Diabetic Peripheral Neuropathy and Urological Complications in Type 1 Diabetes: Findings From the Epidemiology of Diabetes Interventions and Complications Study

Urological symptoms and complications are highly prevalent (1) and important causes of morbidity in individuals with diabetes (2). Among women with diabetes, female sexual dysfunction (FSD), lower urinary tract symptoms (LUTS), and urinary incontinence (UI) have a significant negative impact on quality of life (2,3). Similarly, erectile dysfunction (ED) and LUTS are problems for many men >50 years of age, particularly in men with type 1 diabetes (T1D) (4,5).

Recently, the UroEDIC study, an ancillary study of urological complications in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study (5,6), reported that cardiovascular autonomic neuropathy (CAN) predicted the development of ED/LUTS in men with T1D phenotyped by high-quality, validated measures (7). A significant association between CAN and FSD/UI was also observed in women with T1D (8,9).

Distal symmetric sensorimotor polyneuropathy, the most common form of diabetic neuropathy (10), may also affect genital sensory and/or motor function (11). Furthermore, peripheral neuropathy is one of the most prevalent causes of reduced bladder sensation, including bladder dysfunction associated with diabetes (12,13). Our previous work in UroEDIC suggests a possible association between peripheral neuropathy and urological complications in individuals with T1D (1). However, systematic evaluations of these associations using sensitive and specific markers of DPN while also controlling for known risk factors are lacking. Consequently, the objective of this study was to comprehensively evaluate the associations between diabetic peripheral neuropathy (DPN) and urological complications in participants with long-standing T1D enrolled in the DCCT/EDIC study.

The DCCT and EDIC studies have been described in detail (14,15). Briefly, 1,441 subjects with T1D for 1–15 years with no (primary prevention cohort) or minimal diabetic retinopathy (secondary intervention cohort) were enrolled in DCCT. Subjects were randomly assigned to receive either intensive or conventional treatment and followed for 3–9 years in DCCT (mean 6.5 years). At the end of DCCT in 1993, intensive therapy was recommended for all participants, and they were returned to their health care providers for ongoing diabetes care. Annual EDIC examinations began in 1994, with 1,375 (96%) former DCCT subjects consenting to participate in the follow-up study. A detailed description of EDIC study procedures and baseline characteristics has been published (14).

Of the original 761 men and 680 women enrolled in DCCT, 746 and 676 completed the study in 1993, and 720 (97%) and 655 (96%) elected to participate in the first annual examination in EDIC in 1994. UroEDIC, an ancillary study designed to examine urological complications of diabetes, included UroEDIC I evaluations in 2003 (EDIC year 10) and follow-up UroEDIC II evaluations in 2010 (EDIC year 17). At EDIC year 17, 644 (96%) of the 669 actively participating men and 580 (94%) of the 618 actively participant women agreed to participate in UroEDIC II, and among them, 635 men and 371 women had valid ED/LUTS and FSD/UI information available, respectively. Figure 1 summarizes the timeline for data collection of urological complications and neuropathy data during DCCT/EDIC. All DCCT/EDIC procedures were approved by institutional review boards at participating clinical centers. Written informed consent was provided by all participants.

DPN evaluations were performed at EDIC year 13 or 14 using assessments of symptoms, clinical signs, and electrophysiology as previously described (Fig. 1) (16). Briefly, certified neurologists performed the clinical examinations, including neurological history and physical examination, to detect the presence of distal symmetrical polyneuropathy and identify potential causes of neuropathy, including diabetes. Nerve conduction studies were performed by trained and certified electromyographers on the dominant side median (motor and sensory), peroneal (motor), and sural (sensory) nerves using percutaneous nerve stimulation and surface recordings (16). In addition, the Michigan Neuropathy Screening Instrument (MNSI) (17), a validated instrument with high sensitivity and specificity for DPN comprising a 15-item symptom questionnaire, structured foot examination, and assessment of ankle reflexes and distal vibration perception, was administered annually during EDIC (18).

