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X-ray examinations of the feet, knees, and hands were performed on 20 diabetics with severe neuropathy and 20 diabetics with no evidence of neuropathy but with a similar mean age and duration of diabetes. All were under 53 years old with no clinical evidence of peripheral vascular disease. Medial arterial calcification was much more common and extensive in the patients with neuropathy, occurring in the feet in 15 and in the hands in eight compared with in four (p less than 0.001) and none (p less than 0.001) of the controls respectively. Although there was some correlation between calcification and both proteinuria (p less than 0.05) and proliferative retinopathy (p less than 0.02), the association between calcification and neuropathy (p less than 0.001) was much stronger. Neuropathy, with sympathetic denervation of the smooth muscle of the tunica media, may be important in the aetiology of medial arterial calcification.

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The prevalence of diabetic polyneuropathy (DPN) can approach 50% in subjects with longer-duration diabetes. The most common neuropathies are generalized symmetrical chronic sensorimotor polyneuropathy and autonomic neuropathy. It is important to recognize that 50% of subjects with DPN may have no symptoms and only careful clinical examination may reveal the diagnosis. DPN, especially painful diabetic peripheral neuropathy, is associated with poor quality of life. Although there is a better understanding of the pathophysiology of DPN and the mechanisms of pain, treatment remains challenging and is limited by variable efficacy and side effects of therapies. Intensification of glycemic control remains the cornerstone for the prevention or delay of DPN but optimization of other traditional cardiovascular risk factors may also be of benefit. The management of DPN relies on its early recognition and needs to be individually based on comorbidities and tolerability to medications. To date, most pharmacological strategies focus upon symptom control. In the management of pain, tricyclic antidepressants, selective serotonin noradrenaline reuptake inhibitors, and anticonvulsants alone or in combination are current first-line therapies followed by use of opiates. Topical agents may offer symptomatic relief in some patients. Disease-modifying agents are still in development and to date, antioxidant α-lipoic acid has shown the most promising effect. Further development and testing of therapies based upon improved understanding of the complex pathophysiology of this common and disabling complication is urgently required.

We evaluated the associations between glycemic therapies and prevalence of diabetic peripheral neuropathy (DPN) at baseline among participants in the Bypass-Angioplasty-Revascularization-Investigation-2-Diabetes (BARI 2D) trial on medical and revascularization therapies for coronary artery disease (CAD) and on insulin-sensitizing versus insulin-providing treatments for diabetes. 2368 patients with type 2 diabetes and CAD were evaluated. DPN was defined as clinical examination score >2 using the Michigan Neuropathy Screening Instrument (MNSI). DPN odds ratios across different groups of glycemic therapy were evaluated by multiple logistic regression, adjusted for multiple covariates including age, sex, HbA1c, diabetes duration. 51% BARI 2D subjects with valid baseline characteristics and MNSI scores had DPN. After adjusting for all variables, use of insulin was significantly associated with DPN (OR1.57, 1.15, 2.13). Patients on sulfonylurea or combination of sulfonylurea/metformin/TZD had marginally higher rates of DPN than the metformin/TZD group. This cross-sectional study in a cohort of patients with type 2 diabetes and CAD showed association of insulin use with higher DPN prevalence, independent of disease duration, glycemic control and other characteristics. The causality between a glycemic control strategy and DPN cannot be evaluated in this cross-sectional study, but continued assessment of DPN and randomized therapies in BARI 2D trial may provide further explanations on the development of DPN.

OBJECTIVE

The receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) signaling pathway (RANKL/RANK/OPG signaling) is implicated in the osteolysis associated with diabetic Charcot neuroarthropathy (CN); however, the links with medial arterial calcification (MAC) seen in people with CN are unclear. This study aimed to investigate the role of RANKL/OPG in MAC in patients with CN.

RESEARCH DESIGN AND METHODS

Enzyme-linked immunosorbent assay and Bio-plex multiarray technology were used to quantify a range of cytokines, including RANKL and OPG in sera from 10 patients with diabetes, 12 patients with CN, and 5 healthy volunteers. Human tibial artery segments were immunohistochemically stained with Alizarin red and human RANKL antibody. Human vascular smooth muscle cells (VSMCs) were also explanted from arterial segments for in vitro studies.

