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Objective: To evaluate associations between diabetic peripheral neuropathy (DPN) and urological complications in men and women with type 1 diabetes (T1D)., Research Design and Methods: Measurements of DPN at Epidemiology of Diabetes Intervention and Complications (EDIC) years 1, 14, and 17 and urological complications at EDIC year 17 were examined in 635 men (mean age 51.6 years, diabetes duration 29.5 years) and 371 women (mean age 50.6 years, diabetes duration 29.8 years) enrolled in the Diabetes Control and Complications Trial (DCCT)/EDIC study. DPN was defined by symptoms, signs, and abnormal electrophysiology or by abnormal Michigan Neuropathy Screening Instrument (MNSI) examination or questionnaire scores., Results: Erectile dysfunction (ED) in combination with lower urinary tract symptoms (LUTS) was reported in 15% of men and female sexual dysfunction (FSD), LUTS, and urinary incontinence (UI) in 16% of women. Adjusted for age, drinking status, BMI, depression, DCCT/EDIC time-weighted mean HbA1c, microalbuminuria, hypertension, triglycerides, and statin medication use, the odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17 were 3.52 (95% CI 1.69, 7.31) times greater in men with confirmed DPN at EDIC year 13/14 compared to men without confirmed DPN. Compared to men without DPN, men with DPN based on abnormal MNSI examination or questionnaire scores had significantly higher odds of reporting ED and LUTS versus no ED or LUTS at EDIC year 17. There were no significant differences in DPN between women reporting both FSD and LUTS/UI compared with those without FSD or LUTS/UI at EDIC year 17., Conclusions: In long-standing T1D, DPN is associated with the later development of urological complications in men., (© 2021 by the American Diabetes Association.)

Objective: To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes., Research Design and Methods: We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4 score ≥3)., Results: Among 5,249 patients with data on both DPN and pain, 17.9% ( n = 938) had possible DPN, including 7.4% ( n = 386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L, adjusted prevalence ratio (aPR) 1.36 (95% CI 1.17; 1.59); decreased HDL cholesterol <1.0/1.2 mmol/L (male/female), aPR 1.35 (95% CI 1.12; 1.62); hs-CRP ≥3.0 mg/L, aPR 1.66 (95% CI 1.42; 1.94); C-peptide ≥1,550 pmol/L, aPR 1.72 (95% CI 1.43; 2.07); HbA 1c ≥78 mmol/mol, aPR 1.42 (95% CI 1.06; 1.88); and antihypertensive drug use, aPR 1.34 (95% CI 1.16; 1.55). Smoking, aPR 1.50 (95% CI 1.24; 1.81), and lack of physical activity (0 vs. ≥3 days/week), aPR 1.61 (95% CI 1.39; 1.85), were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain., Conclusions: Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes., (© 2020 by the American Diabetes Association.)

Objective: To assess the contemporaneous prevalence of diabetic peripheral neuropathy (DPN) in people with type 1 diabetes (T1D) in Scotland and study its cross-sectional association with risk factors and other diabetic complications., Research Design and Methods: We analyzed data from a large representative sample of adults with T1D ( N = 5,558). We assessed the presence of symptomatic neuropathy using the dichotomized (≥4) Michigan Neuropathy Screening Instrument Patient Questionnaire score. Logistic regression models were used to investigate associations between DPN and risk factors, as well as with other complications., Results: The burden of DPN is substantial with 13% prevalence overall. Adjusting for attained age, diabetes duration, and sex, the odds of DPN increased mainly with waist-to-hip ratio, lipids, poor glycemic control (odds ratio 1.51 [95% CI 1.21-1.89] for levels of 75 vs. 53 mmol/mol), ever versus never smoking (1.67 [1.37-2.03]), and worse renal function (1.96 [1.03-3.74] for estimated glomerular filtration rate levels <30 vs. ≥90 mL/min/1.73 m 2 ). The odds significantly decreased with higher HDL cholesterol (0.77 [0.66-0.89] per mmol/L). Living in more deprived areas was associated with DPN (2.17 [1.78-2.65]) for more versus less deprived areas adjusted for other risk factors. Finally, individuals with prevalent DPN were much more likely than others to have other diabetes complications., Conclusions: Diabetic neuropathy remains substantial, particularly affecting those in the most socioeconomically deprived groups. Those with clinically manifest neuropathy also have a higher burden of other complications and elevated levels of modifiable risk factors. These data suggest that there is considerable scope to reduce neuropathy rates and narrow the socioeconomic differential by better risk factor control., (© 2020 by the American Diabetes Association.)

Objective: To evaluate whether diabetic polyneuropathy (DPN) follows the hypothesis for the course of nerve fiber damage reflected by symptoms progressing from pure small through mixed to large nerve fiber symptoms with or without symptoms of loss of function of small nerve fibers., Research Design and Methods: Repeated assessments of nerve fiber-specific symptoms were obtained in 518 participants of the ADDITION-Denmark study from the time of a screening-based diagnosis of type 2 diabetes using specific items of the Michigan Neuropathy Screening Instrument questionnaire. DPN was clinically assessed 13 years after inclusion. The course of symptoms reflecting dysfunction of specific nerve fibers was evaluated, and the association between symptoms and DPN was estimated using logistic regression models., Results: An overall stable, yet heterogeneous course of symptoms was seen. According to the hypothesis of symptom progression, 205 (40%) participants remained free of symptoms and 56 (11%) had stable, 114 (23%) progressing, and 132 (26%) improving symptoms. Cross-sectional estimates showed a higher risk of DPN (odds ratios between 2.1 and 4.1) for participants with mixed or large nerve fiber symptoms with or without symptoms of loss of function of small nerve fibers compared with participants without symptoms., Conclusions: There was no evidence for a progressive development of nerve fiber damage in DPN reflected by symptoms going from pure small through mixed to large nerve fiber symptoms with or without symptoms of loss of function of small nerve fibers. Yet overall, neuropathic symptoms were prospectively associated with a higher risk of DPN., (© 2019 by the American Diabetes Association.)

