <0.01 |
| (1.02, 1.12) | (0.99, 1.05) | (1.03, 1.10) | (0.95, 1.04) | ||
| BMI (kg/m2) | 1.04 | 1.02 | 1.02 | 0.99 | 0.02 |
| (1.01, 1.07) | (1.00, 1.04) | (1.00, 1.04) | (0.96, 1.01) | ||
| Waist circumference (1-cm increase) | 1.02 | 1.01 | 1.03 | 1.01 | <0.01 |
| (1.01, 1.03) | (1.00, 1.02) | (1.02, 1.04) | (0.99, 1.02) | ||
| Triglyceride (mg/dL) | 1.02 | 1.00 | 1.01 | 0.99 | 0.12 |
| (1.00, 1.04) | (0.99, 1.02) | (0.99, 1.03) | (0.97, 1.00) | ||
| eGFR (10 mL/min/1.73 m2) | 0.90 | 0.97 | 0.84 | 0.94 | <0.01 |
| (0.81, 0.99) | (0.91, 1.03) | (0.79, 0.90) | (0.86, 1.04) | ||
| Ever low B12 or B12 supplement | 1.02 | 0.96 | 1.51 | 1.48 | 0.15 |
| (0.51, 2.06) | (0.61, 1.50) | (0.97, 2.35) | (0.75, 2.92) | ||
| Diabetes at exam | 1.12 | 0.97 | 1.19 | 1.06 | 0.40 |
| (0.75, 1.66) | (0.76, 1.23) | (0.91, 1.55) | (0.71, 1.59) | ||
| Diabetes duration (years) at exam | 1.01 | 1.00 | 1.03 | 1.02 | <0.01 |
| (0.98, 1.03) | (0.99, 1.02) | (1.01, 1.05) | (1.00, 1.05) | ||
| Metformin (years) | 1.00 | 1.01 | 1.02 | 1.01 | 0.19 |
| (0.98, 1.03) | (0.99, 1.02) | (1.00, 1.04) | (0.99, 1.04) | ||
| HbA1c (%) | 1.18 | 1.00 | 1.37 | 1.15 | <0.01 |
| (0.92, 1.53) | (0.84, 1.18) | (1.15, 1.62) | (0.90, 1.47) | ||
| Retinopathy | 1.01 | 0.95 | 1.33 | 1.32 | 0.12 |
| (0.63, 1.61) | (0.71, 1.28) | (0.98, 1.81) | (0.83, 2.10) | ||
| Nephropathy | 1.21 | 0.90 | 1.52 | 1.26 | <0.01 |
| (0.77, 1.89) | (0.67, 1.21) | (1.12, 2.05) | (0.81, 1.96) |
Statistically significant differences are shown in bold type.
*P value is from the likelihood ratio test comparing a multinomial logistic regression model with the predictor to an intercept-only model.
Finally, we compared the phenotypes using a multivariable multinomial logistic regression model (Table 3). Painful neuropathic symptoms (phenotype 2) versus no symptoms or signs (phenotype 1) were independently associated with female sex, greater weight, and lower eGFR. DSPN (phenotype 4) versus normal (phenotype 1) was independently associated with older age, female sex, White versus Black and Asian race, greater weight, and higher HbA1c (Table 3). DSPN (phenotype 4) versus painful symptoms (phenotype 2) was independently associated with older age, White vs Black and Asian race, and higher HbA1c (Table 3).
Table 3.
Multivariable multinomial logistic regression model odds ratios and 95% CIs
| Painful symptoms vs. normal (2 vs. 1) | Other neuropathic symptoms vs. normal (3 vs. 1) | DSPN vs. normal (4 vs. 1) | DSPN vs. pain (4 vs. 2) | P value* | |
|---|---|---|---|---|---|
| Age (5 years) | 1.08 | 1.10 | 1.36 | 1.26 | <0.01 |
| (0.94, 1.23) | (1.01, 1.20) | (1.23, 1.50) | (1.10, 1.45) | ||
| Sex (female vs. male) | 1.67 | 1.93 | 1.49 | 0.89 | <0.01 |
| (1.04, 2.68) | (1.43, 2.61) | (1.08, 2.06) | (0.55, 1.44) | ||
| Race and ethnicity | <0.01 | ||||
| Black vs. White | 0.94 | 0.95 | 0.47 | 0.50 | |
| (0.56, 1.58) | (0.69, 1.42) | (0.32, 0.68) | (0.29, 0.85) | ||
| Hispanic vs. White | 1.51 | 0.99 | 0.92 | 0.61 | |
| (0.88, 2.57) | (0.69, 1.42) | (0.62, 1.35) | (0.36, 1.04) | ||
| Asian vs. White | 1.16 | 1.91 | 0.31 | 0.27 | |
| (0.47, 2.86) | (0.70, 2.03) | (0.14, 0.69) | (0.09, 0.78) | ||
| American Indian vs. White | 1.87 | 1.62 | 0.88 | 0.47 | |
| (0.86, 4.04) | (0.97, 2.70) | (0.47, 1.64) | (0.21, 1.05) | ||
| Alcohol (g/week) | 1.00 | 1.01 | 1.00 | 1.00 | 0.07 |
| (0.99, 1.01) | (1.00, 1.01) | (1.00, 1.01) | (1.00, 1.01) | ||
| Weight (5-kg increase) | 1.10 | 1.05 | 1.10 | 1.00 | <0.01 |
| (1.04, 1.16) | (1.02, 1.09) | (1.06, 1.15) | (0.95, 1.06) | ||
| eGFR (10 mL/min/1.73 m2) | 0.87 | 0.98 | 0.92 | 1.06 | 0.04 |
| (0.78, 0.98) | (0.91, 1.06) | (0.84, 1.00) | (0.94, 1.18) | ||
| HbA1c (%) | 1.14 | 0.98 | 1.69 | 1.48 | <0.01 |
| (0.86, 1.51) | (0.81, 1.18) | (1.39, 2.07) | (1.12, 1.96) |
Statistically significant differences are shown in bold type.
