Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study.

AIMS/HYPOTHESIS: The aim of this work was to assess the impact of cardiac autonomic neuropathy (CAN) on the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes. METHODS: We conducted a cohort study in adults with type 2 diabetes. Patients with end-stage renal disease were excluded. CKD was defined as the presence of albuminuria (albumin/creatinine ratio GFR > 3.4 mg/mmol) or an estimated (eGFR) < 60 ml min(-1) 1.73 m(-2). CKD progression was based on repeated eGFR measurements and/or the development of albuminuria. CAN was assessed using heart rate variability. RESULTS: Two hundred and four patients were included in the analysis. At baseline, the prevalence of CKD and CAN was 40% and 42%, respectively. Patients with CAN had lower eGFR and higher prevalence of albuminuria and CKD. Spectral analysis variables were independently associated with eGFR, albuminuria and CKD at baseline. After a follow-up of 2.5 years, eGFR declined to a greater extent in patients with CAN than in those without CAN (-9.0 ± 17.8% vs -3.3 ± 10.3%, p = 0.009). After adjustment for baseline eGFR and baseline differences, CAN remained an independent predictor of eGFR decline over the follow-up period (ß = -3.5, p = 0.03). Spectral analysis variables were also independent predictors of eGFR decline. CONCLUSIONS/INTERPRETATION: CAN was independently associated with CKD, albuminuria and eGFR in patients with type 2 diabetes. In addition, CAN was an independent predictor of the decline in eGFR over the follow-up period. CAN could be used to identify patients with type 2 diabetes who are at increased risk of rapid decline in eGFR, so that preventative therapies might be intensified.

Obstructive sleep apnea and diabetic nephropathy: a cohort study.

OBJECTIVE: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Obstructive sleep apnea (OSA) is common in type 2 diabetes and increases oxidative stress. Hence, OSA could promote the development and progression of DN. RESEARCH DESIGN AND METHODS: This was a cohort study in adults with type 2 diabetes. Patients with known OSA or ESRD were excluded. DN was defined as the presence of albuminuria or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. DN progression was based on eGFR measurements. OSA was defined as apnea hypopnea index (AHI) ≥5 events/h. Serum nitrotyrosine abundance (a marker of nitrosative stress) was measured by ELISA. RESULTS: A total of 224 patients were included. OSA and DN prevalence was 64.3 and 40.2, respectively. DN prevalence was higher in patients with OSA (OSA+) compared with those without OSA (OSA-) (49.3% vs. 23.8%, P < 0.001). After adjustment, OSA (odds ratio 2.64 [95% CI 1.13-6.16], P = 0.02) remained independently associated with DN. After an average follow-up of 2.5 (0.7) years, eGFR decline was greater in OSA+ compared with OSA- patients (median -6.8% [interquartile range -16.1 to 2.2] vs. -1.6% [-7.7 to 5.3%], P = 0.002). After adjusting, both baseline OSA (B = -3.8, P = 0.044) and AHI (B = -4.6, P = 0.02) remained independent predictors of study-end eGFR. Baseline serum nitrotyrosine abundance (B = -0.24, P = 0.015) was an independent predictor of study-end eGFR after adjustment. CONCLUSIONS: OSA is independently associated with DN in type 2 diabetes. eGFR declined faster in patients with OSA. Nitrosative stress may provide a pathogenetic link between OSA and DN. Interventional studies assessing the impact of OSA treatment on DN are needed.

Cutaneous structural and biochemical correlates of foot complications in high-risk diabetes.

OBJECTIVE: Impairment of skin quality may contribute to diabetic foot ulceration (DFU). Our goal was to determine whether high-risk patients exhibited specific skin structural and metabolic deficits that could predispose to foot complications. RESEARCH DESIGN AND METHODS: A total of 46 patients comprising 9 diabetic control subjects, 16 with diabetic peripheral neuropathy (DPN) alone, and 21 with recurrent DFUs (including 9 with Charcot neuroarthropathy [CNA]) were recruited and compared with 14 nondiabetic control (NDC) subjects. DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Skin punch biopsies (3 mm) were performed on upper and lower leg skin for measurements of intraepidermal nerve fiber density (IENFD), structural analysis, type 1 procollagen abundance, tissue degrading matrix metalloproteinases (MMPs), and poly(ADP-ribose) (PAR) immunoreactivity. RESULTS: MNSI scores were comparable across DPN groups. IENFD was decreased by diabetes and DPN but did not differ between neuropathic groups. Skin structural deficit scores were elevated in all neuropathic subjects, particularly in the DFU group. Type 1 procollagen abundance was reduced in DFU subjects 387 ± 256 units (mean ± 1 SD) compared with NDC subjects (715 ± 100, P < 0.001). MMP-1 and MMP-2 were activated by diabetes. PAR immunoreactivity was increased in DFU (particularly in the CNA group; P < 0.01) compared with other DPN subjects. CONCLUSIONS: Increased PAR, reduced type 1 procollagen abundance, and impaired skin structure are associated with foot complications in diabetes. The potential of therapies that improve skin quality to reduce DFU needs to be investigated.

Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes.

RATIONALE: Diabetic peripheral neuropathy is common and causes significant morbidity. Obstructive sleep apnea (OSA) is also common in patients with type 2 diabetes. Because OSA is associated with inflammation and oxidative stress, we hypothesized that OSA is associated with peripheral neuropathy in type 2 diabetes. OBJECTIVES: To assess the relationship between OSA and peripheral neuropathy in patients with type 2 diabetes. METHODS: A cross-sectional study of adults with type 2 diabetes recruited randomly from the diabetes clinic of two UK hospitals. MEASUREMENTS AND MAIN RESULTS: Peripheral neuropathy was diagnosed using the Michigan Neuropathy Screening Instrument. OSA (apnea-hypopnea index ≥ 5 events/h) was assessed using home-based, multichannel respiratory monitoring. Serum nitrotyrosine was measured by ELISA, lipid peroxide by spectrophotometer, and microvascular function by laser speckle contrast imaging. Two hundred thirty-four patients (mean [SD] age, 57 [12] yr) were analyzed. OSA prevalence was 65% (median apnea-hypopnea index, 7.2; range, 0-93), 40% of which were moderate to severe. Neuropathy prevalence was higher in patients with OSA than those without (60% vs. 27%, P < 0.001). After adjustment for possible confounders, OSA remained independently associated with diabetic neuropathy (odds ratio, 2.82; 95% confidence interval, 1.44-5.52; P = 0.0034). Nitrotyrosine and lipid peroxide levels (n = 102, 74 with OSA) were higher in OSA and correlated with hypoxemia severity. Cutaneous microvascular function (n = 71, 47 with OSA) was impaired in OSA. CONCLUSIONS: We describe a novel independent association between diabetic peripheral neuropathy and OSA. We identified increased nitrosative/oxidative stress and impaired microvascular regulation as potential mechanisms. Prospective and interventional studies are needed to assess the impact of OSA and its treatment on peripheral neuropathy development and progression in patients with type 2 diabetes.

Effects of a synthetic retinoid on skin structure, matrix metalloproteinases, and procollagen in healthy and high-risk subjects with diabetes.

BACKGROUND: In diabetes, foot ulceration may result from increased skin fragility. Retinoids can reverse some diabetes-induced deficits of skin structure and function, but their clinical utility is limited by skin irritation. The effects of diabetes and MDI 301, a nonirritating synthetic retinoid, and retinoic acid have been evaluated on matrix metalloproteinases (MMPs), procollagen expression, and skin structure in skin biopsies from nondiabetic volunteers and diabetic subjects at risk of foot ulceration using organ culture techniques. METHODS: Zymography and enzyme-linked immunosorbent assay were utilized for analysis of MMP-1, -2, and -9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) and immunohistochemistry for type I procollagen protein abundance. Collagen structure parameters were assessed in formalin-fixed, paraffin-embedded tissue sections. RESULTS: The % of active MMP-1 and -9 was higher and TIMP-1 abundance was lower in subjects with diabetes. Type 1 procollagen abundance was reduced and skin structural deficits were increased in diabetes. Three µM MDI 301 reduced active MMP-1 and -9 abundance by 29% (P < .05) and 40% (P < .05), respectively, and increased TIMP-1 by 45% (P = .07). MDI 301 increased type 1 procollagen abundance by 40% (P < .01) and completely corrected structural deficit scores. Two µM retinoic acid reduced MMP-1 but did not significantly affect skin structure. CONCLUSIONS: These data indicate that diabetic patients at risk of foot ulceration have deficits of skin structure and function. MDI 301 offers potential for repairing this skin damage complicating diabetes.

Abnormal left ventricular torsion and cardiac autonomic dysfunction in subjects with type 1 diabetes mellitus.

