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Background: Studies have shown a connection between psoriasis (PsO) and metabolic syndrome (MS), diabetes mellitus and cardiovascular disease. In addition, MS is associated with autonomic dysfunction (AD). AD has also been associated with chronic arthritis including psoriatic arthritis, but there is lack of similar evidence in patients with PsO. The aim of this study was to look for an association between PsO and AD, independent of the presence of MS. Methods: Cross-sectional study of subjects with PsO without MS; age, sex and BMI matched healthy controls (HC); and age and sex matched subjects with MS. Subjects underwent skin evaluation by dermatologist, blood work for HbA1c, insulin, glucose, and lipids, sudomotor function testing with SudoscanTM device (Impeto Medical-Paris, France) and cardiac autonomic function testing with ANSAR device (ANX 3.0; ANSAR Group, Inc. Philadelphia). Results: We included 47 subjects (13 PsO, 16 HC and 18 MS). PsO subjects had worse cardiac autonomic function compared to the other groups, although glucose and insulin parameters were similar to the HC group (Table 1). No differences were seen in sudomotor function between the groups. Conclusions: PsO seems to have an association with cardiac autonomic dysfunction, independent of its relationship with insulin resistance and MS. Further studies are needed to clarify the significance of these findings and how they relate to MS and diabetes. Disclosure C.M. Casellini: None. H. Parson: None. M.D. Bailey: None. A. Barney: None. A.S. Van Voorhees: Consultant; Self; Celgene. Other Relationship; Self; AbbVie Inc., Lilly Diabetes. A.I. Vinik: None. E.S. Siraj: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Research Support; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc.

Cellular stress and proinflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-I signaling. We therefore examined the effects of mutation of five “inhibitory” Ser phosphorylation sites on IRS2 function in transgenic mice that overexpress, selectively in pancreatic β-cells, either wild-type (WT) or a mutated IRS2 protein (IRS25A). Islets size, number, and mRNA levels of catalase and superoxide dismutase were increased, whereas those of nitric oxide synthase were decreased, in 7- to 10-week-old IRS25A-β mice compared with IRS2WT-β mice. However, glucose homeostasis and insulin secretion in IRS25A-β mice were impaired when compared with IRS2WT-β mice or to nontransgenic mice. This was associated with reduced mRNA levels of Glut2 and islet β-cell transcription factors such as Nkx6.1 and MafA. Similarly, components mediating the unfolded protein response were decreased in islets of IRS25A-β mice in accordance with their decreased insulin secretion. The beneficial effects of IRS25A on β-cell proliferation and β-cell transcription factors were evident only in 5- to 8-day-old mice. These findings suggest that elimination of inhibitory Ser phosphorylation sites of IRS2 exerts short-term beneficial effects in vivo; however, their sustained elimination leads to impaired β-cell function.

Degeneration of nerve fibers due to diabetic peripheral neuropathy (DPN) has been linked to mitochondrial dysfunction. Manipulation of mitochondrial dysfunction through antagonism of muscarinic receptors (MR) promotes neurite outgrowth in adult sensory neurons in vitro and provides neuroprotection in rodent models of DPN. The aim of the study was to assess the efficacy of MR antagonist topical 3% oxybutynin in structural and functional measures of nerve fiber function in subjects with type 2 diabetes (T2DM) and DPN. Pilot, randomized, placebo-controlled, double-blinded study in 40 subjects assessed at baseline and after 20 weeks of treatment with oxybutynin or placebo with the following: intraepidermal nerve fiber density (IENFD) on proximal and distal leg; neuropathy scores and quality of life (Norfolk QoL DN) questionnaire. Baseline demographic characteristics were similar between the treatment groups. IENFD improved significantly after 20 weeks for the treatment group. Neuropathy scores and Norfolk QoL DN also improved significantly in the treatment group (Table 1). No improvements were seen in the placebo group. In this study, oxybutynin proves to be efficacious in improving structural and functional measures of small fiber function, and quality of life in T2DM subjects. These results offer a promising novel therapeutic approach for DPN that needs to be explored further. Disclosure A.I. Vinik: None. N.A. Calcutt: Stock/Shareholder; Self; WinSanTor, Inc.. J.F. Edwards: None. J.R. Weaver: None. M.D. Bailey: None. P. Fernyhough: Stock/Shareholder; Self; WinSanTor, Inc.. L.B. Cundra: None. K.E. Frizzi: None. H. Parson: None. C.M. Casellini: None.

