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Rationale: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. Objective: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. Methods and Results: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-C hi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9 , S100a8 , or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. Conclusions: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.

Diabetic heart disease (DHD) can be classified as a primary consequence from several pathophysiological manifestation of diabetes mellitus (DM) on cardiac tissues or secondarily in extracardiac tissues and is encountered as either primary or secondary complications of DM. Endothelitis is inflammation of the vascular endothelium and is likely to be seen in the majority of patients who start to manifest an end organ complication of DM in this case DHD. Diabetes is a leading cause for many cardiovascular syndromes and diseases including congestive heart failure (CHF) however much remains unknown about the transition from diagnosed DM to clinical state and the contribution of the various mechanical and counterregulatory systems in the manifested complaint. Diastolic heart failure or heart failure with preserved ejection fraction (DHF/HFpEF), accounts for half of all CHF presentations, has DM as a major contributor, however, there remain large gaps in clinical and pathophysiological understanding. This review aims to explore the microscopic aspects in diabetic endothelitis and provide a clinical link to with context to HFpEF.

Background The investigational medicinal product GKT137831 is a selective inhibitor of NOX 1 and 4 isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes, which has the potential to ameliorate diabetic kidney disease. An investigator-initiated, double-blind, randomised, placebo-controlled, multicentre phase 2 clinical trial started recruitment in December 2017, with the aim of evaluating the efficacy and safety of GKT13783, in adults with type 1 diabetes mellitus and persistently elevated urinary albumin excretion over a period of 48 weeks. Methods/design The trial is currently recruiting in Australia and New Zealand, with recruitment expected to end on 30 June 2020. The primary outcome measure of the trial is the urinary albumin excretion level measured at 48 weeks of treatment. This statistical analysis plan presents an update to the published trial protocol and provides a comprehensive description of the statistical methods that will be used for the analysis of the data from this trial. In doing so, we follow the “Guidelines for the content of statistical analysis plans in clinical trials” to support transparency and reproducibility of the trial findings. Discussion With the use of this prior statistical analysis plan, we aim to minimise bias in the reporting of the findings of this trial, which evaluates the investigational medicinal product GKT137831. The results of the trial are expected to be published in 2022. Trial registration ANZCTR registry: ACTRN12617001187336. Registered on 14 July 2017. Universal Trial Number: U1111-1187-2609; Protocol number: T1DGKT137831; Genkyotex trial number: GSN000241.

At least half of all heart failure (CHF) patients will have a comorbidity that could be undertreated, requires additional speciality input and/or polypharmacy. These patients are then at risk of iatrogenic and disease-related complications and readmissions if not closely supervised. Common comorbidities of relevance are cardiorenal and cardiometabolic syndromes (DM, obesity, OSA), chronic airways disease, elderly age, and accompanying pharmacotherapies. The structure of community practice often leaves primary, speciality, and allied health care in silos. For example, cardiology speciality training in Australia creates excellent sub-specialists to deliver diagnostic and therapeutic advances. A casualty of this process has been the gradual alienation of general cardiology toward general internal medical specialists and primary care practitioners. The consequences are largely noticed in community practice. The issue is compounded by suboptimal communication of information. This review explores these issues from a cardiology sub-speciality lens; firstly cross speciality areas that are important for cardiologists to maintain their skill, and finally, to obtain a brief overview of disease management and identify game-changing common denominators such as endothelial dysfunction and self-management.

Ogilvie syndrome, or acute colonic pseudo-obstruction, is a rare disease in adults, and it is seldom seen in pediatric patients. It was first described in 1948 by Dr. William Ogilvie. Unless promptly recognized and treated, it carries the risk of colonic ischemia and perforation. In this report, we present the case of a 10-year-old patient who developed Ogilvie syndrome and was successfully treated with conservative medical management including bowel rest, rectal decompression, along with the addition of erythromycin. The patient responded well to the treatment and was able to be discharged home without event.

Aims Aim of this study is to report severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, responsible for coronavirus disease 2019 (COVID‐19), as a possible cause for type 1 diabetes by providing an illustrative clinical case of a man aged 45 years presenting with antibody‐negative diabetic ketoacidosis post‐recovery from COVID‐19 pneumonia and to explore the potential for SARS‐CoV‐2 to adhere to human islet cells. Methods Explanted human islet cells from three independent solid organ donors were incubated with the SARS‐CoV‐2 spike protein receptor biding domain (RBD) fused to a green fluorescent protein (GFP) or a control‐GFP, with differential adherence established by flow cytometry. Results Flow cytometry revealed dose‐dependent specific binding of RBD‐GFP to islet cells when compared to control‐GFP. Conclusions Although a causal basis remains to be established, our case and in vitro data highlight a potential mechanism by which SARS‐CoV‐2 infection may result in antibody‐negative type 1 diabetes.

