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Glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimetics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) are glucose-lowering therapies with proven cardiovascular safety, but their effect on microvascular disease is not fully understood. Both therapies increase GLP-1 receptor agonism, which is associated with attenuation of numerous pathological processes that may lead to microvascular benefits, including decreased reactive oxygen species (ROS) production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair. Rodent studies demonstrate several benefits of these agents in the prevention or reversal of nephropathy, retinopathy and neuropathy, but evidence from human populations is less clear. For nephropathy risk in human clinical trials, meta-analyses demonstrate that GLP-1RAs reduce the risk of a composite renal outcome (doubling of serum creatinine, eGFR reduction of 30%, end-stage renal disease or renal death), whereas the benefits of DPP-4is appear to be limited to reductions in the risk of albuminuria. The relationship between GLP-1RAs and retinopathy is less clear. Many large trials and meta-analyses show no effect, but an observed increase in the risk of retinopathy complications with semaglutide therapy (a GLP-1RA) in the SUSTAIN-6 trial warrants caution, particularly in individuals with baseline retinopathy. Similarly, DPP-4is are associated with increased retinopathy risk in both trials and meta-analysis. The association between GLP-1RAs and peripheral neuropathy is unclear due to little trial evidence. For DPP-4is, one trial and several observational studies show a reduced risk of peripheral neuropathy, with others reporting no effect. Evidence in other less-established microvascular outcomes, such as microvascular angina, cerebral small vessel disease, skeletal muscle microvascular disease and autonomic neuropathies (e.g. cardiac autonomic neuropathy, gastroparesis, erectile dysfunction), is sparse. In conclusion, GLP-1RAs are protective against nephropathy, whereas DPP-4is are protective against albuminuria and potentially peripheral neuropathy. Caution is advised with DPP-4is and semaglutide, particularly for patients with background retinopathy, due to increased risk of retinopathy. Well-designed trials powered for microvascular outcomes are needed to clarify associations of incretin therapies and microvascular diseases. [ABSTRACT FROM AUTHOR]

Diabetes is associated with excess morbidity and mortality due to both micro- and macrovascular complications, as well as a range of non-classical comorbidities. Diabetes-associated microvascular complications are those considered most closely related to hyperglycaemia in a causal manner. However, some individuals with hyperglycaemia (even those with severe hyperglycaemia) do not develop microvascular diseases, which, together with evidence of co-occurrence of microvascular diseases in families, suggests a role for genetics. While genome-wide association studies (GWASs) produced firm evidence of multiple genetic variants underlying differential susceptibility to type 1 and type 2 diabetes, genetic determinants of microvascular complications are mostly suggestive. Identified susceptibility variants of diabetic kidney disease (DKD) in type 2 diabetes mirror variants underlying chronic kidney disease (CKD) in individuals without diabetes. As for retinopathy and neuropathy, reported risk variants currently lack large-scale replication. The reported associations between type 2 diabetes risk variants and microvascular complications may be explained by hyperglycaemia. More extensive phenotyping, along with adjustments for unmeasured confounding, including both early (fetal) and late-life (hyperglycaemia, hypertension, etc.) environmental factors, are urgently needed to understand the genetics of microvascular complications. Finally, genetic variants associated with reduced glycolysis, mitochondrial dysfunction and DNA damage and sustained cell regeneration may protect against microvascular complications, illustrating the utility of studies in individuals who have escaped these complications. [ABSTRACT FROM AUTHOR]

Award programmes that acknowledge the remarkable accomplishments of long-term survivors with type 1 diabetes have naturally evolved into research programmes to determine the factors associated with survivorship and resistance to chronic complications. In this review, we present an overview of the methodological sources of selection bias inherent in survivorship research (selection of those with early-onset diabetes, incidence–prevalence bias and bias from losses to follow-up in cohort studies) and the breadth and depth of literature focusing on this special study population. We focus on the learnings from the study of longstanding type 1 diabetes on discoveries about the natural history of insulin production loss and microvascular complications, and mechanisms associated with them that may in future offer therapeutic targets. We detail descriptive findings about the prevalence of preserved insulin production and resistance to complications, and the putative mechanisms associated with such resistance. To date, findings imply that the following mechanisms exist: strategies to maintain or recover beta cells and their function; activation of specific glycolytic enzymes such as pyruvate kinase M2; modification of AGE production and processing; novel mechanisms for modification of renin–angiotensin–aldosterone system activation, in particular those that may normalise afferent rather than efferent renal arteriolar resistance; and activation and modification of processes such as retinol binding and DNA damage checkpoint proteins. Among the many clinical and public health insights, research into this special study population has identified putative mechanisms that may in future serve as therapeutic targets, knowledge that likely could not have been gained without studying long-term survivors. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Studies suggest decreased mortality risk among people who are overweight or obese compared with individuals with normal weight in type 2 diabetes (obesity paradox). However, the relationship between body weight or weight change and microvascular vs macrovascular complications of type 2 diabetes remains unresolved. We investigated the association between BMI and BMI change with long-term risk of microvascular and macrovascular complications in type 2 diabetes in a prospective cohort study. Methods: We studied participants with incident type 2 diabetes from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, who were free of cancer, cardiovascular disease and microvascular disease at diagnosis (n = 1083). Pre-diagnosis BMI and relative annual change between pre- and post-diagnosis BMI were evaluated in multivariable-adjusted Cox models. Results: There were 85 macrovascular (myocardial infarction and stroke) and 347 microvascular events (kidney disease, neuropathy and retinopathy) over a median follow-up of 10.8 years. Median pre-diagnosis BMI was 29.9 kg/m2 (IQR 27.4–33.2), and the median relative annual BMI change was −0.4% (IQR −2.1 to 0.9). Higher pre-diagnosis BMI was positively associated with total microvascular complications (multivariable-adjusted HR per 5 kg/m2 [95% CI]: 1.21 [1.07, 1.36], kidney disease 1.39 [1.21, 1.60] and neuropathy 1.12 [0.96, 1.31]) but not with macrovascular complications (HR 1.05 [95% CI 0.81, 1.36]). Analyses according to BMI categories corroborated these findings. Effect modification was not evident by sex, smoking status or age groups. In analyses according to BMI change categories, BMI loss of more than 1% indicated a decreased risk of total microvascular complications (HR 0.62 [95% CI 0.47, 0.80]), kidney disease (HR 0.57 [95% CI 0.40, 0.81]) and neuropathy (HR 0.73 [95% CI 0.52, 1.03]), compared with participants with a stable BMI; no clear association was observed for macrovascular complications (HR 1.04 [95% CI 0.62, 1.74]). The associations between BMI gain compared with stable BMI and diabetes-related vascular complications were less apparent. Associations were consistent across strata of sex, age, pre-diagnosis BMI or medication but appeared to be stronger among never-smokers compared with current or former smokers. Conclusions/interpretation: Among people with incident type 2 diabetes, pre-diagnosis BMI was positively associated with microvascular complications, while a reduced risk was observed with weight loss when compared with stable weight. The relationships with macrovascular disease were less clear. