Cardiovascular autonomic neuropathy and bone metabolism in Type 1 diabetes.

AIM: To investigate the association between cardiovascular autonomic neuropathy and bone metabolism in people with Type 1 diabetes. METHODS: We assessed cardiovascular autonomic neuropathy in 329 people with Type 1 diabetes according to heart rate response to deep breathing, to standing and to the Valsalva manoeuvre, and 2-min resting heart rate. More than one pathological non-resting test was defined as cardiovascular autonomic neuropathy. Bone mineral density of the femoral neck (BMDfn) was assessed by dual energy X-ray absorptiometry. Serum parathyroid hormone levels and other bone markers were measured. RESULTS: The mean (sd) age of the participants was 55.6 (9.4) years, 52% were men, and the mean (sd) diabetes duration was 40 (8.9) years, HbA1c 62 (9) mmol/mol and estimated GFR 78 (26) ml/min/1.73m2 . In all, 36% had cardiovascular autonomic neuropathy. Participants with cardiovascular autonomic neuropathy had 4.2% (95% CI -8.0 to -0.2; P=0.038) lower BMDfn and 33.6% (95% CI 14.3 to 53.8; P=0.0002) higher parathyroid hormone levels compared with participants without cardiovascular autonomic neuropathy in adjusted models. Higher resting heart rate remained associated with higher parathyroid hormone level and lower BMDfn after additional adjustment for eGFR (P<0.0001 and P = 0.042, respectively). CONCLUSIONS: The presence of cardiovascular autonomic neuropathy was associated with reduced BMDfn and increased levels of parathyroid hormone. Kidney function may either confound or mediate these findings. Cardiovascular autonomic neuropathy could be associated with increased risk of osteoporosis in Type 1 diabetes. Whether cardiovascular autonomic neuropathy directly affects bone metabolism detrimentally or if this association is mediated via decreased kidney function should be investigated further.

Soluble urokinase plasminogen activator receptor levels are elevated and associated with complications in patients with type 1 diabetes.

OBJECTIVES: Soluble urokinase plasminogen activator receptor (suPAR) is a marker of inflammation and endothelial dysfunction. We investigated the associations between suPAR and diabetes, including diabetes duration and complications, in patients with type 1 diabetes. DESIGN, SETTING AND SUBJECTS: From 2009 to 2011, 667 patients with type 1 diabetes and 51 nondiabetic control subjects were included in a cross-sectional study at Steno Diabetes Center, Gentofte, Denmark. suPAR levels were measured with an enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: The investigated diabetic complications were cardiovascular disease (CVD: previous myocardial infarction, revascularisation, peripheral arterial disease and stroke), autonomic dysfunction (heart rate variability during deep breathing <11 beats min(-1) ), albuminuria [urinary albumin excretion rate (UAER) ≥30 mg/24 h] or a high degree of arterial stiffness (pulse wave velocity ≥10 m s(-1) ). Analyses were adjusted for gender, age, systolic blood pressure, estimated glomerular filtration rate, UAER, glycated haemoglobin (HbA1c ), total cholesterol, body mass index, C-reactive protein, antihypertensive treatment and smoking. RESULTS: Soluble urokinase plasminogen activator receptor levels were lower in control subjects versus all patients, in control subjects versus normoalbuminuric patients (UAER <30 mg/24 h), in normoalbuminuric patients with short (<10 years) versus long diabetes duration and were increased with degree of albuminuria (adjusted P < 0.001 for all). Furthermore, suPAR levels were higher in patients with versus without CVD (n = 144; 21.3%), autonomic dysfunction (n = 369; 59.2%), albuminuria (n = 357; 53.1%) and a high degree of arterial stiffness (n = 298; 47.2%) (adjusted P ≤ 0.024). The adjusted odds ratio (95% confidence interval) values per 1 ln unit increase in suPAR were as follows: 2.5 (1.1-5.7) for CVD: 2.7 (1.2-6.2) for autonomic dysfunction; 3.8 (1.3-10.9) for albuminuria and 2.5 (1.1-6.1) for a high degree of arterial stiffness (P ≤ 0.039). CONCLUSION: The suPAR level is higher in patients with type 1 diabetes and is associated with diabetes duration and complications independent of other risk factors. suPAR is a potential novel risk marker for the management of diabetes.