*P value is from the likelihood ratio test comparing the full multinomial logistic model, which includes the specified predictor to a model omitting that predictor but including all of the other variables listed in the table.
Conclusions
The DPP studied adults at high risk for type 2 diabetes and randomized them to interventions designed to improve glycemia and reduce progression to overt diabetes. The DPPOS then followed them in an observational study for another 17 years. In a prior analysis, we reported the prevalence of aggregate microvascular disease at ∼15 years after randomization (DPPOS year 11, 2012–2013) (15). At that time, diabetes had developed in nearly 50% of participants. The prevalence of the aggregate microvascular end point (retinopathy, nephropathy, or neuropathy) was ∼13% among DPPOS participants who had progressed to diabetes and ∼10% among those who had not; a 28% higher prevalence of the aggregate microvascular end point among progressors (15). At that time, DSPN was ascertained only by the loss of protective sensation as determined using a 10-g monofilament.
Approximately 21 years after DPP randomization (DPPOS year 17, 2018–2019), new semiquantitative neuropathy examinations were introduced to assess pinprick, vibration, and protective sensation. Results from the MNSI questionnaire and these examinations were analyzed to assess associations between neuropathy and DPP treatment groups, diabetes status, diabetes duration, and cumulative glycemic exposure (20). At that time, diabetes had developed in 66% of participants. DSPN prevalence (MNSI score ≥4 or any abnormal test result among pinprick, vibration, or protective sensation) did not differ by initial randomized DPP treatment group but was higher in participants with diabetes, longer duration of diabetes, and greater cumulative glycemic exposure (20).
Although neuropathy is one of the most common complications of diabetes, it is not easy to establish the presence of a small fiber neuropathy without tests, such as skin biopsy, to evaluate small nerve fiber density, autonomic function testing of blood pressure and heart rate variability, and quantitative sensory testing such as temperature thresholds. This is especially true in association with prediabetes or early diabetes and in patients with early and mild neuropathy.
Currently, hierarchical systems that combine symptoms, signs, and confirmatory tests are recommended for classification of neuropathy. Diagnosing small fiber neuropathy generally relies on the history of positive sensations such as burning pain, hypersensitivity, and allodynia. These symptoms are thought to begin with small unmyelinated nerve fiber injury, followed by damage to small myelinated nerve fibers. Although distal sensation to pinprick can be used to assess small fiber function, painful symptoms may occur without objective findings. Pinprick testing, as performed in DPPOS, may be a measure of discriminative sense rather than pain. Indeed, a preliminary factor analysis performed for this study found that pinprick, vibration, and monofilament testing were highly correlated and likely represented a single construct measuring the same underlying factor (data not shown). A decreased ability to distinguish cold and warm thermal stimuli may be a more sensitive and specific measure of small fiber function but was not performed in our study. Because our focus was on comparing the risk factors for painful symptoms and DSPN in this cohort with prediabetes and early diabetes, because of problems in assessing pin-pain, and because there is currently no single, established standard clinical criterion to diagnose painful small fiber neuropathy, we chose to focus on symptoms of neuropathic pain as a surrogate for small fiber neuropathy and did not use abnormal pinprick sensation to confirm its diagnosis.
The current analyses were performed in DPP/DPPOS participants ∼21 years after DPP randomization to compare and contrast nonmodifiable and modifiable risk factors for neuropathic pain only and DSPN. We found that only 28% of DPP/DPPOS participants were free of symptoms or signs of neuropathy (Table 1). The most common phenotype that occurred in 37% of participants involved those participants having fewer than four nonpainful neuropathic symptoms and no signs of neuropathy. Whether this phenotype represents a mild form of large fiber neuropathy insufficient to fulfill standard criteria for DSPN is unclear. In 8% of participants, pain was defined as burning pain, hyperesthesia, or allodynia without signs, and 27% of participants had symptoms or signs indicative of DSPN.
In univariate analyses, painful neuropathic symptoms without signs were associated with greater weight, BMI, and waist circumference and with lower eGFR, but notably, not with treatment group, diabetes status, diabetes duration, metformin treatment, glycemic exposure, or history of retinopathy and nephropathy. In multivariate analyses, painful symptoms were associated only with female sex, greater weight, and lower eGFR, but again, were not statistically associated with glycemic risk factors. Prior population-based studies have consistently demonstrated a greater prevalence of pain conditions, lower pain thresholds, and greater pain intensity in women compared with men (21). Gonadal hormones have been implicated in the sex-based differences in pain perception, but the mechanisms by which estrogen may modulate neuronal activity remain unclear (22). When Fabry et al. (23) classified patients with symptoms of small fiber neuropathy as having definite versus no small fiber neuropathy based on quantitative sensory testing, laser-evoked potentials, electrochemical skin conductance, and skin biopsy specimen, the only factors associated with small fiber neuropathy were older age and higher BMI. Our results are consistent with those of Fabry et al. (23).
