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Circulating levels of soluble ACE2 are increased by diabetes. Although this increase is associated with the presence and severity of cardiovascular disease, the specific role of soluble ACE2 in atherogenesis is unclear. Previous studies suggested that, like circulating ACE, soluble ACE2 plays a limited role in vascular homeostasis. To challenge this hypothesis, we aimed to selectively increase circulating ACE2 and measure its effects on angiotensin II dependent atherogenesis. Firstly, in Ace2/ApoE DKO mice, restoration of circulating ACE2 with recombinant murine soluble (rmACE219-613; 1 mg/kg/alternate day IP) reduced plaque accumulation in the aortic arch, suggesting that the phenotype may be driven as much by loss of soluble ACE2 as the reduction in local ACE2. Secondly, in diabetic ApoE KO mice, where activation of the renin angiotensin system drives accelerated atherosclerosis, rmACE219-613 also reduced plaque accumulation in the aorta after 6 weeks. Thirdly, to ensure consistent long-term delivery of soluble ACE2, an intramuscular injection was used to deliver a DNA minicircle encoding ACE219-613. This strategy efficiently increased circulating soluble ACE2 and reduced atherogenesis and albuminuria in diabetic ApoE KO mice followed for 10 weeks. We propose that soluble ACE2 has independent vasculoprotective effects. Future strategies that increase soluble ACE2 may reduce accelerated atherosclerosis in diabetes and other states in which the renin angiotensin system is upregulated. [ABSTRACT FROM AUTHOR]

Heart failure is a leading cause for hospitalisation and for readmission, especially in patients over the age of 65. Diabetes is an increasingly common companion to heart failure. The presence of diabetes and its associated comorbidity increases the risk of adverse outcomes and premature mortality in patients with heart failure. In particular, patients with diabetes are more likely to be readmitted to hospital soon after discharge. This may partly reflect the greater severity of heart disease in these patients. In addition, agents that reduce the chances of readmission such as β-blockers, renin-angiotensin-aldosterone system blockers, and mineralocorticoid receptor antagonists are underutilised because of the perceived increased risks of adverse drug reactions and other limitations. In some cases, readmission to hospital is precipitated by acute decompensation of heart failure (re-exacerbation) leading to pulmonary congestion and/or refractory oedema. However, it appears that for most of the patients admitted and then discharged with a primary diagnosis of heart failure, most readmissions are not due to heart failure, but rather due to comorbidity including arrhythmia, infection, adverse drug reactions, and renal impairment/reduced hydration. All of these are more common in patients who also have diabetes, and all may be partly preventable. The many different reasons for readmission underline the critical value of multidisciplinary comprehensive care in patients admitted with heart failure, especially those with diabetes. A number of new strategies are also being developed to address this area of need, including the use of SGLT2 inhibitors, novel nonsteroidal mineralocorticoid antagonists, and neprilysin inhibitors. [ABSTRACT FROM AUTHOR]

The deleterious effects of high glucose levels and enhanced metabolic flux on the vasculature are thought to be mediated by the generation of toxic metabolites, including reactive dicarbonyls like methylglyoxal (MG). In this article, we demonstrate that increasing plasma MG to levels observed in diabetic mice either using an exogenous source (1% in drinking water) or generated following inhibition, its primary clearance enzyme, glyoxalase-1 (with 50 mg/kg IP bromobenzyl-glutathione cyclopentyl diester every second day), was able to increase vascular adhesion and augment atherogenesis in euglycemic apolipoprotein E knockout mice to a similar magnitude as that observed in hyperglycemic mice with diabetes. The effects of MG appear partly mediated by activation of the receptor for advanced glycation end products (RAGE), as deletion of RAGE was able to reduce inflammation and atherogenesis associated with MG exposure. However, RAGE deletion did not completely prevent inflammation or vascular damage, possibly because the induction of mitochondrial oxidative stress by dicarbonyls also contributes to inflammation and atherogenesis. Such data would suggest that a synergistic combination of RAGE antagonism and antioxidants may offer the greatest utility for the prevention and management of diabetic vascular complications. [ABSTRACT FROM AUTHOR]

Current efforts to identify the genetic contribution to abdominal aortic aneurysm (AAA) have mainly focused on the assessment of germ-line variants such as single-nucleotide polymorphisms. The aim of the present study was to assess the presence of acquired chromosomal aberrations in human AAA. Microarray data of ten biopsies obtained from the site of main AAA dilatation (AAA body) and three control biopsies obtained from the macroscopRAGE (receptor for advanced glycation end-products) is expressed on multiple cell types implicated in the progression of atherosclerosis and plays a role in DAA (diabetes-associated atherosclerosis). The aim of the present study was to determine the relative role of either BM (bone marrow)- or non-BM-derived RAGE in the pathogenesis of STZ (streptozotocin)-induced DAA. Male ApoE (apolipoprotein E)-null (ApoE-/-:RAGE+/+) and ApoE:RAGE-null (ApoE-/-:RAGE-/-) mice at 7 weeks of age were rendered diabetic with STZ. At 8 weeks of age, ApoE-/- and ApoE-/-:RAGE-/- control and diabetic mice received BM from either RAGE-null or RAGE-bearing mice, generating various chimaeras. After 10 and 20 weeks of diabetes, mice were killed and gene expression and atherosclerotic lesion formation were evaluated respectively. Deletion of RAGE in either the BM cells or non-BM cells both resulted in a significant attenuation in DAA, which was associated with reduced VCAM-1 (vascular cell adhesion molecule-1) expression and translated into reduced adhesion in vitro. In conclusion, the results of the present study highlight the importance of both BM- and non-BM-derived RAGE in attenuating the development of DAA. [ABSTRACT FROM AUTHOR]

