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The aim of the present study was to determine the prevalence and predictors of an abnormal echocardiogram in patients with Type 2 diabetes. Cardiac function and structure were rigorously assessed by comprehensive transthoracic echocardiographic techniques in 229 patients with Type 2 diabetes. Cardiovascular risk factors and diabetic complications were assessed, and predictors of an abnormal echocardiogram were identified using multivariate logistic regression analysis. An abnormal echocardiogram was present in 166 patients (72%). LVH (left ventricular hypertrophy) occurred in 116 patients (51%), and cardiac dysfunction was found in 146 patients (64%), of whom 109 had diastolic dysfunction alone and 37 had systolic+/-diastolic dysfunction. Independent predictors of an abnormal echocardiogram were obesity, age, the number of antihypertensive drugs used (all P<0.001) and creatinine clearance (P<0.05). The risk of an abnormal echocardiogram increased by 9% for each year over 50 years of age {OR (odds ratio), 1.09 [95% CI (confidence interval), 1.04-1.15]}, 3-fold if obesity was present [BMI (body mass index) >30; OR, 4.2 (95% CI, 1.9-9.0)] and by 80% for each antihypertensive agent used [OR, 1.8 (95% CI, 1.3-2.4) per agent]. In conclusion, an abnormal cardiac echocardiogram is common in patients with Type 2 diabetes. Importantly, although cardiac abnormalities can be predicted by traditional risk factors, such as age, obesity and renal function, the absence of micro- or macro-vascular complications does not predict a normal echocardiogram. We suggest that an echocardiogram identifies those with Type 2 diabetes at increased cardiovascular risk due to occult LVH and diastolic dysfunction, and this information may lead to more aggressive management of known risk factors in the clinic.

Anemia is a common finding in patients with diabetes due to the high burden of chronic kidney disease in this population. Anemia is more prevalent and is found earlier in patients with diabetes than in those with kidney disease from other causes. The increased risk of anemia in diabetes probably reflects changes in the renal tubulointerstitium associated with diabetic kidney disease, which disrupt the delicate interaction between interstitial fibroblasts, capillaries and tubular cells required for normal hemopoietic function. In particular, the uncoupling of the hemoglobin concentration from renal erythropoietin synthesis seems to be the key factor underlying the development of anemia. Systemic inflammation, functional hematinic deficiencies, erythropoietin resistance and reduced red cell survival also drive anemia in the setting of impaired renal compensation. Although anemia can be considered a marker of kidney damage, reduced hemoglobin levels independently identify diabetic patients with an increased risk of microvascular complications, cardiovascular disease and mortality. Nevertheless, a direct role in the development or progression of diabetic complications remains to be clearly established and the clinical utility of correcting anemia in diabetic patients has yet to be demonstrated in randomized controlled trials. Correction of anemia certainly improves performance and quality of life in diabetic patients. In the absence of additional data, treatment should be considered palliative, and any functional benefits must be matched against costs to the patient and the health system.

Anemia is a common finding in diabetes, particularly in patients with albuminuria or renal impairment. We recently showed that at least 1 in 5 outpatients with type 1 or type 2 diabetes in tertiary clinics have anemia, in whom it constitutes a significant additional burden. Anemia is associated strongly with an increased risk of diabetic complications including nephropathy, retinopathy, and heart failure. Although a number of factors contribute to an increased prevalence of anemia in diabetes, an uncoupling of hemoglobin concentration and renal erythropoietin synthesis associated with tubular dysfunction appears to be the dominant factor. In our patients with diabetes and anemia, more than three quarters had functional erythropoietin deficiency. This association was most pronounced in patients with renal impairment, in whom nearly half of all patients had anemia. However, 70% of anemic patients without renal impairment also had inappropriately low erythropoietin levels. Consequently, the likelihood of functional erythropoietin deficiency, as a cause of anemia in patients with diabetes, is not dependent on the severity of renal impairment. Although there is a clear rationale for correction of anemia in diabetes, it remains to be established whether this will lead to improved outcomes. Some small studies suggest improvement in cardiac outcomes and hospitalization. It is anticipated that large ongoing studies will help define the optimal approach to the management of anemia in diabetes.