We investigated the association between diet and risk of hospitalisation for diabetic ketoacidosis (DKA) or hypoglycaemia in type 1 diabetes. Food records were used to assess dietary intake. Data on DKA and hypoglycaemia hospitalisations, within two years of dietary assessments, were obtained from registries. Analyses were conducted with and without macronutrient substitution. Data were available from 1391 participants, 28 (2.0%) and 55 (4.0%) of whom were hospitalised due to DKA or hypoglycaemia, respectively. In the adjusted model, self-reported alcohol intake was associated with increased (per 10 g: B = 1.463, 95% CI = 1.114–1.922, p = 0.006; per E%: B = 1.113, 95% CI = 1.027–1.206, p = 0.009), and fibre intake with reduced (per g/MJ: B = 0.934, 95% CI = 0.878–0.995, p = 0.034) risk of DKA hospitalisation. Substituting carbohydrates for fats was associated with increased risk for hypoglycaemia hospitalisation (B = 1.361, 95% CI = 1.031–1.795, p = 0.029), while substituting alcohol for carbohydrates (B = 1.644, 95% CI = 1.006–2.685, p = 0.047) or proteins (B = 2.278, 95% CI = 1.038–4.999, p = 0.040) increased the risk for DKA hospitalisation. In conclusion, refraining from alcohol intake is a preventable risk factor for DKA, while higher fibre intake seems rather protective. Increasing carbohydrate intake while decreasing that of fats, is associated with higher hypoglycaemia risk. Whether this is a cause or effect of hypoglycaemia remains to be established.

Acute hemorrhagic leukoencephalitis (AHLE) is a rare demyelinating disease of the central nervous system that typically follows a viral or bacterial respiratory infection. We report the first described case of AHLE following influenza A (H3N2) in an otherwise healthy 15-year-old girl with no relevant past medical history who initially presented to the emergency department (ED) by emergency medical services (EMS) with decorticate posturing and right gaze deviation after being found unresponsive at home. Subsequent testing for Influenza A H3N2 via viral polymerase chain reaction (PCR) was positive. Clinical correlation and brain MRI confirmed AHLE. At follow-up three months after discharge, she was found to have intellectual functioning in the extremely low range and she still had deficits in motor skills eight months after discharge. While the patient was reportedly up-to-date on her routine scheduled childhood vaccinations, she had not received her annual influenza vaccination that year. Pediatric infectious disease physicians and neurologists should consider the diagnosis of AHLE in unvaccinated, previously healthy patients with new and rapid onset of neurological symptoms following influenza infection.

Heart failure with preserved ejection fraction (HFpEF) or diastolic heart failure (DHF) makes up more than half of all congestive heart failure presentations (CHF). With an ageing population, the case load and the financial burden is projected to increase, even to epidemic proportions. CHF hospitalizations add too much of the financial and infrastructure strain. Unlike systolic heart failure (SHF), much is still either uncertain or unknown. Specifically, in epidemiology, the disease burden is established; however, risk factors and pathophysiological associations are less clear; diagnostic tools are based on rigid parameters without the ability to accurately monitor treatments effects and disease progression; finally, therapeutics are similar to SHF but without prognostic data for efficacy. The last several years have seen guidelines changing to account for greater epidemiological observations. Most of these remain general observation of shortness of breath symptom matched to static echocardiographic parameters. The introduction of exercise diastolic stress test has been welcome and warrants greater focus. HFpEF is likely to see new thinking in the coming decades. This review provides some of perspective on this topic.

Inhibition of the sodium–glucose cotransporter (SGLT) 2 in the proximal tubule of the kidney has a broad range of effects on renal function and plasma volume homeostasis, as well as on adiposity and energy metabolism across the entire body. SGLT2 inhibitors are chiefly used in type 2 diabetes for glucose control, achieving reductions in HbA1c of 7–10 mmol/mol (0.6–0.9%) when compared with placebo. This glucose-lowering activity is proportional to the ambient glucose concentration and glomerular filtration of this glucose, so may be greater in those with poor glycaemic control and/or hyperfiltration at baseline. Equally, the glucose-lowering effects of SGLT2 inhibitors are attenuated in individuals without diabetes and those with a reduced eGFR. However, unlike the glucose-lowering effects of SGLT2 inhibitors, the spill-over of sodium and glucose beyond the proximal nephron following SGLT2 inhibition triggers dynamic and reversible realignment of energy metabolism, renal filtration and plasma volume without relying on losses into the urine. In addition, these processes are observed in the absence of significant glucosuria or ongoing natriuresis. In the long term, the resetting of energy/salt/water physiology following SGLT2 inhibition has an impact, not only on adiposity, renal function and blood pressure control, but also on the health and survival of patients with type 2 diabetes. A better understanding of the precise biology underlying the acute actions of SGLT2 inhibitors in the kidney and how they are communicated to the rest of the body will likely lead to improved therapeutics that augment similar pathways in individuals with, or even without, diabetes to achieve additional benefits.

Aims To determine the effect of different stages of diabetic nephropathy (DN) and sex on the excess and absolute morbidity of coronary artery disease (CAD) and stroke in people with type 1 diabetes (T1D) in order to distinguish different cardiovascular disease (CVD) risk profiles in people with T1D. Materials and methods The study included 4410 people with T1D from the Finnish Diabetic Nephropathy Study (FinnDiane), divided by DN status, and a control population of 12 434 people without diabetes. CVD events were identified from the Finnish nationwide health registries. Cumulative incidences for CAD and stroke were calculated and standardized incidence ratios (SIRs) were estimated between participants with T1D and the control group, stratified by DN status and sex. Results There were 487 incident CADs and 290 strokes at the end of 2014 (median follow-up 12.9 years). The cumulative incidence rates of CAD and stroke were similar in men and women within different nephropathy groups. The SIR for CAD was 7.5 (95% confidence interval [CI] 6.9-8.2), 17.2 (95% CI 14.9-19.5) in women and 5.3 (95% CI 4.7-5.9) in men. The women-to-men ratio of SIR increased by nephropathy group: 3.3, 3.7, 5.3 and 6.8 in the normo-, micro- and macroalbuminuria and end-stage renal disease (ESRD) groups, respectively. The SIR for stroke was 5.0 (95% CI 4.3-5.5), similar in men and women. The women-to-men ratio of SIR for stroke was 0.8, 1.3, 1.6 and 1.7, in the normo-, micro- and macroalbuminuria and ESRD groups, respectively. The SIR in participants with normoalbuminuria and an estimated glomerular filtration rate ≥90 mL/min/1.73 m2 was 3.5 (95% CI 2.5-4.5) for CAD and 1.6 (95% CI 1.0-2.3) for stroke. Conclusions Although the excess CVD risk is several-fold greater in women compared to men, the absolute CVD risk in men and women was equal when nephropathy was taken into account. Even participants with normoalbuminuria and normal kidney function were found to have an excess CVD risk compared with the control group without diabetes.