Evaluation of placental growth factor and soluble Fms-like tyrosine kinase 1 as predictors of all-cause and cardiovascular mortality in patients with Type 1 diabetes with and without diabetic nephropathy.

AIMS: Placental growth factor is a vascular endothelial growth factor involved in angiogenesis, vascular inflammation and plaque formation. Soluble Fms-like tyrosine kinase 1 is a decoy receptor for placental growth factor, reducing its activity. The aim of this study is to evaluate the predictive value of placental growth factor and soluble Fms-like tyrosine kinase 1 in relation to all-cause and cardiovascular mortality and decline in kidney function in Type 1 diabetes. METHODS: This was a prospective, observational follow-up study with 8 (0-13) years [median (range)] of follow-up, including patients with Type 1 diabetes, of whom 458 had diabetic nephropathy [278 men; age 42 ± 11 years (mean ± sd), diabetes duration 28 ± 9 years, glomerular filtration rate 76 ± 33 ml min(-1) 1.73 m(-2) ] and 442 had long-standing normoalbuminuria (234 men; age 45 ± 12 years, diabetes duration 28 ± 10 years). RESULTS: Placental growth factor and soluble Fms-like tyrosine kinase 1 levels measured at baseline were higher in patients with diabetic nephropathy compared with patients with long-standing normoalbuminuria [median (range)] 15 (4-131) vs. 11 (7-64) ng/l, (P < 0.001) and 86 (42-3462) vs. 77 (43-1557) ng/l (P < 0.001), respectively. In patients with diabetic nephropathy, high levels of placental growth factor predicted all-cause and cardiovascular mortality [hazard ratio 1.94 (1.16-3.24) and hazard ratio 2.91 (1.45-5.85)] after adjustment for sex, age, smoking, systolic blood pressure, HbA(1c) , cholesterol, glomerular filtration rate and previous cardiovascular disease. High levels of placental growth factor predicted increased risk of end-stage renal disease [hazard ratio 2.77 (1.47-5.14)], but covariate adjustments attenuated the association [hazard ratio 1.89 (0.91-3.95)]. Among patients with long-standing normoalbuminuria, placental growth factor levels predicted fatal and non-fatal cardiovascular events [hazard ratio 1.97 (1.03-3.76)], but not all-cause mortality. Baseline soluble Fms-like tyrosine kinase 1 levels did not predict outcome in either group after adjustment. CONCLUSION: Placental growth factor is elevated in patients with Type 1 diabetes and diabetic nephropathy and predicts all-cause and cardiovascular mortality, but not deterioration of kidney function.

Arterial stiffness and endothelial dysfunction independently and synergistically predict cardiovascular and renal outcome in patients with type 1 diabetes.

AIMS: To evaluate whether pulse pressure alone or with placental growth factor as estimates of arterial stiffness and endothelial dysfunction, predicts mortality, cardiovascular disease and progression to end-stage renal disease in patients with Type 1 diabetes. METHODS: Prospective, observational study, median (range) follow-up 8 (0-13) years, 900 patients with Type 1 diabetes, 458 with diabetic nephropathy, mean ± SD age 44 ± 11 years. RESULTS: During follow-up, we recorded 178 (20%) all-cause deaths, 109 (12%) cardiovascular deaths, 213 (24%) cardiovascular events and 73 (16%) progressed to end-stage renal disease. Elevated pulse pressure predicted all-cause and cardiovascular mortality and cardiovascular events [Hazard Ratio (HR) (95% CI) per 10 mmHg increase]: HR 1.2 (1.1-1.3), 1.3 (1.2-1.5) and 1.2 (1.1-1.3), P<0.001 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, creatinine, smoking, previous cardiovascular disease and nephropathy status). Furthermore, pulse pressure predicted the development of end-stage renal disease in patients with diabetic nephropathy: HR 1.2 (1.1-1.4), P=0.011 (adjusted for sex, age, HbA(1c) , cholesterol, diastolic blood pressure, previous cardiovascular disease and glomerular filtration rate). In a two-hit model, patients with pulse pressure and placental growth factor levels above the median vs. below the median had increased risk of all-cause and cardiovascular mortality, cardiovascular events and progression to end-stage renal disease: adjusted HRs 2.3 (1.2-4.2), 4.2 (1.6-11.0), 2.3 (1.3-4.1) and 3.5 (1.0-11.8),P<0.05. CONCLUSIONS: Elevated pulse pressure independently predicts mortality, cardiovascular events and progression to end-stage renal disease in patients with Type 1 diabetes. Placental growth factor adds to the predictive value of pulse pressure on cardiovascular and renal outcome.