RESULTS

We demonstrate colocalization and upregulation of RANKL expression in areas displaying MAC. Systemic levels of RANKL, OPG, and inflammatory cytokines (interleukin-8, granulocyte colony–stimulating factor) were elevated in those with CN compared with diabetic patients and healthy control subjects. Human VSMCs cultured in CN serum showed accelerated osteoblastic differentiation (alkaline phosphatase activity) and mineralization (alizarin red staining) compared with cells treated with diabetic or control serum (P < 0.05). Coincubation with OPG, the decoy receptor for RANKL, attenuated osteogenic differentiation of VSMCs and was independent of a high calcium-phosphate milieu. The accelerated mineralization induced by RANKL and CN serum correlated with nuclear translocation of nuclear factor-κB, a process abrogated by OPG.

CONCLUSIONS

Our data provide direct evidence that RANKL/RANK/OPG signaling is modulated in patients with CN and plays a role in vascular calcification. This study highlights this pathway as a potential target for intervention.

OBJECTIVE

To evaluate the impact of former intensive versus conventional insulin treatment on neuropathy in Diabetes Control and Complications Trial (DCCT) intensive and conventional treatment subjects with type 1 diabetes 13–14 years after DCCT closeout, during which time the two groups had achieved similar A1C levels.

RESEARCH DESIGN AND METHODS

Clinical and nerve conduction studies (NCSs) performed during the DCCT were repeated during the Epidemiology of Diabetes Interventions and Complications (EDIC) study by examiners masked to treatment status on 603 former intensive and 583 former conventional treatment subjects. Clinical neuropathy was defined by symptoms, sensory signs, or reflex changes consistent with distal polyneuropathy and confirmed with NCS abnormalities involving two or more nerves among the median, peroneal, and sural nerves.

RESULTS

The prevalence of neuropathy increased 13–14 years after DCCT closeout from 9 to 25% in former intensive and from 17 to 35% in former conventional treatment groups, but the difference between groups remained significant (P < 0.001), and the incidence of neuropathy remained lower among former intensive (22%) than former conventional (28%) treatment subjects (P = 0.0125). Analytic models of incident neuropathy that adjusted for differences in NCS results at DCCT closeout showed no significant risk reduction associated with former intensive treatment during follow-up (odds ratio 1.17 [95% CI 0.84–1.63]). However, a significant persistent treatment group effect was observed for several NCS measures. Longitudinal analyses of overall glycemic control showed a significant association between mean A1C and measures of incident and prevalent neuropathy.

CONCLUSIONS

The benefits of former intensive insulin treatment persisted for 13–14 years after DCCT closeout and provide evidence of a durable effect of prior intensive treatment on neuropathy.

Objective and design

Low grade inflammation is of pathogenic importance in atherosclerosis and in the development of cardiovascular disease (CVD) and type 2 diabetes (T2D). Matrix GLA protein (MGP), an inhibitor of medial calcification of arteries, is increased in patients with atherosclerosis. In the present study levels of markers of calcification (MGP) and inflammation (YKL-40, hsCRP) were evaluated in patients with T2 D and/or ischemic heart disease (IHD).

Materials and methods

The study population consisted of 1) patients with T2D (n = 45); 2) patients with IHD (n = 37); patients with both T2D and IHD (n = 20) and 4) healthy controls (n = 20). Biochemical parameters were measured in venous blood samples.

Results

Levels of MGP, YKL-40 and hsCRP were increased in patients with IHD and/or T2D (p < 0.0001) and patients with T2D and IHD had higher MGP levels (p < 0.001). In multiple linear regression analyses MGP was associated with patient category (r = 0.36, p < 0.001), and HDL-cholesterol levels (r = 0.29, p < 0.001) adjusting for the significant covariates.

Conclusions

In patients with T2D and/or IHD we found increased levels of plasma MGP indicative of a progressing calcification process. This process is paralleled by increased levels of YKL-40 and hsCRP, which most likely reflect the concomitant low grade inflammatory state in these patients

OBJECTIVE

To estimate the accuracy of Neuropad for the diagnosis and staging of distal symmetric polyneuropathy (DPN) across different stages of neuropathy, using multiple-level likelihood ratios (LRs) to interpret the time necessary to complete the color change of the test.

RESEARCH DESIGN AND METHODS

We conducted a cross-sectional, cohort-type diagnostic accuracy study in 251 consecutive adult type 2 diabetic patients with no peripheral arterial disease or other potential causes of neuropathy, who were recruited between January 2005 and December 2008 from the diabetes outpatient clinics in Alexandroupolis Hospital, Greece. Patients were tested for DPN by means of the neuropathy disability score (NDS) and Neuropad. Multiple-level LRs for time to complete color change were calculated across different stages of neuropathy.

