Mortality In Diabetic Population Research Articles

Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy.

Diabetic cardiomyopathy (DCM) is a major determinant of mortality in diabetic populations, and the potential strategies are insufficient. Canagliflozin has emerged as a potential cardioprotective agent in diabetes, yet its underlying molecular mechanisms remain unclear. We employed a high-glucose challenge (60 mM for 48 h) in vitro to rat cardiomyocytes (H9C2), with or without canagliflozin treatment (20 µM). In vivo, male C57BL/6J mice were subjected to streptozotocin and a high-fat diet to induce diabetes, followed by canagliflozin administration (10, 30 mg·kg-1·d-1) for 12 weeks. Proteomics and echocardiography were used to assess the heart. Histopathological alterations were assessed by the use of Oil Red O and Masson's trichrome staining. Additionally, mitochondrial morphology and mitophagy were analyzed through biochemical and imaging techniques. A proteomic analysis highlighted alterations in mitochondrial and autophagy-related proteins after the treatment with canagliflozin. Diabetic conditions impaired mitochondrial respiration and ATP production, alongside decreasing the related expression of the PINK1-Parkin pathway. High-glucose conditions also reduced PGC-1α-TFAM signaling, which is responsible for mitochondrial biogenesis. Canagliflozin significantly alleviated cardiac dysfunction and improved mitochondrial function both in vitro and in vivo. Specifically, canagliflozin suppressed mitochondrial oxidative stress, enhancing ATP levels and sustaining mitochondrial respiratory capacity. It activated PINK1-Parkin-dependent mitophagy and improved mitochondrial function via increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Notably, PINK1 knockdown negated the beneficial effects of canagliflozin on mitochondrial integrity, underscoring the critical role of PINK1 in mediating these protective effects. Canagliflozin fosters PINK1-Parkin mitophagy and mitochondrial function, highlighting its potential as an effective treatment for DCM.

Lysosomal dysfunction in diabetic cardiomyopathy.

Diabetes is a major risk factor for a variety of cardiovascular complications, while diabetic cardiomyopathy, a disease specific to the myocardium independent of vascular lesions, is an important causative factor for increased risk of heart failure and mortality in diabetic populations. Lysosomes have long been recognized as intracellular trash bags and recycling facilities. However, recent studies have revealed that lysosomes are sophisticated signaling hubs that play remarkably diverse roles in adapting cell metabolism to an ever-changing environment. Despite advances in our understanding of the physiological roles of lysosomes, the events leading to lysosomal dysfunction and how they relate to the overall pathophysiology of the diabetic heart remain unclear and are under intense investigation. In this review, we summarize recent advances regarding lysosomal injury and its roles in diabetic cardiomyopathy.

Prevalence and associated factors of diabetic nephropathy at Tikur Anbessa Comprehensive Specialized University Hospital, Addis Ababa, Ethiopia

ntroduction: Given the global prevalence of diabetes, diabetic nephropathy and its consequences are among the major causes of morbidity and mortality in diabetic populations. However, the prevalence and determinants of diabetic nephropathy in Ethiopia are little studied, and were the main objectives of this study. Methods: A cross-sectional study design was followed among 340 randomly selected diabetic patients attending the national diabetes referral clinics at the diabetes centre of Tikur Anbessa Specialized Hospital, Addis Ababa, using an interviewer-administered structured questionnaire. A total of 340 patients were involved, of whom 200 (59%) were females and 256 (75%) had type 2 diabetes mellitus. Urine and blood samples were drawn from the study population and the corresponding biochemical analyses were conducted at the Ethiopian Public Health Research Institute. Results: The mean age of the participants was 51.6 years (range 18–94 years). The median duration of their diabetes was 11 years (range 1–40 years). Forty-eight pecent of the patients were hypertensive. Only half of the hypertensive cases (53%) were using angiotensin-converting enzyme inhibitors, either alone or in combination with other antihypertensive medicines. Eighty-two percent of the participants had poorly controlled diabetes, with glycated haemoglobin >7%. None was using Sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide agonists. Some (109, 32%) of the participants were diagnosed with diabetic nephropathy in addition to reduced estimated glomerular filtration rate and albuminuria. Age, dyslipidaemia, educational status, presence of diabetic retinopathy, and elevated triglyceride levels were found to be significant predictors of the condition (P < 0.05). Conclusions: Diabetic nephropathy was present in nearly one-third of the diabetics in the study population. The management of diabetes with renoprotective agents, such as renin–angiotensin–aldosterone system inhibitors and SGLT2 inhibitors, are likely to be very important in this context. Keywords: diabetes mellitus, nephropathy, end-stage kidney disease, CKD

Characteristics of the type 2 diabetic patients with hypoglycemia in a tertiary referral hospital