OBJECTIVE Recent studies have suggested that circulating levels of the tumor necrosis factor-a receptor 1 (sTNFαR1) may be a useful predictor for the risk of end-stage renal disease (ESRD) in patients with diabetes. However, its potential utility as a biomarker has not been formally quantified. RESEARCH DESIGN AND METHODS Circulating levels of sTNFαR1 were assessed in 429 patients with type 1 diabetes and overt nephropathy from the Finnish Diabetic Nephropathy (FinnDiane) cohort study. Predictors of incident ESRD over a median of 9.4 years of follow-up were determined by Cox regression and Fine-Gray competing risk analyses. The added value of sTNFαR1 was estimated via time-dependent receiver operating characteristic curves, net reclassification index (NRI), and integrated discrimination improvement (IDI) for survival data. RESULTS A total of 130 individuals developed ESRD (28%; ESRD incidence rate of 3.4% per year). In cause-specific modeling, after adjusting for baseline renal status, predictors of increased incidence of ESRD in patients with overt nephropathy were an elevated HbA1c, shorter duration of diabetes, and circulating levels of sTNFαR1. Notably, sTNFαR1 outperformed estimated glomerular filtration rate in terms of R². Circulating levels of the sTNFαR1 also remained associated with ESRD after adjusting for the competing risk of death. A prediction model including sTNFαR1 (as a -0.5 fractional polynomial) was superior to a model without it, as demonstrated by better global fit, an increment of R², the C index, and area under the curve. Estimates of IDI and NRI(>0) were 0.22 (95% CI 0.16-0.28; P < 0.0001) and 0.98 (0.78-1.23; P < 0.0001), respectively. The median increment in the risk score after including sTNFαR1 in the prediction model was 0.18 (0.12-0.30; P < 0.0001). CONCLUSIONS Circulating levels of sTNFαR1 are independently associated with the cumulative incidence of ESRD. This association is both significant and biologically plausible and appears to provide added value as a biomarker, based on the absolute values of NRI and IDI. [ABSTRACT FROM AUTHOR]

The degradation of ANG II by angiotensin-converting enzyme 2 (ACE2), leading to the formation of ANG(1-7), is an important step in the regulation of the reninangiotensin-aldosterone system (RAAS), and one that is significantly altered in the diabetic kidney. This study examined the role of ACE2 in the hyperfiltration associated with diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and ACE2 knockout (KO) mice. C57BL6 mice were further randomized to receive the selective ACE2 inhibitor MLN-4760. After 2 wk of study, animals were subjected to micropuncture experiments. The renal reserve was further assessed in C57BL6 mice and ACE2 KO mice after exposure to a high-protein diet. The induction of diabetes in wild-type mice was associated with increased renal ACE2 activity, hyperfiltration, and renal hypertrophy. On micropuncture, diabetes was associated with increased tubular free flow and stop-flow pressure, enhanced tubuloglomerular feedback reactivity, and an increased maximal response indicative of increased glomerular hydrostatic capillary pressure. Each of these increases were prevented in diabetic ACE2 KO mice and diabetic mice treated with a selective ACE2 inhibitor for 2 wk. However, unlike chronically treated animals, ACE2 inhibition with MLN-4760 had no acute effect on stop-flow pressure or tubuloglomerular feedback reactivity. ACE2 KO mice also failed to increase their creatinine clearance in response to a high-protein diet. The results of our study suggest that ACE2 plays a key role in the recruitment of the renal reserve and hyperfiltration associated with diabetes. [ABSTRACT FROM AUTHOR]

Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin-angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang- (1-7) [angiotensin-(1-7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxical fall in cardiac AngII levels and no change in Ang-(1-7) following the onset of diabetes. At the same time the major phenotypic differences between Ace2-deficient and Ace2-replete mice with respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of AngII and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of CVD (cardiovascular disease) in diabetes. [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) are important mediators of diabetic nephropathy that act through the receptor for AGEs (RAGE), as well as other mechanisms, to promote renal inflammation and glomerulosclerosis. The relative contribution of RAGE-dependent and RAGE-independent signaling pathways has not been previously studied in vivo. In this study, diabetic RAGE apoE double-knockout (KO) mice with streptozotocin-induced diabetes were treated with the AGE inhibitor, alagebrium (1 mg/kg/day), or the ACE inhibitor, quinapril (30 mg/kg/day), for 20 weeks, and renal parameters were assessed. RAGE deletion attenuated mesangial expansion, glomerular matrix accumulation, and renal oxidative stress associated with 20 weeks of diabetes. By contrast, inflammation and AGE accumulation associated with diabetes was not prevented. However, treatment with alagebrium in diabetic RAGE apoE KO mice reduced renal AGE levels and further reduced glomerular matrix accumulation. In addition, even in the absence of RAGE expression, alagebrium attenuated cortical inflammation, as denoted by the reduced expression of monocyte chemoattractant protein-1, intracellular adhesion molecule-1, and the macrophage marker cluster of differentiation molecule 11b. These novel findings confirm the presence of important RAGE-independent as well as RAGE-dependent signaling pathways that may be activated in the kidney by AGEs. This has important implications for the design of optimal therapeutic strategies for the prevention of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Deficiency of ACE2 (angiotensin-converting enzyme 2), which degrades Ang (angiotensin) II, promotes the development of glomerular lesions. However, the mechanisms explaining why the reduction in ACE2 is associated with the development of glomerular lesions have still to be fully clarified. We hypothesized that ACE2 may regulate the renoprotective actions of ANP (atrial natriuretic peptide). The aim of the present study was to investigate the effect of ACE2 deficiency on the renal production of ANP. We evaluated molecular and structural abnormalities, as well as the expression of ANP in the kidneys of ACE2-deficient mice and C57BL/6 mice. We also exposed renal tubular cells to AngII and Ang-(1-7) in the presence and absence of inhibitors and agonists of RAS (renin-angiotensin system) signalling. ACE2 deficiency resulted in increased oxidative stress, as well as pro-inflammatory and profibrotic changes. This was associated with a down-regulation of the gene and protein expression on the renal production of ANP. Consistent with a role for the ACE2 pathway in modulating ANP, exposing cells to either Ang-(1-7) or ACE2 or the Mas receptor agonist up-regulated ANP gene expression. This work demonstrates that ACE2 regulates renal ANP via the generation of Ang-(1-7). This is a new mechanism whereby ACE2 counterbalances the renal effects of AngII and which explains why targeting ACE2 may be a promising strategy against kidney diseases, including diabetic nephropathy. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Diabetic nephropathy is associated with dedifferentiation of podocytes, losing the specialized features required for efficient glomerular function and acquiring a number of profibrotic, proinflammatory, and proliferative features. These result from tight junction and cytoskeletal rearrangement, augmented proliferation, and apoptosis. RESEARCH DESIGN AND METHODS--Experiments were performed in conditionally immortalized human podocytes developed by transfection with the temperature-sensitive SV40-T gene. Cells were then cultured in the presence of transforming growth factor (TGF)-β1 or angiotensin II in the presence or absence of a selective inhibitor of the TGF-β type I receptor kinase, SB-431542. Gene and protein expression were then examined by real-time RT-PCR and immunofluorescence, and correlated with changes observed in vivo in experimental diabetes. RESULTS--Treatment of cells with TGF-β resulted in dynamic changes in their morphology, starting with retraction and shortening of foot processes and finishing with the formation of broad and complex tight junctions between adjacent podocytes. This dedifferentiation was also associated with dose- and time-dependent reduction in the expression of glomerular epithelial markers (nephrin, p-cadherin, zonnula occludens-1) and increased expression of mesenchymal markers (α-smooth muscle actin, vimentin, nestin), matrix components (fibronectin, collagen I, and collagen IV α3), cellular proliferation, and apoptosis. The induction of diabetes in mice was also associated with similar changes in morphology, protein expression, and proliferation in glomerular podocytes. CONCLUSIONS--In response to TGF-β and other TGF-dependent stimuli, mature podocytes undergo dedifferentialion that leads to effacement of foot processes, morphologic flattening, and increased formation of intercellular tight junctions. This simplification of their phenotype to a more embryonic form is also associated with reentry of mature podocytes into the cell cycle, which results in enhanced proliferation and apoptosis. These "pathoadaptive" changes are seen early in the diabetic glomerulus and ultimately contribute to albuminutia, glomerulosclerosis, and podocytopenia. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Many guidelines recommend reduced consumption of salt in patients with type 1 diabetes, but it is unclear whether dietary sodium intake is associated with mortality and end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS--In a nationwide multicenter study (the FinnDiane Study) between 1998 and 2002, 2,807 enrolled adults with type 1 diabetes without ESRD were prospectively followed. Baseline urinary sodium excretion was estimated on a 24-h urine collection. The predictors of all-cause mortality and ESRD were determined by Cox regression and competing risk modeling, respectively. RESULTS--The median follow-up for survival analyses was 10 years, during which 217 deaths were recorded (7.7%). Urinary sodium excretion was nonlinearly associated with all-cause mortality, such that individuals with the highest daily urinary sodium excretion, as well as the lowest excretion, had reduced survival. This association was independent age, sex, duration of diabetes, the presence and severity of chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] and log albumin excretion rate), the presence of established cardiovascular disease, and systolic blood pressure. During follow-up, 126 patients developed ESRD (4.5%). Urinary sodium excretion was inversely associated with the cumulative incidence of ESRD, such that individuals with the lowest sodium excretion had the highest cumulative incidence of ESRD. CONCLUSIONS--In patients with type 1 diabetes, sodium was independently associated with all-cause mortality and ESRD. Although we have not demonstrated causality, these findings support the calls for caution before applying salt restriction universally. Clinical trials must be performed in diabetic patients to formally test the utility/risk of sodium restriction in this setting. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Many guidelines recommend that patients with type 2 diabetes should aim to reduce their intake of salt. However, the precise relationship between dietary salt intake and mortality in patients with type 2 diabetes has not been previously explored. RESEARCH DESIGN AND METHODS--Six hundred and thirty-eight patients attending a single diabetes clinic were followed in a prospective cohort study. Baseline sodium excretion was estimated from 24-h urinary collections (24hUNa). The predictors of all-cause and cardiovascular mortality were determined by Cox regression and competing risk modeling, respectively. RESULTS--The mean baseline 24hUNa was 184 ± 73 mmol/24 h, which remained consistent throughout the follow-up (intraindividual coefficient of variation [CV] 23 ± 11%). Over a median of 9.9 years, there were 175 deaths, 75 (43%) of which were secondary to cardiovascular events. All-cause mortality was inversely associated with 24hUNa, after adjusting for other baseline risk factors (P < 0.001). For every 100 mmol rise in 24hUNa, all-cause mortality was 28% lower (95% CI 6-45%, P = 0.02). After adjusting for the competing risk of noncardiovascular death and other predictors, 24hUNa was also significantly associated with cardiovascular mortality (sub-hazard ratio 0.65 [95% CI 0.44-0.95]: P = 0.03). CONCLUSIONS--In patients with type 2 diabetes, lower 24-h urinary, sodium excretion was paradoxically associated with increased all-cause and cardiovascular mortality. Interventional studies are necessary to determine if dietary salt has a causative role in determining adverse outcomes in patients with type 2 diabetes and the appropriateness of guidelines advocating salt restriction in this setting. [ABSTRACT FROM AUTHOR]