Objective: To examine the course of cardiovascular autonomic neuropathy (CAN) and related cardiometabolic risk factors in patients with type 2 diabetes., Research Design and Methods: CAN and cardiometabolic risk factors were assessed in the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) at 6-year ( n = 777) and 13-year ( n = 443) follow-up examinations. Cardiovascular autonomic reflex tests (CARTs)-that is, lying to standing, deep breathing, and the Valsalva maneuver-and 2-min resting heart rate variability (HRV) indices were obtained as the main measures of CAN. Risk factors related to CAN status, as determined by CARTs, were studied by using multivariate logistic regressions. The effects of risk factors on continuous CARTs and HRV indices, and their changes over time, were estimated in linear mixed models., Results: A progressive yet heterogeneous course of CAN occurred between the 6- and 13-year follow-ups. Higher HbA 1c , weight, BMI, and triglycerides were associated with prevalent CAN. No significant effect of risk factors on CARTs was found when they were analyzed as continuous variables. CART indices decreased over time, and a trend of decreasing HRV indices was seen. Higher HbA 1c and BMI were associated with lower HRV index values, but these differences diminished over time., Conclusions: These data confirm that hyperglycemia, obesity, and hypertriglyceridemia are negatively related to indices of CAN, although these effects diminish over time. The observed heterogeneous course of CAN may challenge the present clinical approach of categorically classifying CARTs to diagnose CAN and the notion of CAN being irreversible., (© 2018 by the American Diabetes Association.)

Objective: Type 1 diabetes is a complex disease, and development of multiple complications over time can be analyzed only with advanced statistical methods. This study describes the development of microvascular complications and explores the effect of complication burden and important concurrent risk factors by applying a multistate model., Research Design and Methods: We used a clinical cohort at the Steno Diabetes Center Copenhagen to study the development of diabetic kidney disease, retinopathy, and neuropathy. We extracted information from electronic patient records and estimated incidence rates of complications by concurrent complication burden. We explored the extent to which concurrent complications modify the effect of selected risk factors on the development of microvascular complications., Results: We included 3,586 individuals. Incidence rate ratios in individuals with two previous complications were 3.2 (95% CI 2.3-4.5) for diabetic kidney disease, 2.1 (1.5-3.1) for retinopathy, and 1.7 (1.2-2.4) for neuropathy compared with individuals without complications. The models included diabetes duration; calendar time and age as timescales; and sex, HbA 1c , lipid-lowering and antihypertensive treatment, systolic blood pressure, BMI, estimated glomerular filtration rate (eGFR), cardiovascular disease (CVD), LDL cholesterol, insulin dose (units/kg/day), and smoking status as covariates. Effects of HbA 1c , diabetes duration, systolic blood pressure, BMI, eGFR, and LDL cholesterol where not modified by concurrent complication burden, whereas the effect of sex and CVD were., Conclusions: The risk of microvascular complications highly depends on the concurrent complication burden and risk factor profile in individuals with type 1 diabetes. The results emphasize attention to risk factors, regardless of existing number of complications, to prevent development of further microvascular complications., (© 2018 by the American Diabetes Association.)

Objective: To study cardiometabolic risk-factor trajectories (in terms of levels and changes over time) preceding diabetic polyneuropathy (DPN) 13 years after a screen-detected diagnosis of type 2 diabetes., Research Design and Methods: We clinically diagnosed DPN in a nested case-control study of 452 people in the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION). By linear regression models, we estimated preceding risk-factor trajectories during 13 years. Risk of DPN was estimated by multivariate logistic regression models of each individual's risk-factor trajectory intercept and slope adjusting for sex, age, diabetes duration, height, and trial randomization group., Results: Higher baseline levels of HbA 1c (odds ratio [OR] 1.76 [95% CI 1.37; 2.27] and OR 1.68 [95% CI 1.33; 2.12] per 1% and 10 mmol/mol, respectively) and steeper increases in HbA 1c over time (OR 1.66 [95% CI 1.21; 2.28] and OR 1.59 [95% CI 1.19; 2.12] per 1% and 10 mmol/mol increase during 10 years, respectively) were associated with DPN. Higher baseline levels of weight, waist circumference, and BMI were associated with DPN (OR 1.20 [95% CI 1.10; 1.31] per 5 kg, OR 1.27 [95% CI 1.13; 1.43] per 5 cm, and OR 1.24 [95% CI 1.12; 1.38] per 2 kg/m 2 , respectively)., Conclusions: Both higher levels and slopes of HbA 1c trajectories were associated with DPN after 13 years. Our findings indicate that the rate of HbA 1c increase affects the development of DPN over and above the effect of the HbA 1c level. Furthermore, this study supports obesity as a risk factor for DPN., (© 2018 by the American Diabetes Association.)

Objective: Evidence from prospective studies for long-term treatment efficacy of spinal cord stimulation (SCS) in painful diabetic peripheral neuropathy (PDPN) is not available. We report prospective data on the effect of SCS on pain ratings, treatment success and failure, and complications during a 5-year follow-up in patients with PDPN., Research Design and Methods: Patients with PDPN ( n = 48) were included in this prospective multicenter study. The Michigan Diabetic Neuropathy Score (MDNS) was used to assess the severity of neuropathy. Numerical rating scale (NRS) score for pain, Patient's Global Impression of Change (PGIC), and treatment success (50% reduction of NRS score or significant PGIC) during 5 years of follow-up were evaluated. Complications of SCS were reported, and associations between baseline characteristics and SCS trial success or failure during a 5-year follow-up were investigated by using survival analyses., Results: Treatment success was observed in 55% of patients after 5 years. Median duration of SCS treatment was 60 months (minimum 1 month, maximum 60 months), and 80% of patients with a permanent implant still used their SCS device after 5 years. Higher MDNS was associated with treatment failure during the 5-year follow-up (hazard ratio 3.9 [95% CI 1.3-11.6]; P = 0.014)., Conclusions: SCS is successful in reducing chronic pain symptoms in the lower extremities of patients with PDPN up to 5 years after initiation of treatment. Furthermore, 80% of patients with PDPN still use their SCS device after 5 years. Moreover, the severity of neuropathy is associated with a higher chance of long-term treatment failure during a 5-year follow-up., (© 2017 by the American Diabetes Association.)