In univariate regression analyses, DSPN was associated with older age, White versus Black and Asian race, history of thyroid disease, greater height, weight, BMI, and waist circumference, lower eGFR, longer diabetes duration, higher mean updated HbA1c, and history of nephropathy. In the multivariate analysis, DSPN was associated with older age, female sex, White race, greater weight, and higher HbA1c. The literature has suggested that large fiber symptoms, with or without signs, are associated with older age and glycemia (24,25). The literature has also demonstrated that cigarette smoking, neurotoxicants (including alcohol, chemotherapies, and uremia), height as a surrogate of nerve fiber length, and vitamin B12 deficiency are associated with DSPN in type 2 diabetes (24,26). In type 1 diabetes, longer duration of diabetes, higher HbA1c, higher BMI, history of smoking, and cardiovascular disease were all associated with incident DSPN (27). Why White participants in our study were more likely to have DSPN than other racial and ethnic groups is unclear. Elafros et al. (28) recently studied 200 adults aged >40 years presenting to an outpatient internal medicine clinic primarily serving Medicaid patients in Flint, Michigan. Of these participants, 75% met HbA1c criteria for prediabetes or diabetes or used antihyperglycemic medications. They found that non-Hispanic Black participants had lower odds of DSPN (odds ratio 0.10; 95% CI 0.01, 0.40) compared with non-Hispanic White and Hispanic participants (28). In contrast, in a cross-sectional analysis of Black and White individuals in the National Health and Nutrition Examination Survey (NHANES) and the Atherosclerosis Risk in Communities (ARIC) study who underwent monofilament testing to assess peripheral neuropathy, Black race was associated with peripheral neuropathy (odds ratios 1.3–1.5) (29). A multivariate analysis from the same study showed Black race was not independently associated with neuropathy. Instead, older age, male sex, less than college education, greater height, higher BMI, and diabetes were associated with neuropathy (29).
Our multivariate regression analyses showed older age is an independent risk factor for DSPN. Female sex is associated with both painful symptoms and DSPN. However, compared with individuals with painful symptoms, individuals with DSPN tend to be more likely to be men. Black and Asian participants are less likely to have DSPN than White participants. Weight is associated with both painful symptoms and DSPN, but cumulative glycemic exposure, as assessed by HbA1c, was significantly associated with DSPN but not painful neuropathic symptoms. When participants with DSPN were compared with those with painful symptoms, older age, White versus Black and Asian race, and HbA1c were significantly associated with DSPN.
Previous studies in patients with normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance, and diabetes have variously reported risk factors for painful neuropathic symptoms, with and without signs of peripheral neuropathy. When defined based on neuropathic pain in the setting of objective signs of peripheral neuropathy, painful diabetic neuropathy has been associated with both impaired glucose tolerance and diabetes, in addition to older age, greater weight, and peripheral artery disease (5). When defined based on painful neuropathic symptoms and neurologic signs, patients with painful neuropathic symptoms are more likely to have type 2 diabetes than type 1 diabetes and to be women than men (30). Another study in which the characteristics of patients with painful polyneuropathy were compared with the characteristics of those with polyneuropathy without pain reported that patients with polyneuropathy were significantly older, had a longer duration of diabetes, higher HbA1c, and more microvascular complications than patients without polyneuropathy (31). The only difference between patients with painful polyneuropathy and those with painless polyneuropathy was female sex (31). Other studies have found that in patients with type 1 diabetes, female sex is associated with painful compared with painless peripheral neuropathy and that painful polyneuropathy does not appear to be driven by the cardiometabolic factors traditionally associated with microvascular disease (2,32). Other studies in type 1 diabetes have demonstrated that women have a higher prevalence of neuropathic pain independent of the prevalence of neuropathy (2,33).
Prior studies of patients with apparent idiopathic peripheral polyneuropathy have reported that impaired glucose tolerance (IGT) in the setting of both normal fasting plasma glucose and normal HbA1c may be associated with neuropathy and that painful sensory symptoms are more common in patients with IGT and diabetes than those with isolated impaired fasting glucose (34). In addition, electrodiagnostic abnormalities are less prominent in patients with IGT than in those with diabetes, and they are more likely to be confined to sensory fibers than in patients with diabetes, who show more extensive involvement (34). A second study of patients with peripheral polyneuropathy of unknown cause demonstrated that patients with IGT had predominantly small fiber neuropathy compared with patients with diabetes who had more involvement of large nerve fibers (10). A more recent study has demonstrated that the prevalence of symptomatic polyneuropathy increases as the number of metabolic syndrome components increases independent of glycemic status (25). In that study, greater waist circumference and low HDL appeared to be associated with DSPN (25). In another study of patients with obesity and pain who underwent a high-intensity and multicomponent weight loss intervention and lost on average 16% of their baseline weight, pain improved overall, with the greatest change in the lower legs (35). The intervention was associated with significant increase in the levels of the anti-inflammatory cytokine interleukin 10. These findings suggest that hyperalgesia and pain associated with obesity may be mediated by inflammation and that interventions to address inflammation may improve pain (35).