Cardiovascular disease, despite all the recent advances in treatment of the various risk factors, remains the major cause of mortality in both type 1 and type 2 diabetes. Experimental models of diabetes-associated atherosclerosis, despite their limitations in recapitulating the human context, have assisted in the elucidation of molecular and cellular pathways implicated in the development and progression of macrovascular injury in diabetes. Our own studies have emphasized the role of oxidative stress and advanced glycation and identified potential targets for vasoprotective therapies in the setting of diabetes. Furthermore, it has been clearly shown that previous episodes of hyperglycemia play a key role in promoting end-organ injury in diabetes, as shown in clinical trials such as the UK Prospective Diabetes Study (UKPDS), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Observational Study (ADVANCE-ON), and the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). The cause of this phenomenon, known as metabolic memory, remains to be elucidated, but it appears that epigenetic pathways, including glucose-induced histone methylation, play a central role. Further delineation of these pathways and their link to not only glucose but also other factors implicated in vascular injury should lead to more rational, potentially more effective therapies to retard diabetes-associated cardiovascular disease.

OBJECTIVE The current study investigated whether the risk of mortality in patients with type 1 diabetes without any signs of albuminuria is different than in the general population and matched control subjects without diabetes. RESEARCH DESIGN AND METHODS We studied a nationwide, population-based Finnish register of 10,737 patients diagnosed with type 1 diabetes during 1980–2005 and followed for 10 years and 2,544 adults with long-standing diabetes drawn from the Finnish Diabetic Nephropathy Study (FinnDiane). Mortality was compared with the general Finnish population and 6,655 control subjects without diabetes. RESULTS The standardized mortality ratio (SMR) was increased during the first 10 years after the diagnosis (2.58 [95% CI 2.07–3.18], P < 0.001). Mortality in adults with long-standing diabetes, but without albuminuria, was no different from that of the general population (1.02 [0.84–1.22], P = 0.83). However, it was higher compared with that of control subjects without diabetes (1.33 [1.06–1.66], P = 0.01). Excess mortality was largely due to acute diabetes complications and ischemic heart disease, which remained more than fourfold higher (mortality rate ratio 4.34 [2.49–7.57]) in adults with type 1 diabetes than in control subjects without diabetes, despite the absence of albuminuria. By contrast, deaths due to alcohol and drugs were reduced in adults with type 1 diabetes (P = 0.007), especially in men. CONCLUSIONS Excess mortality in type 1 diabetes is the result of its complications. Acute complications drive an increased SMR in the first years. In individuals who remain free of albuminuria, mortality due to ischemic heart disease is still four times higher, and acute complications also occur.

Increased glycolytic flux into the diabetic kidney, combined with glycolytic inefficiencies introduced by oxidative stress, acts to increase the generation of triose-phosphate intermediates, which spontaneously degrade to form methylglyoxal. At the same time, the glyoxalase-catalysed pathway that degrades excess methylglyoxal is impaired. The resulting dicarbonyl stress increases the accumulation of Advanced Glycation End-products (AGEs), as highly reactive dicarbonyls modify proteins, DNA, phospholipids and even small molecules like glutathione and nitric oxide. The resulting molecular dysfunction, contributes to the development and progression of kidney disease in diabetes. The importance of the dicarbonyls in diabetic kidney disease is clearly demonstrated by the reno-protective benefits of structurally-disparate dicarbonyl scavengers in experimental studies. Equally, modulating the glyoxalase pathway is able to alter both dicarbonyl generation and renal dysfunction in the presence and absence of hyperglycaemia. However, beyond improving glycemia control and reducing oxidative stress, an effective way to attenuate dicarbonyl-mediated damage in patients with diabetic kidney disease remains an elusive goal.

Coronary artery disease (CAD) is the leading contributor to cardiovascular disease; it is the most prevalent non-communicable disease globally and has high morbidity, mortality and health care cost. Risk stratification is defined as prevention or containment of disease prior to it occurring or progressing, and non-invasive surrogates include history, examination, biomarkers and non-invasive imaging. This review aims to highlight advancement in current diagnostic strategies and explores gaps for CAD secondary to atherosclerosis and non-obstructive vascular diseases. Cardiac risk scores have largely proven inadequate in risk stratifying heterogeneous patient populations. Greater emphasis should also be provided to posttest risk stratification. Non-invasive imaging with MRI is the most accurate but least cost efficacious presently due to availability and expertise. Echocardiography and nuclear imaging have good accuracy, but radiation limits the latter. Novel echocardiographic technologies may increase its appeal. Cardiac CT angiography is increasingly promising. Non-invasive and minimally invasive imaging has significantly influenced the cost-efficacy trajectory of coronary artery disease diagnosis and management. Recent studies suggest that future guidelines will incorporate more subclassifications from the findings of these novel technologies and for more diverse patient demographics.