Objective: To examine whether cardiovascular autonomic neuropathy (CAN) is an independent risk factor of cardiovascular disease (CVD) events during DCCT/EDIC., Research Design and Methods: Standardized cardiovascular autonomic reflex tests (R-R response to paced breathing, Valsalva maneuver, postural changes in blood pressure) were performed at DCCT baseline, every 2 years throughout DCCT, and at two time points in EDIC. CVD events were ascertained throughout the study and adjudicated by a review committee. Cox proportional hazards models were used to estimate the effect of CAN at DCCT closeout on subsequent CVD risk., Results: There were 299 adjudicated CVD events in 165 participants following the DCCT closeout assessment: 132 of 1,262 subjects (10%) without CAN at DCCT closeout who experienced 244 CVD events versus 33 of 131 subjects (25%) with CAN at DCCT closeout who experienced 55 events (hazard ratio 2.79, 95% CI 1.91-4.09 for time to first CVD event). The cumulative incidence of the first occurrence of any CVD event during EDIC was significantly higher in participants with CAN at DCCT closeout compared with those without CAN. The association remained marginally significant after adjustment for multiple risk factors, including the EDIC updated mean HbA 1c . When analyzed as a continuous variable, R-R variation was significantly lower at DCCT closeout in participants who experienced a CVD event compared with those who did not (P = 0.0012)., Conclusions: In the DCCT/EDIC cohort, individuals diagnosed with CAN at DCCT closeout experienced a higher long-term risk of CVD events during follow-up in EDIC. This association was not independent of historic glycemic exposure and its metabolic memory effect, the principal determinant of both long-term CVD risk and CAN in type 1 diabetes., (© 2017 by the American Diabetes Association.)

Objective: To estimate the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in a pilot study among youth participating in the SEARCH for Diabetes in Youth study., Research Design and Methods: DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI) (examination for foot abnormalities, distal vibration perception, and ankle reflexes). An MNSI exam (MNSIE) score >2 is diagnostic for DPN., Results: The MNSIE was completed in 399 subjects, including 329 youth with type 1 diabetes (mean age 15.7 ± 4.3 years, duration 6.2 ± 0.9 years) and 70 with type 2 diabetes (mean age 21.6 ± 4.1 years, duration 7.6 ± 1.8 years). Glycated hemoglobin (A1C) was similar in both groups (8.8 ± 1.8% for type 1 vs. 8.5 ± 2.9% for type 2). The prevalence of DPN was significantly higher in youth with type 2 compared with those with type 1 diabetes (25.7 vs. 8.2%; P < 0.0001). In unadjusted analyses, diabetes type, older age, longer duration of diabetes, increased waist circumference, elevated blood pressure, lower HDL cholesterol, and presence of microalbuminuria (urinary albumin-to-creatinine ratio >30 mg/g) were associated with DPN. The association between diabetes type and DPN remained significant after adjustment for age and sex (odds ratio 2.29 [95% CI 1.05-5.02], P = 0.03)., Conclusions: DPN prevalence among youth with type 2 diabetes approached rates reported in adult populations with diabetes. Our findings suggest not only that youth with diabetes are at risk for DPN but also that many already show measurable signs of DPN.

Objective: Mild demyelination may contribute more to the pathophysiology of nerve fiber injury in diabetic sensorimotor polyneuropathy (DSP) than previously thought. We investigated the clinical and electrodiagnostic classifications of nerve injury in diabetic patients to detect evidence of conduction slowing in DSP., Research Design and Methods: Type 1 diabetic subjects (n = 62) and type 2 diabetic subjects (n = 111) with a broad spectrum of DSP underwent clinical examination and nerve conduction studies (NCS). Patients were classified as having axonal (group A), conduction slowing (group D), or combined (group C) DSP based on electrodiagnostic criteria. Patients with chronic immune-mediated neuropathies were not included. The groups were compared using ANOVA, contingency tables, and Kruskal-Wallis analyses., Results: Of the 173 type 1 and type 2 diabetic subjects with a mean age of 59.1 ± 13.6 years and hemoglobin A1c (HbA1c) of 8.0 ± 1.8% (64 ± 19.7 mmol/mol), 46% were in group A, 32% were in group D, and 22% were in group C. The severity of DSP increased across groups A, D, and C, respectively, based on clinical and NCS parameters. The mean HbA1c for group D subjects (8.9 ± 2.3% [74 ± 25.1 mmol/mol]) was higher than for group A and group C subjects (7.7 ± 1.4% [61 ± 15.3 mmol/mol] and 7.5 ± 1.3% [58 ± 14.2 mmol/mol]; P = 0.003), and this difference was observed in those with type 1 diabetes., Conclusions: The presence of conduction slowing in patients with suboptimally controlled type 1 diabetes indicates the possibility that this stage of DSP may be amenable to intervention via improved glycemic control.

Objective: To establish if corneal nerve loss, detected using in vivo corneal confocal microscopy (IVCCM), is symmetrical between right and left eyes and relates to the severity of diabetic neuropathy., Research Design and Methods: Patients (n = 111) with type 1 and type 2 diabetes and 47 age-matched healthy control subjects underwent detailed assessment and stratification into no (n = 50), mild (n = 26), moderate (n = 17), and severe (n = 18) neuropathy. IVCCM was performed in both eyes and corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) and the tortuosity coefficient were quantified., Results: All corneal nerve parameters differed significantly between diabetic patients and control subjects and progressively worsened with increasing severity of neuropathy. The reduction in CNFD, CNBD, and CNFL was symmetrical in all groups except in patients with severe neuropathy., Conclusions: IVCCM noninvasively detects corneal nerve loss, which relates to the severity of neuropathy, and is symmetrical, except in those with severe diabetic neuropathy.