OBJECTIVES--This study aimed to identify clinical features associated with premature mortality in a large contemporary cohort of adults with type 1 diabetes. RESEARCH DESIGN AND METHODS--The Finnish Diabetic Nephropathy (FinnDiane) study is a national multicenter prospective follow-up study of 4,201 adults with type I diabetes from 21 university and central hospitals, 33 district hospitals, and 26 primary health care centers across Finland. RESULTS--During a median 7 years of follow-up, there were 291 deaths (7%), 3.6-fold (95% CI 3.2-4.0) more than that observed in the age- and sex-matched general population. Excess mortality was only observed in individuals with chronic kidney disease. Individuals with normoalbuminuria showed no excess mortality beyond the general population (standardized mortality ratio [SMR] 0.8, 95% CI 0.5-1.1), independent of the duration of diabetes. The presence of microalbuminuria, macroaibuminuria, and end-stage kidney disease was associated with 2.8, 9.2, and 18.3 times higher SMR, respectively. The increase in mortality across each stage of albuminuria was equivalent to the risk conferred by preexisting macrovascular disease. In addition, the glomerular filtration rate was independently associated with mortality, such that individuals with impaired kidney function, as well as those demonstrating hyperfiltration, had an increased risk of death. CONCLUSIONS--An independent graded association was observed between the presence and severity of kidney disease and mortality in a large contemporary cohort of individuals with type 1 diabetes. These findings highlight the clinical and public health importance of chronic kidney disease and its prevention in the management of type 1 diabetes. Diabetes 58:1651-1658, 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE--The degradation of angiotensin (Ang) II by ACE2, leading to the formation of Ang 1-7, is an important step in the renin-angiotensin system (RAS) and one that is significantly altered in the diabetic kidney. This study examines the role of ACE2 in early renal changes associated with diabetes and the influence of ACE2 deficiency on ACE inhibitor-mediated renoprotection. RESEARCH DESIGN AND METHODS--Diabetes was induced by streptozotocin in male c57bl6 mice and ACE2 knockout (KO) mice. After 5 weeks of study, animals were randomized to receive the ACE inhibitor perindopril (2 mg ⋅ kg-1 ⋅ day-1). Wild-type mice were further randomized to receive the selective ACE2 inhibitor MLN-4760 (10 mg ⋅ kg-1 ⋅ day-1) and followed for an additional 5 weeks. Markers of renal function and injury were then assessed. RESULTS--Induction of diabetes in wild-type mice was associated with a reduction in renal ACE2 expression and decreased Ang 1-7. In diabetic mice receiving MLN-4760 and in ACE2 KO mice, diabetes-associated albuminuria was enhanced, associated with an increase in blood pressure. However, renal hypertrophy and fibrogenesis were reduced in diabetic mice with ACE2 deficiency, and hyperfiltration was attenuated. Diabetic wild-type mice treated with an ACE inhibitor experienced a reduction in albuminuria and blood pressure. These responses were attenuated in both diabetic ACE2 KO mice and diabetic mice receiving MLN-4760. However, other renoprotective and antifibrotic actions of ACE inhibition in diabetes were preserved in ACE2-deficient mice. CONCLUSIONS--The expression of ACE2 is significantly modified by diabetes, which impacts both pathogenesis of kidney disease and responsiveness to RAS blockade. These data indicate that ACE2 is a complex and site-specific modulator of diabetic kidney disease. Diabetes 57: 1018-1025, 2008 [ABSTRACT FROM AUTHOR]

Advanced glycation end-products (AGEs) contribute to the development and progression of diabetic kidney disease. Several different strategies have been developed to prevent the accumulation of AGEs in experimental diabetes, many of which have proved highly effective in attenuating renal damage in experimental models, even the absence of blood glucose control. These data suggests that if AGEs can be directly treated, some of the complications of diabetes may also be prevented. [Copyright &y& Elsevier]