Our study had a number of limitations. First, it is difficult to objectively diagnose small fiber neuropathy in large epidemiologic studies, and there is currently no single, established clinical criterion to diagnose it. For that reason, we chose to focus on symptoms of neuropathic pain without signs. Second, although we used three questions from the MNSI questionnaire to assess neuropathic pain, those questions were not specifically designed to assess painful small fiber neuropathy or validated as a measure of painful small fiber neuropathy. Future research should use validated pain scales such as the Neuropathic Pain Questionnaire (36). Third, although pin-pain sensation is generally considered to be a sign of small fiber neuropathy, we chose not to include it in our definition because as implemented in DPPOS, pinprick sensation was highly correlated with both vibration and monofilament testing (large fiber signs). Future research should use better measures of small fiber neuropathy such as quantitative sensory testing or skin biopsy. Finally, although we attempted to assess the potential impact of other secondary causes of neuropathy on our findings, we were not always able to rigorously rule all of them out.
Our results suggest that in the DPP/DPPOS cohort, risk factors for painful neuropathic symptoms and for DSPN differ. Compared with those with neither symptoms nor signs, those with painful neuropathic symptoms alone are more likely to be women and more likely to have greater body weight. In contrast, patients with DSPN, compared with patients with painful neuropathic symptoms alone, are more likely to be older, White, and have higher cumulative glycemic exposure. These results suggest that the risk factors for painful neuropathic symptoms may differ from those of DSPN. Improved recognition of painful symptoms and greater consensus on diagnostic criteria will facilitate research into its causes, prevention, and treatment.
This article contains supplementary material online at https://doi.org/10.2337/figshare.29161553.
Article Information
Acknowledgments. The DPP Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and DPPOS. R.B.G. is deceased.
Merck KGaA provided medication for DPPOS. DPP/DPPOS have also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The sponsor of this study was represented on the Steering Committee and played a part in study design, how the study was done, and publication.
The opinions expressed are those of the study group and do not necessarily reflect the views of the funding agencies. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Duality of Interest. B.C.C. receives research contracts from the American Academy of Neurology, is an associate editor of Neurology, consults for DynaMed, and performs medical legal consultations, including for the Vaccine Injury Compensation Program. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. W.H.H., A.C., B.C.C., S.L.E., R.G., N.H.W., and J.W.A. researched the data, edited and reviewed the manuscript, and contributed to the discussion. W.H.H., A.C., and J.W.A. wrote the manuscript. A.C. analyzed the data. All authors in the writing group had access to all data. W.H.H. and A.C. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Handling Editor. The journal editor responsible for overseeing the review of the manuscript was Mark A. Atkinson.
Funding Statement
Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under award U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400, by providing funding during DPP and DPPOS to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart Lung and Blood Institute, the National Cancer Institute, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers.
Footnotes
Clinical trial reg. nos. NCT00004992 and NCT00038727, clinicaltrials.gov
A complete list of members of the Diabetes Prevention Program Research Group can be found in the supplementary material online.
This article is part of a special article collection available at https://diabetesjournals.org/collection/2292/DPP-and-DPPOS-Article-Collection.
Contributor Information
William H. Herman, Email: dppmail@bsc.gwu.edu.
Diabetes Prevention Program Research Group:
George A. Bray, Kishore M. Gadde, Iris W. Culbert, Jennifer Arceneaux, Annie Chatellier, Amber Dragg, Catherine M. Champagne, Crystal Duncan, Barbara Eberhardt, Frank Greenway, Fonda G. Guillory, April A. Herbert, Michael L. Jeffirs, Betty M. Kennedy, Erma Levy, Monica Lockett, Jennifer C. Lovejoy, Laura H. Morris, Lee E. Melancon, Donna H. Ryan, Deborah A. Sanford, Kenneth G. Smith, Lisa L. Smith, Julia A. St. Amant, Richard T. Tulley, Paula C. Vicknair, Donald Williamson, Jeffery J. Zachwieja, Kenneth S. Polonsky, Janet Tobian, David A. Ehrmann, Margaret J. Matulik, Karla A. Temple, Bart Clark, Kirsten Czech, Catherine DeSandre, Brittnie Dotson, Ruthanne Hilbrich, Wylie McNabb, Ann R. Semenske, Celeste C. Thomas, Jose F. Caro, Kevin Furlong, Barry J. Goldstein, Pamela G. Watson, Kellie A. Smith, Jewel Mendoza, Marsha Simmons, Wendi Wildman, Renee Liberoni, John Spandorfer, Constance Pepe, Richard P. Donahue, Ronald B. Goldberg, Ronald Prineas, Jeanette Calles, Anna Giannella, Patricia Rowe, Juliet Sanguily, Paul Cassanova-Romero, Sumaya Castillo-Florez, Hermes J. Florez, Rajesh Garg, Lascelles Kirby, Olga Lara, Carmen Larreal, Valerie McLymont, Jadell Mendez, Arlette Perry, Patrice Saab, Bertha Veciana, Steven M. Haffner, Helen P. Hazuda, Maria G. Montez, Kathy Hattaway, Juan Isaac, Carlos Lorenzo, Arlene Martinez, Monica Salazar, Tatiana Walker, Dana Dabelea, Richard F. Hamman, Patricia V. Nash, Sheila C. Steinke, Lisa Testaverde, Jennifer Truong, Denise R. Anderson, Larry B. Ballonoff, Alexis Bouffard, Brian Bucca, B. Ned Calonge, Lynne Delve, Martha Farago, James O. Hill, Shelley R. Hoyer, Tonya Jenkins, Bonnie T. Jortberg, Dione Lenz, Marsha Miller, Thomas Nilan, Leigh Perreault, David W. Price, Judith G. Regensteiner, Emily B. Schroeder, Helen Seagle, Carissa M. Smith, Brent VanDorsten, Edward S. Horton, Medha Munshi, Kathleen E. Lawton, Sharon D. Jackson, Catherine S. Poirier, Kati Swift, Ronald A. Arky, Marybeth Bryant, Jacqueline P. Burke, Enrique Caballero, Karen M. Callaphan, Barbara Fargnoli, Therese Franklin, Om P. Ganda, Ashley Guidi, Mathew Guido, Alan M. Jacobsen, Lyn M. Kula, Margaret Kocal, Lori Lambert, Kathleen E. Lawton, Sarah Ledbury, Maureen A. Malloy, Roeland J.W. Middelbeek, Maryanne Nicosia, Cathryn F. Oldmixon, Jocelyn Pan, Marizel Quitingon, Riley Rainville, Stacy Rubtchinsky, Ellen W. Seely, Jessica Sansoucy, Dana Schweizer, Donald Simonson, Fannie Smith, Caren G. Solomon, Jeanne Spellman, James Warram, Steven E. Kahn, Brenda K. Montgomery, Basma Fattaleh, Celeste Colegrove, Wilfred Fujimoto, Robert H. Knopp, Edward W. Lipkin, Michelle Marr, Ivy Morgan-Taggart, Anne Murillo, Kayla O’Neal, Dace Trence, Lonnese Taylor, April Thomas, Elaine C. Tsai, Samuel Dagogo-Jack, Abbas E. Kitabchi, Mary E. Murphy, Laura Taylor, Jennifer Dolgoff, William B. Applegate, Michael Bryer-Ash, Debra Clark, Sandra L. Frieson, Uzoma Ibebuogu, Raed Imseis, Helen Lambeth, Lynne C. Lichtermann, Hooman Oktaei, Harriet Ricks, Lily M.K. Rutledge, Amy R. Sherman, Clara M. Smith, Judith E. Soberman, Beverly Williams-Cleaves, Avnisha Patel, Ebenezer A. Nyenwe, Ethel Faye Hampton, Boyd E. Metzger, Mark E. Molitch, Amisha Wallia, Mariana K. Johnson, Daphne T. Adelman, Catherine Behrends, Michelle Cook, Marian Fitzgibbon, Mimi M. Giles, Deloris Heard, Cheryl K.H. Johnson, Diane Larsen, Anne Lowe, Megan Lyman, David McPherson, Samsam C. Penn, Thomas Pitts, Renee Reinhart, Susan Roston, Pamela A. Schinleber, Matthew O’Brien, Monica Hartmuller, David M. Nathan, Charles McKitrick, Heather Turgeon, Mary Larkin, Marielle Mugford, Kathy Abbott, Ellen Anderson, Laurie Bissett, Kristy Bondi, Enrico Cagliero, Jose C. Florez, Linda Delahanty, Valerie Goldman, Elaine Grassa, Lindsery Gurry, Kali D’Anna, Fernelle Leandre, Peter Lou, Alexandra Poulos, Elyse Raymond, Valerie Ripley, Christine Stevens, Beverly Tseng, Kathy Chu, Nopporn Thangthaeng, Jerrold M. Olefsky, Elizabeth Barrett-Connor, Sunder Mudaliar, Maria Rosario Araneta, Mary Lou Carrion-Petersen, Karen Vejvoda, Sarah Bassiouni, Madeline Beltran, Lauren N. Claravall, Jonalle M. Dowden, Steven V. Edelman, Pranav Garimella, Robert R. Henry, Javiva Horne, Marycie Lamkin, Simona Szerdi Janesch, Diana Leos, William Polonsky, Rosa Ruiz, Jean Smith, Jennifer Torio-Hurley, F. Xavier Pi-Sunyer, Blandine Laferrere, Jane E. Lee, Susan Hagamen, David B. Allison, Nnenna Agharanya, Nancy J. Aronoff, Maria Baldo, Jill P. Crandall, Sandra T. Foo, Kim Kelly-Dinham, Jose A. Luchsinger, Carmen Pal, Kathy Parkes, Mary Beth Pena, Ellen S. Rooney, Gretchen E.H. Van Wye, Kristine A. Viscovich, Mary de Groot, David G. Marrero, Kieren J. Mather, Melvin J. Prince, Susie M. Kelly, Marcia A. Jackson, Gina McAtee, Paula Putenney, Ronald T. Ackermann, Carolyn M. Cantrell, Yolanda F. Dotson, Edwin S. Fineberg, Megan Fultz, John C. Guare, Angela Hadden, James M. Ignaut, Marion S. Kirkman, Erin