Objective: Long-term diabetes leads to severe peripheral, autonomous, and central neuropathy in combination with clinical gastrointestinal symptoms. The brain-gut axis thus expresses a neurophysiological profile, and heart rate variability (HRV) can be correlated with clinical gastrointestinal symptoms., Research Design and Methods: Fifteen healthy volunteers and 15 diabetic patients (12 with type 1 diabetes) with severe gastrointestinal symptoms and clinical suspicion of autonomic neuropathy were included. Psychophysics and evoked brain potentials were assessed after painful rectosigmoid electrostimulations, and brain activity was modeled by brain electrical source analysis. Self-reported gastrointestinal symptoms (per the Patient Assessment of Upper Gastrointestinal Disorder Severity Symptom Index) and quality of life (SF-36 Short Form Survey) were collected., Results: Diabetic patients had autonomous neuropathy, evidenced by decreased electrocardiographic R-R interval (P = 0.03) and lower HRV (P = 0.008). Patients were less sensitive to painful stimulation (P = 0.007), had prolonged latencies of evoked potentials (P ≤ 0.001), and showed diminished amplitude of the N2-P2 component in evoked potentials (P = 0.01). There was a caudoanterior shift of the insular brain source (P = 0.01) and an anterior shift of the cingulate generator (P = 0.01). Insular source location was associated with HRV assessments (all P < 0.02), and the shift (expressed in mm) correlated negatively with physical health (P < 0.001) and positively with nausea (P = 0.03) and postprandial fullness (P = 0.03). Cingulate source shift was correlated negatively with physical health (P = 0.005) and positively with postprandial fullness (P ≤ 0.001)., Conclusions: This study provides evidence for interaction between autonomic neuropathy and peripheral nervous degeneration, as well as changes in dipole sources in diabetic patients with gastrointestinal symptoms. The findings may lead to improved treatment modalities targeting pharmacological neuroprotection or neuromodulation.

Objective: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN)., Research Design and Methods: DPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score>2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates., Results: Results are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62±9 years, mean HbA1c 7.7±1.6%, diabetes duration 10±9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P=0.02), which remained significant after adjusting for the in-trial HbA1c (P=0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58-0.99], P<0.01)., Conclusions: Among patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.

Objective: Reduced heart rate variability (HRV) is classically viewed as an early phenomenon in diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the characteristics of HRV across the spectrum of clinical DSP in type 1 diabetes., Research Design and Methods: Eighty-nine diabetic subjects and 60 healthy volunteers underwent assessment of RR interval variation (RR(var)) during deep breathing and clinical and electrophysiological examination. We examined the distribution of age-standardized RR(var) across the spectrum of clinical DSP, identified variables associated with RR(var) in multivariate regression, and compared RR(var) with validated measures of neuropathy., Results: Age-standardized RR(var) had a significant, step-wise, inverse relationship with ordinal categories of increasing DSP severity (β = -5.4, P < 0.0001) among subjects with diabetes. Case subjects with DSP had substantially lower age-standardized RR(var) compared with diabetic control subjects without DSP (β = -5.2, P < 0.01), although there was substantial overlap of RR(var) between diabetic case subjects and control subjects and the healthy volunteer cohort. In multivariate analysis, advanced age was independently associated with lower RR(var) in both healthy volunteers and diabetic subjects, whereas higher glycated hemoglobin A(1c) and systolic blood pressure were independently associated with lower RR(var) in diabetic subjects. RR(var) had a significant association with validated measures of large and small fiber neuropathy., Conclusions: HRV may be a biomarker for clinical DSP and is associated cross-sectionally with both early and late measures of neuropathy. The low HRV observed in some control subjects without DSP and in most case subjects with severe DSP may signify that HRV has different prognostic implications in these groups, requiring further longitudinal study.

Objective: We aimed to determine the corneal confocal microscopy (CCM) parameter that best identifies diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes and to describe its performance characteristics., Research Design and Methods: Concurrent with clinical and electrophysiological examination for classification of DSP, CCM was performed on 89 type 1 diabetic and 64 healthy subjects to determine corneal nerve fiber length (CNFL), density, tortuosity, and branch density. Area under the curve (AUC) and optimal thresholds for DSP identification in those with diabetes were determined by receiver operating characteristic (ROC) curve analysis., Results: DSP was present in 33 (37%) subjects. With the exception of tortuosity, CCM parameters were significantly lower in DSP case subjects. In ROC curve analysis, AUC was greatest for CNFL (0.88) compared with fiber density (0.84, P = 0.0001), branch density (0.73, P < 0.0001), and tortuosity (0.55, P < 0.0001). The threshold value that optimized sensitivity and specificity for ruling in DSP was a CNFL of ≤14.0 mm/mm(2) (sensitivity 85%, specificity 84%), associated with positive and negative likelihood ratios of 5.3 and 0.18. An alternate approach that used separate threshold values maximized sensitivity (threshold value ≥15.8 mm/mm(2), sensitivity 91%, negative likelihood ratio 0.16) and specificity (≤11.5 mm/mm(2), specificity 93%, positive likelihood ratio 8.5)., Conclusions: Among CCM parameters, CNFL best discriminated DSP cases from control subjects. A single threshold offers clinically acceptable operating characteristics, although a strategy that uses separate thresholds to respectively rule in and rule out DSP has excellent performance while minimizing unclassified subjects. We hypothesize that values between these thresholds indicate incipient nerve injury that represents those individuals at future neuropathy risk.

Objective: There is limited evidence on how intensive multifactorial treatment (IT) improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. We examined the effects of early detection and IT of type 2 diabetes in primary care on the prevalence of diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) 6 years later in a pragmatic, cluster-randomized parallel group trial., Research Design and Methods: A stepwise screening program in 190 general practices in Denmark was used to identify 1,533 people with type 2 diabetes. General practices were randomized to deliver either IT or routine care (RC) as recommended through national guidelines. Participants were followed for 6 years and measures of DPN and PAD were applied., Results: We found no statistically significant effect of IT on the prevalence of DPN and PAD compared with RC. The prevalence of an ankle brachial index ≤0.9 was 9.1% (95% CI 6.0-12.2) in the RC arm and 7.3% (5.0-9.6) in the IT arm. In participants tested for vibration detection threshold and light touch sensation, the prevalence of a least one abnormal test was 34.8% (26.7-43.0) in the RC arm and 30.1% (24.1-36.1) in the IT arm., Conclusions: In a population with screen-detected type 2 diabetes, we did not find that screening followed by IT led to a statistically significant difference in the prevalence of DPN and PAD 6 years after diagnosis. However, treatment levels were high in both groups.