OBJECTIVE We aimed to identify doses of mirogabalin (DS-5565) providing clinically meaningful efficacy with manageable side effects for treatment of diabetic peripheral neuropathic pain (DPNP). RESEARCH DESIGN AND METHODS Adults (≥18 years) with type 1 or 2 diabetes, HbA1c ≤10% at screening, and DPNP for ≥6 months were eligible for study participation. Subjects (n = 452) were randomized (2:1:1:1:1:1:1 ratio) to placebo, dose-ranging mirogabalin (5, 10, 15, 20, and 30 mg/day), or pregabalin (300 mg/day) for 5 weeks. The primary end point was weekly change in average daily pain score (ADPS; 0 to 10 numeric rating scale) from baseline to week 5 (minimally meaningful effect, ≥1.0-point decrease versus placebo). ANCOVA was conducted using last observation carried forward, and treatment effect least squares (LS) means were provided for each contrast. Safety assessments included adverse events (AEs), clinical laboratory tests, and electrocardiograms. RESULTS LS mean differences in change in ADPS from baseline to week 5 versus placebo were –0.22, –0.53, –0.94, –0.88, and –1.01 for the mirogabalin 5-, 10-, 15-, 20-, and 30-mg/day treatment groups, respectively, and –0.05 in the pregabalin group (P < 0.05 versus placebo for mirogabalin 15, 20, and 30 mg/day). Most frequent AEs (n = 277) were primarily mild to moderate dizziness (9.4%), somnolence (6.1%), and headache (6.1%); otherwise, mirogabalin was well tolerated. CONCLUSIONS Mirogabalin 15, 20, and 30 mg/day had statistically significant reductions in ADPS versus placebo, and mirogabalin 30 mg/day also met the criteria of minimally meaningful effect. Mirogabalin may be a promising new treatment option for patients with DPNP.

OBJECTIVE This study evaluated the efficacy and tolerability of tapentadol extended release (ER) for the management of chronic pain associated with diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS Adults with moderate to severe DPN pain were titrated to tapentadol ER 100–250 mg bid during a 3-week open-label period; patients with ≥1-point reduction in pain intensity (11-point numerical rating scale) at end of titration were randomized to receive placebo or tapentadol ER (optimal dose from titration) for 12 weeks (double-blind, fixed-dose maintenance phase). The primary end point was mean change in average pain intensity from the start to week 12 (last observation carried forward [LOCF]) of the double-blind maintenance phase. RESULTS A total of 358 patients completed the titration period; 318 patients (placebo, n = 152; tapentadol ER, n = 166) were randomized and received one or more doses of double-blind study medication. Mean (SD) pain intensity (observed case) was 7.33 (1.30) at the start and 4.16 (2.12) at week 3 of the open-label titration period (mean [SD] change, –3.22 [1.97]). The mean (SD) change in pain intensity (LOCF) from start of double-blind treatment to week 12 was as follows: placebo, 1.30 (2.43); tapentadol ER, 0.28 (2.04; least squares mean difference, –0.95 [95% CI –1.42 to –0.49]; P < 0.001). Treatment-emergent adverse events (≥10%) in the tapentadol ER group during the double-blind maintenance phase were nausea (21.1%) and vomiting (12.7%). CONCLUSIONS Tapentadol ER (100–250 mg bid) was effective and well tolerated for the management of moderate to severe chronic pain associated with DPN.

OBJECTIVE To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). RESULTS Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). CONCLUSIONS Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.

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.

Foot ulcers in patients with diabetes lead to infections, amputations, and high costs, and their prevention is a stated goal of the American Diabetes Association. To assess the benefits of various interventions on the prevention of future diabetic foot ulcers, we searched for and reviewed all randomized clinical trials (RCTs) on the prevention of diabetic foot ulcers and evaluated their efficacy and scientific validity on the basis of an established systemic grading system. Only 13 RCTs were identified. All involved secondary prevention or a mixture of primary and secondary prevention. Most were small and of poor quality, with negative studies generally being of better quality than positive studies. Of all methods proposed to prevent diabetic foot ulcers, only foot temperature-guided avoidance therapy was found beneficial in RCTs, although this needs to be validated in other populations. These observations only apply to high-risk populations, and the benefits to the general population with diabetes are unclear. ### Introduction Diabetic foot ulcers are the cause of immense suffering and health system costs (1). The lifetime risk of a person with diabetes developing a foot ulcer may be as high as 25%, whereas the annual incidence of foot ulcers is as high as 2% (2–6). Multiple component causes, including peripheral neuropathy, peripheral vascular disease (PVD), foot deformity, and smoking, interact in the causal pathway to foot ulceration. In several cross-sectional and retrospective studies, the prevalence of PVD and peripheral neuropathy in patients was found to be as high as 40%. However, no prospective study clearly documented their relative contribution. This review is concerned primarily with clinical trials on the prevention of foot ulcers in the neuropathic, or insensate, foot. Several physiologic measurements of the presence and degree of peripheral neuropathy have been shown to be predictive of the risk of future foot ulcer in …