DPN was defined as either 1) confirmed DPN based on two or more positive responses among symptoms, sensory signs, and ankle reflex changes consistent with distal symmetrical polyneuropathy plus nerve conduction abnormalities involving two or more nerves among the median, peroneal, and sural nerves or 2) abnormal MNSI based on either a clinical examination score of ≥2.5 or ≥4 positive responses on the questionnaire using validated cut points developed in this cohort (19). We further defined sustained DPN as a persistent MNSI clinical examination score of ≥2.5 or ≥4 positive responses on the MNSI questionnaire for ≥2 consecutive years during EDIC years 1–17.

Presence of ED was assessed with the International Index of Erectile Function, a reliable, validated instrument (20). Because 20% of participants responded “did not attempt intercourse” on questions in the erectile function (EF) domain, we created a proxy item to assess EF in the entire cohort, regardless of sexual activity and presence of a partner. A single question in the EF domain asks participants, “Over the past 4 weeks, how would you rate your confidence that you get and keep your erection?” Those who answered very low or low were classified as having ED. Those who answered moderate, high, or very high were classified as not having ED. Among the men who engaged in sexual intercourse during the preceding 4 weeks, this definition of ED correlated strongly with total EF domain scores (r = 0.77, P < 0.001) and ED bother (r = 0.80, P < 0.001).

FSD was evaluated by the abbreviated version of the Female Sexual Function Index (FSFI-R), a widely used, multidimensional, well-validated, self-reported measure that assesses sexual function across six domains, including sexual desire, arousal, lubrication, orgasm, satisfaction, and pain, among sexually active women (21). Presence of FSD among women who reported being sexually active was defined by a score ≤22.75 on the FSFI-R.

LUTS severity was determined in men and women during EDIC year 17 using the American Urological Association Symptom Index (22). This index includes a seven-item questionnaire that quantifies the presence and frequency of the following LUTS: nocturia, frequency, urgency, weak urinary stream, intermittency, straining, and sensation of incomplete emptying. Scores range from 0 to 35, and LUTS was defined with widely accepted validated cut points of 0–7 and 8–35 for none/mild and moderate/severe, respectively.

UI in women was determined on the basis of incontinence frequency and amount of urine lost per episode (drops, small splashes, more) using the validated Sandvik Severity Index (23). This index is calculated from frequency and amount of urine loss on a scale of 0–12 (dry/mild 0–2, moderate 3–6, severe 8–9, very severe 12). For the current study, presence of UI was defined as Sandvik Severity Index of 3–12 (moderate/very severe UI).

Hemoglobin A_1c (HbA_1c) was measured at baseline and quarterly during DCCT and annually in EDIC, as previously described (14). The time-weighted mean value for HbA_1c during DCCT and EDIC was calculated by weighting each value by the time interval since the last measurement up to EDIC year 17. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured quarterly during DCCT and annually during EDIC. Hypertension was defined as sitting SBP ≥140 mmHg and/or DBP ≥90 mmHg or the use of antihypertensive medication. Fasting lipids (triglycerides, total and HDL cholesterol) were measured centrally on alternate years during EDIC. Retinopathy was assessed in one-quarter of the cohort annually during EDIC using fundus photographs that were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale (24). Proliferative diabetic retinopathy was defined by neovascularization observed on standardized stereoscopic seven-field fundus photography grading or evidence of scatter photocoagulation. Albumin excretion rate was measured in one-half of the cohort annually during EDIC, and kidney disease was defined as microalbuminuria (albumin excretion rate ≥30 mg/24 h at two consecutive visits). Depression symptoms were assessed using the Psychiatric Symptom Checklist 90-R (SCL-90R), a widely used and well-validated measure that provides an assessment of psychiatric symptoms and generates a total score on the global severity index and subscales, including depression T-scores that are derived from normative samples. Higher scores reflect more symptoms (25).

Descriptive analyses examined the distribution of sociodemographic and clinical characteristics, markers of diabetes control and treatment, BP control, diabetic complications, and neuropathy measures by ED/LUTS status in men and FSD/LUTS/UI status in sexually active women. The Kruskal-Wallis test was used to assess differences in continuous variables and the χ² test for differences in categorical variables. For men and women separately, multivariable logistic regression models were used to evaluate the associations between measures of neuropathy at EDIC years 1, 14, and 17 and the presence of ED/LUTS or FSD/LUTS/UI at EDIC year 17. Variables that were significant at the P < 0.05 level in the bivariate analyses, with no adjustment for multiple comparisons, were entered into the multivariable models as covariates. For men, adjustments were made for age, drinking status, BMI, SCL-90R depression T-score, DCCT/EDIC time-weighted mean HbA_1c, microalbuminuria, hypertension, triglycerides, and statin medication use. For women, adjustments were made for age, menopausal status, SCL-90R depression T-score, SBP, and statin medication use. All analyses were performed using SAS 9.3 statistical software (SAS Institute, Cary, NC).

