Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis.

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-Chi 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.

Severe acute respiratory syndrome coronavirus 2 as a potential cause of type 1 diabetes facilitated by spike protein receptor binding domain attachment to human islet cells: An illustrative case study and experimental data.

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.

Empagliflozin modulates renal sympathetic and heart rate baroreflexes in a rabbit model of diabetes.

AIMS/HYPOTHESIS: We determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits. METHODS: Diabetes was induced by alloxan, and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1 week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits. RESULTS: Four weeks after alloxan administration, blood glucose was threefold and MAP 9% higher than non-diabetic controls (p < 0.05). One week of treatment with empagliflozin produced a stable fall in blood glucose (-43%) and increased water intake (+49%) but did not change RSNA, MAP or heart rate compared with untreated diabetic rabbits. The maximum RSNA to hypotension was augmented by 75% (p < 0.01) in diabetic rabbits but the heart rate baroreflex was unaltered. Empagliflozin and acetazolamide reduced the augmentation of the RSNA baroreflex (p < 0.05) to be similar to the non-diabetic group. Noradrenaline (norepinephrine) spillover was similar in untreated diabetic and non-diabetic rabbits but twofold greater in empagliflozin- and acetazolamide-treated rabbits (p < 0.05). CONCLUSIONS/INTERPRETATION: As empagliflozin can restore diabetes-induced augmented sympathetic reflexes, this may be beneficial in diabetic patients. A similar action of the diuretic acetazolamide suggests that the mechanism may involve increased sodium and water excretion. Graphical abstract.

Non-invasive Risk Stratification for Coronary Artery Disease: Is It Time for Subclassifications?

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure.

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.

Risk of coronary artery disease and stroke according to sex and presence of diabetic nephropathy in type 1 diabetes.

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.

Resveratrol Inhibits Growth of Experimental Abdominal Aortic Aneurysm Associated With Upregulation of Angiotensin-Converting Enzyme 2.

OBJECTIVE: Recent evidence suggests an important role for angiotensin-converting enzyme 2 (ACE2) in limiting abdominal aortic aneurysm (AAA). This study examined the effect of ACE2 deficiency on AAA development and the efficacy of resveratrol to upregulate ACE2 in experimental AAA. APPROACH AND RESULTS: Ace2 deletion in apolipoprotein-deficient mice (ApoE-/-Ace2-/y ) resulted in increased aortic diameter and spontaneous aneurysm of the suprarenal aorta associated with increased expression of inflammation and proteolytic enzyme markers. In humans, serum ACE2 activity was negatively associated with AAA diagnosis. ACE2 expression was lower in infrarenal biopsies of patients with AAA than organ donors. AAA was more severe in ApoE-/-Ace2-/y mice compared with controls in 2 experimental models. Resveratrol (0.05/100-g chow) inhibited growth of pre-established AAAs in ApoE-/- mice fed high-fat chow and infused with angiotensin II continuously for 56 days. Reduced suprarenal aorta dilatation in mice receiving resveratrol was associated with elevated serum ACE2 and increased suprarenal aorta tissue levels of ACE2 and sirtuin 1 activity. In addition, the relative phosphorylation of Akt and ERK (extracellular signal-regulated kinase) 1/2 within suprarenal aorta tissue and gene expression for nuclear factor of kappa light polypeptide gene enhancer in B cells 1, angiotensin type-1 receptor, and metallopeptidase 2 and 9 were significantly reduced. Upregulation of ACE2 in human aortic smooth muscle cells by resveratrol in vitro was sirtuin 1-dependent. CONCLUSIONS: This study provides experimental evidence of an important role for ACE2 in limiting AAA development and growth. Resveratrol upregulated ACE2 and inhibited AAA growth in a mouse model.

Management of patients with diabetes and CKD: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.

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.

Epigenetic Mechanisms in Diabetic Kidney Disease.