Context The long-term natural history of diabetic ketoacidosis (DKA) and its risk factors are poorly understood. Objective To determine the long-term incidence and predictors of DKA in adults with longstanding type 1 diabetes (T1D). Design All hospitalizations and deaths due to DKA between 1996 and 2016 were identified in 4758 adults with T1D from the Finnish Diabetic Nephropathy Study (FinnDiane), and a cohort of 16 224 adults with T1D from the Finnish general population. Results Between 1996 and 2015, there were 1228 DKA events in the FinnDiane participants (1.4/100 person-years) and 4914 DKA events (1.8/100 person-years) in adults with T1D from the general population. The majority were hospitalized only once. There was a modest increase in the frequency of DKA in the FinnDiane over the follow-up (~2.4%/year [95% CI, 0.3–4.5%]; P = 0.03). Predictors of DKA were glucose control, CSII, smoking and alcohol consumption, and raised high-density lipoprotein cholesterol and triacylglycerides. Diabetic nephropathy and renal impairment were associated with DKA; patients with end-stage renal disease, macroalbuminuria, and microalbuminuria had 2.09-fol (95% CI, 1.40–3.12), 1.65-fold (95% CI, 1.23–2.19), and 0.87-fold (95% CI, 0.61–1.24) risk of DKA compared with patients with normal albumin excretion rate, respectively. Patients with an estimated glomerular filtration rate Conclusions DKA remains a common cause of hospitalization in individuals with longstanding T1D. These data suggest that the goal to use SGLT2 inhibitors for their vasculo- and renoprotective actions may be problematic, as those most likely to benefit may also have the highest risk for DKA.

The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.

Background Beta-blockers (BBs) are the mainstay prognostic medication for all stages of chronic heart failure (CHF). There are many classes of BBs, each of which has varying levels of evidence to support its efficacy in CHF. However, most CHF patients have one or more comorbid conditions such as diabetes, renal impairment, and/or atrial fibrillation. Patient enrollment to randomized controlled trials (RCTs) often excludes those with certain comorbidities, particularly if the symptoms are severe. Consequently, the extent to which evidence drawn from RCTs is generalizable to CHF patients has not been well described. Clinical guidelines also underrepresent this point by providing generic advice for all patients. The aim of this review is to examine the evidence to support the use of BBs in CHF patients with common comorbid conditions. Methods We searched MEDLINE, PubMed, and the reference lists of reviews for RCTs, post hoc analyses, systematic reviews, and meta-analyses that report on use of BBs in CHF along with patient demographics and comorbidities. Results In total, 38 studies from 28 RCTs were identified, which provided data on six BBs against placebo or head to head with another BB agent in ischemic and nonischemic cardiomyopathies. Several studies explored BBs in older patients. Female patients and non-Caucasian race were underrepresented in trials. End points were cardiovascular hospitalization and mortality. Comorbid diabetes, renal impairment, or atrial fibrillation was detailed; however, no reference to disease spectrum or management goals as a focus could be seen in any of the studies. In this sense, enrollment may have limited more severe grades of these comorbidities. Conclusions RCTs provide authoritative information for a spectrum of CHF presentations that support guidelines. RCTs may provide inadequate information for more heterogeneous CHF patient cohorts. Greater Phase IV research may be needed to fill this gap and inform guidelines for a more global patient population.

Introduction Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the management of patients with type 2 diabetes mellitus (T2DM) and renal impairment (RI). A systematic literature review was performed to compare the efficacy and safety of DPP-4 inhibitors in patients with T2DM and RI. Methods We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials (cut-off, June 2015) to identify ≥12-week, randomized, placebo-controlled trials on DPP-4 inhibitors in ≥50 patients with T2DM and RI. Outcomes of interest included change in glycated hemoglobin (HbA1c), overall safety, and incidence of hypoglycemic events (HEs). Results Seven trials of ≤52–54 weeks duration were retrieved, which included one study each on vildagliptin, saxagliptin, and sitagliptin, two on linagliptin, and the remaining two were extension studies of vildagliptin and saxagliptin. Majority of patients were on insulin at baseline (53–86%), except in the sitagliptin study, where approximately 11% received insulin during the placebo-controlled phase. After 52 weeks, vildagliptin and saxagliptin reduced HbA1c levels by 0.6–0.7% (baseline 7.8–8.4%) versus placebo in the overall population. HbA1c reductions were similar at weeks 12 and 52. In the 12-week, placebo-controlled phase, sitagliptin and linagliptin reduced mean HbA1c by approximately 0.4% (baseline 7.7–8.1%) versus placebo. Rates of HEs with DPP-4 inhibitors were not significantly different versus placebo in any study. Rates of adverse events (AEs) and changes involving renal function were similar in the active- and placebo-treated groups. Conclusion These results suggest that DPP-4 inhibitors have the potential to improve glycemic control in patients with RI without increasing the risk of HEs or overall AEs. Funding Novartis Pharma AG. Electronic supplementary material The online version of this article (doi:10.1007/s13300-016-0189-4) contains supplementary material, which is available to authorized users.

Increasing numbers of older patients with type 2 diabetes, and their improved survival from cardiovascular events is seeing a massive increase in patients with both diabetes and heart failure. Already, at least a third of all patients with heart failure have diabetes. This close association is partly because all the major risk factors for heart failure also cluster in patients with type 2 diabetes, including obesity, hypertension, advanced age, sleep apnoea, dyslipidaemia, anaemia, chronic kidney disease, and coronary heart disease. However, diabetes may also cause cardiac dysfunction in the absence of overt macrovascular disease, as well as complicate the response to therapy. Current management is focused on targeting modifiable risk factors for heart failure including hyperglycaemia, dyslipidaemia, hypertension, obesity and anemia. But although these are important risk markers, none of these interventions substantially prevents heart failure or improves its outcomes. Much more needs to be done to focus on this issue, including the inclusion of hospital admission for heart failure as a pre-specified component of the primary composite cardiovascular outcomes and new trials in heart failure management specifically in the context of diabetes.