Left ventricular torsion is increased and cardiac energetics are reduced in uncomplicated type 1 diabetes mellitus (T1DM). Our aim was to determine the relationships of these abnormalities to cardiovascular autonomic neuropathy (CAN) in subjects with T1DM. A cross-sectional study was conducted in 20 subjects with T1DM free of known coronary heart disease attending an outpatient clinic. Cardiovascular autonomic neuropathy was assessed using heart rate variability studies and the continuous wavelet transform method. Left ventricular function was determined by speckle tracking echocardiography. Magnetic resonance spectroscopy and stress magnetic resonance imaging were used to measure cardiac energetics and myocardial perfusion reserve index, respectively. Twenty subjects (age, 35 ± 8 years; diabetes duration, 16 ± 9 years; hemoglobin A(1c), 8.0% ± 1.1%) were recruited. Forty percent of the subjects exhibited definite or borderline CAN. Log peak radial strain was significantly increased in subjects with CAN compared with those without (1.56 ± 0.06 vs 1.43 ± 0.14, respectively; P = .011). Data were adjusted for log duration of diabetes, and log left ventricular torsion correlated (r = 0.593, P = .01) with log low-frequency to high-frequency ratio during the Valsalva maneuver. Log isovolumic relaxation time correlated significantly with log Valsalva ratio and log proportion of differences in consecutive RR intervals of normal beats greater than 50 milliseconds during deep breathing. However, CAN did not correlate with cardiac energetics or myocardial perfusion reserve index. Spectral analysis of low-frequency to high-frequency ratio power during the Valsalva maneuver is associated with altered left ventricular torsion in subjects with T1DM. Parasympathetic dysfunction is closely associated with diastolic deficits. Cardiovascular autonomic neuropathy is not however the principal cause of impaired cardiac energetics. The role of CAN in the development of cardiomyopathy warrants further evaluation.

Circulating levels of adiponectin, leptin, and tumour necrosis factor alpha in hypertension.

BACKGROUND: Abnormal adipocyte function is implicated in the coalition of multiple cardiovascular risk factors, where aberrant circulating levels of the adipose-derived hormones adiponectin, leptin, and tumour necrosis factor (TNF) alpha may provide the putative link between hypertension and increased cardiovascular risk. The pragmatic utility of these 'adipocytokines' in the clinical setting of hypertension is unclear, and we hypothesized a relationship of circulating adipocytokines to hypertension, and associated cardiovascular morbidity. METHOD: Using a cross-sectional approach, we measured plasma adipocytokines in 278 'high-risk' treated hypertensive participants of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study (mean (SD) age 62.9 (7.7) years), who were compared to 54 newly diagnosed untreated hypertensives (61.3 (10.9) years) and 55 healthy controls (48.3 (12.3) years). RESULTS: Levels of all three adipocytokines were lower amongst treated hypertensives compared to newly diagnosed hypertensives and healthy controls (P<0.001 for leptin and adiponectin), and varied with gender, co-morbidities (e.g. diabetes, cardiovascular disease (CVD), left ventricular hypertrophy) and by treatments (e.g. statins and beta-blockade). Levels of adiponectin (P<0.001) and leptin (P=0.02) rose in an ordinal fashion with increasing hypertension severity (grade). Levels of leptin were associated with diastolic blood pressure in a positive fashion (P<0.001). CONCLUSIONS: While hypertension affects adipocytokine levels, the clinical interpretation of circulating levels in hypertension is confounded by a range of factors. The positive relation between leptin and adiponectin with hypertension severity may reflect an underlying adaptive response that is attenuated during pharmacological hypertension management.

Effects of omega-3 polyunsaturated fatty acids on metabolically active hormones in patients post-myocardial infarction.

BACKGROUND: Long-chain omega-3 polyunsaturated fatty acids (PUFA) supplementation is used as a therapeutic secondary prevention strategy among post-myocardial infarction (MI) patients. The effects of omega-3 PUFA on markers of energy homeostasis among post-MI patients are unclear. METHODS: We investigated the effects of Omacor (a pharmaceutical capsule formulation of highly refined, concentrated omega-3 PUFA; Solvay Healthcare, Southampton, UK; 1 g/day) in addition to usual care (cardiovascular therapy) in a pilot randomised study of 35 post-MI men. Following randomisation to Omacor (n=16), or 'usual care' controls (n=19), fasting levels of insulin, non-esterified fatty acids (NEFA), triglycerides, glucose and adipocytokines (adiponectin, leptin and tumour necrosis factor (TNF)-alpha), as indices of markers of energy homeostasis, were measured at baseline and after 3-month treatment. RESULTS: There were no baseline differences in age, body mass index, blood pressure, fasting triglycerides, plasma glucose, NEFA and adipocytokines between the two treatment arms (P=0.07). There were no significant changes in metabolically active hormones within groups after 3-month treatment. Across arms, the direction of baseline to follow-up changes in insulin levels were significantly different (P= 0.03), with a mean increase with Omacor (+3.39 mU/ml) and a decrease among controls (-17.6 mU/ml), without associated deteriorating changes in triglycerides, NEFA or plasma glucose. CONCLUSION: This pilot study suggests that Omacor had little effect on glycaemic control among male post-MI patients. However, Omacor was associated with raised insulin levels, compared to usual care; thus, a metabolic basis for the cardioprotective action of Omacor, outside of its lipid lowering effects, merits further investigation.