Progressive kidney disease is a common companion to both type 1 and type 2 diabetes. However, the majority of people with diabetes do not develop diabetic kidney disease. This may in part be explained by good control of glucose, blood pressure, obesity and other risk factors for kidney disease. It may also be partly due to their genetic makeup or ethnicity. However, the vast majority of the variability in incident nephropathy remains unaccounted for by conventional risk factors or genetics. Epigenetics has recently emerged as an increasingly powerful paradigm to understand and potentially explain complex non-Mendelian conditions-including diabetic kidney disease. Persistent epigenetic changes can be acquired during development or as adaptations to environmental exposure, including metabolic fluctuations associated with diabetes. These epigenetic modifications-including DNA methylation, histone modifications, non-coding RNAs and other changes in chromatin structure and function-individually and co-operatively act to register, store, retain and recall past experiences in a way to shape the transcription of specific genes and, therefore, cellular functions. This review will explore the emerging evidence for the role of epigenetic modifications in programming the legacy of hyperglycaemia for kidney disease in diabetes.

Angiotensin-converting enzyme 2 mediates hyperfiltration associated with diabetes.

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.

Transforming growth factor-ß1-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b.

Renal fibrosis results from excessive accumulation of extracellular matrix mainly driven by transforming growth factor-ß1 (TGF-ß1). Certain microRNAs have been implicated in this disease, and here we examine the role of let-7b. Rat proximal tubular epithelial cells (NRK52E) were treated with TGF-ß1 for 3 days to assess the expression of markers of fibrosis and let-7b. These factors were also assessed in two mouse models representing early and more advanced diabetic nephropathy and in the non-diabetic adenine-induced renal fibrosis model. TGF-ß1 downregulated the expression of let-7b and induced fibrogenesis in NRK52E cells. Ectopic expression of let-7b repressed TGF-ß1 receptor 1 (TGFBR1) expression directly by targeting the two let-7b binding sites in the 3'-untranslated region of that gene, reduced expression of extracellular matrix proteins, decreased SMAD3 activity, and attenuated the profibrotic effects of TGF-ß1. Knockdown of let-7b elevated TGFBR1 expression and mimicked some of the profibrotic effects of TGF-ß1. Consistent with these observations, let-7b expression was also reduced in models of both diabetic and non-diabetic renal fibrosis with the upregulation of TGFBR1. Thus, let-7b microRNA represents a potential new target for the treatment of renal fibrosis in diabetic and non-diabetic nephropathy.

Role of bone-marrow- and non-bone-marrow-derived receptor for advanced glycation end-products (RAGE) in a mouse model of diabetes-associated atherosclerosis.

RAGE (receptor for advanced glycation end-products) is expressed on multiple cell types implicated in the progression of atherosclerosis and plays a role in DAA (diabetes-associated atherosclerosis). The aim of the present study was to determine the relative role of either BM (bone marrow)- or non-BM-derived RAGE in the pathogenesis of STZ (streptozotocin)-induced DAA. Male ApoE (apolipoprotein E)-null (ApoE-/-:RAGE+/+) and ApoE:RAGE-null (ApoE-/-:RAGE-/-) mice at 7 weeks of age were rendered diabetic with STZ. At 8 weeks of age, ApoE-/- and ApoE-/-:RAGE-/- control and diabetic mice received BM from either RAGE-null or RAGE-bearing mice, generating various chimaeras. After 10 and 20 weeks of diabetes, mice were killed and gene expression and atherosclerotic lesion formation were evaluated respectively. Deletion of RAGE in either the BM cells or non-BM cells both resulted in a significant attenuation in DAA, which was associated with reduced VCAM-1 (vascular cell adhesion molecule-1) expression and translated into reduced adhesion in vitro. In conclusion, the results of the present study highlight the importance of both BM- and non-BM-derived RAGE in attenuating the development of DAA.

Distinguishing hyperglycemic changes by Set7 in vascular endothelial cells.