Congestive heart failure (CHF) is a chronic and often devastating cardiovascular disorder with no cure. There has been much advancement in the last two decades that has seen improvements in morbidity and mortality. Clinicians have also noted variations in the responses to therapies. More detailed observations also point to clusters of diseases, phenotypic groupings, unusual severity and the rates at which CHF occurs. Medical genetics is playing an increasingly important role in answering some of these observations. This developing field in many respects provides more information than is currently clinically applicable. This includes making sense of the established single gene mutations or uncommon private mutations. In this thematic series which discusses the many factors that could be relevant for CHF care, once established treatments are available in the communities; this section addresses a contextual role for medical genetics.

Incretins are gut-derived peptide hormones that modulate glucose homeostasis as well as other physiologic pathways. Pharmacologic inhibition of dipeptidyl peptidase-4 (DPP-4) potentiates incretin action by reducing their degradation ([Figure 1][1]). Glucagon-Like Peptide-1 Receptor agonists (GLP

Purpose Kidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox − 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. Design This is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. Primary outcome measures Difference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. Conclusion This study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.

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.

OBJECTIVE This study explored whether activation of the receptor for advanced glycation end products (RAGE) is implicated in the development of diabetes complications. RESEARCH DESIGN AND METHODS A case-cohort study was performed in 3,763 participants with prevalent diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. The hazard ratios (HRs) for death, major cardiovascular events, and new or worsening nephropathy were derived using Cox regression models, and the ability of sRAGE and AGE levels to reclassify the risk of nephropathy was assessed. RESULTS After adjustment for a range of possible confounders and other risk factors, sRAGE levels were associated with all-cause mortality (HR 1.11 for a 1-SD increase of log sRAGE [95% CI 1.00–1.22]; P = 0.045) and new or worsening nephropathy (HR 1.20 for a 1-SD increase of log sRAGE [95% CI 1.02–1.41]; P = 0.032). Circulating AGE levels were also independently associated with new or worsening nephropathy (HR 1.21 for a 1-SD increase [95% CI 1.08–1.36]; P = 0.001). Both markers also significantly improved the accuracy with which the 5-year risk of new or worsening nephropathy could be predicted (net reclassification index in continuous model, 0.25 for sRAGE and 0.24 for AGE levels). CONCLUSIONS In adults with type 2 diabetes, increased levels of sRAGE are independently associated with new or worsening kidney disease and mortality over the next 5 years. Higher levels of AGE are also associated with an increased risk of adverse renal outcomes. The AGE/RAGE axis may be of importance in the prevention and management of diabetes complications.

Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) offer substantial benefits for the management of glucose levels in type 2 diabetes. In addition, recent data from clinical trials have demonstrated that treatment with Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) are also able to reduce new onset macroalbuminuria. These benefits may be consistent with the known effects of GLP-1 RA on traditional risk factors for progressive kidney disease including glucose lowering, blood pressure lowering, reduced insulin levels and weight reduction. However, emerging evidence suggests that GLP-1 RA can also have direct effects in the kidney, including inhibiting NHE3-dependent sodium reabsorption in the proximal tubule. Additional effects on the intrarenal renin angiotensin system, ischaemia/hypoxia, inflammation, apoptosis and neural signalling may also contribute to renal benefits. The extent to which these effects are mediated by the GLP-1R remains to be established. Recent studies confirm that the metabolic products of GLP-1 retain important antioxidant and anti-apoptotic activities that are GLP-1 R independent. Moreover the divergent peptide sequences of the currently available GLP-1 RA may mean that divergent reno-protective efficacy could be anticipated from different GLP-1 RA on this basis. Kidney disease is an important and deadly clinical outcome, and one worth preventing. Although both experimental and clinical data now support the possibility of renoprotective effects arising from treatment with GLP-1 RA, further work is needed to optimise these effects. A logical synergism with SGLT2 inhibition also exists, and at least in the short term, this combination approach may become the most useful way to protect the kidney in type 2 diabetes.

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.

Diabetes mellitus was originally conceived as a renal disorder. In the last decade, however, there has been renewed interest in role of the kidney in the development and maintenance of high glucose levels. This has led to the development of novel agents to inhibit sodium glucose transporter-2 (SGLT2) as a means to better control glucose levels and at the same time augment calorie wasting and lower insulin, blood pressure and uric acid levels. Such actions, indirectly, may also have benefits for the prevention of diabetic complications including renal disease. However, there are also data to support the potential for direct renoprotective actions arising from inhibition of SGLT2, including actions to attenuate diabetes-associated hyperfiltration and tubular hypertrophy, as well as reduce the tubular toxicity of glucose. Some studies have demonstrated significant reductions in albumin excretion in various experimental models, independent of its effects on blood pressure or glucose control. Although promising, such actions remain to be established by comprehensive clinical trials with a renal focus, many of which are currently in progress. This article reviews the clinical and experimental data pertaining to the renal effects of SGLT2 inhibition with a particular focus on dapaglifozin.

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 renin-angiotensin-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.