RESULTS

The areas under the curve for the diagnosis of any (NDS of ≥3), at least moderate (NDS of ≥6), or severe (NDS of ≥9) DPN were 0.91, 0.96, and 0.97, respectively. The calculation of multiple-level LRs showed that time to complete color change <360 s suggested the absence of neuropathy. Values between 360 and 1,000 s were indicative of mild neuropathy. Finally, values between 1,000 and 1,200 or >1,200 s were strongly suggestive of moderate or severe DPN, respectively.

CONCLUSIONS

Neuropad could be used as a triage test for the diagnosis and staging of DPN in patients with type 2 diabetes, prompting referral to specialized care setting.

Background

On the basis of the Framingham risk algorithm, overestimation of clinical events has been reported in some European populations. Electron-beam computed tomography-derived quantification of coronary artery calcification (CAC) allows for noninvasive assessment of coronary atherosclerosis in the general population and may thus add important in vivo information on the path from risk factor exposure to formation of clinical events. The current study was undertaken to compare the relationship between risk factors and subclinical coronary atherosclerosis between non-Hispanic white cohorts in Germany and US-America, the hypothesis being that subclinical coronary atherosclerosis might be less prevalent in Europe at the same level of classical risk factor exposure.

Methods

The Heinz Nixdorf Recall (HNR) study, conducted in the German Ruhr area and the Epidemiology of Coronary Calcification (ECAC) study, conducted in Olmsted County, Minnesota, both recruited large unselected cohorts, men and women aged 45 – 74 years, from the general population. All subjects with no history of coronary artery disease (CAD) or stroke were included (n = 3,120 in HNR, n = 703 in ECAC). Coronary risk factors were assessed by personal and computer-assisted interviews and direct laboratory measurements. Cardiovascular medication use (antihypertensive, lipid-lowering, and anti-diabetic) was noted. CAC scores were determined using the Agatston method in an identical fashion in both studies.

Results

Adverse levels of risk factors were more prevalent, and the Framingham risk score was higher (10.6 ± 7.6 vs. 9.3 ± 7.1, p < 0.001) in HNR than ECAC, respectively. There was no difference in body mass index (BMI). CAC scores were greater in HNR than in ECAC (mean values, 155.7 ± 423.0 versus 107.2 ± 280.0; median values, 11.9 versus 2.4; p < 0.001, respectively). When subjects were matched on CAD risk factors, presence and quantity of CAC were similar in the 2 cohorts. Risk factors significantly associated with CAC score in both studies included: age, male sex, current and former smoking, systolic blood pressure, and non HDL-cholesterol. Inferences were similar after excluding subjects using lipid- or blood pressure-lowering medications. Using the same risk factor variables for modelling, the predicted CAC scores were comparable in both cohorts.

Conclusions

In the higher-risk German cohort, presence and quantity of CAC were greater than in the lower-risk US-American cohort. Risk factor associations, however, with CAC were very similar in both unselected populations. As opposed to studies concerning clinical endpoints, we could not demonstrate a relative increase in subclinical coronary atherosclerosis in the US-American cohort.

OBJECTIVE

Depression is associated with poor glycemic control and complications in people with type 1 diabetes. We assessed the prevalence of depression and antidepressant medication use among adults with and without type 1 diabetes and the association between depression and diabetes complications.

RESEARCH DESIGN AND METHODS

In 2006–2008, the Coronary Artery Calcification in Type 1 Diabetes Study applied the Beck Depression Inventory II (BDI-II) to 458 participants with type 1 diabetes (47% male, aged 44 ± 9 years, type 1 diabetes duration 29 ± 9 years) and 546 participants without diabetes (nondiabetic group) (51% male, aged 47 ± 9 years). Use of antidepressant medication was self-reported. Depression was defined as a BDI-II score >14 and/or use of antidepressant medication. Occurrence of diabetes complications (retinopathy, blindness, neuropathy, diabetes-related amputation, and kidney or pancreas transplantation) was self-reported.