RATIONALE: Epigenetic changes are implicated in the persisting vascular effects of hyperglycemia. The precise mechanism whereby chromatin structure and subsequent gene expression are regulated by glucose in vascular endothelial cells remain to be fully defined. OBJECTIVE: We have studied the molecular and functional mechanism whereby the Set7 methyltransferase associates with chromatin formation and histone methylation in vascular cells in response to current and previous exposure to glucose. METHODS AND RESULTS: To characterize the molecular and functional identity of the Set7 protein, we used vascular cells overexpressing or lacking Set7. Chromatin fractionation for mono-methylation of lysine 4 on histone H3 identified methyltransferase activity. Immunofluorescence experiments strongly suggest that Set7 protein accumulates in the nucleus in response to hyperglycemia. Moreover, activation of proinflammatory genes by high glucose is dependent on Set7 but distinguished by H3K4m1 gene patterns. We show that transient hyperglycemia regulates the expression of proinflammatory genes in vascular endothelial cells in vitro and the persistent increase in glucose-induced gene expression in the aorta of nondiabetic mice. CONCLUSIONS: This study uncovers that the response to hyperglycemia in vascular endothelial cells involves the H3K4 methyltransferase, Set7. This enzyme appears to regulate glucose-induced chromatin changes and gene expression not only by H3K4m1-dependent but also H3K4m1-independent pathways. Furthermore, Set7 appears to be responsible for sustained vascular gene expression in response to prior hyperglycemia and is a potential molecular mechanism for the phenomenon of hyperglycemic memory.

Genetic deletion of cell division autoantigen 1 retards diabetes-associated renal injury.

Cell division autoantigen 1 (CDA1) enhances TGF-ß 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-ß1, TGF-ß 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-ß1 receptors in the kidney, resulting in a functionally attenuated response to exogenous TGF-ß, 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-ß signaling. Because direct antagonism of TGF-ß or its receptors has unwanted effects, CDA1 may be a potential therapeutic target for retarding DN and perhaps, other kidney diseases associated with TGF-ß-mediated fibrogenesis.

Empagliflozin and Rapid Kidney Function Decline Incidence in Type 2 Diabetes: An Exploratory Analysis From the EMPA-REG OUTCOME Trial.

Rationale & Objective: Kidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a "rapid decliner" phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of >3 mL/min/1.73 m2. Study Design: This was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of ≥30 mL/min/1.73 m2. Setting & Participants: Analysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available. Interventions: Patients were randomized (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo in addition to standard of care. Outcomes: Annual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups. Results: Over the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P < 0.001) among participants receiving empagliflozin versus placebo. A comparable risk reduction was observed using a threshold of eGFR decline of >5 mL/min/1.73 m2/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P < 0.001). Limitations: This is a post hoc analysis of a trial undertaken in participants with T2DM and CVD. Generalization of findings to other settings remains to be established. Conclusions: Patients receiving empagliflozin were significantly less likely to experience a rapid decline in eGFR over a median of 2.6 years of exposure to the study drug. Funding: The Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Trial Registration: clinicaltrials.gov ID: NCT01131676.

In most people with type 2 diabetes, their kidney function starts to decline over time. However, in some people, this can happen more rapidly, which can increase their risk of kidney or cardiovascular disease. A major study, EMPA-REG OUTCOME, has shown that empagliflozin, which helps to control blood sugar in people with type 2 diabetes, also reduced the risk of cardiovascular disease events and slowed the progression of kidney disease, when compared with people in the study who received placebo. In this new research from the same major study empagliflozin, compared with a placebo, was shown to reduce the risk of people having a rapid decline in their kidney function over the 3 years of the study.

Association of dietary sodium intake with atherogenesis in experimental diabetes and with cardiovascular disease in patients with Type 1 diabetes.