Cell division autoantigen 1 (CDA1) enhances TGF-β signaling in renal and vascular cells, and renal expression of CDA1 is elevated in animal models of diabetes. In this study, we investigated the genetic deletion of Tspyl2 , the gene encoding CDA1, in C57BL6 and ApoE knockout mice. The increased renal expression of TGF-β1, TGF-β type I and II receptors, and phosphorylated Smad3 associated with diabetes in wild-type mice was attenuated in diabetic CDA1 knockout mice. Notably, CDA1 deletion significantly reduced diabetes-associated renal matrix accumulation and immunohistochemical staining for collagens III and IV and attenuated glomerular and tubulointerstitial injury indices, despite the presence of persistent hyperglycemia, polyuria, renal hypertrophy, and hyperfiltration. Furthermore, CDA1 deletion reduced gene expression of TGF-β1 receptors in the kidney, resulting in a functionally attenuated response to exogenous TGF-β, including reduced levels of phosphorylated Smad3 and ERK1/2, in primary kidney cells from CDA1 knockout animals. Taken together, these data suggest that CDA1 deletion reduces but does not block renal TGF-β signaling. Because direct antagonism of TGF-β or its receptors has unwanted effects, CDA1 may be a potential therapeutic target for retarding DN and perhaps, other kidney diseases associated with TGF-β–mediated fibrogenesis.

Feedback activation of neurohormonal pathways in the setting of kidney or heart failure contributes to the development and progression of dysfunction in the other. Diabetes and its management independently activate these same pathogenic pathways, feeding into this vicious cycle and contributing to a poor prognosis. One of the most important of these neurohormonal pathways is the sympathetic nervous system (SNS). The activity of the SNS in increased in patients with chronic kidney disease, even in the absence of renal impairment or heart failure. There is a strong relationship between SNS overactivity and prognosis, and evidence that blockade of SNS reduces morbidity and mortality in patients with diabetes. However, modulation of SNS is underutilised as a strategy to protect both the diabetic kidney and the heart. This is partly because of the historically poor tolerability, adverse haemodynamic and metabolic effects, lack of selectivity of β-blockers and the lack of specificity of other interventions that might modify SNS activation. The advent of "vasodilating β-blockers" with better tolerability as well as more favourable effects on renal function and metabolic profiles opens the door for their more widespread utility in patients with diabetes. Radiofrequency renal sympathectomy and baroreflex activation technologies also offer exciting new ways to tackle the challenge of sympathetic overactivity.

Objectives Although a diagnosis of coeliac disease (CD) may be confronting to children with type 1 diabetes and their families, we hypothesize that children with CD have lower urinary albumin excretion, a marker of renal dysfunction. Research design Twenty-four children with type 1 diabetes and biopsy-proven CD, on a gluten-free diet for at least 1 yr, were recruited from a single paediatric diabetes clinic alongside 55 children with type 1 diabetes but without CD matched for age, gender, duration of diabetes, and glycaemic control. Results Despite comparable diabetes exposure, glycaemic control and nutritional status, children with type 1 diabetes and CD had a lower urinary albumin creatinine ratio than in diabetic subjects without CD (0.9 ± 0.3 mg/mmol vs. 1.6 ± 0.3 mg/mmol; p = 0.01). Participants with CD also showed slower progression in albuminuria over 5-yr of follow-up while a small but significant increase was observed in the children with diabetes alone (1.6 ± 0.3 mg/mmol; follow-up 2.4 ± 0.5 mg/mmol; p = 0.02). Conclusions As urinary albumin excretion is continuously associated with the risk of kidney disease, it is possible to speculate that CD or its management confers a degree of renoprotection. Larger studies are required to test this hypothesis.

SUMMARY The enzyme indoleamine 2,3-dioxigenase (IDO) is critical for the regulation of immune responses in pro-tolerogenic antigen-presenting cell. To address the profile of immune responses associated with Chagas disease, we measured IDO activity of peripheral blood mononuclear cells from 168 chronic patients and 13 healthy donors. We found that IDO activity was increased in patients with Chagas disease when compared with controls. Moreover, the IDO activity of patients with Chagas disease in the symptomatic chronic phase, involving cardiac or digestive alterations, was higher than that detected in asymptomatic patients and correlated with the severity of the symptoms. Furthermore, benznidazole treatment induced a long-lasting decrease in IDO activity in symptomatic patients, reaching levels comparable with those of healthy donors. These results suggest that a pro-tolerogenic state is associated with the severity of Chagas disease and that benznidazole treatment is a valuable tool for breaking the parasite-driven immune tolerance in the symptomatic chronic phase of Chagas disease.

SUMMARY There is an urgent need for new approaches to protect the kidney and its functions in the increasing number of patients with diabetes. Although current strategies are effective, their effect is only partial and the majority of cases are not prevented, even by best practice. A number of new targets have been proposed, including direct renin inhibition, inhibition of fibrosis, activation of Nrf-2, sulodexide, endothelin I and urotensin II. However, the most advanced of these have all recently failed, while the remainder have demonstrated plausible efficacy only in small underpowered studies, and much research remains to both establish their efficacy and get them to the clinic. The development of better-targeted (‘smarter’) drugs appears to be the best hope for renoprotective therapy in the future.