Background: Indigenous Australians have high rates of diabetes and its complications. This study examines ethnic differences in the management of patients with type 2 diabetes in Australian primary care. Methods: Diabetes management and outcomes in Indigenous patients enrolled in the NEFRON study (n = 144) was systematically compared with that in non-Indigenous patients presenting consecutively to the same practitioner (n = 449), and the NEFRON cohort as a whole (n = 3893). Results: Indigenous Australians with diabetes had high rates of micro- and macrovascular disease. 60% of Indigenous patients had an abnormal albumin to creatinine ratio compared to 33% of non-Indigenous patients (p < 0.01). When compared to non-Indigenous patients, Indigenous patients were more likely to have established macrovascular disease ((adjusted Odds ratio 2.7). This excess in complications was associated with poor glycemic control, with an HbA1c ≥ 8.0%, observed in 55% of all Indigenous patients, despite the similar frequency use of oral antidiabetic agents and insulin. Smoking was also more common in Indigenous patients (38%vs 10%, p < 0.01). However, the achievement of LDL and blood pressure targets was the same or better in Indigenous patients. Conclusion: Although seeing the same doctors and receiving the same medications, glycaemic and smoking cessation targets remain unfulfilled in Indigenous patients. This cross-sectional study confirms Aboriginal ethnicity as a powerful risk factor for microvascular and macrovascular disease, which practitioners should use to identify candidates for intensive multifactorial intervention. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background. Advanced glycation end products (AGEs) accumulate in patients with diabetes, particularly at sites of vascular damage and within atherosclerotic lesions, but whether they have direct actions on vascular smooth muscle cells (VSMCs) is controversial. Methods. AGEs were constructed and characterized by protein content, level of modification, fluorescence, and molecular size. Human VSMCs were derived from different vascular beds. Glucose consumption, de novo protein synthesis, and proteoglycan biosynthesis were measured using a colorimetric assay and metabolic radiolabeling. Receptor for AGEs (RAGE) expression was assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Results. Treatment with AGEs under low or high glucose conditions showed no change in cellular glucose consumption or in cellular protein synthesis under low glucose conditions. Treatment of VSMCs with Nε-(carboxymethyl)lysine in the presence of low glucose increased [35S]-sulfate incorporation into secreted proteoglycans by 72% ( P < 0.001) and 67% ( P < 0.001); however, the control proteins also increased [35S]-sulfate incorporation into proteoglycans by 56% ( P < 0.01), with similar effects observed under high glucose conditions. Human VSMCs showed no difference in response to glycated and non-glycated protein. Protein and gene expression of RAGE in VSMC was approximately 50-fold lower compared to HMEC-1 and U937 cells, consistent with the immunohistochemical staining of RAGE in vivo. Conclusion. VSMCs show very low levels of RAGE expression; thus, activation of VSMCs by AGEs does not occur. In diabetes, RAGE expression in VSM may increase to the extent that it becomes activated by AGEs in a manner that would contribute to the process of atherosclerosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE-- The aim of this study was to estimate the prevalence of the metabolic syndrome in Finnish type 1 diabetic patients and to assess whether it is associated with diabetic nephropathy or poor glycemic control. RESEARCH DESIGN AND METHODS -- In all, 2,415 type 1 diabetic patients (51% men, mean age 37 years, duration of diabetes 22 years) participating in the nationwide, multi-center Finnish Diabetic Nephropathy (FinnDiane) study were included. Metabolic syndrome was defined according to the National Cholesterol Education Program diagnostic criteria. Patients were classified as having normal albumin excretion rate (AER) (n = 1,261), microalbuminuria (n = 326), macroalbuminuria (n = 383), or end-stage renal disease (ESRD) (n = 164). Glycemic control was classified as good (HbA[sub 1c], <7.5%), intermediate (7.5-9.0%), or poor (>9.0%). Creatinine clearance was estimated with the Cockcroft-Gault formula. RESULTS -- The overall prevalence of metabolic syndrome was 38% in men and 40% in women. The prevalence was 28% in those with normal AER, 44% in microalbuminuric patients, 62% in macroalbuminuric patients, and 68% in patients with ESRD (P < 0.001). Patients with metabolic syndrome had a 3.75-fold odds ratio for diabetic nephropathy (95% CI 2.89-4.85), and all of the separate components of the syndrome were independently associated with diabetic nephropathy. The prevalence of metabolic syndrome was 31% in patients with good glycemic control, 36% in patients with intermediate glycemic control, and 51% in patients with poor glycemic control (P < 0.001). Similarly, metabolic syndrome increased with worsening creatinine clearance. CONCLUSIONS -- The metabolic syndrome is a frequent finding in type 1 diabetes and increases with advanced diabetic nephropathy and worse glycemic control. [ABSTRACT FROM AUTHOR]