O’Kelly Phillips, Kisha L. Pinner, Beverly D. Porter, Paris J. Roach, Nancy D. Rowland, Madelyn L. Wheeler, Vanita Aroda, Michelle Magee, Robert E. Ratner, Michelle Magee, Gretchen Youssef, Sue Shapiro, Natalie Andon, Catherine Bavido-Arrage, Geraldine Boggs, Marjorie Bronsord, Ernestine Brown, Holly Love Burkott, Wayman W. Cheatham, Susan Cola, Cindy Evans, Peggy Gibbs, Tracy Kellum, Lilia Leon, Milvia Lagarda, Claresa Levatan, Milajurine Lindsay, Asha K. Nair, Jean Park, Maureen Passaro, Angela Silverman, Gabriel Uwaifo, Debra Wells-Thayer, Renee Wiggins, Mohammed F. Saad, Karol Watson, Christine Darwin, Preethi Srikanthan, Tamara Horwich, Adrian Casillas, Arleen Brown, Maria Budget, Sujata Jinagouda, Medhat Botrous, Anthony Sosa, Sameh Tadros, Khan Akbar, Claudia Conzues, Perpetua Magpuri, Carmen Muro, Noemi Neira, Kathy Ngo, Michelle Chan, Veronica Villarreal, Amer Rassam, Debra Waters, Kathy Xapthalamous, Julio V. Santiago, Samuel Dagogo-Jack, Neil H. White, Angela L. Brown, Samia Das, Prajakta Khare-Ranade, Tamara Stich, Ana Santiago, Edwin Fisher, Emma Hurt, Tracy Jones, Michelle Kerr, Lucy Ryder, Cormarie Wernimont, Sherita Hill Golden, Christopher D. Saudek, Vanessa Bradley, Emily Sullivan, Tracy Whittington, Caroline Abbas, Adrienne Allen, Frederick L. Brancati, Sharon Cappelli, Jeanne M. Clark, Jeanne B. Charleston, Janice Freel, Katherine Horak, Alicia Greene, Dawn Jiggetts, Deloris Johnson, Hope Joseph, Kimberly Loman, Nestoras Mathioudakis, Henry Mosley, John Reusing, Richard R. Rubin, Alafia Samuels, Thomas Shields, Shawne Stephens, Kerry J. Stewart, LeeLana Thomas, Evonne Utsey, Paula Williamson, David S. Schade, Karwyn S. Adams, Janene L. Canady, Carolyn Johannes, Claire Hemphill, Penny Hyde, Leslie F. Atler, Patrick J. Boyle, Mark R. Burge, Lisa Chai, Kathleen Colleran, Ateka Fondino, Ysela Gonzales, Doris A. Hernandez-McGinnis, Patricia Katz, Carolyn King, Julia Middendorf, Amer Rassam, Sofya Rubinchik, Willette Senter, Debra Waters, Jill Crandall, Harry Shamoon, Janet O. Brown, Gilda Trandafirescu, Danielle Powell, Norica Tomuta, Elsie Adorno, Liane Cox, Helena Duffy, Samuel Engel, Allison Friedler, Angela Goldstein, Crystal J. Howard-Century, Jennifer Lukin, Stacey Kloiber, Nadege Longchamp, Helen Martinez, Dorothy Pompi, Jonathan Scheindlin, Elissa Violino, Elizabeth A. Walke, Judith Wylie-Rosett, Elise Zimmerman, Joel Zonszein, Trevor Orchard, Elizabeth Venditti, Rena R. Wing, Susan Jeffries, Gaye Koenning, M. Kaye Kramer, Marie Smith, Susan Barr, Catherine Benchoff, Miriam Boraz, Lisa Clifford, Rebecca Culyba, Marlene Frazier, Ryan Gilligan, Stephanie Guimond, Susan Harrier, Louann Harris, Andrea Kriska, Qurashia Manjoo, Monica Mullen, Alicia Noel, Amy Otto, Jessica Pettigrew, Bonny Rockette-Wagner, Debra Rubinstein, Linda Semler, Cheryl F. Smith, Valarie Weinzierl, Katherine V. Williams, Tara Wilson, Bonnie Gillis, Marjorie K. Mau, Narleen K. Baker-Ladao, John S. Melish, Richard F. Arakaki, Renee W. Latimer, Mae K. Isonaga, Ralph Beddow, Nina E. Bermudez, Lorna Dias, Jillian Inouye, Kathy Mikami, Pharis Mohideen, Sharon K. Odom, Raynette U. Perry, Robin E. Yamamoto, William C. Knowler, Robert L. Hanson, Harelda Anderson, Norman Cooeyate, Charlotte Dodge, Mary A. Hoskin, Carol A. Percy, Alvera Enote, Camille Natewa, Kelly J. Acton, Vickie L. Andre, Rosalyn Barber, Shandiin Begay, Peter H. Bennett, Mary Beth Benson, Evelyn C. Bird, Brenda A. Broussard, Brian C. Bucca, Marcella Chavez, Sherron Cook, Jeff Curtis, Tara Dacawyma, Matthew S. Doughty, Roberta Duncan, Cyndy Edgerton, Jacqueline M. Ghahate, Justin Glass, Martia Glass, Dorothy Gohdes, Wendy Grant, Ellie Horse, Louise E. Ingraham, Merry Jackson, Priscilla Jay, Roylen S. Kaskalla, Karen Kavena, David Kessler, Kathleen M. Kobus, Jonathan Krakoff, Jason Kurland, Catherine Manus, Cherie McCabe, Sara Michaels, Tina Morgan, Yolanda Nashboo, Julie A. Nelson, Steven Poirier, Evette Polczynski, Christopher Piromalli, Mike Reidy, Jeanine Roumain, Debra Rowse, Robert J. Roy, Sandra Sangster, Janet Sewenemewa, Miranda Smart, Chelsea Spencer, Darryl Tonemah, Rachel Williams, Charlton Wilson, Michelle Yazzie, Raymond Bain, Sarah Fowler, Marinella Temprosa, Michael D. Larsen, Kathleen Jablonski, Tina Brenneman, Sharon L. Edelstein, Solome Abebe, Julie Bamdad, Melanie Barkalow, Joel Bethepu, Tsedenia Bezabeh, Anna Bowers, Nicole Butler, Jackie Callaghan, Caitlin E. Carter, Costas Christophi, Gregory M. Dwyer, Mary Foulkes, Yuping Gao, Robert Gooding, Adrienne Gottlieb, Kristina L. Grimes, Nisha Grover-Fairchild, Lori