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Diabetic cardiomyopathy is characterised in its early stages by diastolic relaxation abnormalities and later by clinical heart failure in the absence of dyslipidaemia, hypertension and coronary artery disease. Insulin resistance, hyperinsulinaemia and hyperglycaemia are each independent risk factors for the development of diabetic cardiomyopathy. The pathophysiological factors in diabetes that drive the development of cardiomyopathy include systemic metabolic disorders, inappropriate activation of the renin–angiotensin–aldosterone system, subcellular component abnormalities, oxidative stress, inflammation and dysfunctional immune modulation. These abnormalities collectively promote cardiac tissue interstitial fibrosis, cardiac stiffness/diastolic dysfunction and, later, systolic dysfunction, precipitating the syndrome of clinical heart failure. Recent evidence has revealed that dysregulation of coronary endothelial cells and exosomes also contributes to the pathology behind diabetic cardiomyopathy. Herein, we review the relationships among insulin resistance/hyperinsulinaemia, hyperglycaemia and the development of cardiac dysfunction. We summarise the current understanding of the pathophysiological mechanisms in diabetic cardiomyopathy and explore potential preventative and therapeutic strategies.

Key Points Reported rises in the prevalence of diabetic cardiomyopathy among developed nations have occurred in parallel with increased rates of obesity, insulin resistance and hyperinsulinaemia Insulin resistance and/or hyperinsulinaemia seem to underpin the development of diabetic cardiomyopathy, which is initially characterized by diastolic dysfunction in the absence of coronary artery disease and hypertension Pathophysiological mechanisms include impaired insulin signalling, cardiac mitochondrial dysfunction, endoplasmic reticulum stress, impaired autophagy, impaired myocardial calcium handling, abnormal coronary microcirculation, inappropriate neurohumoral activation and maladaptive immune responses Insulin resistance, or hyperinsulinaemia, independently predisposes to the development of diabetic cardiomyopathy and targeting insulin resistance or hyperinsulinaemia could be a potential therapeutic strategy to prevent the development of diabetic cardiomyopathy Diabetic cardiomyopathy is a major cause of morbidity and mortality, and its prevalence is increasing. This Review discusses the latest research in diabetic cardiomyopathy, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies. Insulin resistance, type 2 diabetes mellitus and associated hyperinsulinaemia can promote the development of a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Termed diabetic cardiomyopathy, this form of cardiomyopathy is a major cause of morbidity and mortality in developed nations, and the prevalence of this condition is rising in parallel with increases in the incidence of obesity and type 2 diabetes mellitus. Of note, female patients seem to be particularly susceptible to the development of this complication of metabolic disease. The diabetic cardiomyopathy observed in insulin- resistant or hyperinsulinaemic states is characterized by impaired myocardial insulin signalling, mitochondrial dysfunction, endoplasmic reticulum stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system, activation of the renin–angiotensin–aldosterone system and maladaptive immune responses. These pathophysiological changes result in oxidative stress, fibrosis, hypertrophy, cardiac diastolic dysfunction and eventually systolic heart failure. This Review highlights a surge in diabetic cardiomyopathy research, summarizes current understanding of the molecular mechanisms underpinning this condition and explores potential preventive and therapeutic strategies.

Background Bread wheat ( Triticum aestivum ) is an allohexaploid that is generated by two subsequent allopolyploidization events. The large genome size (16 Gb) and polyploid complexity impede our understanding of how regulatory elements and their interactions shape chromatin structure and gene expression in wheat. The open chromatin enrichment and network Hi-C (OCEAN-C) is a powerful antibody-independent method to detect chromatin interactions between open chromatin regions throughout the genome. Results Here we generate open chromatin interaction maps for hexaploid wheat and its tetraploid and diploid relatives using OCEAN-C. The anchors of chromatin loops show high chromatin accessibility and are concomitant with several active histone modifications, with 67% of them interacting with multiple loci. Binding motifs of various transcription factors are significantly enriched in the hubs of open chromatin interactions (HOCIs). The genes linked by HOCIs represent higher expression level and lower coefficient expression variance than the genes linked by other loops, which suggests HOCIs may coordinate co-expression of linked genes. Thousands of interchromosomal loops are identified, while limited interchromosomal loops (0.4%) are identified between homoeologous genes in hexaploid wheat. Moreover, we find structure variations contribute to chromatin interaction divergence of homoeologs and chromatin topology changes between different wheat species. The genes with discrepant chromatin interactions show expression alteration in hexaploid wheat compared with its tetraploid and diploid relatives. Conclusions Our results reveal open chromatin interactions in different wheat species, which provide new insights into the role of open chromatin interactions in gene expression during the evolution of polyploid wheat.