The Joslin Gold Medalists comprise 351 U.S. residents who have survived with type 1 diabetes for >50 years. A high proportion of Medalists remain free from proliferative diabetic retinopathy (PDR) (42.6%), nephropathy (86.9%), neuropathy (39.4%), or cardiovascular disease (51.5%). Current and longitudinal (the past 15 years) glycemic control were unrelated to complications. Advanced glycation end product (AGE) concentrations include carboxyethyl-lysine (CEL), an AGE derived from methylglyoxal; pentosidine, a glycoxidation ascorbate product; and carboxymethyl-lysine (CML), a glycoxidation and advanced lipoxidation product. Fructose-lysine CML and CEL were significantly elevated in the Medalists as compared with nondiabetic, age-matched control subjects ( N = 23, mean age 67.7 years). Subjects with both CEL >5.3 μmol/mol lysine and pentosidine (>1.0 pmol/mg protein) were the most likely to have any complication (7.2 times more likely) ( P = 0.001), or suffer from nephropathy (3.1 times more likely) ( P = 0.007), neuropathy (2.5 times more likely) ( P = 0.005), or cardiovascular disease (2.3 times more likely) ( P = 0.002). These data are the first to suggest that specific AGEs may decrease risk for diabetes complications because high current CML and fructose-lysine concentrations were negatively correlated with PDR development. Previous reports indicated that AGEs and their precursors may be important in the pathogenesis of diabetes complications; however, it is unexpected that lower current levels of CML and fructose-lysine are inversely related to PDR development in light of reports indicating an association between elevations of these AGEs measured in other tissues and retinopathy. The Medalist population is likely enriched for protective factors against complications. The question is, what are the protective factors? ### Metabolic memory in diabetes The notion of good metabolic memory has been applied to the beneficial effects of an initial period of good glycemic, lipid, and blood pressure control resulting in effects going beyond that of the period of near euglycemia and followed …

OBJECTIVE—Poor peripheral nerve function is prevalent in diabetes and older populations, and it has great potential to contribute to poor physical performance. RESEARCH DESIGN AND METHODS—Cross-sectional analyses were done for the Health, Aging, and Body Composition (Health ABC) Study participants (n = 2,364; 48% men; 38% black; aged 73–82 years). Sensory and motor peripheral nerve function in legs/feet was assessed by 10- and 1.4-g monofilament perception, vibration detection, and peroneal motor nerve conduction amplitude and velocity. The Health ABC lower-extremity performance battery was a supplemented version of the Established Populations for the Epidemiologic Studies of the Elderly battery (chair stands, standing balance, and 6-m walk), adding increased stand duration, single foot stand, and narrow walk. RESULTS—Diabetic participants had fewer chair stands (0.34 vs. 0.36 stands/s), shorter standing balance time (0.69 vs. 0.75 ratio), slower usual walking speed (1.11 vs. 1.14 m/s), slower narrow walking speed (0.80 vs. 0.90 m/s), and lower performance battery score (6.43 vs. 6.93) (all P < 0.05). Peripheral nerve function was associated with each physical performance measure independently. After addition of peripheral nerve function in fully adjusted models, diabetes remained significantly related to a lower performance battery score and slower narrow walking speed but not to chair stands, standing balance, or usual walking speed. CONCLUSIONS—Poor peripheral nerve function accounts for a portion of worse physical performance in diabetes and may be directly associated with physical performance in older diabetic and nondiabetic adults. The impact of peripheral nerve function on incident disability should be evaluated in older adults.

The importance of insulin and glucagon as fine regulators of glycemic excursions is well established (1). Alterations in gastric emptying are generally not considered important contributors to postprandial hyperglycemia until late complications of diabetes such as gastroparesis have occurred (2,3). It is now emerging that the rate of gastric emptying may be a major determinant of postprandial glycemic excursions in healthy subjects, as well as in type 1 and type 2 diabetic patients (4). Gastroparesis is a relatively rare complication that occurs late in diabetes because of irreversible intestinal nerve damage (4); it must be distinguished from the physiological inhibitory effects of acute hyperglycemia on gastric motility (5,6). The latter has been proposed as a defense mechanism existing to minimize postprandial hyperglycemia by reducing the rate of efflux of glucose into the circulation from the gut (7). This may be of special importance for people with type 1 diabetes who have a reduced ability to delay gastric emptying in response to hyperglycemia (8). Cross-sectional studies suggest that an inverse relationship between the rate of gastric emptying and blood glucose concentration also exists in type 2 diabetic patients (4) and, thus, that similar regulatory mechanisms may exist in both conditions. ### Extrinsic pathway. Normally, the rate of gastric emptying is tightly regulated as a result of neural and hormonal feedback triggered by the interaction of nutrients within the small intestine known as the ileal break mechanism or “extrinsic pathway” of control. This feedback is caloric-load dependent, relates to the length of small intestine exposed to nutrient, and regulates the overall rate of emptying to about 2–3 kcal/min (9,10). When food reaches the intestine, L- and K-cells in the distal small bowel are stimulated to produce glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), respectively, both of …