RESULTS

Mean BDI-II score, adjusted for age and sex, was significantly higher in participants with type 1 diabetes than in nondiabetic participants (least-squares mean ± SE: 7.4 ± 0.3 vs. 5.0 ± 0.3; P < 0.0001). Type 1 diabetic participants reported using more antidepressant medications (20.7 vs. 12.1%, P = 0.0003). More type 1 diabetic than nondiabetic participants were classified as depressed by BDI-II cut score (17.5 vs. 5.7%, P < 0.0001) or by either BDI-II cut score or antidepressant use (32.1 vs. 16.0%, P < 0.0001). Participants reporting diabetes complications (n = 209) had higher mean BDI-II scores than those without complications (10.7 ± 9.3 vs. 6.4 ± 6.3, P < 0.0001).

CONCLUSIONS

Compared with nondiabetic participants, adults with type 1 diabetes report more symptoms of depression and more antidepressant medication usage. Depression is highly prevalent in type 1 diabetes and requires further study on assessment and treatment.

Introduction

The significance of non-alcoholic fatty liver disease (NAFLD) among patients with diabetes is unknown. We sought to determine whether a diagnosis of NAFLD influenced mortality among a community-based cohort of patients with type 2 diabetes mellitus.

Methods

337 residents of Olmsted County, Minnesota with diabetes mellitus diagnosed between 1980–2000 were identified using the Rochester Epidemiology Project and the Mayo Laboratory Information System and followed for 10.9 ± 5.2 years (range 0.1–25). Survival was analysed using Cox proportional hazards modelling with NAFLD treated as a time-dependent covariate.

Results

Among the 337 residents, 116 were diagnosed with NAFLD 0.9 ±4.6 years after diabetes diagnosis. Patients with NAFLD were younger, and more likely to be female, and obese. Overall 99/337 (29%) patients died. In multivariate analysis to adjust for confounders, overall mortality was significantly associated with a diagnosis of NAFLD (hazard ratio [HR] 2.2; 95% confidence Interval [CI] 1.1, 4.2; p = 0.03), presence of ischemic heart disease (HR 2.3; 95% CI 1.2, 4.4), and duration of diabetes (HR per 1 year, 1.1; 95% CI 1.03, 1.2). The most common causes of death in the NAFLD cohort were malignancy (33% of deaths), liver-related complications (19% of deaths), and ischemic heart disease (19% of deaths). In adjusted multivariate models, NAFLD was borderline associated with an increased risk of dying from malignancy (HR 2.3; 95% CI 0.9, 5.9; p = 0.09), and not from cardiovascular disease (HR 0.9; 95% CI 0.3, 2.4; p = 0.81)

Conclusions

The diagnosis of NAFLD is associated with an increased risk of overall death among patients with diabetes mellitus.

OBJECTIVE

To assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls.

RESEARCH DESIGN AND METHODS

Insulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m2/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 ± 8 years; 55% female).

RESULTS

Peripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 ± 0.72 vs. 12.71 ± 0.66, mean ± SE, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (μM) during 8 mU/m2/min insulin infusion = 370 ± 27 vs. 185 ± 25, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = −0.42, P < 0.0001 and r = 0.41, P < 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22–0.93, P = 0.03; OR = 2.4, 95% CI = 1.08–5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters.

CONCLUSIONS

Type 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes.

Background

Patients with diabetic polyneuropathy (DPN) are often confronted with ulceration of foot soles. Increased plantar pressure under the forefoot has been identified as a major risk factor for ulceration. This study sets out to test the hypothesis that changes in gait characteristics induced by DPN related muscle weakness are the origin of the elevated plantar pressures.

Methods

Three groups of subjects participated: people diagnosed with diabetes without polyneuropathy (DC), people diagnosed with diabetic polyneuropathy (DPN) and healthy, age-matched controls (HC). In all subjects isometric strength of plantar and dorsal flexors was assessed. Moreover, joint moments at ankle, knee and hip joints were determined while walking barefoot at a velocity of 1.4 m/s. Simultaneously plantar pressure patterns were measured.

Results

Compared to HC-subjects, DPN-participants walked with a significantly increased internal plantar flexor moment at the first half of the stance phase. Also in DPN-subjects the maximal braking and propelling force applied to the floor was decreased. Moreover, in DPN-subjects the ratio of forefoot-to-rear foot plantar pressures was increased. Body-mass normalized strength of dorsal flexors showed a trend to be reduced in people with diabetes, both DC and DPN, compared to HC-subjects. Plantar flexors tended to be less weak in DC compared to HC and in DPN relative to DC.

Conclusion

The results of this study suggest that adverse plantar pressure patterns are associated with redistribution of joint moments, and a consequent reduced capacity to control forward velocity at heel strike.