Objective: This study investigated the relationship between circulating soluble receptor for advanced glycation end products (sRAGE) and parameters of bone health in patients with Charcot neuroarthropathy (CNA)., Research Design and Methods: Eighty men (aged 55.3±9.0 years), including 30 healthy control subjects, 30 type 2 diabetic patients without Charcot, and 20 type 2 diabetic patients with stage 2 (nonacute) CNA, underwent evaluations of peripheral and autonomic neuropathy, nerve conduction, markers of bone turnover, bone mineral density, and bone stiffness of the calcaneus., Results: CNA patients had worse peripheral and autonomic neuropathy and a lower bone stiffness index than diabetic or control individuals (77.1, 103.3, and 105.1, respectively; P<0.05), but no difference in bone mineral density (P>0.05). CNA subjects also had lower sRAGE levels than control (162 vs. 1,140 pg/mL; P<0.01) and diabetic (162 vs. 522 pg/mL; P<0.05) subjects, and higher circulating osteocalcin levels., Conclusions: CNA patients had significantly lower circulating sRAGE, with an accompanying increase in serum markers of bone turnover, and reduced bone stiffness in the calcaneus not accompanied by reductions in bone mineral density. These data suggest a failure of RAGE defense mechanisms against oxidative stress in diabetes. Future studies should determine if medications that increase sRAGE activity could be useful in mitigating progression to CNA.

Objective: The severity of peripheral neuropathy in diabetic patients varies for unclear reasons. Long-term use of metformin is associated with malabsorption of vitamin B(12) (cobalamin [Cbl]) and elevated homocysteine (Hcy) and methylmalonic acid (MMA) levels, which may have deleterious effects on peripheral nerves. The intent of this study was to clarify the relationship among metformin exposure, levels of Cbl, Hcy, and MMA, and severity of peripheral neuropathy in diabetic patients. We hypothesized that metformin exposure would be associated with lower Cbl levels, elevated Hcy and MMA levels, and more severe peripheral neuropathy., Research Design and Methods: This was a prospective case-control study of patients with type 2 diabetes and concurrent symptomatic peripheral neuropathy, comparing those who had received >6 months of metformin therapy (n = 59) with those without metformin exposure (n = 63). Comparisons were made using clinical (Toronto Clinical Scoring System and Neuropathy Impairment Score), laboratory (serum Cbl, fasting Hcy, and fasting MMA), and electrophysiological measures (nerve conduction studies)., Results: Metformin-treated patients had depressed Cbl levels and elevated fasting MMA and Hcy levels. Clinical and electrophysiological measures identified more severe peripheral neuropathy in these patients; the cumulative metformin dose correlated strongly with these clinical and paraclinical group differences., Conclusions: Metformin exposure may be an iatrogenic cause for exacerbation of peripheral neuropathy in patients with type 2 diabetes. Interval screening for Cbl deficiency and systemic Cbl therapy should be considered upon initiation of, as well as during, metformin therapy to detect potential secondary causes of worsening peripheral neuropathy.

Objective: Diabetic large-nerve fiber dysfunction, as measured by vibration perception threshold (VPT), predicts foot ulceration, amputation, and mortality. Thus, determination of modifiable risk factors is of great clinical importance., Research Design and Methods: We assessed 1,407 patients with type 1 diabetes and a normal VPT participating in the EURODIAB Prospective Complications Study, at baseline mean +/- SD age of 32.7 +/- 10.2 years with diabetes duration of 14.7 +/- 9.3 years and follow-up of 7.3 +/- 0.6 years. VPT was measured using biothesiometry on the right big toe and medial malleolus. An abnormal result was defined as >2 SD from the predicted mean for the patient s age., Results: An abnormal VPT was associated with an increased incidence of gangrene, amputation, foot ulceration, leg bypass or angioplasty, and mortality (P < OR = 0.02). The incidence of abnormal VPT was 24% over the 7.3-year follow-up. Duration of diabetes and A1C significantly influenced the incidence of abnormal VPT (P < 0.0001). After correction for these, established risk factors for cardiovascular disease (CVD), including male sex (P = 0.0004), hypertension (P < 0.0001), total cholesterol (P = 0.002), LDL cholesterol (P = 0.01), smoking (P < 0.0001), weight (P < 0.0001), and diabetes complications (retinopathy [P = 0.0001], nephropathy [P = 0.01], and autonomic neuropathy [P = 0.001]), were all found to be significant risk factors. A previous history of CVD doubled the incidence of abnormal VPT., Conclusions: This prospective study indicates that cardiovascular risk factors predict development of large-fiber dysfunction, which may account for the high mortality rate in patients with an abnormal VPT, and emphasizes the importance of early determination of VPT to detect subclinical neuropathy and to address cardiovascular risk factors.

Objective: Debate remains as to whether short- or long-term glycemic instability confers a risk of microvascular complications in addition to that predicted by mean glycemia alone. In this study, we analyzed data from the Diabetes Control and Complications Trial (DCCT) to assess the effect of A1C variability on the risk of retinopathy and nephropathy in patients with type 1 diabetes., Research Design and Methods: A1C was collected quarterly during the DCCT in 1,441 individuals. The mean A1C and the SD of A1C variability after stabilization of glycemia (from 6 months onwards) were compared with the risk of retinopathy and nephropathy with adjustments for age, sex, disease duration, treatment group, and baseline A1C., Results: Multivariate Cox regression showed that the variability in A1C added to mean A1C in predicting the risk of development or progression of both retinopathy (hazard ratio 2.26 for every 1% increase in A1C SD [95% CI 1.63-3.14], P < 0.0001) and nephropathy (1.80 [1.37-2.42], P < 0.0001), with the relationship a feature in conventionally treated patients in particular., Conclusions: This study has shown that variability in A1C adds to the mean value in predicting microvascular complications in type 1 diabetes. Thus, in contrast to analyses of DCCT data investigating the effect of short-term glucose instability on complication risk, longer-term fluctuations in glycemia seem to contribute to the development of retinopathy and nephropathy in type 1 diabetes.