OBJECTIVE—Diabetes leads to protein kinase C (PKC)-β overactivation and microvascular dysfunction, possibly resulting in disordered skin microvascular blood flow (SkBF) and other changes observed in diabetic peripheral neuropathy (DPN) patients. We investigate the effects of the isoform-selective PKC-β inhibitor ruboxistaurin mesylate on neurovascular function and other measures of DPN. RESEARCH DESIGN AND METHODS—Endothelium-dependent and C fiber–mediated SkBF, sensory symptoms, neurological deficits, nerve fiber morphometry, quantitative sensory and autonomic function testing, nerve conduction studies, quality of life (using the Norfolk Quality-of-Life Questionnaire for Diabetic Neuropathy [QOL-DN]), and adverse events were evaluated for 20 placebo- and 20 ruboxistaurin-treated (32 mg/day) DPN patients (aged ≥18 years; with type 1 or type 2 diabetes and A1C ≤11%) during a randomized, double-masked, single-site, 6-month study. RESULTS—Endothelium-dependent (+78.2%, P < 0.03) and C fiber–mediated (+56.4%, P < 0.03) SkBF at the distal calf increased from baseline to end point. Significant improvements from baseline within the ruboxistaurin group were also observed for the Neuropathy Total Symptom Score-6 (NTSS-6) (3 months −48.3%, P = 0.01; end point −66.0%, P < 0.0006) and the Norfolk QOL-DN symptom subscore and total score (end point −41.2%, P = 0.01, and −41.0, P = 0.04, respectively). Between-group differences in baseline–to–end point change were observed for NTSS-6 total score (placebo −13.1%; ruboxistaurin −66.0%, P < 0.03) and the Norfolk QOL-DN symptom subscore (placebo −4.0%; ruboxistaurin −41.2%, P = 0.041). No significant ruboxistaurin effects were demonstrated for the remaining efficacy measures. Adverse events were consistent with those observed in previous ruboxistaurin studies. CONCLUSIONS—In this cohort of DPN patients, ruboxistaurin enhanced SkBF at the distal calf, reduced sensory symptoms (NTSS-6), improved measures of Norfolk QOL-DN, and was well tolerated.

OBJECTIVE—We sought to assess health-related quality of life (HRQOL) in patients with type 2 diabetes treated with insulin glargine or rosiglitazone as add-on therapy to sulfonylurea plus metformin. RESEARCH DESIGN AND METHODS—HRQOL was evaluated in 217 subjects uncontrolled with sulfonylurea plus metformin, enrolled in a 24-week, multicenter, randomized, open-label, parallel-group trial of add-on insulin glargine versus rosiglitazone. A 40-item, self-administered questionnaire at baseline and at weeks 2, 6, 12, 18, and 24 was given, including the 34-item Diabetes Symptom Checklist-Revised (DSC-R), a 5-item mental health scale from the 36-item Short-Form Health Survey (SF-36), and a single-item health rating from the SF-36. These assessments do not specify route of therapy. RESULTS—Both treatment groups showed similar improvements in glycemic control from baseline to week 24 (change in A1C: −1.66% in the insulin glargine group, −1.51% in the rosiglitazone group, P = 0.1446). Both groups also showed improvement in HRQOL, although subjects treated with insulin glargine experienced significantly greater improvements compared with rosiglitazone in the DSC-R total symptom score (P = 0.005), total symptom distress score (P = 0.03), individual domain scores for mood symptoms (P = 0.007), ophthalmologic symptoms (P = 0.007), ophthalmologic distress (P = 0.013), fatigue distress (P = 0.033), and SF-36 perception of general health (P = 0.047). CONCLUSIONS—Although addition of insulin glargine and rosiglitazone achieved comparable improvements in glycemic control, insulin glargine was associated with greater improvements in HRQOL, indicating that other factors (e.g., safety profile and nonglycemic actions) may further enhance HRQOL in patients with type 2 diabetes.