The need for new approaches to manage the increasing numbers of patients with diabetes and their burden of complications is urgent. Of these, chronic kidney disease imposes some of the highest costs, both in dollars and in terms of human suffering. In individuals with diabetes, the presence and severity of kidney disease adversely affects their well-being, contributes to disease morbidity and increases their risk of a premature death.To collect information for the strategies previously or currently under investigation for managing kidney disease in patients with diabetes, a literature search was performed through the search engines PubMed and ClinicalTrials.gov.Despite advancing knowledge on the pathogenesis of diabetic kidney disease, and promising effects in experimental models, at present there are no new drugs that come close to providing the solutions we desire for our patients. Even when used in combination with standard care, renal complications are at best only modestly reduced, at the considerable expense of additional pill burden and exposure to serious off-target effects. Some of the most exciting advances over the last decade, including thiazolidinediones, direct renin inhibitors, endothelin antagonists and most recently bardoxolone methyl have all fallen at this last hurdle. Better targeted ('smarter') drugs appear to be the best hope for renoprotective therapy.

The kidney is arguably the most important target of microvascular damage in diabetes. At least half of all patients with type 2 diabetes mellitus and one-third of those with type 1 diabetes will develop kidney disease owing to their disease and/or other comorbidity, including hypertension, dyslipidaemia, obesity, intra-renal vascular disease, glomerular atherosclerosis, renal ischaemia or ageing-related nephron loss. The presence and severity of chronic kidney disease (CKD) identify individuals who are at increased risk for adverse health outcomes and premature mortality. Consequently, preventing and managing CKD in patients with diabetes is now a key aim of their overall management. Intensive management of patients with diabetes includes controlling blood glucose levels and blood pressure as well as blockade of the renin–angiotensin–aldosterone system; these approaches will reduce the incidence of diabetic kidney disease and slow its progression. Indeed, the major decline in the incidence of diabetic kidney disease over the past thirty years and improved patient prognosis is largely attributable to improved diabetes care. However, an unmet need remains for innovative treatment strategies for preventing, arresting, treating and reversing diabetic kidney disease. In this Primer, we summarize what is now known about the molecular pathogenesis of CKD in diabetic patients and the key pathways and targets implicated in its progression. In addition, we discuss the current evidence for the prevention and management of diabetic kidney disease as well as the many controversies. Finally, we explore the opportunities to develop new interventions through urgently needed investment in dedicated and focused research. For an illustrated summary of this Primer, visit: go.nature.com/NKHDzg

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.

The coordinated activation of Nrf-2-dependent signaling pathway is currently being investigated in a range of chronic diseases. Bardoxolone methyl is a potent, orally bioavailable Nrf-2 agonist. In a recent 52-week study, treatment with bardoxolone methyl improved renal function in patients with chronic kidney disease (CKD) and type 2 diabetes. This improvement was sustained for the duration of the treatment. Such agonists potentially offer new options for the complex management of renal impairment.A literature search was performed to analyze the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of bardoxolone methyl in both healthy volunteers and patients. Updated information about bardoxolone methyl, either after single administration or after chronic administration is also included. A special focus has been put on the putative mechanisms of action and potential toxicity profiles as well as an ongoing trials in patients with CKD and type 2 diabetes.The development of an agent that leads to sustained improvement in renal function comes as a welcome relief to the millions of individuals with diabetes and CKD. However, much remains to be established regarding its actions in a complex and pleiotropic signalling cascade. Other triterpenoids with different PK/PD profiles are currently under development.

Electronic supplementary material: The online version of this article (doi:10.1007/s00125-012-2570-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Aims/hypothesis: We investigated the contribution of AGEs to the impairment of reverse cholesterol transport (RCT) variables in diabetic individuals and in two animal models of diabetic obesity and of renal impairment. Conclusions/interpretation: AGEs are unlikely to contribute significantly to the impairment of RCT in type 2 diabetes. Methods: The capacity of plasma and HDL from 26 individuals with moderately controlled type 2 diabetes to support cholesterol efflux was compared with 26 age- and sexmatched individuals without diabetes. We also compared the rates of RCT in vivo in two animal models: db/db mice and mice with chronic renal failure. Results: Diabetic individuals had characteristic dyslipidaemia and higher levels of plasma AGEs. The capacity of whole plasma, ApoB-depleted plasma and isolated HDL to support cholesterol efflux was greater for diabetic patients compared with controls despite their lower HDL-cholesterol levels. The capacity of plasma to support cholesterol efflux correlated with plasma levels of cholesteryl ester transfer protein and levels of ApoB, but not with levels of AGE. RCT was severely impaired in db/db mice despite elevated HDL-cholesterol levels and no change in AGE concentration, whereas RCT in uraemic mice was unaffected despite elevated AGE levels. Refereed/Peer-reviewed

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.

Pharmaceutical agonists of peroxisome proliferator-activated receptors (PPARs) are widely used in the management of type 2 diabetes, chiefly as lipid-lowering agents and oral hypoglycaemic agents. Although most of the focus has been placed on their cardiovascular effects, both positive and negative, these agents also have significant renoprotective actions in the diabetic kidney. Over and above action on metabolic control and effects on blood pressure, PPAR agonists also appear to have independent effects on a number of critical pathways that are implicated in the development and progression of diabetic kidney disease, including oxidative stress, inflammation, hypertrophy, and podocyte function. This review will examine these direct and indirect actions of PPAR agonists in the diabetic kidney and explore recent findings of clinical trials of PPAR agonists in patients with diabetes.

Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin-converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1–7 (Ang 1–7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1–7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection.

SUMMARY There is clear evidence for the pathogenic role of the renin–angiotensin system (RAS) in the progression of diabetic kidney. Treatment with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker have been shown to reduce proteinuria and preserve renal function in patients with diabetes and chronic kidney disease. While such data provide a strong rationale for early and sustained blockade of the RAS for the primary prevention of kidney disease, clinical trial evidence to support this goal is limited and inconsistent. By contrast, data from observational and clinical trials clearly demonstrate the primacy of blood-pressure control in the development of diabetic kidney disease, especially in hypertensive patients. Whether RAS blockade offers additional benefits for primary prevention, over-and-above blood-pressure control, remains contentious. At best, any ‘independent effects’ on primary prevention are modest, and certainly not the panacea envisaged by many practitioners. ...