Objective: The degree to which chronic glycemic exposure (CGE) (fasting plasma glucose [FPG], HbA1c [A1C], duration of diabetes, age at onset of diabetes, or combinations of these) is associated with or predicts the severity of microvessel complications is unsettled. Specifically, we test whether combinations of components correlate and predict complications better than individual components., Research Design and Methods: Correlations and predictions of CGE and complications were assessed in the Rochester Diabetic Neuropathy Study, a population-based, cross-sectional, and longitudinal epidemiologic survey of 504 patients with diabetes followed for up to 20 years., Results: In multivariate analysis, A1C and duration of diabetes (and to a lesser degree age at onset of diabetes but not FPG) were the main significant CGE risk covariates for complications. A derived glycemic exposure index (GE(i)) correlated with and predicted complications better than did individual components. Composite or staged measures of polyneuropathy provided higher correlations and better predictions than did dichotomous measures of whether polyneuropathy was present or not. Generally, the mean GE(i) was significantly higher with increasing stages of severity of complications., Conclusions: A combination of A1C, duration of diabetes, and age at onset of diabetes (a mathematical index, GE(i)) correlates significantly with complications and predicts later complications better than single components of CGE. Serial measures of A1C improved the correlations and predictions. For polyneuropathy, continuous or staged measurements performed better than dichotomous judgments. Even with intensive assessment of CGE and complications over long times, only about one-third of the variability of the severity of complications is explained, emphasizing the role of other putative risk covariates.

Objective: Cardiovascular autonomic neuropathy is associated with microalbuminuria in young and middle-aged patients with type 2 diabetes. We examined this relationship and the potential mediating role of blood pressure in older patients., Research Design and Methods: At least two of three components of cardiovascular autonomic testing were completed by 132 patients (mean age 70 +/- 5.6 years). Relative rankings on each of the components were averaged to create a summary heart rate variability (HRV) measure. The urine microalbumin-to-creatinine ratio (milligrams albumin/grams creatinine) was calculated. Blood pressure was measured at rest and by 24-h ambulatory recording., Results: Urine microalbumin-to-creatinine ratio was higher in those with lower HRV (mean urine microalbumin-to-creatinine ratio 28, 56, and 191 mg/g from the highest to lowest tertile of HRV; P < 0.0001). Resting and ambulatory blood pressure levels were negatively correlated with HRV and positively correlated with urine microalbumin-to-creatinine ratio. In multivariate analysis adjusting for age, duration of diabetes, HbA(1c), and HDL cholesterol, HRV and blood pressure were both independently associated with urine microalbumin-to-creatinine ratio, with no evidence that either mediates the effect of the other., Conclusions: Cardiovascular autonomic neuropathy and blood pressure are independently associated with microalbuminuria in older patients with type 2 diabetes.

Objective: Pupillary autonomic neuropathy is considered an early sign of the development of systemic autonomic neuropathy. Sympathetic denervation is related to the duration of diabetes and the development of systemic autonomic dysfunction. We investigated pupil responsiveness to directly and indirectly acting sympathomimetics in type 1 diabetic patients with and without long-term complications, defined as cardiac autonomic neuropathy (CAN), peripheral sensomotor neuropathy, retinopathy, and nephropathy, and in healthy subjects., Research Design and Methods: A total of 47 randomly chosen type 1 diabetic patients and 20 healthy subjects were selected for this study. Patients were divided into groups determined by whether they had long-term diabetic complications. Pharmacological tests were performed with cocaine 4%, epinephrine 1%, and pholedrine 5% eye drops. Horizontal pupil diameter (HPD) was measured at the beginning of the pharmacological tests and at defined time points after instillation of the eye drops., Results: Statistical analysis showed a significantly smaller HPD in the patients before instillating eye drops (P = 0.011). In particular, the HPD was significantly smaller in the patient group without CAN when compared with healthy subjects (P = 0.004). Maximal cocaine reaction was diminished in the complication group (P < 0.001). Epinephrine test, visual acuity, ocular pressure, and HbA(1c) did not differ in patients with or without long-term complications. The noncomplication group showed no significant differences in pupillary responses as compared with healthy subjects. The complication group showed a smaller HPD (P = 0.022), reduced pupillary responses in the cocaine (P = 0.037) and pholedrine tests (P < 0.001), and anisocor pupil sizes after instillation of the eye drops (P = 0.034)., Conclusions: Our results clearly show that sympathetic denervation does exist in the pupil of diabetic patients and that it can be rapidly assessed using the cocaine test. These data and the results of the epinephrine test suggest a mixed pre- and postganglionic dysfunction of the sympathetic plexus. The significant smaller HPD in patients without CAN compared with that of healthy subjects could be a sign for early involvement of the pupil function before cardiac manifestation of systemic autonomic diabetic neuropathy.

Objective: To study the prevalence of chronic diabetic complications in patients with the slowly progressing autoimmune form of type 1 diabetes, also referred to as latent autoimmune diabetes in adults (LADA)., Research Design and Methods: We evaluated factors associated with chronic diabetic complications in 59 patients with GAD antibodies (GADAs) and age at onset of diabetes >35 years and in 59 GADA-negative type 2 diabetic patients. The prevalence of chronic complications was further compared with the prevalence in 111 type 1 diabetic patients., Results: The LADA patients had lower BMI (P = 0.04), waist-to-hip ratio (P = 0.02 for men and P = 0.03 for women), and fasting C-peptide concentrations (P<0.001) higher HDL2 concentrations (P = 0.04), and less hypertension (58 vs. 75%, P = 0.05) than the type 2 diabetic patients. These differences were even more marked in patients with short disease duration. The prevalence of retinopathy (51 vs. 56%), neuropathy (29 vs. 27%), and microalbuminuria (27 vs. 29%) did not differ between the groups. The type 1 diabetic patients had lower prevalence of neuropathy (13%, P = 0.02) and higher prevalence of retinopathy (76%, P = 0.002) compared with the other groups. Neither the prevalence of coronary heart disease (CHD) (56 vs. 58%) nor cardiovascular mortality (7.4 vs. 12.4%, P = 0.2) significantly differed between the LADA and type 2 diabetic patients. In a multiple logistic regression analysis, glycemic control was associated with CHD (P = 0.02) in the LADA group but not in the type 2 diabetic group., Conclusions: Glycemic control is a stronger risk factor for cardiovascular disease in LADA patients than in patients with type 2 diabetes. This could be related to the lower prevalence of the metabolic syndrome seen in the former.