Haffner, Heather Hoffman, Steve Jones, Tara L. Jones, Richard Katz, Preethy Kolinjivadi, John M. Lachin, Yong Ma, Pamela Mucik, Robert Orlosky, Qing Pan, Susan Reamer, James Rochon, Alla Sapozhnikova, Hanna Sherif, Charlotte Stimpson, Ashley Hogan Tjaden, Fredricka Walker-Murray, Audrey McMaster, Rhea Mundra, Hannah Rapoport, Nolan Kuenster, Elizabeth M. Venditti, Andrea M. Kriska, Linda Semler, Valerie Weinzierl, Santica Marcovina, F. Alan Aldrich, Jessica Harting, John Albers, Greg Strylewicz, Robert Janicek, Anthony Killeen, Deanna Gabrielson, R. Eastman, Judith Fradkin, Sanford Garfield, Christine Lee, Edward Gregg, Ping Zhang, Dan O’Leary, Gregory Evans, Matthew Budoff, Chris Dailing, Elizabeth Stamm, Ann Schwartz, Caroline Navy, Lisa Palermo, Pentti Rautaharju, Ronald J. Prineas, Teresa Alexander, Charles Campbell, Sharon Hall, Yabing Li, Margaret Mills, Nancy Pemberton, Farida Rautaharju, Zhuming Zhang, Elsayed Z. Soliman, Julie Hu, Susan Hensley, Lisa Keasler, Tonya Taylor, Barbara Blodi, Ronald Danis, Matthew Davis, Larry Hubbard, Ryan Endres, Deborah Elsas, Samantha Johnson, Dawn Myers, Nancy Barrett, Heather Baumhauer, Wendy Benz, Holly Cohn, Ellie Corkery, Kristi Dohm, Amitha Domalpally, Vonnie Gama, Anne Goulding, Andy Ewen, Cynthia Hurtenbach, Daniel Lawrence, Kyle McDaniel, Jeong Pak, James Reimers, Ruth Shaw, Maria Swift, Pamela Vargo, Sheila Watson, Jose A. Luchsinger, Jennifer Manly, Elizabeth Mayer-Davis, Robert R. Moran, Ted Ganiats, Kristin David, Andrew J. Sarkin, Erik Groessl, Naomi Katzir, Helen Chong, William H. Herman, Michael Brändle, Morton B. Brown, Jose C. Florez, David Altshuler, Liana K. Billings, Ling Chen, Maegan Harden, Robert L. Hanson, William C. Knowler, Toni I. Pollin, Alan R. Shuldiner, Kathleen Jablonski, Paul W. Franks, and Marie-France Hivert
Supporting information
References
- 1. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care 2017;40:136–154 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Braffett BH, El ghormli L, Albers JW, et al. ; DCCT/EDIC Research Group . Neuropathic pain with and without diabetic peripheral neuropathy in type 1 diabetes. Diabetes Care 2024;47:1559–1567 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Diabetes Control and Complications Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993;329:977–986 [DOI] [PubMed] [Google Scholar]
- 4. Diabetes Control and Complications Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995;38:869–880 [DOI] [PubMed] [Google Scholar]
- 5. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, KORA Study Group . Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/KORA Augsburg Surveys S2 and S3. Pain Med 2009;10:393–400 [DOI] [PubMed] [Google Scholar]
- 6. Callaghan BC, Xia R, Reynolds E, et al. Association between metabolic syndrome components and polyneuropathy in an obese population. JAMA Neurol 2016;73:1468–1476 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Callaghan BC, Xia R, Reynolds E, et al. Better diagnostic accuracy of neuropathy in obesity: a new challenge for neurologists. Clin Neurophysiol 2018;129:654–662 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Divisova S, Vlckova E, Hnojcikova M, et al. Prediabetes/early diabetes-associated neuropathy predominantly involves sensory small fibres. J Peripher Nerv Syst 2012;17:341–350 [DOI] [PubMed] [Google Scholar]
- 9. Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS.. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes [published correction appears in Lancet Neurol 2017;16:954]. Lancet Neurol 2017;16:934–944 [DOI] [PubMed] [Google Scholar]
- 10. Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M.. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003;60:108–111 [DOI] [PubMed] [Google Scholar]
- 11. Bender C, Dove L, Schmid AB.. Does your bedside neurological examination for suspected peripheral neuropathies measure up? J Orthop Sports Phys Ther 2023;53:107–112 [DOI] [PubMed] [Google Scholar]
- 12. The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 1999;22:623–634 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Knowler WC, Fowler SE, Hamman RF, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677–1686 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention on metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015;3:866–875 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Herman WH, Pop-Busui R, Braffett BH, et al. ; DCCT/EDIC Research Group . Use of the Michigan Neuropathy Screening Instrument as a measure of distal symmetrical peripheral neuropathy in Type 1 diabetes: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications. Diabet Med 2012;29:937–944 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Perkins BA, Olaleye D, Zinman B, Bril V.. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 2001;24:250–256 [DOI] [PubMed] [Google Scholar]