Cardiovascular mortality is associated with vascular calcification (VC) in hemodialysis (HD) patients. The present study was designed to find factors related with medial artery calcification on the plain radiography of feet by comparing C-reactive protein (CRP), plasminogen activator inhibitor type 1 (PAI-1) and lipid profile including oxidized low density lipoprotein (ox-LDL) and to elucidate associations among these factors in HD patients. Forty-eight HD patients were recruited for this study. VC in the feet was detected in 18 patients (37.5%) among total patients and 12 patients (85.7%) among diabetic patients. Diabetes, cardiovascular disease (CVD), pulse pressure, ox-LDL/LDL were higher and high density lipoprotein (HDL) was lower in patients with VC than in patients without VC. Negative associations were found between HDL and CRP, PAI-1. PAI-1 had positive association with ox-LDL/LDL. History of CVD was the only determinant of vascular calcification on the plain radiography of feet. Ox-LDL/LDL, HDL, CRP, and PAI-1 were closely related with one another in HD patients. History of CVD is the most important factor associated with the presence of VC and low HDL and relatively high oxidized LDL/LDL ratio may affect VC formation on the plain radiography in the feet of HD patients.

OBJECTIVE

Our goal was to ascertain the prevalence of pruritus in diabetic and nondiabetic subjects and the relevance of symptoms, signs, and nerve functions of diabetic polyneuropathy (DPN) of pruritus.

RESEARCH DESIGN AND METHODS

A large-scale survey of 2,656 diabetic outpatients and 499 nondiabetic subjects was performed. In diabetic subjects, the relationship between pruritus and age, sex, diabetic duration, A1C, Achilles tendon reflex (ATR), and abnormal sensation in legs was evaluated. In 105 diabetic subjects, nerve conduction studies, quantitative vibratory threshold (QVT), heart rate variability, and a fall of systolic blood pressure at a head-up tilt test (ΔBP) were performed, and the relationships between pruritus and nerve functions were evaluated.

RESULTS

Although the prevalence of truncal pruritus of unknown origin (TPUO) in diabetic subjects was significantly higher than that in age-matched nondiabetic subjects (11.3 vs. 2.9%, P = 0.0001), the prevalence of other pruritus was not different between the two groups. Multiple logistic regression analysis revealed that abnormal sensation and ATR areflexia were independent risk factors for TPUO in age, sex, duration of diabetes, and A1C. ΔBP in diabetic subjects with TPUO was significantly impaired compared with that in those without TPUO. Larger ΔBP was identified as a significant risk factor of TPUO independent of other nerve dysfunctions by multiple logistic regression analysis.

CONCLUSIONS

TPUO is significantly more frequent in diabetic than in nondiabetic individuals. TPUO is significantly associated with symptoms and signs of DPN, including impaired blood pressure response in a head-up tilt test. TPUO, therefore, might be a newly recognized symptom of DPN.

Diabetes mellitus (DM) alters circulating progenitor cells relevant for the pathophysiology of coronary artery disease (CAD). While endothelial progenitor cells (EPCs) are reduced, there is no data on procalcific polarization of circulating progenitors, which may contribute to vascular calcification in these patients. In a cohort of 107 subjects with and without DM and CAD, we analyzed the pro-calcific versus endothelial differentiation status of circulating CD34+ progenitor cells. Endothelial commitment was determined by expression of VEGFR-2 (KDR) and pro-calcific polarization by expression of osteocalcin (OC) and bone alkaline phosphatase (BAP). We found that DM patients had significantly higher expression of OC and BAP on circulating CD34+ cells than control subjects, especially in the presence of CAD. In patients with DM and CAD, the ratio of OC/KDR, BAP/KDR, and OC+BAP/KDR was about 3-fold increased than in other groups. EPCs cultured from DM patients with CAD occasionally formed structures highly suggestive of calcified nodules, and the expression of osteogenic markers by EPCs from control subjects was significantly increased in response to the toll-like receptor agonist LPS. In conclusion, circulating progenitor cells of diabetic patients show a phenotypic drift toward a pro-calcific phenotype that may be driven by inflammatory signals.