It is recommended that individuals with diabetes restrict their dietary sodium intake. However, although salt intake is correlated with BP (blood pressure), it also partly determines the activation state of the RAAS (renin-angiotensin-aldosterone system), a key mediator of diabetes-associated atherosclerosis. apoE KO (apolipoprotein E knockout) mice were allocated for the induction of diabetes with streptozotocin or citrate buffer (controls) and further randomized to isocaloric diets containing 0.05%, 0.3% or 3.1% sodium with or without the ACEi [ACE (angiotensin-converting enzyme) inhibitor] perindopril. After 6 weeks of study, plaque accumulation was quantified and markers of atherogenesis were assessed using RT-PCR (reverse transcription-PCR) and ELISA. The association of sodium intake and adverse cardiovascular and mortality outcomes were explored in 2648 adults with Type 1 diabetes without prior CVD (cardiovascular disease) from the FinnDiane study. A 0.05% sodium diet was associated with increased plaque accumulation in diabetic apoE KO mice, associated with activation of the RAAS. By contrast, a diet containing 3.1% sodium suppressed atherogenesis associated with suppression of the RAAS, with an efficacy comparable with ACE inhibition. In adults with Type 1 diabetes, low sodium intake was also associated with an increased risk of all-cause mortality and new-onset cardiovascular events. However, high sodium intake was also associated with adverse outcomes, leading to a J-shaped relationship overall. Although BP lowering is an important goal for the management of diabetes, off-target actions to activate the RAAS may contribute to an observed lack of protection from cardiovascular complications in patients with Type 1 diabetes with low sodium intake.

Emerging drugs for managing kidney disease in patients with diabetes.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Coeliac disease, gluten-free diet and the development and progression of albuminuria in children with type 1 diabetes.

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.

The postprandial actions of GLP-1 receptor agonists: The missing link for cardiovascular and kidney protection in type 2 diabetes.

Recent clinical trials in people with type 2 diabetes have demonstrated beneficial actions on heart and kidney outcomes following treatment with GLP-1RAs. In part, these actions are consistent with improved glucose control and significant weight loss. But GLP-1RAs may also have additive benefits by improving postprandial dysmetabolism. In diabetes, dysregulated postprandial nutrient excursions trigger inflammation, oxidative stress, endothelial dysfunction, thrombogenicity, and endotoxemia; alter hormone levels; and modulate cardiac output and regional blood and lymphatic flow. In this perspective, we explore the actions of GLP-1RAs on the postprandial state and their potential role in end-organ benefits observed in recent trials.

SGLT2 inhibitors for patients with type 2 diabetes and CKD: a narrative review.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have recently emerged as an effective means to protect kidney function in people with type 2 diabetes and chronic kidney disease (CKD). In this review, we explore the role of SGLT2 inhibition in these individuals. SGLT2 inhibitors specifically act to inhibit sodium and glucose reabsorption in the early proximal tubule of the renal nephron. Although originally developed as glucose-lowering agents through their ability to induce glycosuria, it became apparent in cardiovascular outcome trials that the trajectory of kidney function decline was significantly slowed and the incidence of serious falls in kidney function was reduced in participants receiving an SGLT2 inhibitor. These observations have recently led to specific outcome trials in participants with CKD, including DAPA-CKD, CREDENCE and EMPA-KIDNEY, and real-world studies, like CVD-REAL-3, that have confirmed the observation of kidney benefits in this setting. In response, recent KDIGO Guidelines have recommended the use of SGLT2 inhibitors as first-line therapy in patients with CKD, alongside statins, renin-angiotensin-aldosterone system inhibitors and multifactorial risk factor management as indicated. However, SGLT2 inhibitors remain significantly underutilized in the setting of CKD. Indeed, an inertia paradox exists, with patients with more severe disease less likely to receive an SGLT2 inhibitor. Concerns regarding safety appear unfounded, as acute kidney injury, hyperkalaemia, major acute cardiovascular events and cardiac death in patients with CKD appear to be lower following SGLT2 inhibition. The first-in-class indication of dapagliflozin for CKD may begin a new approach to managing kidney disease in type 2 diabetes.