Background Arterial stiffness is emerging as an independent risk factor for the development of chronic kidney disease. The sodium glucose co-transporter 2 (SGLT2) inhibitors, which lower serum glucose by inhibiting SGLT2-mediated glucose reabsorption in renal proximal tubules, have shown promise in reducing arterial stiffness and the risk of cardiovascular and kidney disease in individuals with type 2 diabetes mellitus. Since hyperglycemia contributes to arterial stiffness, we hypothesized that the SGLT2 inhibitor empagliflozin (EMPA) would improve endothelial function, reduce aortic stiffness, and attenuate kidney disease by lowering hyperglycemia in type 2 diabetic female mice (db/db). Materials/methods Ten-week-old female wild-type control (C57BLKS/J) and db/db (BKS.Cg-Dock7m+/+Leprdb/J) mice were divided into three groups: lean untreated controls (CkC, n = 17), untreated db/db (DbC, n = 19) and EMPA-treated db/db mice (DbE, n = 19). EMPA was mixed with normal mouse chow at a concentration to deliver 10 mg kg −1  day −1 , and fed for 5 weeks, initiated at 11 weeks of age. Results Compared to CkC, DbC showed increased glucose levels, blood pressure, aortic and endothelial cell stiffness, and impaired endothelium-dependent vasorelaxation. Furthermore, DbC exhibited impaired activation of endothelial nitric oxide synthase, increased renal resistivity and pulsatility indexes, enhanced renal expression of advanced glycation end products, and periarterial and tubulointerstitial fibrosis. EMPA promoted glycosuria and blunted these vascular and renal impairments, without affecting increases in blood pressure. In addition, expression of “reversion inducing cysteine rich protein with Kazal motifs” (RECK), an anti-fibrotic mediator, was significantly suppressed in DbC kidneys and partially restored by EMPA. Confirming the in vivo data, EMPA reversed high glucose-induced RECK suppression in human proximal tubule cells. Conclusions Empagliflozin ameliorates kidney injury in type 2 diabetic female mice by promoting glycosuria, and possibly by reducing systemic and renal artery stiffness, and reversing RECK suppression.

Bone morphogenic protein-2 (BMP-2) is the most documented member of BMP family and plays a crucial role in bone formation and growth. In this study, we systematically analyze and compare the complex crystal structures and interaction properties of BMP-2 with its cognate receptors BMPR-I/BMPR-II and with its natural antagonist crossveinless-2 (CV-2) using an integrated in silico-in vitro strategy. It is found that the antagonist-binding site is not fully overlapped with the two receptor-binding sites on BMP-2 surface; the antagonist can competitively disrupt BMP-2–BMPR-II interaction using a blocking-out-of-site manner, but has no substantial influence on BMP-2–BMPR-I interaction. Here, the antagonist-binding site is assigned as a new functional epitope armpit to differ from the traditional conformational epitope wrist and linear epitope knuckle at receptor-binding sites. Structural analysis reveals that the armpit comprises three sequentially discontinuous, structurally vicinal peptide segments, separately corresponding to a loop region and two β-strands crawling on the protein surface. The three segments cannot work independently when splitting from the protein context, but can restore binding capability to CV-2 if they are connected to a single peptide. A systematic combination of different-length polyglycine linkers between these segments obtains a series of designed single peptides, from which several peptides that can potently interact with the armpit-recognition site of CV-2 with high affinity and specificity are identified using energetic analysis and fluorescence assay; they are expected to target BMP-2–CV-2 interaction in a self-inhibitory manner.