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Microvascular disease in type 2 diabetes is a significant cause of end-stage renal disease, blindness and peripheral neuropathy. The strict control of known risk factors, e.g. lifestyle, hyperglycaemia, hypertension and dyslipidaemia, reduces the incidence of microvascular complications, but a residual risk remains. Lipoprotein (a) [Lp(a)] is a strong risk factor for macrovascular disease in the general population. We hypothesised that plasma Lp(a) levels and the LPA gene SNPs rs10455872 and rs3798220 are associated with the incident development of microvascular complications in type 2 diabetes. Methods: Analyses were performed of data from the DiaGene study, a prospective study for complications of type 2 diabetes, collected in the city of Eindhoven, the Netherlands (n = 1886 individuals with type 2 diabetes, mean follow-up time = 6.97 years). To assess the relationship between plasma Lp(a) levels and the LPA SNPs with each newly developed microvascular complication (retinopathy n = 223, nephropathy n = 246, neuropathy n = 236), Cox proportional hazards models were applied and adjusted for risk factors for microvascular complications (age, sex, mean arterial pressure, non-HDL-cholesterol, HDL-cholesterol, BMI, duration of type 2 diabetes, HbA1c and smoking). Results: No significant associations of Lp(a) plasma levels and the LPA SNPs rs10455872 and rs3798220 with prevalent or incident microvascular complications in type 2 diabetes were found. In line with previous observations the LPA SNPs rs10455872 and rs3798220 did influence the plasma Lp(a) levels. Conclusions/interpretation: Our data show no association between Lp(a) plasma levels and the LPA SNPs with known effect on Lp(a) plasma levels with the development of microvascular complications in type 2 diabetes. This indicates that Lp(a) does not play a major role in the development of microvascular complications. However, larger studies are needed to exclude minimal effects of Lp(a) on the development of microvascular complications. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We examined whether candidate biomarkers in serum or urine can improve the prediction of renal disease progression in type 1 diabetes beyond prior eGFR, comparing their performance with urinary albumin/creatinine ratio (ACR). Methods: From the population-representative Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) we sampled 50% and 25% of those with starting eGFR below and above 75 ml min−1 [1.73 m]−2, respectively (N = 1629), and with median 5.1 years of follow-up. Multiplexed ELISAs and single molecule array technology were used to measure nine serum biomarkers and 13 urine biomarkers based on our and others' prior work using large discovery and candidate studies. Associations with final eGFR and with progression to <30 ml min−1 [1.73] m−2, both adjusted for baseline eGFR, were tested using linear and logistic regression models. Parsimonious biomarker panels were identified using a penalised Bayesian approach, and their performance was evaluated through tenfold cross-validation and compared with using urinary ACR and other clinical record data. Results: Seven serum and seven urine biomarkers were strongly associated with either final eGFR or progression to <30 ml min−1 [1.73 m]−2, adjusting for baseline eGFR and other covariates (all at p<2.3 × 10−3). Of these, associations of four serum biomarkers were independent of ACR for both outcomes. The strongest associations with both final eGFR and progression to <30 ml min−1 [1.73 m]−2 were for serum TNF receptor 1, kidney injury molecule 1, CD27 antigen, α-1-microglobulin and syndecan-1. These serum associations were also significant in normoalbuminuric participants for both outcomes. On top of baseline covariates, the r2 for prediction of final eGFR increased from 0.702 to 0.743 for serum biomarkers, and from 0.702 to 0.721 for ACR alone. The area under the receiver operating characteristic curve for progression to <30 ml min−1 [1.73 m]−2 increased from 0.876 to 0.953 for serum biomarkers, and to 0.911 for ACR alone. Other urinary biomarkers did not outperform ACR. Conclusions/interpretation: A parsimonious panel of serum biomarkers easily measurable along with serum creatinine may outperform ACR for predicting renal disease progression in type 1 diabetes, potentially obviating the need for urine testing. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to provide data from a contemporary population-representative cohort on rates and predictors of renal decline in type 1 diabetes. Methods: We used data from a cohort of 5777 people with type 1 diabetes aged 16 and older, diagnosed before the age of 50, and representative of the adult population with type 1 diabetes in Scotland (Scottish Diabetes Research Network Type 1 Bioresource; SDRNT1BIO). We measured serum creatinine and urinary albumin/creatinine ratio (ACR) at recruitment and linked the data to the national electronic healthcare records. Results: Median age was 44.1 years and diabetes duration 20.9 years. The prevalence of CKD stages G1, G2, G3 and G4 and end-stage renal disease (ESRD) was 64.0%, 29.3%, 5.4%, 0.6%, 0.7%, respectively. Micro/macroalbuminuria prevalence was 8.6% and 3.0%, respectively. The incidence rate of ESRD was 2.5 (95% CI 1.9, 3.2) per 1000 person-years. The majority (59%) of those with chronic kidney disease stages G3–G5 did not have albuminuria on the day of recruitment or previously. Over 11.6 years of observation, the median annual decline in eGFR was modest at −1.3 ml min−1 [1.73 m]−2 year−1 (interquartile range [IQR]: −2.2, −0.4). However, 14% experienced a more significant loss of at least 3 ml min−1 [1.73 m]−2. These decliners had more cardiovascular disease (OR 1.9, p = 5 × 10−5) and retinopathy (OR 1.3 p = 0.02). Adding HbA1c, prior cardiovascular disease, recent mean eGFR and prior trajectory of eGFR to a model with age, sex, diabetes duration, current eGFR and ACR maximised the prediction of final eGFR (r2 increment from 0.698 to 0.745, p < 10−16). Attempting to model nonlinearity in eGFR decline or to detect latent classes of decliners did not improve prediction. Conclusions: These data show much lower levels of kidney disease than historical estimates. However, early identification of those destined to experience significant decline in eGFR remains challenging. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We aimed to identify a sparse panel of biomarkers for improving the prediction of renal disease progression in type 1 diabetes. Methods: We considered 859 individuals recruited from the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) and 315 individuals from the Finnish Diabetic Nephropathy (FinnDiane) study. All had an entry eGFR between 30 and 75 ml min−1[1.73 m]−2, with those from FinnDiane being oversampled for albuminuria. A total of 297 circulating biomarkers (30 proteins, 121 metabolites, 146 tryptic peptides) were measured in non-fasting serum samples using the Luminex platform and LC electrospray tandem MS (LC-MS/MS). We investigated associations with final eGFR adjusted for baseline eGFR and with rapid progression (a loss of more than 3 ml min−1[1.73 m]−2 year−1) using linear and logistic regression models. Panels of biomarkers were identified using a penalised Bayesian approach, and their performance was evaluated through 10-fold cross-validation and compared with using clinical record data alone. Results: For final eGFR, 16 proteins and 30 metabolites or tryptic peptides showed significant association in SDRNT1BIO, and nine proteins and five metabolites or tryptic peptides in FinnDiane, beyond age, sex, diabetes duration, study day eGFR and length of follow-up (all at p < 10−4). The strongest associations were with CD27 antigen (CD27), kidney injury molecule 1 (KIM-1) and α1-microglobulin. Including the Luminex biomarkers on top of baseline covariates increased the r2 for prediction of final eGFR from 0.47 to 0.58 in SDRNT1BIO and from 0.33 to 0.48 in FinnDiane. At least 75% of the increment in r2 was attributable to CD27 and KIM-1. However, using the weighted average of historical eGFR gave similar performance to biomarkers. The LC-MS/MS platform performed less well. Conclusions/interpretation: Among a large set of associated biomarkers, a sparse panel of just CD27 and KIM-1 contains most of the predictive information for eGFR progression. The increment in prediction beyond clinical data was modest but potentially useful for oversampling individuals with rapid disease progression into clinical trials, especially where there is little information on prior eGFR trajectories. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: As part of the Surrogate Markers for Micro- and Macrovascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) programme we previously reported that large panels of biomarkers derived from three analytical platforms maximised prediction of progression of renal decline in type 2 diabetes. Here, we hypothesised that smaller (n ≤ 5), platform-specific combinations of biomarkers selected from these larger panels might achieve similar prediction performance when tested in three additional type 2 diabetes cohorts.Methods: We used 657 serum samples, held under differing storage conditions, from the Scania Diabetes Registry (SDR) and Genetics of Diabetes Audit and Research Tayside (GoDARTS), and a further 183 nested case-control sample set from the Collaborative Atorvastatin in Diabetes Study (CARDS). We analysed 42 biomarkers measured on the SDR and GoDARTS samples by a variety of methods including standard ELISA, multiplexed ELISA (Luminex) and mass spectrometry. The subset of 21 Luminex biomarkers was also measured on the CARDS samples. We used the event definition of loss of >20% of baseline eGFR during follow-up from a baseline eGFR of 30-75 ml min−1 [1.73 m]−2. A total of 403 individuals experienced an event during a median follow-up of 7 years. We used discrete-time logistic regression models with tenfold cross-validation to assess association of biomarker panels with loss of kidney function.Results: Twelve biomarkers showed significant association with eGFR decline adjusted for covariates in one or more of the sample sets when evaluated singly. Kidney injury molecule 1 (KIM-1) and β2-microglobulin (B2M) showed the most consistent effects, with standardised odds ratios for progression of at least 1.4 (p < 0.0003) in all cohorts. A combination of B2M and KIM-1 added to clinical covariates, including baseline eGFR and albuminuria, modestly improved prediction, increasing the area under the curve in the SDR, Go-DARTS and CARDS by 0.079, 0.073 and 0.239, respectively. Neither the inclusion of additional Luminex biomarkers on top of B2M and KIM-1 nor a sparse mass spectrometry panel, nor the larger multiplatform panels previously identified, consistently improved prediction further across all validation sets.Conclusions/interpretation: Serum KIM-1 and B2M independently improve prediction of renal decline from an eGFR of 30-75 ml min−1 [1.73 m]−2 in type 2 diabetes beyond clinical factors and prior eGFR and are robust to varying sample storage conditions. Larger panels of biomarkers did not improve prediction beyond these two biomarkers. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Elevated circulating adipocyte fatty acid-binding protein (AFABP) levels have been found to correlate with diabetic nephropathy staging in cross-sectional studies. However, it remains unclear whether these higher serum levels reflect a role of AFABP in the development of diabetic kidney disease (DKD), or simply result from its impaired renal clearance in DKD. Here we investigated prospectively the prognostic importance of serum AFABP level in the development of adverse renal outcomes in a large clinic-based cohort of participants with type 2 diabetes.Methods: Baseline serum AFABP levels were measured in 5454 Chinese participants from the Hong Kong West Diabetes Registry. The association between circulating AFABP levels and incident adverse renal outcomes—defined as a composite endpoint of a sustained 40% decline in eGFR, end-stage renal disease requiring renal replacement therapy or kidney transplantation, or renal deaths—was evaluated using multivariable Cox regression analysis.Results: Over a median follow-up of 5 years, 754 of the 5454 participants developed incident adverse renal outcomes. Elevated circulating AFABP levels were independently associated with incident adverse renal outcomes (HR 1.43, 95% CI 1.31, 1.57, p < 0.001) after adjustments for conventional risk factors for DKD progression. Importantly, the prognostic role of serum AFABP was independent of the baseline albuminuria status or eGFR levels of the study participants.Conclusions/interpretation: Circulating AFABP levels were predictive of incident adverse renal outcomes, even in participants with relatively well-preserved kidney function at baseline, suggesting its potential to be a useful marker for early risk stratification in DKD. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) remains one of the leading causes of reduced lifespan in diabetes. The quest for both prognostic and surrogate endpoint biomarkers for advanced DKD and end-stage renal disease has received major investment and interest in recent years. However, at present no novel biomarkers are in routine use in the clinic or in trials. This review focuses on the current status of prognostic biomarkers. First, we emphasise that albuminuria and eGFR, with other routine clinical data, show at least modest prediction of future renal status if properly used. Indeed, a major limitation of many current biomarker studies is that they do not properly evaluate the marginal increase in prediction on top of these routinely available clinical data. Second, we emphasise that many of the candidate biomarkers for which there are numerous sporadic reports in the literature are tightly correlated with each other. Despite this, few studies have attempted to evaluate a wide range of biomarkers simultaneously to define the most useful among these correlated biomarkers. We also review the potential of high-dimensional panels of lipids, metabolites and proteins to advance the field, and point to some of the analytical and post-analytical challenges of taking initial studies using these and candidate approaches through to actual clinical biomarker use. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We conducted an analysis of data collected during the Veterans Affairs Diabetes Trial (VADT) and the follow-up study (VADT-F) to determine whether intensive (INT) compared with standard (STD) glycaemic control during the VADT resulted in better long-term kidney outcomes. Methods: VADT randomly assigned 1791 veterans from 20 Veterans Affairs (VA) medical centres who had type 2 diabetes mellitus and a mean HbA of 9.4 ± 2% (79.2 mmol/mol) at baseline to receive either INT or STD glucose control for a median of 5.6 years (randomisation December 2000 to May 2003; intervention ending in May 2008). After the trial, participants received routine care through their own physicians within the VA. This is an interim analysis of the VADT-F (June 2008 to December 2013). We collected data using VA and National databases and report renal outcomes based on serum creatinine, eGFR and urine albumin to creatinine ratio (ACR) in 1033 people who provided informed consent to participate in the VADT-F. Results: By the end of the VADT-F, significantly more people who received INT treatment during the VADT maintained an eGFR >60 ml min 1.73 m (OR 1.34 [95% CI 1.05, 1.71], p = 0.02). This benefit was most evident in those who were classified as at moderate risk (INT vs STD, RR 1.3, p = 0.03) or high risk (RR 2.3, p = 0.04) of chronic kidney disease on the Kidney Disease Improving Global Outcomes (KDIGO-CKD) at the beginning of VADT. At the end of VADT-F, significantly more people from the INT group improved to a low KDIGO risk category (RR 6.1, p = 0.002). During the VADT-F there were no significant differences between INT and STD for average HbA, blood pressure or lipid levels. Conclusions/interpretation: After just over 11 years of follow-up, there was a 34% greater odds of maintaining an eGFR of >60 ml min 1.73 m and of improving the KDIGO category in individuals with type 2 diabetes who had received INT for a median of 5.6 years. VADT clinical number: NCT 00032487. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Oxidative stress is a promising target in diabetes-associated vasculopathies, with inhibitors of NADPH oxidases (NOX), in particular isoforms 1 and 4, shown to be safe in early clinical development. We have explored a highly relevant late-stage intervention protocol using the clinically most advanced compound, the NOX1/4 inhibitor GKT137831, to determine whether end-organ damage can be reversed/attenuated when GKT137831 is administered in the setting of established diabetic complications. Methods: GKT137831 was administered at two doses, 30 mg kg day and 60 mg kg day, to ApoE mice 10 weeks after diabetes induction with streptozotocin (STZ), for a period of 10 weeks. Results: Consistent with Nox4 mouse data, GKT137831 was protective in a model of diabetic nephropathy at both the 30 mg kg day and 60 mg kg day doses, through suppression of proinflammatory and profibrotic processes. Conversely, in diabetic atherosclerosis, where Nox1 and Nox4 mice have yielded qualitatively opposing results, the net effect of pharmacological NOX1/4 inhibition was protection, albeit to a lower extent and only at the lower 30 mg kg day dose. Conclusions/interpretation: As dose-dependent and tissue-specific effects of the dual NOX1/4 inhibitor GKT137831 were observed, it is critical to define in further studies the relative balance of inhibiting NOX4 vs NOX1 in the micro- and macrovasculature in diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Baseline circulating fibroblast growth factor 21 (FGF21) levels can predict total cardiovascular disease events in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. This paper describes the relationship of baseline FGF21 levels and new on-study microvascular disease in patients with type 2 diabetes from the FIELD study. Methods: Baseline FGF21 levels were measured in plasma by enzyme-linked immunosorbent assay in 9697 study participants. Total microvascular disease was defined as the presence of any nephropathy, retinopathy, neuropathy and/or microvascular amputation. The relationship between FGF21 levels and microvascular disease was assessed by multivariable logistic regression. Results: Higher baseline FGF21 levels were found in patients with baseline total microvascular disease ( p < 0.001). The association remained significant after adjusting for potential confounding factors (OR [95% CI] 1.13 [1.08, 1.19] per SD increase in log-transformed FGF21 levels, p < 0.001). Of 6465 patients without baseline total microvascular disease, 1517 developed new on-study total microvascular disease over 5 years of follow-up. Higher baseline FGF21 levels were associated with a higher risk of new on-study total microvascular disease after adjusting for potential confounding factors (OR [95% CI] 1.09 [1.02, 1.16] per SD increase in log-transformed FGF21 levels, p = 0.01). Addition of FGF21 levels in a model of new on-study total microvascular disease with established risk factors significantly, but modestly, increased the integrated discrimination improvement and the net reclassification improvement (both p < 0.01). Conclusions/interpretation: Higher baseline FGF21 levels are seen in patients with type 2 diabetes and established microvascular disease, and predict the future development of new microvascular disease. [ABSTRACT FROM AUTHOR]

The advent of insulin treatment in 1923 meant fewer diabetes deaths from acute metabolic deterioration and sepsis and a progressive increase in the burden of disease caused by end-organ damage. These diabetic complications are the major cause of morbidity and premature mortality among diabetic subjects. Over the last 50 years it has become apparent that diabetic complications in disparate tissues may result from a combination of common pathological processes. Pathways activated by initial metabolic insults are promoted by co-factors such as renin-angiotensin-aldosterone system activation, hyperinsulinaemia, underlying genetic susceptibility, and traditional vascular risk factors, particularly hypertension and lipids. These common pathways include AGE formation, reactive oxygen species overproduction, protein kinase C activation, mitochondrial dysfunction and activation of proinflammatory and profibrotic signalling cascades. Once established, these interlinked pathways become self-perpetuating. Many drugs acting against individual downstream targets in these pathways have failed due to lack of efficacy or adverse effects. Gains in the future may be made by better control of existing risk factors, more sophisticated modulation of tissue glucose and insulin signalling, and interventions to improve mitochondrial function and reduce oxidative stress. Epigenetic and microRNA research may lead to methods to disrupt the mechanisms whereby pathological pathways are perpetuated. Expansion in capacity and expertise in biomarker measurement and analysis may allow better targeting of therapies to patients who are most likely to benefit. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015). [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We aimed to examine the effects of bariatric surgery on microvascular complications in patients with type 2 diabetes using objective measures. Methods: Prospective case-control study of 70 obese surgical patients with type 2 diabetes undergoing gastric bypass surgery matched for age, sex and duration of diabetes to 25 medical patients treated using international guidelines. Microvascular complications were assessed before and 12-18 months after intervention using urine albumin creatinine ratio (ACR) measurements, two-field digital retinal images and peripheral nerve conduction studies (in the surgical group only). Results: Urine ACR decreased significantly in the surgical group but increased in the medical group. There were no significant differences between the surgical and medical groups in the changes in retinopathy. There were no changes in the nerve conduction variables in the surgical group. Conclusions/interpretation: In the short term, bariatric surgery may be superior to medical care in the treatment of diabetic nephropathy, but not retinopathy or neuropathy. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The canonical nuclear factor-κB (NF-κB) pathway mediated by the inhibitor of NF-κB kinase (IKK) regulates the transcription of inflammatory genes involved in the pathogenesis of diabetes, from the early phase to progression and final complications. The NF-κB essential modulator binding domain (NBD) contained in IKKα/β is essential for IKK complex assembly. We therefore investigated the functional consequences of targeting the IKK-dependent NF-κB pathway in the progression of diabetes-associated nephropathy and atherosclerosis. Methods: Apolipoprotein E-deficient mice with diabetes induced by streptozotocin were treated with a cell-permeable peptide derived from the IKKα/β NBD region. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-κB activity and gene expression. In vitro studies were performed in renal and vascular cells. Results: NBD peptide administration did not affect the metabolic severity of diabetes but resulted in renal protection, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leucocyte infiltration and fibrosis), intranuclear NF-κB activity and proinflammatory and pro-fibrotic gene expression. Furthermore, peptide treatment limited atheroma plaque formation in diabetic mice by decreasing the content of lipids, leucocytes and cytokines and increasing plaque stability markers. This nephroprotective and anti-atherosclerotic effect was accompanied by a decline in systemic T helper 1 cytokines. In vitro, NBD peptide prevented IKK assembly/activation, p65 nuclear translocation, NF-κB-regulated gene expression and cell proliferation induced by either high glucose or inflammatory stimulation. Conclusions/interpretation: Peptide-based inhibition of IKK complex formation attenuates NF-κB activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to assess how physical activity predicts the development and progression of diabetic nephropathy in patients with type 1 diabetes. Methods: This prospective study (follow-up time 6.4 ± 3.1 years) included 1,390 patients (48.5% men, mean age 37.0 ± 12.4 years, duration of diabetes 20.4 ± 12.3 years) participating in the nationwide multicentre Finnish Diabetic Nephropathy (FinnDiane) Study. Leisure-time physical activity (LTPA) was assessed using a validated self-report questionnaire. Renal status was defined according to standard clinical cut-off values for urinary AER. Results: The total amount of LTPA was not associated with progression in renal status. For the intensity of LTPA, however, the 10 year cumulative progression rate was 24.0% (95% CI 18.8, 28.8), 13.5% (95% CI 10.3, 16.6) or 13.1% (95% CI 10.3%, 16.6%; p = 0.01) of the patients with low, moderate or high intensity LTPA. This pattern was similar to that for the development of de novo microalbuminuria. Corresponding progression rates for LTPA frequency of <1, 1-2 or >2 sessions/week was 24.7% (95% CI 18.3, 30.7), 14.7% (95% CI 10.2, 19.0) or 12.6% (95% CI 9.4, 15.7), respectively ( p = 0.003). Conclusions/interpretation: This study demonstrates for the first time in a prospective setting the relationship between physical activity and the risk of diabetic nephropathy in patients with type 1 diabetes. The data suggest that physical activity, and in particular its intensity, may have an impact on the initiation and progression of diabetic nephropathy in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this study was to estimate absolute and relative mortality rates in patients with type 1 diabetes at the Steno Diabetes Centre relative to the general Danish background population. Methods: Patients with type 1 diabetes ( n = 4,821) were followed from 1 January 2002 until 1 January 2011, with death from any cause as the main outcome. Poisson regression was used to model mortality rates by age, diabetes duration and calendar time, according to sex. Results: In the period 2002-2010, a total of 673 deaths (402 men, 271 women) occurred in the study population during 33,847 years of follow-up of type 1 diabetes. The predominant cause of death in patients with type 1 diabetes was cardiovascular disease. Mortality rates were highest among those with the lowest age at onset, particularly men. The mortality rate in the diabetic population decreased over that time period by 6.6% and 4.8% per year in men and women, respectively; this was substantially greater than the decrease in mortality rates in the background population. The decline in standard mortality rate was 4.3% per year in men and 2.6% per year in women. Patients who did not develop nephropathy had only slightly elevated mortality rates compared with the background population. Conclusions/interpretation: Despite advances in care, mortality rates in the past decade continue to be greater in patients with type 1 diabetes than in those without diabetes; however, the mortality rate in patients decreased over the study period faster than that of the background population. Nephropathy seems to be the main driver of the excess mortality. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes. Methods: We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmö Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [ n = 345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [ n = 784]) and non-diabetic (Malmö Preventive Project [ n = 2,523], Botnia study [ n = 2,247]) cohorts. Results: In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p = 0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes ( n = 1,233 cases, n = 2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p = 0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes ( n = 2,499, β ± SEM, −3.7 ± 1.2 ml/min, p = 0.002) and also in non-diabetic individuals ( n = 17,602, β ± SEM, −0.008 ± 0.003 ml/min (log), p = 0.006). Conclusions/interpretation: These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: In early type 1 diabetes mellitus, renal salt handling is dysregulated, so that the glomerular filtration rate becomes inversely proportional to salt intake. The salt paradox occurs in both humans and rats and, with low salt intake, results in diabetic hyperfiltration. We tested whether increased salt intake could reduce the susceptibility to injury of non-clipped kidneys in diabetic rats with pre-existing Goldblatt hypertension. Methods: Male Long-Evans rats were made hypertensive and half were then made diabetic. Blood glucose was maintained at ∼20-25 mmol/l by insulin implants. One half of each received only the salt in normal chow (1% by weight) and the other half received added salt in drinking water to equal 2.7% by weight of food intake. Weekly 24 h blood pressure records were acquired by telemetry during the 4-month experiment. Results: Systolic blood pressure was not affected by diabetes or increased salt intake, alone or together. Autoregulation was highly efficient in the non-clipped kidney of both intact and diabetic rats. Histological examination showed minor injury in the clipped kidney, which did not differ among groups. The non-clipped kidney showed extensive pressure-dependent glomerular and vascular injury in both intact and diabetic rats. Conclusions/interpretation: The relationship between pressure and injury was shifted toward lower blood pressure in diabetic rats, indicating that diabetes increased the susceptibility of the kidney to injury despite preservation of autoregulation. The increased susceptibility was not affected by high salt intake in the diabetic rats, thus disproving the hypothesis. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to quantify the risk of major congenital anomaly, and to assess the influence of peri-conception HbA and other clinical and socio-demographic factors on the risk of congenital anomaly occurrence in offspring of women with type 1 and type 2 diabetes diagnosed before pregnancy. Methods: This was a population-based cohort study using linked data from registers of congenital anomaly and diabetes in pregnancy. A total of 401,149 singleton pregnancies (1,677 in women with diabetes) between 1996 and 2008 resulting in live birth, fetal death at ≥20 weeks' gestation or termination of pregnancy for fetal anomaly were included. Results: The rate of non-chromosomal major congenital anomaly in women with diabetes was 71.6 per 1,000 pregnancies (95% CI 59.6, 84.9), a relative risk of 3.8 (95% CI 3.2, 4.5) compared with women without diabetes. There was a three- to sixfold increased risk across all common anomaly groups. In a multivariate analysis, peri-conception glycaemic control (adjusted OR [aOR] 1.3 [95% CI 1.2, 1.4] per 1% [11 mmol/mol] linear increase in HbA above 6.3% [45 mmol/mol]) and pre-existing nephropathy (aOR 2.5 [95% CI 1.1, 5.3]) were significant independent predictors of congenital anomaly. Associations with gestation at booking (aOR 1.1 [95% CI 1.0, 1.1]) and parity (aOR 1.6 [95% CI 1.0, 2. 5]) were not significant. Unadjusted risk was higher for women from deprived areas or who did not take folate. Type and duration of diabetes, ethnicity, age, BMI, preconception care, smoking and fetal sex were not associated with congenital anomaly risk. Conclusions: Peri-conception glycaemia is the most important modifiable risk factor for congenital anomaly in women with diabetes. The association with nephropathy merits further study. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Red blood cell distribution width (RDW) has been reported to be a risk marker of morbidity and mortality for cardiovascular disease in various study populations. However, no studies have investigated the relationship between RDW and diabetes complications. We therefore evaluated RDW as a marker of macrovascular and microvascular complications in a nationally representative sample of the adult diabetes population in the USA. Methods: A cross-sectional study was performed using the nationwide 1988 to 1994 data set from the Third National Health and Nutrition Examination Survey. The association between RDW quartiles and macrovascular and microvascular complications was evaluated in 2,497 non-pregnant adults aged 20 years and older and affected by diabetes. Logistic regression modelling was used to adjust for potential confounding. Results: Compared with the lowest RDW quartile, higher RDW values (3rd and 4th quartiles) were associated with increased adjusted odds of any vascular complication (OR 4th quartile 2.06 [95% CI 1.11, 3.83]), myocardial infarction (OR 4th quartile 2.45 [95% CI 1.13, 5.28]), heart failure (OR 4th quartile 4.40 [95% CI 1.99, 9.72]), stroke (OR 4th quartile 2.56 [95% CI 1.21, 5.42]) and nephropathy (OR 4th quartile 2.33 [95% CI 1.42, 3.82]). The odds of developing diabetic retinopathy were not significantly increased across RDW quartiles. Conclusions/interpretation: Higher RDW values are associated with increased odds of developing cardiovascular disease and nephropathy in a nationally representative sample of USA adults with diabetes. RDW may be an important clinical marker of vascular complications in diabetes and one that is independent of traditional risk factors and disease duration. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The activation of platelet-derived growth factor receptor-β (PDGFR-β) signalling is increased in the glomeruli and tubules of diabetic animals. In this study, we examined the role of PDGFR-β signalling during the development of diabetic nephropathy. Methods: We recently generated pancreatic beta cell-specific Ca/calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice (CaMKIIα mice), which show very high plasma glucose levels up to 55.5 mmol/l and exhibit the features of diabetic nephropathy. These mice were crossed with conditional knockout mice in which Pdgfr-β (also known as Pdgfrb) was deleted postnatally. The effect of the deletion of the Pdgfr-β gene on diabetic nephropathy in CaMKIIα mice was evaluated at 10 and 16 weeks of age. Results: The plasma glucose concentrations and HbA levels were elevated in the CaMKIIα mice from 4 weeks of age. Variables indicative of diabetic nephropathy, such as an increased urinary albumin/creatinine ratio, kidney weight/body weight ratio and mesangial area/glomerular area ratio, were observed at 16 weeks of age. The postnatal deletion of the Pdgfr-β gene significantly decreased the urinary albumin/creatinine ratio and mesangial area/glomerular area ratio without affecting the plasma glucose concentration. Furthermore, the increased oxidative stress in the kidneys of the CaMKIIα mice as shown by the increased urinary 8-hydroxydeoxyguanosine (8-OHdG) excretion and the increased expression of NAD(P)H oxidase 4 (NOX4), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (MnSOD) was decreased by Pdgfr-β gene deletion. Conclusions/interpretation: The activation of PDGFR-β signalling contributes to the progress of diabetic nephropathy, with an increase in oxidative stress and mesangial expansion in CaMKIIα mice. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Chemokines and their receptors such as chemokine (C-C motif) receptor 2 (CCR2) may contribute to the pathogenesis of the metabolic syndrome via their effects on inflammatory monocytes. Increased accumulation of CCR2-driven inflammatory monocytes in epididymal fat pads is thought to favour the development of insulin resistance. Ultimately, the resulting hyperglycaemia and dyslipidaemia contribute to development of the metabolic syndrome complications such as cardiovascular disease and diabetic nephropathy. Our goal was to elucidate the role of CCR2 and inflammatory monocytes in a mouse model that resembles the human metabolic syndrome. Methods: We generated a model of the metabolic syndrome by backcrossing KK Ay with Apoe mice (KK Ay Apoe) and studied the role of CCR2 in this model system. Results: KK Ay Apoe mice were characterised by the presence of obesity, insulin resistance, dyslipidaemia and increased systemic inflammation. This model also manifested two complications of the metabolic syndrome: atherosclerosis and diabetic nephropathy. Inactivation of Ccr2 in KK Ay Apoe mice protected against the metabolic syndrome, as well as atherosclerosis and diabetic nephropathy. This protective phenotype was associated with a reduced number of inflammatory monocytes in the liver and muscle, but not in the epididymal fat pads; circulating levels of adipokines such as leptin, resistin and adiponectin were also not reduced. Interestingly, the proportion of inflammatory monocytes in the liver, pancreas and muscle, but not in the epididymal fat pads, correlated significantly with peripheral glucose levels. Conclusions/interpretation: CCR2-driven inflammatory monocyte accumulation in the liver and muscle may be a critical pathogenic factor in the development of the metabolic syndrome. [ABSTRACT FROM AUTHOR]

ims/hypothesis: A meta-analysis was performed to assess the association of C47T (rs4880) (also called Val16Ala) polymorphism in SOD2 gene with reduced risk of diabetes mellitus, including type 1 and type 2 diabetes, and diabetic microvascular complications (DMI) including diabetic nephropathy, diabetic retinopathy and diabetic polyneuropathy. Methods: A comprehensive search was conducted to identify all case-control or cohort design studies of the above-mentioned associations. The fixed or random effect pooled measure was selected on the basis of homogeneity test among studies. Heterogeneity among studies was evaluated using the I. Meta-regression and the 'leave one out' sensitive analysis of Patsopoulos et al. were used to explore potential sources of between-study heterogeneity. Publication bias was estimated using modified Egger's linear regression test as proposed by Harbord et al. Results: Seventeen articles were included. After excluding articles that deviated from Hardy-Weinberg equilibrium in cases and/or in controls, and were also the key contributors to between-study heterogeneity, the meta-analysis showed a significant association of the C allele with reduced risk of DMI in dominant (OR 0.788, 95% CI 0.680-0.914), recessive (OR 0.808, 95% CI 0.685-0.953) and codominant (OR 0.828, 95% CI 0.751-0.913) models. It also showed a significant association with reduced risk of diabetic nephropathy in the dominant model (OR 0.801, 95% CI 0.664-0.967), and reduced risk of diabetic retinopathy in the dominant (OR 0.601, 95% CI 0.423-0.855), recessive (OR 0.548, 95% CI 0.369-0.814) and codominant (OR 0.651, 95% CI 0.517-0.820) models. Conclusions/interpretation: The meta-analysis suggested that C allele of C47T polymorphism in SOD2 gene has protective effects on risk of DMI, diabetic nephropathy and diabetic retinopathy. This risk needs to be confirmed by further studies. [ABSTRACT FROM AUTHOR]

ims/hypothesis: We determined the effects of 6 years of lifestyle intervention in persons with impaired glucose tolerance (IGT) on the development of retinopathy, nephropathy and neuropathy over a 20 year period. Methods: In 1986, 577 adults with IGT from 33 clinics in Da Qing, China were randomly assigned by clinic to a control group or one of three lifestyle intervention groups (diet, exercise, and diet plus exercise). Active intervention was carried out from 1986 to 1992. In 2006 we conducted a 20 year follow-up study of the original participants to compare the incidence of microvascular complications in the combined intervention group vs the control group. Results: Follow-up information was obtained on 542 (94%) of the 577 original participants. The cumulative incidence of severe retinopathy was 9.2% in the combined intervention group and 16.2% in the control group ( p = 0.03, log-rank test). After adjusting for clinic and age, the incidence of severe retinopathy was 47% lower in the intervention group than the control group (hazard rate ratio 0.53, 95% CI 0.29-0.99, p = 0.048). No significant differences were found in the incidence of severe nephropathy (hazard rate ratio 1.05, 95% CI 0.16-7.05, intervention vs control, p = 0.96) or in the prevalence of neuropathy (8.6% vs 9.1%, p = 0.89) among the 20 year survivors. Conclusions/interpretation: Lifestyle intervention for 6 years in IGT was associated with a 47% reduction in the incidence of severe, vision-threatening retinopathy over a 20 year interval, primarily due to the reduced incidence of diabetes in the intervention group. However, similar benefits were not seen for nephropathy or neuropathy. [ABSTRACT FROM AUTHOR]

ims/hypothesis: Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate's renal effects overall and in a FIELD washout sub-study. Methods: Type 2 diabetic patients ( n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate ( n = 4,895) or placebo ( n = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat. Results: During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l ( p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min 1.73 m annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min 1.73 m, p = 0.065) than on placebo (6.9 ml min 1.73 m, p < 0.001), sparing 5.0 ml min 1.73 m (95% CI 2.3-7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia ( n = 169 vs 491 without) alone, or combined with low HDL-cholesterol ( n = 140 vs 520 without) and reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) ( n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% ( p < 0.001; mean difference 14% [95% CI 9-18]; p < 0.001), with 14% less progression and 18% more albuminuria regression ( p < 0.001) than in participants on placebo. End-stage renal event frequency was similar ( n = 21 vs 26, p = 0.48). Conclusions/interpretation: Fenofibrate reduced albuminuria and slowed estimated GFR loss over 5 years, despite initially and reversibly increasing plasma creatinine. Fenofibrate may delay albuminuria and GFR impairment in type 2 diabetes patients. Confirmatory studies are merited. Trial registration: ISRCTN64783481 Funding: The study was funded by grants from Laboratoires Fournier SA (Dijon, France; now part of Abbott Pharmaceuticals) and the National Health and Medical Research Council, Australia [ABSTRACT FROM AUTHOR]