Increased tubular organic ion clearance following chronic ACE inhibition in patients with type 1 diabetes.Background.The tubular excretion of creatinine significantly contributes to its clearance. Administration of an angtiotensin-converting enzyme (ACE) inhibitor is associated with increased organic ion clearance in experimental diabetes. This study examines the effect and implications of chronic ACE inhibition on renal organic ion excretion in patients with type 1 diabetes.Methods.Samples were obtained from the Melbourne Diabetic Nephropathy Study Group (MDNSG) that randomized patients to receive perindopril (N= 11), nifedipine (N= 11), or placebo (N= 8). Albumin excretion rate, creatinine clearance, and isotopic glomerular filtration rate (GFR) were assessed at baseline and after 24 months. In addition, the clearance of the endogenous cations N-methylynicotinamide (NMN), creatinine, and the anion hippurate were determined by high-performance liquid chromatography (HPLC).Results.Following treatment with the ACE inhibitor, perindopril, renal clearance of NMN was increased (+96%) (P<0.05). There was no difference in patients treated with nifedipine (P= 0.25) and NMN clearance fell in the placebo-treated patients (−26%) (P<0.05). Changes in NMN clearance were unaffected after adjusting for the effects of perindopril on GFR. However, they were attenuated after adjusting for hippurate clearance, a marker of renal blood flow. This effect of perindopril on NMN clearance was seen in both men and women, regardless of baseline clearance and was correlated with reduced albuminuria following perindopril treatment.Conclusion.Organic ion clearance is increased in patients with diabetes following chronic ACE inhibition. This is consistent with experimental models showing increased ion transporter expression and improved tubular blood flow, following blockade of the renin-angiotensin system (RAS). These findings may have implications for the interpretation of creatinine-based indices in patients with diabetes. [ABSTRACT FROM AUTHOR]

Incomplete digestion of advanced glycation end product (AGE)- modified protein results in the formation of low-molecular weight degradation products incorporating AGE modifications (LMW-AGEs). In addition to being biomarkers of AGE modification, LMW-AGEs may have a high toxic potential, being free to interact with AGE receptors at distant sites via the circulation. Several free AGEs have been identified, including pentosidine, Nε--(carboxymethyl) lysine (CML), and free-imidazole AGEs. In addition, fluorescence (370 nm [excitation]/440 nm [emission]) in the LMW phase of serum correlates with tissue fluorescence, an established marker for AGE modification. In experimental diabetes, LMW fluorescence increases with duration of disease and is normalized with the AGE inhibitor aminoguanidine. LMW fluorescence is also higher in patients with diabetes, in whom it is associated with glomerular filtration rate and hemoglobin. Patients with hyperfiltration have lower LMW fluorescence than those with normal renal function, which may protect them from AGE accumulation in the short term. These findings provide clinical support for the association between AGEs and progressive renal injury in diabetes. [ABSTRACT FROM AUTHOR]

Background Diabetes mellitus is associated with an increased prevalence of anemia, particularly in patients with nephropathy. We undertook this survey to determine the relationship between anemia and the renal production of erythropoietin in patients with diabetes mellitus. Methods The clinical data of 722 patients were obtained, including markers of diabetic complications. Erythropoietin levels were measured in the same samples. Patients with a full blood cell count, iron indexes, and renal function within the normal range (n = 151) were used to define the reference range for this population. Anemic patients who had erythropoietin levels within this range were defined as having an “inappropriate erythropoietin response to anemia.” Results Of the 722 patients, 168 (23.3%) had anemia, of whom 130 (77.4%) had erythropoietin levels inappropriately within the normal range. Although 55.4% of anemic patients had moderate renal impairment, erythropoietin levels were also inappropriately low in 69.2% of anemic patients with normal renal function. However, most of these patients (17 of 26) had diabetic kidney disease, as denoted by albuminuria. Conclusions The failure to produce erythropoietin in response to a declining hemoglobin level is a common contributor to anemia in patients with diabetes mellitus. This seems to be a manifestation of diabetic kidney disease, in the presence or absence of renal impairment. [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]

Advanced glycation end product (AGE) formation may contribute to the progression of atherosclerosis, particularly in diabetes. The present study explored atherosclerosis in streptozotocin-induced diabetic apolipoprotein E-deficient (apoE-/-) mice that were randomized (n = 20) to receive for 20 weeks no treatment, the AGE cross-link breaker ALT-711, or the inhibitor of AGE formation aminoguanidine (AG). A sixfold increase in plaque area with diabetes was attenuated by 30% with ALT-711 and by 40% in AG-treated mice. Regional distribution of plaque demonstrated no reduction in plaque area or complexity within the aortic arch with treatment, in contrast to the thoracic and abdominal aortas, where significant attenuation was seen. Diabetes-associated accumulation of AGEs in aortas and plasma and decreases in skin collagen solubility were ameliorated by both treatments, in addition to reductions in the vascular receptor for AGE. Collagen-associated reductions in the AGEs carboxymethyllysine and carboxyethyllysine were identified with both treatments. Diabetes was also accompanied by aortic accumulation of total collagen, specifically collagens I, III, and IV, as well as increases in the profibrotic cytokines transforming growth factor-beta and connective tissue growth factor and in cellular alpha-smooth muscle actin. Attenuation of these changes was seen in both treated diabetic groups. ALT-711 and AG demonstrated the ability to reduce vascular AGE accumulation in addition to attenuating atherosclerosis in these diabetic mice. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) has an important role in the endocrine pancreas. Although angiotensin II has significant effects on cell proliferation and apoptosis, the contribution of the RAS to changes in islet structure and function associated with type 2 diabetes is yet to be defined. This study examined the specific effects of RAS blockade on islet structure and function in diabetes. Thirty-six male Zucker diabetic fatty (ZDF) rats, 10 weeks of age, were randomized to receive the angiotensin-converting enzyme inhibitor perindopril (8 mg/l in drinking water; n = 12), irbesartan (15 mg/kg via gavage; n = 12), or no treatment (n = 12) for 10 weeks. Results were compared with lean littermates (ZL) (n = 12) studied concurrently. ZDF rats had increased intraislet expression of components of the RAS correlating with increased intraislet fibrosis, apoptosis, and oxidative stress. Disordered islet architecture, seen in ZDF rats, was attenuated after treatment with perindopril or irbesartan. Islet fibrogenesis was also diminished, as measured by picrosirins staining and expression of collagens I and IV. Gene expression of transforming growth factor-β1 was increased in the ZDF pancreas (ZL, 1.0 ± 0.1; ZDF, 2.0 ± 0.3; P < 0.05) and reduced after blockade of the RAS (ZDF + P, 1.3 ± 0.2; ZDF + I, 1.5 ± 0.1; vs. ZDF, both P < 0.05). Improvements in structural parameters were also associated with functional improvements in first-phase insulin secretion. These findings provide a possible mechanism for the reduced incidence of new-onset diabetes that has been observed in clinical trials of RAS blockade. [ABSTRACT FROM AUTHOR]