Objective: To examine longitudinal hyperglycemia and peripheral nerve responses in a population-based incident cohort., Research Design and Methods: A sample from an incident cohort of young people was comprehensively followed from diagnosis of IDDM. Participants were invited to submit blood samples three times per year for central testing of GHb. During their 4th year of diabetes, nerve conduction studies were performed on the median sensory and motor, peroneal motor, and sural sensory nerves. Relationships between mean GHb and nerve latencies, velocities, and amplitudes were explored., Results: GHb was positively related to all nerve latencies and negatively related to all nerve velocities. The relationships between mean GHb and nerve conduction latencies and velocities differed by sex for the peroneal nerve latency (beta = 0.17 male subjects, beta = -0.01 female subjects; P < 0.001). Pubertal participants had lower velocities and longer latencies than prepubertal participants (beta = 0.37; P = 0.05 peroneal latency), after adjustment for GHb, height, and extremity temperature. Sensory and motor nerve amplitudes were related to GHb, and these relationships did not differ by sex., Conclusions: Our study indicates that sustained hyperglycemia is related to functional changes, at the minimum, in peripheral sensory and motor nerve conduction at a diabetes duration of 4 years. Our findings are consistent with a dying-back neuropathy, and there is some suggestion that chronic hyperglycemia may be more detrimental to nerves in male subjects than in female subjects.

Objective: To determine the reliability and validity of autonomic function tests (AFTs) as clinical tools for diagnosing diabetic autonomic dysfunction., Research Design and Methods: Twenty-one healthy control subjects and 21 insulin-dependent diabetes mellitus (IDDM) patients (11 with no symptomatology and 10 with symptomatic diabetic autonomic neuropathy [DAN]) were matched for age, and administered three standard cardiovascular tests and two new vasomotor tests of autonomic function. Each of the cardiovascular tests (change in heart rate [delta bpm], Valsalva ratio [VR], change in systolic blood pressure [delta sBP]) and vasomotor tests (total pulse amplitude [TPA] and percent vasoconstriction [%VC]) were repeated within 1 week. Infrared photoplethysmography measured sympathetic-mediated vasomotor function. Reliability was determined by intraclass correlation coefficients. Validity was determined by analysis of variance procedures to test for differences between known groups and by computing sensitivity, specificity, and positive and negative predictive values., Results: All AFTs were reliable, with %VC having highest reproducibility (r = 0.90). AFT scores were not different from time 1 to time 2. After controlling for age, two cardiovascular tests had significantly different values for control subjects and asymptomatic diabetic patients. AFTs, except delta sBP, were significantly different between symptomatic diabetic patients and asymptomatic diabetic patients after controlling for age and duration of disease simultaneously. Sensitivity, specificity, and predictive values for %VC were comparable to the values for delta bpm and VR. TPA indexes were lower but clinically acceptable., Conclusions: AFTs were found to be reliable and valid tests for detecting DAN. TPA and %VC are important because they measure an aspect of sympathetic function not assessed by standard cardiovascular AFTs, and they do not depend on the patient's cooperation or ability to exert effort.

Objective: To investigate risk factors for distal symmetric (sensory) neuropathy among prevalent cases of non-insulin-dependent diabetes mellitus (NIDDM) in a population-based study in southern Colorado., Research Design and Methods: Prevalent neuropathy was identified in 77 of 277 people with NIDDM by a standardized history and neurologic examination. Fifteen known or suspected risk factors for neuropathy were determined without knowledge of neuropathy status., Results: Older age at examination, longer duration of diabetes, higher glycohemoglobin percentage, lower fasting C-peptide, insulin use, and presence of retinopathy and nephropathy (microalbumin > or = 200 micrograms/ml) were all significantly associated with neuropathy. Sex, ethnicity (Hispanic versus non-Hispanic white), height, systolic blood pressure, peripheral vascular disease, cigarette and alcohol use, and serum lipid levels were not significantly associated with neuropathy. In a multivariate logistic model, increasing age (odds ratio [OR] = 1.3, 95% confidence interval [CI] = 1.1-1.6), longer duration of diabetes (OR = 1.3, CI = 1.0-1.6), increased glycohemoglobin percentage (OR = 1.5, CI = 1.1-2.1), and insulin use (OR = 2.8, CI = 1.3-6.1) were associated with neuropathy. Retinopathy (OR = 3.0, CI = 1.2-7.7), but not nephropathy, was important when added to this model., Conclusions: Worse glycemic control and insulin use were independently associated with neuropathy in people with NIDDM. Whether insulin use represents another marker for severity of the metabolic disturbance or is an independent risk factor for neuropathy requires further study. We could not confirm associations of neuropathy with height, with nephropathy, or with retinopathy, independent of duration of diabetes.

Objective: Foot problems are common in the remaining foot of diabetic amputees. Because high foot pressures are associated with foot ulceration, we studied foot pressures of the remaining foot of diabetic and nondiabetic unilateral amputees., Research Design and Methods: Four age-matched groups of 11 subjects were studied. The groups were comprised of diabetic subjects with previous major amputation, nondiabetic nonneuropathic amputees, diabetic nonamputee patients with similar peripheral nerve involvement as the diabetic amputees, and nondiabetic control subjects. Vibration perception threshold (VPT) was assessed by biothesiometry and foot pressures with an optical pedobarograph., Results: Mean +/- SE VPT in the diabetic amputees was significantly higher than the nondiabetic amputees (40.2 +/- 3.7 vs. 17.7 +/- 2.8 V, P less than 0.002) and similar to diabetic nonamputees (43.4 +/- 3.3 V, NS). VPT was abnormal in 9 (82%) diabetic amputees, 2 (18%) nondiabetic amputees, and 10 (91%) nonamputee diabetic patients. The mean peak foot pressure in the diabetic amputees was higher compared with nondiabetic amputees (18.3 +/- 2.2 vs. 11.3 +/- 1.4 kg/cm2, P less than 0.05) and control subjects (10.0 +/- 1.5 kg/m2, P less than 0.01), but no difference existed with diabetic nonamputees. Abnormally high foot pressures (greater than 12.3 kg/cm2) were present in 8 (73%) diabetic amputees, 3 (27%) nondiabetic amputees, 8 (73%) diabetic nonamputees, and 4 (36%) healthy subjects., Conclusions: We conclude that high pressures are present under the remaining foot in diabetic amputees, and that these pressures are associated with diabetic neuropathy. Prosthetic usage does not increase the pressures under the remaining foot in nondiabetic amputees.