A 68-year-old woman with a 3-year history of type 2 diabetes had been treated with metformin 500 mg b.i.d. since her diagnosis. Hemoglobin A1c (HbA1c) was 6.5%, and she had no evidence of diabetic retinopathy or nephropathy. She complained of progressive numbness in her extremities for the past 3 months. The symptoms started in her feet and progressed to affect her lower legs up to her knees as well as her hands bilaterally. She denied pain or tingling but complains of mild weakness in her legs.

A 61-year-old Caucasian man with poorly controlled type 2 diabetes presented to our clinic with a 5-month history of right foot drop and severe excruciating pain in the right leg that progressed to the right buttock, left buttock, and left leg resulting in left foot drop. Before the visit, a neurologist had diagnosed him with diabetic amyotrophy and ganglioside GM1 antibody–mediated autoimmune neuropathy. Magnetic resonance imaging (MRI) of the brain was unremarkable. Nerve conduction studies showed absent sural, ulnar, and radial potentials with a right peroneal motor nerve conduction velocity of 19.6 m/sec, and a right posterior tibial conduction velocity of 32.9 m/sec. The patient could walk a few steps using a cane but mainly used a wheelchair. He complained of numbness and burning sensations in his feet and legs. Pain control was inadequate using duloxetine 60 mg/d, pregabalin 75 mg in the morning and 150 mg in the afternoon and evening, gabapentin 300 mg as needed, tramadol 50 mg three times daily, and hydrocodone acetaminophen 7.5/750 mg as needed.

The diabetic neuropathies are heterogeneous, affecting different parts of the nervous system that present with diverse clinical manifestations. They may be focal or diffuse. Most common among the neuropathies are chronic sensorimotor distal symmetric polyneuropathy (DPN) and the autonomic neuropathies. DPN is a diagnosis of exclusion. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons. 1 ) Nondiabetic neuropathies may be present in patients with diabetes. 2 ) A number of treatment options exist for symptomatic diabetic neuropathy. 3 ) Up to 50% of DPN may be asymptomatic, and patients are at risk of insensate injury to their feet. As >80% of amputations follow a foot ulcer or injury, early recognition of at-risk individuals, provision of education, and appropriate foot care may result in a reduced incidence of ulceration and consequently amputation. 4 ) Autonomic neuropathy may involve every system in the body. 5 ) Autonomic neuropathy causes substantial morbidity and increased mortality, particularly if cardiovascular autonomic neuropathy (CAN) is present. Treatment should be directed at underlying pathogenesis. Effective symptomatic treatments are available for the manifestations of DPN and autonomic neuropathy. This statement is based on two recent technical reviews (1,2), to which the reader is referred for detailed discussion and relevant references to the literature. An internationally agreed simple definition of DPN for clinical practice is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” (3). However, the diagnosis cannot be made without a careful clinical examination of the lower limbs, as absence of symptoms should never be assumed to indicate an absence of signs. This definition conveys the important message that not all patients with peripheral nerve dysfunction have a neuropathy caused by diabetes. Confirmation can be established with …

OBJECTIVE—Small-fiber neuropathies may be symptomatic yet escape detection by standard tests. We hypothesized that morphologic changes in intraepidermal nerves would correlate with clinical measures of small-fiber neuropathy. RESEARCH DESIGN AND METHODS—We studied 25 diabetic and 23 nondiabetic patients with neuropathy defined by signs, symptoms, and quantitative testing and 20 control subjects. Skin biopsies were obtained from forearm, thigh, proximal leg, and distal leg, and nerves identified using immunofluorescence with antibody to protein gene product (PGP) 9.5. RESULTS—Mean dendritic length (MDL) (P < 0.01) and intraepidermal nerve fiber density (IENF) (P < 0.001) progressively decreased from proximal to distal sites only in patients with neuropathy. There was a significant reduction in IENF when comparing control subjects and patient groups in the distal leg (P < 0.001). MDL was significantly decreased in the thigh (P < 0.005) and in the proximal (P < 0.01) and distal (P < 0.002) leg in patients compared with control subjects. IENF was not significantly altered in diabetic patients of 5 years’ duration. MDL showed a linear decrease with increasing duration of diabetes. Distal leg IENF showed significant negative correlations with warm (P < 0.02) and cold (P < 0.05) thermal threshold, heat pain (P < 0.05), pressure sense (P < 0.05), and neurological disability score total sensory (P < 0.03) and total neuropathy (P < 0.03) values. CONCLUSIONS—IENF was not significantly altered in these patients at