The Epidemiology of Diabetes Interventions and Complications (EDIC) study, an observational follow-up of the Diabetes Control and Complications Trial (DCCT) type 1 diabetes cohort, measured coronary artery calcification (CAC), an index of atherosclerosis, with computed tomography (CT) in 1,205 EDIC patients at ~7–9 years after the end of the DCCT. We examined the influence of the 6.5 years of prior conventional versus intensive diabetes treatment during the DCCT, as well as the effects of cardiovascular disease risk factors, on CAC. The prevalences of CAC >0 and >200 Agatston units were 31.0 and 8.5%, respectively. Compared with the conventional treatment group, the intensive group had significantly lower geometric mean CAC scores and a lower prevalence of CAC >0 in the primary retinopathy prevention cohort, but not in the secondary intervention cohort, and a lower prevalence of CAC >200 in the combined cohorts. Waist-to-hip ratio, smoking, hypertension, and hypercholesterolemia, before or at the time of CT, were significantly associated with CAC in univariate and multivariate analyses. CAC was associated with mean HbA1c (A1C) levels before enrollment, during the DCCT, and during the EDIC study. Prior intensive diabetes treatment during the DCCT was associated with less atherosclerosis, largely because of reduced levels of A1C during the DCCT.

Objectives. There are limited clinical data revealing the relationship between mitral annular calcification (MAC) and systemic inflammation. The goal of the present study was to compare high-sensitivity C-reactive protein (hs-CRP) levels in patients with and without MAC and investigate the relationship between MAC and hs-CRP. Methods. One hundred patients with MAC who underwent transthoracic echocardiography (TTE) and 100 age-matched controls without MAC who underwent TTE were included in our study. Hs-CRP levels were compared between groups. Results. Prevalence of female gender, hypertension, and coronary artery disease were significantly higher in the MAC group than in the control group (64% versus 45%, P = 0.007, 42% versus 28%, P = 0.03 and 37% versus 18%, P = 0.003, resp.). On multivariate analysis, age, gender, and coronary artery disease were the only independent predictors of MAC. The levels of hs-CRP were higher in the MAC group than in the control group (2.02 ± 0.35 versus 1.43 ± 0.47 mg/dl, P < 0.001). This increase in hs-CRP levels in the MAC group persisted in patients without hypertension, coronary artery disease, and in male patients when compared to the control group. Conclusions. Our study demonstrated that hs-CRP, which is a sensitive marker of systemic inflammation, increased in patients with MAC.

Background

Process of accelerated atherosclerosis specific for uremia increases cardiovascular risk in patients with chronic kidney disease (CKD) and may be influenced by the different structure of arteries. The study assesses the influence of traditional and novel risk factors on calcification of coronary arteries (CAC) and abdominal aorta (AAC) in hemodialysis patients (HD).

Methods

CAC and AAC were assessed by CT in 104 prevalent adult HD and 14 apparently healthy subjects with normal kidney function (control group). Mineral metabolism parameters, plasma levels of FGF-23, MGP, osteoprotegerin, osteopontin, fetuin-A, CRP, IL-6 and TNF-α were measured.

Results

CAC and AAC (calcification score ≥ 1) were found in 76 (73.1%) and 83 (79.8%) HD respectively, more frequent than in the control group. In 7 HD with AAC no CAC were detected. The frequency and severity of calcifications increased with age. Both CAC and AAC were more frequently detected in diabetics (OR = 17.37 and 13.00, respectively). CAC score was significantly greater in males. CAC and AAC scores were correlated significantly with pack-years of smoking and plasma osteoprotegrin levels. However the independent contribution of plasma osteoprotegerin levels was not confirmed in multiple regression analysis. Age (OR = 1.13) and hemodialysis vintage (OR = 1.14) were the independent risk factor favoring the occurrence of CAC; while age (OR = 1.20) was the only predictor of AAC occurrence in HD.

Conclusions

1. AAC precedes the occurrence of CAC in HD patients. 2. The exposition to uremic milieu and systemic chronic microinflammation has more deteriorative effect on the CAC than the AAC.

OBJECTIVE

To test whether diabetic polyneuropathies (DPNs), retinopathy, or nephropathy is more prevalent in subjects with impaired glycemia (IG) (abnormality of impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or impaired HbA1c [IA1C]) than in healthy subjects (non-IG).

RESEARCH DESIGN AND METHODS

Matched IG and non-IG volunteers were randomly identified from population-based diagnostic and laboratory registries, restudied, and reclassified as non-IG (n = 150), IG (n = 174), or new diabetes (n = 218).