ims/hypothesis: To assess the effect of an angiotensin receptor blocker (ARB) on serum potassium and the effect of a serum potassium change on renal outcomes in patients with type 2 diabetes and nephropathy. Methods: We performed a post hoc analysis in patients with type 2 diabetes participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. Renal outcomes were defined as a composite of doubling of serum creatinine or end-stage renal disease. Results: At month 6, 259 (38.4%) and 73 (10.8%) patients in the losartan group and 151 (22.8%) and 34 (5.1%) patients in the placebo group had serum potassium ≥5.0 mmol/l and ≥5.5 mmol/l, ( p < 0.001), respectively. Losartan was an independent predictor for serum potassium ≥5.0 mmol/l at month 6 (OR 2.8; 95% CI 2.0-3.9). Serum potassium at month 6 ≥ 5.0 mmol/l was in turn associated with increased risk for renal events (HR 1.22; 95% CI 1.00-1.50), independent of other risk factors. Adjustment of the overall treatment effects for serum potassium augmented losartan's renoprotective effect from 21% (6-34%) to 35% (20-48%), suggesting that the renoprotective effects of losartan are offset by its effect on serum potassium. Conclusions/interpretation: In this study, we found that treatment with the ARB losartan is associated with a high risk of increased serum potassium levels, which is in turn associated with an increased risk of renal outcomes in patients with diabetes and nephropathy. Whether additional management of high serum potassium would further increase the renal protective properties of losartan is an important clinical question. [ABSTRACT FROM AUTHOR]

ims/hypothesis: The receptor for AGEs (RAGE) contributes to the development and progression of diabetic nephropathy. In this study, we examined whether the protective effects of RAGE blockade are exerted via modulation of the renal angiotensin II type 2 (AT2) receptor. Methods: Control and streptozotocin diabetic mice, wild-type or deficient in the AT2 receptor ( At2 knockout [KO]) or RAGE ( Rage KO), were studied for 24 weeks. Adenoviral overexpression of full-length Rage in primary rat mesangial cells was also used to determine the effects on AT2 production. Results: With diabetes, Rage-deficient mice had less albuminuria, and an attenuation of hyperfiltration and glomerulosclerosis as compared with diabetic wild-type and At2 KO mice. Renal gene and protein expression of RAGE was elevated with diabetes. Diabetic Rage KO mice had a greater increase in renal AT2 receptor protein than was seen in diabetic wild-type mice. Diabetes-induced increases in renal cytosolic and mitochondrial superoxide generation were prevented in diabetic Rage KO mice, but enhanced in all At2 KO mice. Adenoviral overexpression of RAGE or AGE treatment decreased cell surface AT2 expression, in association with increasing superoxide generation; both were reversed using antioxidants N-acetylcysteine and apocynin, and soluble RAGE in primary mesangial cells. Conclusions/interpretation: RAGE appears to be a common and key modulator of AT2 receptor expression, a finding that would implicate a newly defined RAGE-AT2 axis in the development and progression of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

We examined whether retinal vessel diameter in persons with type 1 diabetes mellitus is associated with changes in subclinical anatomical and functional indicators of diabetic nephropathy. Persons with type 1 diabetes mellitus had gradable fundus photographs and renal biopsy data at baseline and 5-year follow-up ( n = 234). Retinal arteriolar and venular diameters were measured at baseline and follow-up. Central retinal arteriole equivalent (CRAE) and central retinal venule equivalent (CRVE) were computed. Baseline and 5-year follow-up renal structural variables were assessed by masked electron microscopic morphometric analyses from percutaneous renal biopsy specimens. Variables assessed included: mesangial fractional volume, glomerular basement membrane width, mesangial matrix fractional volume and glomerular basement membrane width composite glomerulopathy index. While controlling for other covariates, baseline CRAE was positively associated with change in the glomerulopathy index over the 5-year period. Change in CRAE was inversely related to a change in mesangial matrix fractional volume and abnormal mesangial matrix fractional volume, while change in CRVE was directly related to change in the volume fraction of cortex that was interstitium [ Vv(Int/cortex)] over the 5-year period. Baseline CRAE or CRVE or changes in these diameters were not related to changes in other anatomical or functional renal endpoints. Independently of other factors, baseline CRAE correlated with changes in glomerulopathy index, a composite measure of extracellular matrix accumulation in the mesangium and glomerular basement membrane. A narrowing of the CRAE was related to mesangial matrix accumulation. Changes in CRVE were related to changes in Vv(Int/cortex), a measure of interstitial expansion in persons with type 1 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy has been associated with low-grade inflammation and activation of the complement system in cross-sectional studies. Data from prospective studies are sparse. We investigated the associations of the complement activator mannose-binding lectin (MBL) and the inflammatory marker high-sensitivity C-reactive protein (hsCRP) with the development of nephropathy in a large prospective study of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. Baseline MBL and hsCRP were measured in 1,564 type 1 diabetes patients from the FinnDiane study, of whom 1,010 had a normal albumin excretion rate, 236 had microalbuminuria and 318 had macroalbuminuria. The main outcome was progression in renal disease during follow-up. Both baseline MBL ( p = 0.038) and hsCRP ( p < 0.001) increased with increasing level of albuminuria. During 5.8 ± 2.2 years of follow-up, progression to a higher albuminuria level or end-stage renal disease (ESRD) occurred in 201 patients. MBL levels were higher in progressors compared with non-progressors at all steps of progression, and in a covariate adjusted multivariate Cox-regression analysis MBL levels above the median were significantly associated with progression from macroalbuminuria to ESRD (hazard ratio 1.88, 95% CI 1.06–3.32, p = 0.030). In a univariate analysis, hsCRP levels above the median were significantly associated with progression from normal albumin excretion rate to microalbuminuria, but the association was only borderline significant after adjustment for covariates (hazard ratio 1.56, 95% CI 0.97–2.51, p = 0.068). This study demonstrates that concentrations of both MBL and hsCRP are associated with the progression of renal disease in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a chronic disease leading to complications such as peripheral neuropathies, nephropathy and cardiovascular disease. Pancreatic islet transplantation is being extensively investigated for blood glucose control in animals and in human type 1 diabetic patients, but the question of whether it can reverse long-term diabetic complications has not been fully explored. We investigated the effects of islet transplantation on diabetic complications in a rat model of streptozotocin-induced diabetes. Three groups of rats were used: healthy controls, diabetic and diabetic rats transplanted with microencapsulated islets at 2 months after diabetes induction, when neuropathy was detectable by a decrease in tail nerve conduction velocity (NCV) and impaired nociceptive thresholds. Blood glucose levels and body weight were measured weekly. The variables considered were: thermal (hot plate test) and mechanical sensitivity (Randal–Selitto paw withdrawal test), NCV and Na+, K+-ATPase activity in the sciatic nerve. At the end of the experiments hearts were removed for morphometric determination and myocyte number, and kidneys removed for histological examination. Islet transplantation in diabetic rats induced normoglycaemia in a few days, accompanied by a rapid rise in body weight and amelioration of impaired nociceptive thresholds, as well as normalisation of NCV and Na+, K+-ATPase, which were both about 25% below normal in diabetic rats. Myocyte loss was reduced (−34%) by islet transplantation and the observed mild kidney damage of diabetic rats was prevented. Besides controlling glycaemia, transplantation of microencapsulated pancreatic islets induced almost complete regression of neuropathy and prevented cardiovascular alterations. [ABSTRACT FROM AUTHOR]