At EDIC year 17, 30% of men reported ED only, 10% LUTS only, and 15% both ED and LUTS, while 25% of women reported FSD only, 18% LUTS/UI only, and 16% both FSD and LUTS/UI. Table 1 summarizes the sociodemographic, clinical, and diabetes-related characteristics of the study participants by ED and LUTS status and FSD and LUTS/UI status. Compared with men without ED and LUTS, men with ED and LUTS were significantly older, with higher time-weighted mean HbA_1c, SBP, and triglyceride levels; prevalence of hypertension and self-reported use of BP medication; statin use; depression T-scores; and prevalence of microalbuminuria. Although women reporting both FSD and LUTS/UI were significantly older, were more likely to be postmenopausal, had higher depression T-scores, and had higher reported use of statins compared with women without FSD and LUTS/UI, the risk factor profile for women was not similar to men. Most notably, a significant difference in HbA_1c between categories of FSD and LUTS/UI was not observed (Table 1). A large number (n = 198) of women were excluded from analyses because of reporting no sexual activity. Importantly, there were no significant differences in covariates examined or in the associations observed between women who were excluded versus those included in the current analysis (data not shown).

The prevalence of DPN by ED/LUTS and FSD/LUTS/UI status is shown in Table 2. In unadjusted analyses, men with ED and LUTS at EDIC year 17 had a higher prevalence of DPN at all time points, defined as either confirmed DPN at EDIC year 13/14 or as abnormal MNSI examination and questionnaire scores at EDIC years 1, 14, and 17, compared with participants without ED or LUTS. The highest DPN prevalence was observed among men reporting both ED and LUTS, with 62% with confirmed DPN at EDIC year 13/14 and 72% with sustained DPN based on examination vs. 22% and 45% among those with no ED or LUTS, respectively (P < 0.0001 for both). There were no significant differences in DPN prevalence between women reporting both FSD and LUTS/UI and those without FSD or LUTS/UI at EDIC year 1 or 17. However, among women, there was a significant difference in prevalence of symptomatic DPN reported at EDIC year 14 based on abnormal scores on the MNSI questionnaire (P = 0.03).

The odds of reporting ED and LUTS and FSD and LUTS/UI by measures of DPN adjusted for sex-specific risk factors are shown in Table 3. Adjusted for potential confounders, among men the odds of ED and LUTS versus no ED or LUTS at EDIC year 17 were 3.52 (95% CI 1.69, 7.31) times greater in those with confirmed DPN at EDIC year 13/14 than in those without confirmed DPN. Additionally, men with abnormal MNSI examination or questionnaire scores at EDIC years 1, 14, and 17 had significantly higher odds of ED and LUTS versus no ED or LUTS at EDIC year 17 than men without DPN. Finally, men with sustained DPN based on abnormal MNSI questionnaire scores at two or more consecutive visits had significantly higher odds of ED and LUTS versus no ED or LUTS at EDIC year 17 than those without sustained DPN (odds ratio [OR] 4.24 [95% CI 1.68, 10.69]).

Among women, there were no statistically significant associations between any measures of DPN at EDIC years 1 and 17 and reports of FSD and UI at EDIC year 17 after adjustment for potential confounders. At EDIC year 14, women with abnormal MNSI examination scores had a decreased odds of FSD only versus no FSD or LUTS/UI at EDIC year 17 than women without DPN (OR 0.33 [95% CI 0.16, 0.69]).

This study examined the association between measures of DPN and ED/LUTS and FSD/UI among a large and well-phenotyped cohort of men and women with T1D participating in the DCCT/EDIC study. These data provide strong evidence that DPN is associated with ED and LUTS in men and are in concert with our prior reports demonstrating an association of ED/LUTS with peripheral neuropathy (1) and CAN (7), strengthening the pathogenetic link between neuropathic and urological complications in men with T1D. Consistent with our previous reports (1,8), we observed little to no impact of DPN on FSD/UI in women.