Reduced tubular cation transport in diabetes: Prevented by ACE inhibition. Background. The renal clearance of organic cations is important for the homeostasis of a number of exogenous and endogenous compounds. The organic cation transporters (OCTs) situated on the basolateral surface of proximal tubular cells mediate active cation excretion. Alterations of cation transport may occur in diabetes, although the role of the OCTs has not been previously assessed. Methods. Experimental diabetes was induced in rats with streptozotocin (55 mg/kg) and animals were randomly assigned to receive ramipril (3 mg/mL) in drinking water for 24 weeks. In a second protocol, rats were infused with angiotensin II (Ang II) at a dose of 58.3 ng/kg/min for 2 weeks via an implanted osmotic pump. Expression of the OCTs and renal clearance of the endogenous cation N -methyl-nicotinamide (NMN) was assessed. Results. Diabetes was associated with a reduction in gene and protein expression of both OCT-1 and OCT-2 and a reduction in NMN clearance. These effects were prevented by ramipril, associated with the prevention of albuminuria and tubular injury as demonstrated by the expression of osteopontin and glutathione peroxidase 3 (GPX-3). An infusion of Ang II also reduced NMN clearance but without altering the renal expression of OCTs. Conclusion. We hypothesize that reduced expression of OCTs in diabetes may be a marker of tubular injury. However, Ang II may also directly augment renal cation clearance independent of changes in transporter expression. Together these effects may provide additional mechanism to explain treatment-related improvements in creatinine clearance and renoprotection in diabetes following blockade of the renin-angiotensin system (RAS). [ABSTRACT FROM AUTHOR]

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[sub 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. [ABSTRACT FROM AUTHOR]

Background: Patients with diabetes have an increased risk for allograft rejection, possibly related to peri-operative hyperglycaemia. Hyperglycaemia is also common following transplantation in patients without diabetes. We hypothesise that exposure of allograft tissue to hyperglycaemia could influence the risk for rejection in any patient with high sugars. To investigate the relationship of peri-operative glucose control to acute rejection in renal transplant patients without diabetes, all patients receiving their first cadaveric graft in a single center were surveyed and patients without diabetes receiving cyclosporin-based immunosuppression were reviewed (n = 230). Records of the plasma blood glucose concentration following surgery and transplant variables pertaining to allograft rejection were obtained. All variables suggestive of association were entered into multivariate logistic regression analysis, their significance analysed and modeled. Results: Hyperglycaemia (>8.0 mmol/L) occurs in over 73% of non-diabetic patients following surgery. Glycaemic control immediately following renal transplantation independently predicted acute rejection (Odds ratio=1.08). 42% of patients with a glucose < 8.0 mmol/L following surgery developed rejection compared to 71% of patients who had a serum glucose above this level. Hyperglycaemia was not associated with any delay of graft function. Conclusion: Hyperglycaemia is associated with an increased risk for allograft rejection. This is consistent with similar findings in patients with diabetes. We hypothesise a causal link concordant with epidemiological and in vitro evidence and propose further clinical research. [ABSTRACT FROM AUTHOR]

The article presents an overview of a study describing the frequency of obesity in patients with type 2 diabetes in Australian general practice. The study also examined the identification of obesity by general practitioners. Using classification based on race-specific BMI criteria, patients with type 2 diabetes who were seen in general practice were obese. Abdominal obesity, defined by race-specific waist circumference criteria, was also common.

Investigates the hypothesis that renal injury in diabetes is partly mediated by AGE and that the cross-link breaker ALT-711 as a delayed intervention, once early renal injury is evident. Assessment of the potential molecular mediators of AGE induced renal injury; Field where systolic blood pressure increased; Condition of serum AGE peptide levels in the diabetic group.

The authors discuss research on predictors of end-stage renal disease (ESRD) in patients with type 2 diabetes. They reference the study "Derivation and Validation of a Renal Risk Score for People With Type 2 Diabetes" by C. R. Elley and colleagues published in the journal "Diabetes Care" in 2013. They note the importance of accurate stratification of renal risk for the effective management of patients with type 2 diabetes.