Anaemia is common in patients with diabetes and associated with an increased risk of diabetic complications. Although the role of anaemia in heart failure is established, we hypothesize that anaemia also contributes to an increased risk of cardiac dysfunction in patients with Type II diabetes. In the present study, 228 consecutive adults with diabetes were investigated using transthoracic echocardiography. Echocardiographic parameters were correlated with the Hb (haemoglobin) level and adjusted for other risk factors for cardiac dysfunction using multivariate analysis. More than one in five patients (23%) had anaemia, which was an independent risk factor for cardiac dysfunction on echocardiography. Over one-third of all patients with evidence of abnormal cardiac function (diastolic and/or systolic dysfunction) on echocardiography had anaemia compared with <5% of patients with normal echocardiographic findings. Most patients with anaemia had cardiac dysfunction (94%), with the major abnormality being diastolic dysfunction associated with an increased left ventricular mass and impaired relaxation indices. A continuous association between diastolic function and Hb was also observed in patients without anaemia. In patients with a history of cardiovascular disease, systolic dysfunction was twice as common in patients with anaemia. Anaemia was also correlated with plasma markers of cardiac risk, including BNP (brain natriuretic peptide), CRP (C-reactive protein) and AVP (arginine vasopressin). Notably, the predictive utility of these markers was eliminated after adjusting for Hb. Consequently, the inexpensive measurement of Hb may be a useful tool to identify diabetic patients at increased risk of cardiac dysfunction.

The current pandemic of diabetes mellitus will inevitably be followed by an epidemic of chronic kidney disease. It is anticipated that 25-40% of patients with type 1 diabetes and 5-40% of patients with type 2 diabetes will ultimately develop diabetic kidney disease. The control of blood pressure represents a key component for the prevention and management of diabetic nephropathy. There is a strong epidemiological connection between hypertension in diabetes and adverse outcomes in diabetes. Hypertension is closely linked to insulin resistance as part of the 'metabolic syndrome'. Diabetic nephropathy may lead to hypertension through direct actions on renal sodium handling, vascular compliance and vasomotor function. Recent clinical trials also support the utility of blood pressure reduction in the prevention of diabetic kidney disease. In patients with normoalbuminuria, transition to microalbuminuria can be prevented by blood pressure reduction. This action appears to be significant regardless of whether patients have elevated blood pressure or not. The efficacy of ACE inhibition appears to be greater than that achieved by other agents with a similar degree of blood pressure reduction; although large observational studies suggest the risk of microalbuminuria may be reduced by blood pressure reduction, regardless of modality. In patients with established microalbuminuria, ACE inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) consistently reduce the risk of progression from microalbuminuria to macroalbuminuria, over and above their antihypertensive actions. The clinical utility of combining these strategies remains to be established. In patients with overt nephropathy, blood pressure reduction is associated with reduced urinary albumin excretion and, subsequently, a reduced risk of renal impairment or end stage renal disease. In addition to actions on systemic blood pressure, it is now clear that ACE inhibitors and ARBs also reduce proteinuria in patients with diabetes. This anti-proteinuric activity is distinct from other antihypertensive agents and diuretics. Although there is a clear physiological rationale for blockade of the renin angiotensin system, which is strongly supported by clinical studies, to achieve the optimal lowering of blood pressure, particularly in the setting of established diabetic renal disease, a number of different antihypertensive agents will always be needed. In the end, the choice of agents should be individualised to achieve the maximal tolerated reduction in blood pressure and albuminuria. Ultimately, no matter how it is achieved, so long as it is achieved, renal risk can be reduced by agents that lower blood pressure and albuminuria.

Objective: Anemia is common in diabetes, potentially contributing to the pathogenesis of diabetes complications. This study aims to establish the prevalence and independent predictors of anemia in a cross-sectional survey of 820 patients with diabetes in long-term follow-up in a single clinic., Research Design and Methods: A full blood count was obtained in addition to routine blood and urine test results for all patients over a 2-year period to encompass all patterns of review. Predictors of the most recent Hb concentration and anemia were identified using multiple and logistic regression analysis., Results: A total of 190 patients (23%) had unrecognized anemia (Hb <12 g/dl for women and <13 g/dl for men). This prevalence is two to three times higher than for patients with comparable renal impairment and iron stores in the general population. Independent predictors for Hb were transferrin saturation, glomerular filtration rate (GFR), sex, albumin excretion rate, and HbA(1c) level (all P < 0.0001). Microalbuminuric patients were >2 times (odds ratio [OR] 2.3) and macroalbuminuric patients >10 times (OR 10.1) as likely to have anemia than normoalbuminuric patients with preserved renal function (GFR >80 ml/min)., Conclusions: Anemia is a common accompaniment to diabetes, particularly in those with albuminuria or reduced renal function. Additional factors present in diabetes may contribute to the development of increased risk for anemia in patients with diabetes.