RESULTS

Frequency (%) of DPN in non-IG, IG, and new diabetes was 3 (2.0%), 3 (1.7%), and 17 (7.8%) narrowly defined (no other cause for polyneuropathy) and 19 (12.7%), 22 (12.6%), and 38 (17.4%) broadly defined. Mean and frequency distribution of composite scores of nerve conduction and quantitative sensation tests were not significantly different between IG and non-IG but were worse in new diabetes. Frequency of retinopathy and nephropathy was significantly increased only in new diabetes. In secondary analysis, small but significant increases in retinopathy and nephropathy were found in IGT, IFG, and IGT combined groups.

CONCLUSIONS

In population studies of Olmsted County, Minnesota, inhabitants, prevalence of typical DPN, retinopathy, and nephropathy was significantly increased only in subjects with new diabetes—not in subjects with IG as defined by American Diabetes Association (ADA) criteria of abnormality of IFG, IGT, or IA1C. For atypical DPN, such an increase was not observed even in subjects with new diabetes. In medical practice, explanations other than IG should be sought for patients with atypical DPN (chronic idiopathic axonal polyneuropathy) who have IG.

The purpose of the present study was to determine the associations of age and history of non- and low-traumatic fractures with the severity of abdominal aortic calcification in Japanese postmenopausal women and men. Four hundred and one Japanese persons (24 men and 377 postmenopausal women, mean age: 73.8 years) for whom thoracic and lumbar spine radiographs had been obtained to evaluate their posture prior to patient participation in a fall-prevention exercise program were enrolled. The associations of sex, age, history of hip fracture, prevalence of vertebral fracture, and spondylosis grade (the Nathan degree) with the severity of abdominal aortic calcification (length of calcification, as evaluated according to the number of vertebral bodies) were analyzed. Nine subjects (2.2%) had a history of hip fracture, and 221 (55.1%) had at least one prevalent vertebral fracture. Two hundred and sixty-seven subjects (66.6%) had first-degree spondylosis. Age and the number of prevalent vertebral fractures, but not sex, history of hip fracture, or spondylosis grade, were significantly associated with the severity of abdominal aortic calcification. The present study confirmed that age and the number of vertebral fractures were associated with the severity of abdominal aortic calcification in Japanese postmenopausal women and men.

Objective

Racial differences are known to account for a higher incidence of systemic lupus erythematosus (SLE), as well as increased disease severity and mortality. The purpose of this study was to determine if there are any race-specific risk factors that affect measures of subclinical atherosclerosis in SLE patients.

Methods

Traditional and SLE-related cardiovascular disease (CVD) risk factors were assessed in 106 female SLE patients. Carotid medial intimal medial thickness (mIMT) and coronary artery calcification (CAC) were measured on all subjects. Differences were evaluated between races for all clinical, serologic, and CVD risk factors and the racial interactions with all covariables. Outcomes included mIMT and CAC.

Results

There were no significant differences between races with regard to mIMT or CAC. Significant covariables in the final model for mIMT included age, triglycerides, glucose, and race-age and race-smoking interactions. A prediction model with fixed significant covariables demonstrated that Black subjects with a smoking history had a significantly higher mIMT than Blacks who had never smoked, an effect not seen in Whites. There were no differences between having CAC or with the CAC scores between the races. In the final model for CAC, age and SLE disease duration were significant covariables impacting CAC.

Conclusion

When controlling for other significant CVD covariables and interactions, Black women, but not White, with SLE with a history of smoking have higher mIMT measurements than those who have never smoked. This is the first report documenting the race-specific effect of smoking on subclinical measures of CVD in SLE.

OBJECTIVE

To determine how thermoregulation of the feet is affected by diabetes and diabetic polyneuropathy in both wakefulness and sleep.

RESEARCH DESIGN AND METHODS

Normal subjects, diabetic subjects without neuropathy, diabetic subjects with small-fiber diabetic polyneuropathy, and those with advanced diabetic polyneuropathy were categorized based on neurological examination, nerve conduction studies, and quantitative sensory testing. Subjects underwent foot temperature monitoring using an iButton device attached to the foot and a second iButton for recording of ambient temperature. Socks and footwear were standardized, and subjects maintained an activity diary. Data were collected over a 32-h period and analyzed.

RESULTS

A total of 39 normal subjects, 28 patients with diabetes but without diabetic polyneuropathy, 14 patients with isolated small-fiber diabetic polyneuropathy, and 27 patients with more advanced diabetic polyneuropathy participated. No consistent differences in foot temperature regulation between the four groups were identified during wakefulness. During sleep, however, multiple metrics revealed significant abnormalities in the diabetic patients. These included reduced mean foot temperature (P < 0.001), reduced maximal temperature (P < 0.001), increased rate of cooling (P < 0.001), as well as increased frequency of variation (P = 0.005), supporting that patients with diabetic polyneuropathy and even those with only diabetes but no diabetic polyneuropathy have impaired nocturnal thermoregulation.