- 18. Kästenbauer T, Sauseng S, Brath H, Abrahamian H, Irsigler K.. The value of the Rydel-Seiffer tuning fork as a predictor of diabetic polyneuropathy compared with a neurothesiometer. Diabet Med 2004;21:563–567 [DOI] [PubMed] [Google Scholar]
- 19. The R Project for Statistical Computing . R: a language and environment for statistical computing, 2020. Accessed 4 October 2024. Available from https://www.R-project.org/
- 20. Lee CG, Ciarleglio A, Edelstein SL, et al. ; Diabetes Prevention Program Research Group . Prevalence of distal symmetrical polyneuropathy by Diabetes Prevention Program treatment group, diabetes status, duration of diabetes, and cumulative glycemic exposure. Diabetes Care 2024;47:810–817 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Maurer AJ, Lissounov A, Knezevic I, Candido KD, Knezevic NN.. Pain and sex hormones: a review of current understanding. Pain Manag 2016;6:285–296 [DOI] [PubMed] [Google Scholar]
- 22. Chen Q, Zhang W, Sadana N, Chen X.. Estrogen receptors in pain modulation: cellular signaling. Biol Sex Differ 2021;12:22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Fabry V, Gerdelat A, Acket B, et al. Which method for diagnosing small fiber neuropathy? Front Neurol 2020;11:342. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Liu X, Xu Y, An M, Zeng Q.. The risk factors for diabetic peripheral neuropathy: a meta-analysis. PLoS One 2019;14:e0212574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Callaghan BC, Xia R, Banerjee M, et al. ; Health ABC Study . Metabolic syndrome components are associated with symptomatic polyneuropathy independent of glycemic status. Diabetes Care 2016;39:801–807 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Elliott J, Tesfaye S, Chaturvedi N, et al. ; EURODIAB Prospective Complications Study Group . Large-fiber dysfunction in diabetic peripheral neuropathy is predicted by cardiovascular risk factors. Diabetes Care 2009;32:1896–1900 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Tesfaye S, Chaturvedi N, Eaton SEM, et al. ; EURODIAB Prospective Complications Study Group . Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341–350 [DOI] [PubMed] [Google Scholar]
- 28. Elafros MA, Brown A, Marcus H, et al. Prevalence and risk factors of distal symmetric polyneuropathy among predominantly non-Hispanic Black, low-income patients. Neurology 2024;102:e209390. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Hicks CW, Wang D, Windham BG, Matsushita K, Selvin E.. Prevalence of peripheral neuropathy defined by monofilament insensitivity in middle-aged and older adults in two US cohorts. Sci Rep 2021;11:19159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Abbott CA, Malik RA, van Ross ERE, Kulkarni J, Boulton AJM.. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care 2011;34:2220–2224 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Truini A, Spallone V, Morganti R, et al. ; Neuropathic Pain Special Interest Group of the Italian Society of Neurology . A cross-sectional study investigating frequency and features of definitely diagnosed diabetic painful polyneuropathy. Pain 2018;159:2658–2666 [DOI] [PubMed] [Google Scholar]
- 32. Elliott J, Sloan G, Stevens L, et al. ; EURODIAB Prospective Complications Study Group . Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study. Diabetologia 2024;67:190–198 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Cardinez N, Lovblom LE, Orszag A, Bril V, Cherney DZ, Perkins BA.. Sex differences in neuropathy & neuropathic pain: a brief report from the Phase 2 Canadian Study of Longevity in Type 1 Diabetes. J Diabetes Complications 2019;33:107397. [DOI] [PubMed] [Google Scholar]
- 34. Singleton JR, Smith AG, Bromberg MB.. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 2001;24:1448–1453 [DOI] [PubMed] [Google Scholar]
- 35. Schrepf A, Harte SE, Miller N, et al. Improvement in the spatial distribution of pain, somatic symptoms, and depression after a weight loss intervention. J Pain 2017;18:1542–1550 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Krause SJ, Backonja M-M.. Development of a neuropathic pain questionnaire. Clin J Pain 2003;19:306–314 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.