The author reflects on effective screening for chronic kidney disease (CKD). It says that screening for CKD is an essential part of diabetes care which does not end once a patient has been classified as likely or unlikely to develop complications. It states that two key requirements for any type of screening which are that there is an effective intervention available for patients identified as high risk and that early access to this intervention leads to better outcomes.

The article focuses on a study which found that high density lipoproteins (HDL) composition predicts new-onset cardiovascular disease (CVD) in patients with type 1 diabetes. It was revealed that patients with a low ratio of HDL particles containing apolipoprotein (apo) A-I but not apo A-II (lipoprotein [Lp] A-I) to those containing both apo A-I and A-II (Lp A-I:A-II) had a fourfold increased risk of new-onset CVD.

The effects of valsartan on the accumulation of circulating and renal advanced glycation end products in experimental diabetes.Background.Blockade of the RAS with the ACE inhibitor ramipril prevents the accumulation of advanced glycation end products (AGEs) in experimental diabetes. Although AT1 receptor antagonists may inhibit AGE formation in vitro, their effect in normotensive animals with type 1 diabetes has not been established.Methods.Streptozotocin-induced diabetic and control animals were randomized (N= 10/group) to receive the AT1 antagonist valsartan at a dose of 30 mg/kg/day by oral gavage for 24 weeks, or no intervention. Renal and plasma AGE accumulation was correlated with renal functional parameters.Results.Valsartan reduced the albumin excretion rate consistent with its renoprotective effects. Renal and skin collagen accumulation of the non-fluorescent AGE carboxymethyllysine (CML) were increased in animals with diabetes, but normalized following treatment with valsartan. Renal fluorescence and skin collagen pentosidine levels were also increased by diabetes. However, valsartan only provided a modest attenuation of these parameters. In addition, diabetes was associated with increased plasma fluorescence, which was unaffected by AT1 antagonism.Conclusion.Renoprotective doses of valsartan are associated with a significant reduction in the accumulation of tissue and plasma CML. These effects were not the same for all AGEs, suggesting combination approaches will be required to optimize renoprotection in diabetes. [ABSTRACT FROM AUTHOR]

Reports on the estimated number of people worldwide who will have diabetes by the year of 2025, according to the World Health Organization. Percentage of newly diagnosed patients with type 2 diabetes; Development of diabetic nephropathy; Total number of people with type 1 diabetes.

Methylglyoxal (MGO) is a reactive glucose metabolite linked to diabetic cardiovascular disease (CVD). MGO levels surge during intermittent hyperglycemia. We hypothesize that these MGO spikes contribute to atherosclerosis, and that pyridoxamine as a MGO quencher prevents this injury. To study this, we intravenously injected normoglycemic 8-week old male C57Bl6 ApoE-/- mice with normal saline (NS, n = 10) or 25 µg MGO for 10 consecutive weeks (MGO iv , n = 11) with or without 1 g/L pyridoxamine (MGO iv +PD, n = 11) in the drinking water. We measured circulating immune cells by flow cytometry. We quantified aortic arch lesion area in aortic roots after Sudan-black staining. We quantified the expression of inflammatory genes in the aorta by qPCR. Intermittent MGO spikes weekly increased atherosclerotic burden in the arch 1.8-fold (NS: 0.9 ± 0.1 vs 1.6 ± 0.2 %), and this was prevented by pyridoxamine (0.8 ± 0.1 %). MGO iv spikes increased circulating neutrophils and monocytes (2-fold relative to NS) and the expression of ICAM (3-fold), RAGE (5-fold), S100A9 (2-fold) and MCP1 (2-fold). All these changes were attenuated by pyridoxamine. This study suggests that MGO spikes damages the vasculature independently of plasma glucose levels. Pyridoxamine and potentially other approaches to reduce MGO may prevent excess cardiovascular risk in diabetes [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Objective: Recent reports have suggested that dual peroxisome proliferator-activated receptor (PPAR) α/γ agonists are associated with adverse cardiovascular events. This study aimed to investigate the actions of the non-thiazolidinedione PPARα/γ agonist, compound 3q, on plaque development in the apolipoprotein E knockout (apoE KO) mouse, a recognised model of accelerated plaque development. Methods: Six-week-old male apoE KO mice were randomised to receive the dual PPARα/γ agonist, compound 3q (3mg/kg/day), the PPARγ agonist, rosiglitazone (20mg/kg/day), the PPARα agonist, gemfibrozil (100mg/kg/day) by gavage or no treatment for 20 weeks (n =12/group). Results: Gemfibrozil and rosiglitazone significantly reduced lesion area. However, compound 3q was associated with a three-fold increase in total plaque area (versus control p <0.001). This was associated with an upregulation of markers of plaque instability including vascular cell adhesion molecule-1 (3.5-fold, p <0.001), P-selectin (3.4-fold, p <0.001) monocyte chemoattractant protein-1 (3.4-fold; p <0.001) as well as the scavenger receptor, CD36 (2-fold, p <0.01). These disparate effects were observed with the dual PPAR agonist despite lowering LDL cholesterol and improving insulin sensitivity to a similar extent to PPARα and γ agonists used individually. Conclusion: The finding of increased atherogenesis following a dual PPARα/γ agonist is consistent with recent clinical findings. These data provide an important framework for further exploring the potential utility and safety of combinatorial approaches. [Copyright &y& Elsevier]