We studied whether lifetime cigarette smoking is associated with the presence of diabetic neuropathy. The research design consisted of a case-control study conducted from a referral-based diabetes clinic at a major medical center. The patients were a 65% sample (163 insulin-dependent diabetes mellitus [IDDM] and 166 non-insulin-dependent diabetes mellitus [NIDDM] patients) of all patients admitted during a 26-mo period. Neuropathy was diagnosed on the basis of signs and symptoms. Smoking history was obtained by mailed questionnaire (66% response rate). Diabetes duration, HbA1, age, sex, peripheral vascular disease, hypertension history, and lifetime alcohol consumption were measured as covariates. The prevalence of neuropathy was 49 and 38% in IDDM (n = 113) and NIDDM (n = 104) patients, respectively. In IDDM, but not NIDDM, current or ex-smokers were significantly more likely to have neuropathy than individuals who had never smoked (odds ratio 2.46, P = 0.02), and the prevalence of neuropathy increased with increasing number of pack-years smoked (P less than 0.001). After adjustment for covariates, IDDM patients smoking greater than or equal to 30 pack-yr were 3.32 times more likely to have neuropathy than patients smoking less than this amount (95% confidence interval 1.15-9.58, P = 0.026). Cigarette smoking was associated with the presence of neuropathy in this clinic-based population of IDDM patients. The hypothesis that cigarette smoking is associated with diabetic neuropathy should be investigated further, both prospectively and in a more representative population.

The relationship between diabetic complications and age, sex, duration, mode of therapy, body weight, control of blood glucose, blood pressure, and serum triglyceride and cholesterol was analyzed in a population with non-insulin-dependent diabetes in Japan. The prevalences of complications in the subjects varied from 6.5% for cerebrovascular strokes to 85.1% for sclerotic changes in retinal vessels; 35.8% of the patients had diabetic retinopathy and 19.8% had proteinuria. Univariate and multivariate analyses revealed that control of diabetes (blood glucose, mode of therapy, and duration) was closely correlated with retinopathy and proteinuria. However, blood glucose did not correlate with coronary insufficiency or cerebrovascular strokes. These macrovascular complications were related to aging and blood pressure. The data suggested that not only good glycemic control but also sufficient antihypertensive therapy was necessary for treating diabetic patients. The coefficient of determination of the risk factors was calculated for each diabetic complication. Except for sclerotic changes in retinal vessels, the coefficients were too small to fully explain the development of diabetic complications, especially for macrovascular diseases. The current data suggest that susceptibility of the individual patients to the diabetic complications is an important determinant.

In a group of 541 white diabetic men aged 20--59 yr attending one clinic it was found that 91 (15%) drank heavily, while a further 39 (7%) had frank alcoholism. The prevalence of symptomatic peripheral neuropathy was much higher in the 120 men who drank excessively. It is considered important, therefore, when treating diabetic patients with peripheral neuropathy not to assume that the diabetes itself is the cause in all cases. The alcoholic intake of the patient should be ascertained and, if excessive, it should be pointed out to the patient that this may well be the predominant factor causing symptoms.

In order to evaluate a possible relation between cigarette smoking and prevalence of diabetic microangiopathy, a series of 180 consecutive patients suffering from insulin-dependent juvenile-onset diabetes mellitus with different durations of disease (60 patients each with diabetes for 10 to 19 years, 20 to 29 years, and 30 to 39 years, respectively) were examined for clinical signs of retinopathy, nephropathy, and peripheral neuropathy. The results were compared with the patients' previous and actual smoking habits. Cigarette smoking was defined as daily smoking of at least ten cigarettes for one year or more. Smoking habits of the total diabetic sample were not significantly different from those of a nondiabetic control sample. However, a decline in the number of cigarette smokers and a rising number of ex-smokers were noted with increasing duration of diabetes. In comparing smokers and nonsmokers, no difference was found in the prevalence of peripheral neuropathy, background retinopathy, and proliferative retinopathy. However, the prevalence of nephropathy (persistent proteinuria) was significantly higher (p less than 0.05) among these patients who were or had been cigarette smokers. Thus, cigarette smoking might be considered a risk factor for the development of diabetic nephropathy.

Recent animal and in vitro studies have identified several interrelated metabolic abnormalities in diabetic nerve that are attributable to elevated ambient glucose concentrations. In combination, these metabolic changes may induce a variety of biochemical and biophysical alterations in peripheral nerve that are highly relevant to the pathogenesis of diabetic neuropathy. This article reviews the current status of several of these metabolic defects and describes ways in which their interaction could lead to pathogenetically important changes in nerve metabolism, function, and structure. Areas of related future research are also discussed.

There is increasing interest in the possibility that diabetes mellitus may be associated with a series of neurobehavioral, or neuropsychological, changes; i.e., learning, memory, problem solving, mental and motor speed, and eye-hand coordination may sometimes be disrupted in diabetic children and adults, and this disruption may be a consequence of certain disease-related variables. To date, four neurobehavioral risk factors have been identified. For children and adolescents, the most potent risk factors appear to be age at diagnosis and the occurrence of schoolroom-related problems. Children who develop diabetes early in life are more likely to show serious cognitive impairments on virtually all measures. In addition, diabetic children with school attendance problems tend to score lower than expected on verbal IQ tests and school achievement tests. For adults, the most carefully studied risk factor is degree of metabolic control. Adults in poor control are far more likely to manifest subtle changes on measures of mental efficiency. This may be particularly evident on tasks that require the development and deployment of sophisticated information-processing strategies. A fourth variable--severe episodes of hypoglycemia--is known to disrupt functioning in diabetic subjects of any age, although it has not yet been studied systematically in large-scale studies. Indeed, because virtually all extant studies have been based on limited neurobehavioral and biomedical assessments of relatively few volunteer subjects, this list of risk factors must be considered tentative at best.