Heart failure mortality is significantly increased in patients with baseline renal impairment and those with underlying heart failure who subsequently develop renal dysfunction. This accelerated progression occurs independent of the cause or grade of renal dysfunction and baseline risk factors. Recent large prospective databases have highlighted the depth of the current problem, while longitudinal population studies support an increasing disease burden. We have extensively reviewed the epidemiological and therapeutic data among these patients. The evidence points to a progression of heart failure early in renal impairment, even in the albuminuric stage. The data also support poor prescription of prognostic therapies. As renal function is the most important prognostic factor in heart failure, it is important to establish the current understanding of the disease burden and the therapeutic implications.

The prevalence of diabetic nephropathy, a serious complication of diabetes, has been increasing worldwide. Therefore, there is an urgent need to identify a new therapeutic target to prevent diabetic nephropathy. “Nutrient-sensing” pathways are generally well conserved among eukaryotes. Accumulating evidence indicates that alteration of nutrient-sensing pathways and subsequent impairment of cell function in insulin-sensitive organs of mammals are involved in the pathogenesis of type 2 diabetes. According to recent reports, nutrient-sensing in the kidney also seems to be altered under diabetic conditions. In this review, we discuss the possibility that nutrient-sensing pathways can be a therapeutic target for diabetic nephropathy and suggest future directions for research. Each cell has the ability to recognize and specifically respond to nutrient fuel substrates, such as glucose, lipids, and amino acids, to ensure their efficient use. These nutrient-sensing pathways appear critical for cellular homeostasis, for coping with starvation, and making the most of nutrient abundance. These pathways also represent important regulators of cell growth and proliferation, motility, mitochondrial function, autophagy, and survival (1–4). Nutrient sensing is highly conserved across eukaryotic species. These pervasive regulatory pathways use posttranslational modifications of target proteins to link substrate availability to cellular homeostasis and stress responses (1–4). The best known of these pathways include the mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and the sirtuins (SIRT). Under low-energy conditions, AMPK and SIRT are activated by increases in intracellular AMP and NAD+ levels, respectively (1,2). In excessive nutrient conditions, mTOR is activated (3,4). Each of these nutrient-sensing pathways has been implicated in the pathogenesis of obesity and diabetes, including actions on β-cell, adipocyte, hepatic and skeletal muscle metabolism, and the central regulation of nutrition (1–4). However, the same pathways may also be directly relevant to …

Forsblom C, Thomas MC, Moran J, Saraheimo M, Thorn L, Waden J, Gordin D, Frystyk J, Flyvbjerg A, Groop P-H, on behalf of the FinnDiane Study Group (Folkhalsan Institute of Genetics, Helsinki; Department of Medicine Helsinki University Central Hospital, Helsinki, Finland; The Baker IDI Heart and Diabetes Institute, Melbourne, Vic.; The Queen Elizabeth Hospital, Woodville, SA, Australia; and Aarhus University Hospital, Aarhus C., Denmark). Serum adiponectin concentration is a positive predictor of all-cause and cardiovascular mortality in type 1 diabetes. J Intern Med 2011; 270: 346–355. Background. Adiponectin is widely regarded as an anti-atherogenic, antioxidant and anti-inflammatory molecule. However, adiponectin concentration is paradoxically increased in individuals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes. Objective. To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes. Design. Multicentre prospective cohort study. Setting. Primary and tertiary care. Subjects. Finnish adults with type 1 diabetes (n = 2034). Main outcome measures. All-cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models. Results. During a median of 11 years of follow-up, there were 173 deaths (8.5%, 1.0 per hundred person-years). Adiponectin was linearly associated with all-cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01–1.03, P

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.

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.

Background: The intestinal vitamin D receptor (VDR) remains poorly characterized in patients with inflammatory bowel disease (IBD). Methods: Colonoscopic biopsies and intestinal resection specimens from the terminal ileum, ascending and sigmoid colon, from patients with and without IBD, were analyzed for VDR mRNA quantification by polymerase chain reaction, and protein localization and semi-quantification by immunohistochemistry. The relationship between VDR and intestinal inflammation, serum 25(OH)D and oral vitamin D intake was elicited. Results: A total of 725 biopsies from 20 patients with Crohn’s disease (CD), 15 with ulcerative colitis (UC) and 14 non-IBD controls who underwent colonoscopy were studied. VDR gene expression and protein staining intensity was similar across all three groups, and across the intestinal segments. Sigmoid colon VDR mRNA expression inversely correlated with faecal calprotectin ( r = −0.64, p = 0.026) and histological score ( r = −0.67, p = 0.006) in UC, and histological score ( r = −0.58, p = 0.019) in patients with CD. VDR staining intensity was higher in quiescent than diseased segments. No relationship with serum 25(OH)D or oral vitamin D intake was noted. Immunohistochemical staining of 28 intestinal resection specimens from 15 patients (5 each with CD, UC and non-IBD controls) showed diffuse VDR staining in the mucosa, submucosa and circular muscle. Conclusions: VDR transcript expression and protein staining intensity are inversely related to inflammation in IBD, but unrelated to serum 25(OH)D, and similar to non-IBD controls. Strategies to upregulate intestinal VDR, potentially translating to modulation of disease activity, require investigation.