Prior studies have reported associations between ED and DPN, but the results have been inconsistent. For instance, in a small study that included 49 men with ED who were phenotyped for DPN on the basis of nerve conduction and quantitative sensory testing, DPN was not associated with ED (26). In contrast, the opposite was true in another small study of 30 subjects with type 2 diabetes (T2D) with symptomatic ED and 30 subjects without ED who were matched for age. In that study, DPN was most common in patients with ED (27). Finally, in a large cross-sectional study that included >2,000 men across 143 health care practices in Italy, a history of diabetic neuropathy was associated with an increased risk of ED (28). The pathogenesis of ED in diabetes is multifactorial, but experimental evidence suggests an important role for neuropathy. Male erectile function is sustained by vascular and neuronal feedback loops. The sensory nervous system likely plays a role in these loops by mediating feedback through impaired nitric oxide release and nitric oxide synthase function of nonadrenergic noncholinergic neurons, decreased smooth muscle relaxation of the corpus cavernosum, impaired sensation of the glans, and abnormal motor function of skeletal muscles participating in erection (9).

Compared with ED, there are limited studies on predictors of FSD in diabetes. Although FSD that is due to diabetes is likely multifactorial, a neurogenic component has been proposed, albeit mostly autonomically mediated. A small study found that women with diabetes had reduced reflexive capillary engorgement measured by vaginal photoplethysmography in response to erotic stimuli compared with control subjects without diabetes (29). Consistent with our findings, another study evaluated biothesiometric (vibratory) sensation of multiple genital and extragenital sites among 30 women with diabetes and 20 control subjects (11). Although women with diabetes showed significantly higher mean FSFI-R scores and higher biothesiometric values (reduced sensation) at each genital and extragenital site, there was no significant difference in biothesiometric values between women with diabetes with and without FSD. While we largely observed little to no impact of DPN on FSD in our cohort overall, we did find a significant decreased odds of FSD only in women with abnormal MNSI examination scores at EDIC year 14. These findings suggest that denervation of peripheral nerves associated with DPN may involve, beyond the classical stocking-and-glove neuropathy, sensation of the genital areas. As pain with intercourse is a component of FSD, women with DPN may report less FSD because of general loss of sensation and decreased pain intensity.

Several explanations can be offered to account for the different pattern of urological complications, specifically sexual dysfunction, in men and women. It is possible, for example, that these differences in sex risk factor profiles are due to differences in the underlying physiological mechanisms (e.g., differences in neurotransmitter involvement) of sexual response in men and women (30,31). Additionally, it has been suggested that diabetes-related vasculopathy or neuropathy might be less readily perceived by women and that women with diabetes might not be aware of a relative decreased lubrication response and therefore not likely to report it (32), in contrast to men who readily experience and report ED. Alternatively, it has been proposed that in general, cultural and/or psychosocial factors may play a larger role in female sexuality and that depression is a more prevalent and potentially more impactful factor in women (33).

Likewise, beyond studies of bladder dysfunction and prevalence, there are limited data on mechanisms and predictors of bladder dysfunction in diabetes, particularly in women. Mechanistically, alterations in bladder innervation, detrusor smooth muscle function, and urothelial dysfunction may contribute to overall bladder dysfunction and UI (13,34). Physiological evaluation of neuropathy in diabetes as a marker of bladder dysfunction has been explored in two previous studies (35,36). In a study of 52 men with diabetes, Bansal et al. (35) reported an association between autonomic and peripheral neuropathy and diabetic cystopathy. Sympathetic skin response and motor and sensory nerve condition studies of the hands and feet were moderately predictive of urodynamic profiles consistent with diabetic cystopathy. Similarly, Ueda et al. (36) found an association between decreased sympathetic skin response and cystometrogram findings in 23 patients with diabetes and 10 control subjects without diabetes. Although the mechanisms are still debated, reduced bladder sensation in diabetes is attributable to lesions involving peripheral afferent fibers, particularly Aδ (myelinated)/C (unmyelinated) small-diameter distal fibers, with additional damage of the mechanosensitive afferent nerves and impaired transmission to the spinal cord (12). Some earlier human studies reported that vesicourethral dysfunction is highly correlated with abnormal nerve conduction velocity in diabetes (37). In addition, the autonomic nervous system plays a central role in the regulation of the urinary bladder function (38). Experimental evidence suggests that sympathetic stimulation regulates urine storage, whereas parasympathetic activation predominates during voiding (39). More recent data from human studies support a continuous interplay between sympathetic and parasympathetic innervation, with complex, mutually interacting mechanisms involving muscarinic and adrenoreceptors that control bladder smooth muscle reactivity and bladder afferent signaling (38).

