Distinct, common and synergistic effects of insulin and IGF-1 receptors on healthy murine ageing.

Objective: Reduced IGF-1 signalling is an evolutionarily conserved mediator of longevity, yet the magnitude of this effect is substantially larger in organisms retaining a common insulin and IGF-1 receptor. Whether this reflects the failure to simultaneously reduce IGF-1 and insulin signalling in mammalian model systems remains unexplored, as is the associated impact on markers of healthy ageing. We set out to address these uncertainties. Methods: We compared the duration of healthy life (healthspan) in male mice with haploinsufficiency of the insulin receptor (IRKO), IGF-1 receptor (IGF-1RKO), or both (DKO), versus wildtype (WT) littermates. Cognitive performance was defined using nesting studies at 3- and 24-months of age. Brain transcriptome was characterised at 3- and 18-months of age using RNA-seq. Results: Healthspan was longer in DKO versus WT, with IRKO and IGF-1RKO being intermediate. At 2 years of age, DKO also exhibited preserved nesting behaviour in contrast with all other genotypes. Differential insulin sensitivity or weight gain during ageing did not explain the preserved healthspan of DKO, since these were comparable to IRKO littermates. Brain transcriptomics at 18 months of age revealed lower expression of canonical ageing-associated genes in DKO versus WT, although many of these findings were replicated in IRKO versus WT or IGF-1RKO vs WT. Conclusions: Reduced insulin and IGF-1 receptor expression have both common and synergistic effects upon elements of healthy mammalian ageing, suggesting future ageing studies should consider targeting both insulin and IGF-1 signalling.

Diabetes mellitus and the causes of hospitalisation in people with heart failure.

INTRODUCTION: Diabetes mellitus (DM) is associated with increased risk of hospitalisation in people with heart failure and reduced ejection fraction (HFrEF). However, little is known about the causes of these events. METHODS: Prospective cohort study of 711 people with stable HFrEF. Hospitalisations were categorised by cause as: decompensated heart failure; other cardiovascular; infection or other non-cardiovascular. Rates of hospitalisation and burden of hospitalisation (percentage of follow-up time in hospital) were compared in people with and without DM. RESULTS: After a mean follow-up of 4.0 years, 1568 hospitalisations occurred in the entire cohort. DM (present in 32% [n=224]) was associated with a higher rate (mean 1.07 vs 0.78 per 100 patient-years; p<0.001) and burden (3.4 vs 2.2% of follow-up time; p<0.001) of hospitalisation. Cause-specific analyses revealed increased rate and burden of hospitalisation due to decompensated heart failure, other cardiovascular causes and infection in people with DM, whereas other non-cardiovascular causes were comparable. Infection made the largest contribution to the burden of hospitalisation in people with and without DM. CONCLUSIONS: In people with HFrEF, DM is associated with a greater burden of hospitalisation due to decompensated heart failure, other cardiovascular events and infection, with infection making the largest contribution.

Diabetes, gender and deterioration in estimated glomerular filtration rate in patients with chronic heart failure: Ten-year prospective cohort study.

INTRODUCTION: We aimed to evaluate the relationship between temporal changes in renal function and long-term mortality in patients with heart failure with reduced ejection fraction (HFrEF) and identify correlates of deteriorating renal function. METHODS: A total of 381 patients with HFrEF enrolled in a prospective cohort study between 2006-2014 had eGFR measured at initial visit and at 1 year. Baseline characteristics were used in a multivariate analysis to establish variables that predict deterioration in eGFR. Follow-up data were used to assess whether declining eGFR was related to outcomes. RESULTS: Patients were grouped into tertiles based on percentage change in eGFR. In a multivariate logistic regression analysis, male sex was associated with a 1.77-fold ([95% CI 1.01-2.89]; p = 0.045) and diabetes a 1.66-fold ([95% CI 1.02-2.70]; p = 0.041) greater risk of a decline in eGFR compared to those with stable/improving eGFR. Declining eGFR was associated with a 1.4-fold greater risk of death over 10 years ([95% CI 1.08-1.86]; p = 0.01) and a 3.12-fold ([1.44-6.75]; p = 0.004) greater risk of death at 1 year from second eGFR measurement. CONCLUSIONS: In patients with HFrEF diabetes and male sex are independent predictors of a decline in eGFR at 1 year. A decline eGFR over 1 year is associated with higher long-term all-cause mortality.

Diabetes mellitus is associated with adverse structural and functional cardiac remodelling in chronic heart failure with reduced ejection fraction.

BACKGROUND: Diabetes mellitus is associated with an increased risk of death and hospitalisation in patients with chronic heart failure. Better understanding of potential underlying mechanisms may aid the development of diabetes mellitus-specific chronic heart failure therapeutic strategies. METHODS: Prospective observational cohort study of 628 patients with chronic heart failure associated with left ventricular systolic dysfunction receiving contemporary evidence-based therapy. Indices of cardiac structure and function, along with symptoms and biochemical parameters, were compared in patients with and without diabetes mellitus at study recruitment and 1 year later. RESULTS: Patients with diabetes mellitus (24.2%) experienced higher rates of all-cause [hazard ratio, 2.3 (95% confidence interval, 1.8-3.0)] and chronic heart failure-specific mortality and hospitalisation despite comparable pharmacological and device-based therapies. At study recruitment, patients with diabetes mellitus were more symptomatic, required greater diuretic doses and more frequently had radiologic evidence of pulmonary oedema, despite higher left ventricular ejection fraction. They also exhibited echocardiographic evidence of increased left ventricular wall thickness and pulmonary arterial pressure. Diabetes mellitus was associated with reduced indices of heart rate variability and increased heart rate turbulence. During follow-up, patients with diabetes mellitus experienced less beneficial left ventricular remodelling and greater deterioration in renal function. CONCLUSION: Diabetes mellitus is associated with features of adverse structural and functional cardiac remodelling in patients with chronic heart failure.

Sudden cardiac death in patients with diabetes mellitus and chronic heart failure.

In patients with diabetes mellitus, around 50% of deaths due to cardiovascular causes are sudden cardiac deaths. The prevalence of diabetes in cohorts with chronic heart failure is increasing, and while sudden cardiac death is an increasingly rare mode of death in chronic heart failure patients as a whole, the risk of this outcome remains high in those with diabetes. This review summarises the current knowledge on the incidence of sudden cardiac death in patients with diabetes and chronic heart failure, before discussing the causes of the excess risk seen in those with these coexistent conditions. We then describe current strategies for risk stratification and prevention of sudden cardiac death in these patients before discussing the priorities for further study in this area.

Contemporary treatment strategies for Type 2 diabetes-related macrovascular disease.

Type 2 diabetes mellitus poses a major challenge to healthcare providers in the coming years as its prevalence increases across the globe. The disease doubles the risk of cardiovascular morbidity and mortality, with 70% of sufferers dying from a cardiac cause. Large clinical trials of current glucose-lowering therapies for Type 2 diabetes have shown no benefit in reducing the risk of macrovascular events. Blood pressure control, angiotensin-converting enzyme inhibitor therapy and improvement of dyslipidemia with statins have proven benefit in reducing cardiovascular risk in Type 2 diabetes. A growing understanding of the importance of pathological processes including endothelial dysfunction, abnormal growth factor biology, oxidative stress, dysregulation of adipokines and deficient vascular repair and regeneration in insulin-resistant states promises new treatments to combat the problem.