Associations between advanced glycation endproducts and matrix metalloproteinases and its inhibitor in individuals with type 1 diabetes.

AIMS: Advanced glycation endproducts (AGEs) and altered extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) are associated with vascular complications in type 1 diabetes. Experimental studies have shown that AGEs regulate the production of MMPs and/or TIMP-1. Therefore, we investigated associations between specific AGEs and MMP-1, -2, -3, -9, and -10, and TIMP-1 in individuals with type 1 diabetes. METHODS: In 670 type 1 diabetic individuals we determined serum levels of protein-bound AGEs Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL), 5-hydro-5-methylimidazolone (MG-H1) and pentosidine, and MMP-1, -2, -3, -9, and -10, and TIMP-1. We performed linear regression analyses to investigate associations between AGEs and markers of the MMP-TIMP system. Analyses were adjusted for age, sex, HbA1c and duration of diabetes, and additionally for other potential confounders and presence of vascular complication. RESULTS: After full adjustment, levels of CML were positively associated with levels of MMP-2 and inversely with MMP-9. CEL was positively associated with MMP-3 and TIMP-1. MG-H1 was only associated with TIMP-1, whereas pentosidine was not associated with MMPs or TIMP-1. CONCLUSIONS: We showed independent associations between several AGEs and markers of the MMP-TIMP system, which indicate specific AGE-MMP/TIMP-1 interactions potentially contributing to vascular complications in patients with type 1 diabetes.

Pulse pressure is not an independent predictor of outcome in type 2 diabetes patients with chronic kidney disease and anemia--the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT).

Pulse pressure (PP) remains an elusive cardiovascular risk factor with inconsistent findings. We clarified the prognostic value in patients with type 2 diabetes, chronic kidney disease (CKD) and anemia in the Trial to Reduce cardiovascular Events with Aranesp (darbepoetin alfa) Therapy. In 4038 type 2 diabetes patients, darbepoetin alfa treatment did not affect the primary outcome. Risk related to PP at randomization was evaluated in a multivariable model including age, gender, kidney function, cardiovascular disease (CVD) and other conventional risk factors. End points were myocardial infarction (MI), stroke, end stage renal disease (ESRD) and the composite of cardiovascular death, MI or hospitalization for myocardial ischemia, heart failure or stroke (CVD composite). Median (interquartile range) age, gender, eGFR and PP was 68 (60-75) years, 57.3% women, 33 (27-42) ml min(-1) per 1.73 m2 and 60 (50-74) mm Hg. During 29.1 months (median) follow-up, the number of events for composite CVD, MI, stroke and ESRD was 1010, 253, 154 and 668. In unadjusted analyses, higher quartiles of PP were associated with higher rates per 100 years of follow-up of all end points (P⩽0.04), except stroke (P=0.52). Adjusted hazard ratios (95% confidence interval) per one quartile increase in PP were 1.06 (0.99-1.26) for MI, 0.96 (0.83-1.11) for stroke, 1.01 (0.94-1.09) for ESRD and 1.01 (0.96-1.07) for CVD composite. Results were similar in continuous analyses of PP (per 10 mm Hg). In patients with type 2 diabetes, CKD and anemia, PP did not independently predict cardiovascular events or ESRD. This may reflect confounding by aggressive antihypertensive treatment, or PP may be too rough a risk marker in these high-risk patients.