Our study has several limitations. The lack of ED/LUTS and FSD/UI assessments concomitant with the full battery of confirmed DPN assessments is a notable limitation. However, during EDIC, both the full battery of confirmed DPN assessments and the MNSI were done concomitantly at years 13 and 14 and validated the use of the MNSI as an appropriate alternative to assess DPN annually (19). Furthermore, the confirmed DPN assessments at year 13/14 conducted before the assessment of urological complications is consistent with our hypothesis that neuropathy may be a predictor/potential cause of urinary and sexual dysfunction. We view this temporal sequence as a strength rather than as a limitation. Additionally, there were notable differences in exclusion criteria between men and women. While the use of the proxy item to assess erectile function allowed for the inclusion of men regardless of sexual activity, the FSFI-R was specifically validated to be used only in sexually active women. As a result, women who reported no sexual activity (n = 198) were excluded from the analyses. Importantly, there were no significant differences in the covariates examined or in the associations observed between women who were excluded and those who were included in the current analysis (data not shown). Finally, the lack of racial diversity of this cohort of men and women with T1D limits the generalizability of our results to other races or to patients with T2D.

Strengths of this study include the large sample size of men and women with T1D, the comprehensive DPN assessments performed by highly trained personnel using standardized procedures, and assessment of ED, LUTS, FSD, and UI using standardized and validated questionnaires. Additionally, patients T1D within DCCT/EDIC have been carefully evaluated for a vast array of risk factors besides glycemia that could affect both urological complications and DPN, including BP, lipids, obesity, smoking, alcohol consumption, other microvascular and macrovascular complications, medications, and quality of life.

In conclusion, in men with T1D participating in DCCT/EDIC, we found that the presence of DPN substantially increased the risk for ED and LUTS, even after extensive adjustments for other established and putative risk factors for DPN and urological complications. The association with FSD and LUTS/UI in women was inconsistent and observed for symptomatic DPN alone. Sex-related variation in these urological complications and their underlying mechanisms may explain some of these divergent findings. Future studies confirming the associations between DPN and development and progression of sexual and urinary dysfunction in other cohorts with T1D and T2D are warranted.

Funding. The DCCT/EDIC has been supported by cooperative agreement grants (1982–1993, 2012–2017, 2017–2022), and contracts (1982–2012) with the Division of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (current grants U01-DK-094176 and U01-DK-094157) and through support by the National Eye Institute, the National Institute of Neurological Disorders and Stroke, the General Clinical Research Centers Program (1993–2007), and the Clinical Translational Science Center Program (2006–present). Additional support for this DCCT/EDIC collaborative study was provided by the National Institutes of Health through National Institute of Diabetes and Digestive and Kidney Diseases grant 5R01-DK-083927.

Duality of Interest. The following industry contributors have had no role in the DCCT/EDIC study but have provided free or discounted supplies or equipment to support participants’ adherence to the study: Abbott Diabetes Care, Animas, Bayer Diabetes Care, Becton Dickinson, Eli Lilly, Extend Nutrition, Insulet Corporation, LifeScan, Medtronic Diabetes, Nipro Home Diagnostics, Nova Diabetes Care, Omron, Perrigo Diabetes Care, Roche Diabetes Care, and Sanofi. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. R.P.B., B.H.B., and A.V.S. designed the study, drafted the initial manuscript, and reviewed and edited subsequent versions of the manuscript. B.H.B. conducted the statistical analyses. H.W., W.H.H., C.L.M., and A.M.J. reviewed and edited the manuscript. B.H.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Data and Resource Availability. Data collected for the DCCT/EDIC study through 30 June 2017 are available to the public through the National Institute of Diabetes and Digestive and Kidney Diseases Central Repository (https://repository.niddk.nih.gov/studies/edic). Data collected in the current cycle (July 2017–June 2022) will be available within 2 years after the end of the funding cycle.