The purpose of the study was to evaluate the association between retinal vascular calibre and micro- and macrovascular complications in a population-based cohort of Danish type 1 diabetic patients. This was a cross-sectional study of 208 long-surviving type 1 diabetic patients from a population-based Danish cohort. Retinal photographs were obtained at a clinical examination attended by each participant in 2007–2008, and retinal vascular calibre was measured and summarised as the central retinal artery or vein equivalent (CRAE or CRVE) using a computer-based program and a standardised protocol. Associations between retinal vascular calibre and micro- and macrovascular complications were examined after adjusting for confounding clinical characteristics. Retinal photographs were gradable for 188 of 208 patients (90.3%). The median age and duration of diabetes for patients with gradable photos were 57.9 and 42 years, respectively. After multivariate adjustments, individuals with narrower retinal arterioles were more likely to have nephropathy (OR 2.17, 95% CI 1.29–3.68, per SD decrease in CRAE) and macrovascular disease (OR 3.17, 95% CI 1.59–6.34, per SD decrease in CRAE), but not neuropathy (OR 1.10, 95% CI 0.70–1.71, per SD decrease in CRAE). Retinal venular calibre was not associated with any micro- or macrovascular complications. In type 1 diabetic patients, retinal arteriolar narrowing is associated with nephropathy and macrovascular disease independently of other clinical characteristics. If supported by further prospective studies, measurement of retinal vessel diameter may allow a non-invasive evaluation of the risk of diabetes-related complications. [ABSTRACT FROM AUTHOR]

We followed type 2 diabetic patients over a long period to evaluate the predictive value of ambulatory pulse pressure (PP) and decreased nocturnal BP reduction (non-dipping) for nephropathy progression. Type 2 diabetic patients ( n = 112) were followed for an average of 9.5 (range 0.5–14.5) years. At baseline, all patients underwent 24 h ambulatory BP measurement. Urinary albumin excretion rate was evaluated by three urinary albumin:creatinine ratio measurements at baseline and follow-up. At baseline, patients who subsequently progressed to a more advanced nephropathy stage ( n = 35) had reduced diastolic night/day BP variation and higher 24 h systolic BP and PP values; they also had more advanced nephropathy and were more likely to smoke than those with no progression of nephropathy ( n = 77). In a Cox regression analysis, independent predictors of nephropathy progression were 24 h PP ( p < 0.01), diastolic night:day BP ratio ( p = 0.02) and smoking ( p = 0.02). The adjusted hazards ratio (95% CI) for each mmHg increment in 24 h PP was 1.04 (1.01–1.07), whereas the adjusted hazards ratio (95% CI) for each 1% increase in diastolic night:day BP ratio was 1.06 (1.01–1.11). Only one of 33 patients (3.0%) with both a diastolic night:day BP ratio and a 24 h PP below the median progressed, whereas 17 of 32 patients (53.1%) with both a diastolic night:day BP ratio and a 24 h PP equal to or above the median progressed to a more advanced nephropathy stage ( p < 0.001). Ambulatory PP, impaired nocturnal BP decline and smoking are strong, independent predictors of nephropathy progression in type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the association between alcohol consumption and risk of microvascular complications (retinopathy, neuropathy, nephropathy) in type 1 diabetes mellitus patients in the EURODIAB Prospective Complications Study. The EURODIAB Prospective Complications Study is a follow-up study including 3,250 type 1 diabetes mellitus patients from 16 different European countries. We investigated the cross-sectional association between moderate alcohol consumption and risk of retinopathy, neuropathy and nephropathy among 1,857of these patients. We documented 304 cases of proliferative retinopathy, 660 cases of neuropathy and 157 cases of nephropathy (macroalbuminuria). Alcohol consumption was associated with risk of proliferative retinopathy, neuropathy and macroalbuminuria in a U-shaped fashion. Moderate consumers (30–70 g alcohol per week) had a lower risk of microvascular complications with odds ratios of 0.60 (95% CI 0.37–0.99) for proliferative retinopathy, 0.61 (0.41–0.91) for neuropathy and 0.36 (0.18–0.71) for macroalbuminuria in multivariate-adjusted models. These results were similar when excluding patients who had been advised to drink less alcohol because of their health. The relation was most pronounced for alcohol consumption from wine. Drinking frequency was significantly, inversely associated with risk of neuropathy, but a similar trend was visible for proliferative retinopathy and macroalbuminuria. Alcohol consumption was not associated with occurrence of ketoacidosis or hypoglycaemic attacks. Consistent with its effects on macrovascular complications, moderate alcohol consumption is associated with a lower risk of all microvascular complications among type 1 diabetes patients. [ABSTRACT FROM AUTHOR]

AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation. ROS generation is regulated by the Src homology 2 domain-containing transforming protein C1 (Shc1) isoform p66Shc, whose deletion has been shown to protect from tissue injury induced by ageing, diabetes, hyperlipidaemia and ischaemia-reperfusion by preventing oxidative stress. This study was aimed at assessing the role of p66Shc in the modulation of oxidative stress and oxidant-dependent renal injury induced by AGEs. For 10 weeks, male p66 shc knockout (KO) and wild-type (WT) mice were injected with 60 μg/day albumin modified or unmodified by $$N^\varepsilon - \left( {carboxymethyl} \right)\;\text{lysine}$$ (CML). Mice were then killed for the assessment of renal function and structure, as well as systemic and renal tissue oxidative stress. Upon CML injection, KO mice, in contrast to WT mice, showed no or only mild forms of proteinuria, glomerular hypertrophy, mesangial expansion, glomerular sclerosis, renal/glomerular cell apoptosis and extracellular matrix upregulation. Moreover, KO mice had lower circulating and tissue AGEs than WT mice and unchanged plasma isoprostane 8-epi-prostaglandin- $${\text{F}}_{{2{\text{ $ \alpha $ }}}} $$ levels, renal/glomerular CML, 4-hydroxy-2-nonenal, AGE receptor and NAD(P)H oxidase 4 (NOX4) content (and expression of the corresponding genes), and nuclear factor κB activation (NFκB). Mesangial cells from KO mice exposed to CML showed no or slight increase in ROS levels and NFκB activation, again at variance with WT cells. These data indicate that p66Shc participates in the pathogenesis of AGE-dependent glomerulopathy by mediating AGE-induced tissue injury and further AGE formation through ROS-dependent mechanisms involving NFκB activation and upregulation of Nox4 expression and NOX4 production. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We investigated the relationship between haemoglobin (Hb) and diabetes in patients with renal disease. Subjects, materials and methods: All adult patients with stable chronic kidney disease attending renal or diabetic outpatient clinics in a six-month period were identified. Patients' notes and electronic patient records were used to build a comprehensive biochemical and clinical database. Results were analysed for the predictors of Hb, the severity of anaemia in both groups and the relative impact of diabetes on haemoglobin and anaemia. Results: The study group consisted of 468 patients, of whom 204 had diabetes and 264 did not. At every level of renal function haemoglobin levels were lower by an average of 10 g/l in subjects with diabetes than in those without. Likewise, anaemia was found to occur at an earlier stage of chronic kidney disease (and to be of greater severity) in diabetic patients. Independent predictors of haemoglobin included female sex, diabetes, renal function and serum albumin, with diabetes and renal function being the greatest predictors. Multiple logistic regression showed that patients with diabetes had an odds ratio of 4 for being anaemic. Had we used an estimated GFR of less than 60 ml/min to trigger investigation of anaemia, we would have detected 85% of anaemic patients. Conclusions/interpretation: Anaemia is frequently found in diabetic patients with renal disease, occurs earlier and is more severe than in similar but non-diabetic subjects. In contrast to previous publications, our findings suggest that anaemia is prevalent at the earliest stages of chronic kidney disease. We advocate an estimated GFR threshold of <60 ml/min to trigger investigation for anaemia in diabetic subjects. [ABSTRACT FROM AUTHOR]