Objective Cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy. Methods Sixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg −1 •day −1 ; ZOSV); Group 3: valsartan (31 mg•kg −1 •day −1 ; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg −1 •day −1 ; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. Results Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD. Conclusions These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

Vascular disease is the leading cause of morbidity and mortality in the Western world, and vascular function is determined by structural and functional properties of the arterial vascular wall. Cardiorenal metabolic syndrome such as obesity, diabetes, hypertension, kidney disease, and aging are conditions that predispose to arterial stiffening, which is a pathological alteration of the vascular wall and ultimately results in target organ damage in heart and kidney. In this review, we provide new insights on the interactions between arterial stiffness, vascular resistance and pulse wave velocity as well as final end-organ damage in heart and kidney. Better understanding of the mechanisms of arterial functional and hemodynamic alteration may help in developing more refined therapeutic strategies aimed to reduce cardiovascular and chronic kidney diseases.

Excess blood lipids increase the total intramyocellular (IMC) lipid content and ectopic fat storage resulting in lipotoxicity and insulin resistance in skeletal muscle, which is one of the main targets of insulin whose action is central for the maintenance of glucose homeostasis. Consumption of a diet high in fat and refined sugars, a Western Diet (WD), has been shown to activate mineralocorticoid receptors (MRs) to promote insulin resistance. However, our understanding of the precise mechanisms by which enhanced MR activation promotes skeletal muscle insulin resistance remains unclear. In this study we investigated the roles and mechanisms by which enhanced MR signaling in soleus muscle promotes ectopic lipid accumulation and related insulin resistance in diet-induced obesity. Six week-old C57BL6J mice were fed either a mouse chow diet or WD with or without spironolactone (1 mg/kg/day) for 16 weeks. Spironolactone attenuated 16 weeks of WD - induced in vivo glucose intolerance and improved soleus insulin metabolic signaling (protein kinase B and AMP kinase α pathways). Improved insulin sensitivity was accompanied by increased Glut-4 expression in conjunction with decreased IMC lipid content and reduced free fatty acid (FFA) levels and CD36 expression in soleus skeletal muscle tissue. Related to this, miR-99a was identified to negatively target CD36(www.targetscan.org/vert_72/) and elevated CD36 induced excessive FFA uptake, ectopic lipid accumulation, as well as systemic and tissue insulin resistance. Furthermore, in skeletal muscle cells spironolactone prevented enhanced MR signaling mediated reduction of miR-99a and related increased CD36. These data indicate that inhibition of MR activation with spironolactone reversed diet - induced reduction of miR-99a, thereby reducing CD36 expression, leading to reduced IMC lipid content and improved soleus insulin sensitivity. Presentation: Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Clinical and basic studies have documented that both hyperglycemia and insulin-resistance/hyperinsulinemia not only constitute metabolic disorders contributing to cardiometabolic syndrome, but also predispose to diabetic vasculopathy, which refers to diabetes-mellitus-induced microvascular and macrovascular complications, including retinopathy, neuropathy, atherosclerosis, coronary artery disease, hypertension, and peripheral artery disease. The underlying molecular and cellular mechanisms include inappropriate activation of the renin angiotensin–aldosterone system, mitochondrial dysfunction, excessive oxidative stress, inflammation, dyslipidemia, and thrombosis. These abnormalities collectively promote metabolic disorders and further promote diabetic vasculopathy. Recent evidence has revealed that endothelial progenitor cell dysfunction, gut dysbiosis, and the abnormal release of extracellular vesicles and their carried microRNAs also contribute to the development and progression of diabetic vasculopathy. Therefore, clinical control and treatment of diabetes mellitus, as well as the development of novel therapeutic strategies are crucial in preventing cardiometabolic syndrome and related diabetic vasculopathy. The present review focuses on the relationship between insulin resistance and diabetes mellitus in diabetic vasculopathy and related cardiovascular disease, highlighting epidemiology and clinical characteristics, pathophysiology, and molecular mechanisms, as well as management strategies.