OBJECTIVE Osteopontin (OPN) is a multifunctional protein suggested to be a player in the arterial disease of patients with type 2 diabetes. However, its role for complications in patients with type 1 diabetes (T1D) is unknown. We therefore investigated the associations between OPN and diabetic vascular complications and all-cause mortality in patients with T1D. RESEARCH DESIGN AND METHODS Serum OPN was measured in 2,145 adults with T1D without end-stage renal disease (ESRD; dialysis or transplantation) as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Data on renal status, cardiovascular disease (CVD), and all-cause mortality during follow-up were verified from medical files, hospital discharge registries, and the Finnish National Death Registry, respectively. The median follow-up time was 10.5 (interquartile range 8.9-11.8) years. RESULTS Serum OPN was higher at baseline in patients who developed incident microalbuminuria (16.0 ± 0.9 vs. 14.1 ± 0.2 µg/L; P = 0.04), progressed to ESRD (28.3 ± 1.7 vs. 15.4 ± 0.2 µg/L; P < 0.001), suffered an incident CVD event (20.2 ± 1.2 vs. 15.5 ± 0.2 µg/L; P < 0.001), or died (23.3 ± 1.4 vs. 15.8 ± 0.2 µg/L; P < 0.001) during follow-up. In multivariate Cox regression analysis, OPN was independently associated with the development of incident microalbuminuria, an incident CVD event, and death, after adjustments for associated risk factors. Even after calculating reclassification indexes, OPN was predictive of CVD and all-cause mortality beyond the Framingham risk score covariates and hs-CRP. CONCLUSIONS Serum OPN is a strong predictor of incipient diabetic nephropathy, a first-ever CVD event, and all-cause mortality in patients with T1D. Serum OPN may be of clinical significance for the risk prediction of CVD events in patients with T1D. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Osteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS--Serum OPG was measured in 1,939 adults with T1D participating in the Finnish Diabetic Nephropathy (FinnDiane) Study. Patients with end-stage renal disease (dialysis or transplantation) at baseline were excluded from analysis. Data on cardiovascular (CV) events and mortality during follow-up were verified from hospital discharge registries (ICD codes) and the Finnish National Death Registry, respectively. The follow-up time was 10.4 ± 2.0 (mean ± SD) years. RESULTS--Only patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01-1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.4 [1.13-1.88]; P = 0.004) during follow-up. CONCLUSIONS--We showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D. [ABSTRACT FROM AUTHOR]

The article explains the possible use of nutrient-sensing pathways as a therapeutic target for diabetic nephropathy. It explains the physiological mechanisms of nutrient sensing, the process of autophagy, and diabetic nephropathy. Particular focus is given to the role of mammalian target of rapamycin (mTOR) and sirtuins (silent information regulator 2[Sir2]) in diabetic nephropathy.