CONCLUSIONS

Nocturnal foot thermoregulation is impaired in patients with diabetes and diabetic polyneuropathy. Because neurons are highly temperature sensitive and because foot warming is part of the normal biology of sleep onset and maintenance, these findings suggest new potentially treatable mechanisms of diabetes-associated nocturnal pain and sleep disturbance.

Context

Coronary artery calcification is a subclinical predictor of coronary heart disease. Recent studies have found that sleep duration is correlated with established risk factors for calcification including glucose regulation, blood pressure, sex, age, education, and body mass index.

Objective

To determine whether objective and subjective measures of sleep duration and quality are associated with incidence of calcification over five years and whether calcification risk factors mediate the association.

Design

Observational cohort 2000–2006. Potential confounders (age, sex, race, education, apnea risk, smoking status) and mediators (lipids, blood pressure, body mass index, diabetes, inflammatory markers, alcohol, depression, hostility, self reported medical conditions) were measured at both baseline and follow-up. We examined sleep metrics (wrist actigraphy measured duration and fragmentation, daytime sleepiness, overall quality, self-reported duration) for association with incident calcification.

Setting

Home monitoring of healthy middle-aged population.

Participants

494 participants from the CARDIA cohort Chicago site (African American and white men and women aged 35–47 at baseline) with sleep, demographic and calcification measurements and no detectable baseline calcification.

Outcome

Coronary artery calcification was measured by CT in 2000–2001 and 2005–2006; incidence of new calcification over that time was the primary outcome.

Results

Five-year calcification incidence was 12.3% (n=61). Longer measured sleep duration was significantly associated with decreased adjusted odds of calcification (OR = 0.67 per hour, p=.011; 95% CI 0.49–0.91). No potential mediators appreciably altered the magnitude or significance of sleep (adjusted OR estimates ranged from 0.64 to 0.68 per sleep hour, maximum p-value=.020). Alternative sleep metrics were not significantly associated with calcification.

Conclusions

Longer measured sleep is associated with lower calcification incidence independently of examined potential mediators and confounders.

Background

Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) generates inorganic pyrophosphate, a solute that serves as an essential physiological inhibitor of calcification. Inactivating mutations of ENPP1 are associated with generalized calcification in infancy and an increased risk of developing type 2 diabetes mellitus (T2DM). We hypothesized that the ENPP1 K121Q variant may be associated with increased coronary artery calcification in T2DM patients.

Methods

The study subjects were aged 34 to 85 years and showed no evidence of clinical cardiovascular disease prior to recruitment. A total of 140 patients with T2DM were assessed for their coronary artery calcium (CAC) scores and ENPP1 K121Q polymorphisms were identified.

Results

The prevalence of subjects carrying the KQ genotype was 12.9% (n = 18). There were no 121QQ homozygotes. Patients with the KQ genotype did not show a significantly higher CAC score (122 vs. 18; P = 0.858). We matched each patient with the KQ genotype to a respective control with the KK genotype by gender, age, and duration of diabetes. When compared to matched controls, we observed no significant difference in CAC score (P = 0.959).

Conclusions

The ENPP1 K121Q polymorphism does not appear to be associated with coronary artery calcification in patients with T2DM.

OBJECTIVE

This study was conducted to investigate the association of diabetic peripheral neuropathy (DPN) with both arterial stiffness and intima–media thickness (IMT).

RESEARCH DESIGN AND METHODS

We conducted a cross-sectional analysis of 731 subjects with type 2 diabetes. DPN was diagnosed on the basis of neuropathic symptoms, insensitivity to a 10-g monofilament, abnormal pin-prick sensation, and abnormal current perception threshold. Arterial stiffness was assessed by cardio-ankle vascular index (CAVI), and IMT was assessed by B-mode ultrasonography.

RESULTS

Patients with DPN had higher CAVI than those without DPN in multivariate-adjusted models, whereas no differences in IMT were observed between patients with and without DPN after adjustment for age and sex. In the multivariate analysis, CAVI was a significant determinant of DPN (odds ratio 1.36 [95% CI 1.13–1.65], P = 0.001).

CONCLUSIONS

DPN is significantly associated with arterial stiffness without carotid intimal changes in patients with type 2 diabetes.