OBJECTIVE--To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress. RESEARCH DESIGN AND METHODS--The study was performed using diabetic apolipoprotein E/GPx1 (ApoE-/-GPx1-/-)-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks. RESULTS--Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways. CONCLUSIONS--Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy. Diabetes 59:3198-3207, 2010 [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) generate ROS, and therefore this study evaluated the effects of RAGE deletion, decreasing AGE accumulation, or lowering dietary AGE content on oxidative parameters in diabetic nephropathy (DN). Control and diabetic male wild-type and RAGE-deficient (RAGE-/-) mice were fed high- or low-AGE diets, with two groups given the inhibitor of AGE accumulation, alagebrium chloride, and followed for 24 wk. Diabetic RAGE-/-mice were protected against albuminuria, hyperfiltration, glomerulosclerosis, decreased renal mitochondrial ATP production, and excess generation of both mitochondrial and cytosolic superoxide. Whereas glomerulosclerosis, tubulointerstitial expansion, and hyperfiltration were improved in diabetic mice treated with alagebrium, there was no effect on urinary albumin excretion. Both diabetic RAGE-/- and alagebrium-treated mice had an attenuation of renal RAGE expression and decreased renal and urinary AGE (carboxymethyllysine) levels. Low-AGE diets did not confer renoprotection, lower the AGE burden or renal RAGE expression, or improve cytosolic or mitochondrial superoxide generation. Renal uncoupling protein-2 gene expression and mitochondrial membrane potential were attenuated by all therapeutic interventions in diabetic mice. In the present study, diverse approaches to block the AGE-RAGE axis had disparate effects on DN, which has potential clinical implications for the way this axis should be targeted in humans. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Most diabetic patients with impaired renal function have a urinary albumin excretion rate in the normal range. In these patients, the etiology of renal impairment is unclear, and it is also unclear whether this nonalbumunuric renal impairment is unique to diabetes. RESEARCH DESIGN AND METHODS-- In this study, we examined the frequency and predictors of nonalbumunuric renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m²) in a nationally representative cohort of 3,893 patients with type 2 diabetes and compared our findings with rates observed in the general population from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) survey (n = 11,247). RESULTS -- Of the 23.1% of individuals with type 2 diabetes who had eGFR <60 ml/min per 1.73 m² (95% CI 21.8-24.5%), more than half (55%) had a urinary albumin excretion rate that was persistently in the normal range. This rate of renal impairment was predictably higher than that observed in the general population (adjusted odds ratio 1.3, 95% CI 1.1-1.5, P < 0.01) but was solely due to chronic kidney disease associated with albuminuria. In contrast, renal impairment in the absence of albuminuria was less common in those with diabetes than in the general population, independent of sex, ethnicity, and duration of diabetes (0.6, 0.5-0.7, P < 0.001). CONCLUSIONS-- Nonalbuminuric renal impairment is not more common in those with diabetes. However, its impact may be more significant. New studies are required to address the pathogenesis, prevention, and treatment of nonalbuminuric renal disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropatby. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS-- A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8-9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion (in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression. RESULTS--In patients with normoalbuminuria (n = 66), progression was associated with male sex (P < 0.05), borderline albuminuria (P = 0.02), and LDL-free cholesterol (P = 0.02). In patients with microalbuminuria (n = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P < 0.05). In patients with macroalbuminuria (n = 36), a significant decline in the renal function (>3 ml ⋅ min-1 ⋅ year-1 was independently associated with poor glycemic control, hypertension, and LDL size (P < 0.05). When all patients with progressive nephropathy were analyzed together, only LDL cholesterol was predictive on multivariate analysis (P < 0.05), which masked the importance of triglyceride enrichment in microalbuminuria. CONCLUSIONS-- Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Low-molecular-weight AGEs are associated with GFR and anemia in patients with type 2 diabetes. Background. Advanced glycation end products (AGEs) are implicated in the development and progression of diabetic nephropathy. We examined the predictors of low-molecular-weight (LMW) AGEs in a cross-sectional survey of 604 patients with type 2 diabetes in a single clinic. Methods. A clinical history and results of routine blood and urine testing were obtained for all patients over a 2-year period. Fluorescent LMW AGEs were estimated in serum samples taken concurrently, using an established flow injection method. Predictors of LMW AGEs were identified using multiple regression analysis. Results. LMW AGEs were 34% higher in patients with diabetes than nondiabetic volunteers from the same community ( P < 0.001). Independent predictors for LMW AGEs in patients with diabetes were glomerular filtration rate (GFR) and hemoglobin (both P < 0.001). While patients with renal impairment and anemia had the highest levels of LMW AGEs, both GFR and hemoglobin remained predictive when patients with a serum creatinine or hemoglobin within the “normal range” were analyzed separately. Patients with hyperfiltration had significantly lower LMW AGEs than those with normal renal function. Gender was also a significant independent predictor of LMW AGEs in patients without anemia. However, LMW AGEs were not associated with metabolic control or the presence of macrovascular disease. Conclusion. Circulating levels of LMW AGEs are elevated in patients with diabetes, especially those with impaired renal function or anemia. These findings extend the evidence for an association between AGEs and progressive renal injury in patients with type 2 diabetes. Whether LMW AGEs contribute to, or are a marker of, renal damage needs to be established by prospective studies. [ABSTRACT FROM AUTHOR]

The article explores the influence of urinary sodium excretion over time on type 2 diabetes (T2D) mortality. Topics discussed include the results of the prospective cohort study of patients with T2D attending a single tertiary hospital diabetes clinic including the association of low 24-hour urinary sodium excretion over time with increased mortality in people with T2D. Also mentioned are the limitations of the study they conducted.

The accumulation of advanced glycation end products is thought to be a key factor in the initiation and progression of diabetic nephropathy. Here we determined whether the size of the ligands for the receptor for advanced glycation end products (RAGEs) that were present in the serum of patients with type 2 diabetes modulates their pathogenic potential. Serum was collected from control subjects and patients with type 2 diabetes with varying degrees of renal disease (normo-, micro-, or macroalbuminuria). The titers of the RAGE ligands N-carboxymethyllysine (CML), S100A, S100B, and high-mobility group box 1 (HMGB1) were measured by enzyme-linked immunosorbent assay in serum as well as in pooled size-fractionated serum. We also measured cellular binding of serum fractions to mesangial cells transfected with RAGE and examined the downstream signaling pathways. Circulating CML was increased in patients with type 2 diabetes, whereas HMGB1 was decreased. S100A8, S100BA9, and soluble RAGE were unchanged. The high-molecular-weight (over 50 kDa) serum fraction contained the greatest proportion of RAGE ligands, with all immunoreactivity and cellular binding observed only with serum fractions over 30 kDa. High-molecular-weight serum from macroalbuminuric patients showed greater RAGE binding capacity, modulation of cell-surface RAGE expression, increased phospho-protein kinase C-α, and p65 nuclear factor κB DNA-binding activity, which were competitively inhibited by soluble RAGE or CML neutralizing antibodies. These data show that ligands that activate RAGE present in the circulation of patients with type 2 diabetes and nephropathy are predominantly of high molecular weight. [ABSTRACT FROM AUTHOR]