Background. Hypoglycemia is an important complication of the treatment of type 2 diabetes mellitus, which constitutes a barrier in stringent diabetic control. Beside it constitutes nearly 10 % of emergency department admissions that caused by adverse drug events, it may also increase morbidities and mortality by inducing, cardiac arrhythmias, neurological impairment and ischemic events. Hypoglycemia is the most common side effect of insulin treatment, however, oral antidiabetic agents may also induce hypoglycemic complications. In present retrospective study, we purposed to observe general characteristics and laboratory data of the type 2 diabetic patients whom presented with mild or moderate/severe hypoglycemia. Materials and methods. Patients with type 2 diabetes mellitus whom presented to our institution with hypoglycemia between January 2019 and January 2020 were retrospectively analyzed. General characteristics and laboratory data of the subjects recorded. Patients grouped into two groups, group I consisted of subjects with mild hypoglycemia and group II consisted of patients with moderate/severe hypoglycemia. Data of the subjects in groups I and II were compared. Results. There were 15 subjects in group I and 23 in group II. HbA1c and other laboratory markers were not significantly different in study groups. Similarly diabetes duration and anti-diabetic treatment were not significantly different in study groups. The rate of geriatric patients was significantly higher in group II compared to group I (p = 0.04). Conclusions. Subjects with moderate/severe hypoglycemia tend to be more frequently in geriatric age and HbA1c not correlates with the degree of the hypoglycemia. Since neither duration of diabetes, nor anti-diabetic treatment were associated with the severity of the hypoglycemia, each case should be evaluated individually to prevent further episodes which could increase morbidity and mortality in diabetic population.

Economic Impact of COVID-19 Lockdown on Italian NHS: Focus on Diabetes Mellitus.

BackgroundIn Italy, the adoption of a total lockdown has generated almost total suspension of outpatient visits except for emergencies. Even after lockdown, the pandemic fear created additional barriers to access the health services. The aim of our study is to evaluate the economic impact of the lockdown for COVID-19 on public health in Italy, focusing on its effects on diabetic population.Materials and MethodsWe analyzed the impact of the lockdown on excess mortality and morbidity in the Italian diabetic population during 2020. The analysis was divided into several steps: a quantification of specialist visit reduction, the calculation of excess mortality in the diabetic population, the economic evaluation of the slowdown in the use of innovative diabetic therapies. Furthermore, the impact of the lockdown on the reduction of procedures and follow-up visits in diabetic population was evaluated. The overall impact of the pandemic and lockdown effects on costs and quality of life was then calculated.ResultsDuring 2020, a drop of 28% in patient access has been observed. Diabetic patients recorded a twice higher mortality value compared to general population (20.4% vs 10.2%). The analysis of market data revealed a slowdown in consumption of new antidiabetic therapies (−14%, 27% vs 41%). We estimated an expense of €26.6 million for NHS and a loss of 257 utilities in diabetic population due to the missed benefits related to slowdown in innovative antidiabetic drugs use and non-optimal follow-up and control of diabetes complications. In simulation scenarios, we also estimated an overall expenditure ranging from €38.7 to 94.0 million and a loss of 294–836 utilities.ConclusionDiabetic population paid a high tribute to pandemic and lockdown, both in terms of number of deaths and burden of diabetic complications, together with an overall deterioration of quality of life.

176-LB: Long-Term Glycemic Variability in Diabetic Patients According to Their Glycemic Control in Follow-Up

Long term glycemic variability is linked to a higher rate of chronic complications and mortality in diabetic population and is also regarded a synonymous of poor glycemic control. However, the relationship between glycemic variability and glycemic control has not been studied properly. Aims to describe differences in glycemic variability in diabetic patients according to their trends in glucose level during follow-up. Methods from our database we selected those patients identified as diabetic (fasting glucose ≥ 126 mg/dl and/or Hba1c≥ 6.5%) who attended to our laboratory from January 2010 to august 2016 for a simultaneous Hba1c and glucose determinations. From the whole sample we selected those with at least 3 Hba1c determinations for 2 years. In all cases mean (M), standard deviation (SD) and variation coefficient (VC) were calculated from Hba1c during follow-up. Patients were categorized in four groups according to their first (i) and last determination (f) of Hba1c: group 1: i and f < 7%, group 2: i < 7% and f > 7%, group 3: i > 7% and f < 7% and group 4 i and f > 7%. We compared between groups VC. Results we studied results from 1589 patients (men 52%, age 60.95 (SD 14.83) years, mean number of determinations: 6.65 (95% CI 6.39-6.84). The percent of patients in group 1 to 4 respectively were : 22.7%, 10.2%, 23.5% and 43.6% . The mean (SD) Hba1c i and f were for group 1: 6.33% (0.41), 6.26% (0.43), group 2: 6.30% (0.55), 8.71% (1.99) , group 3: 8.96% (2.01), 6.23% (0.49) and group 4: 9.4% (2.01), 8.78% (1.71) . Mean VC (SD) were from group 1 to 4: 9.16(9.53), 18.36(11.17), 18.37(11.41), 12.68(8.09))(p <0.05 groups 1 vs. 2,3 and 4, group 2 vs. 1, 4, group 3 vs. 1 and 4, group 4 vs. 1, 2 and 3, P NS group 2 vs. 3). Conclusions: long term glycemic variability measured by VC is very similar in groups that migrates from their original glycemic level, no matter if their final Hba1c is within the goal. High VC is not necessarily related to poor metabolic control. Disclosure H. Garcia-Alcala: None.

Short-term effects of a standardized beverage from aqueous extracts of Hibiscus sabdariffa and Stevia rebaudiana on diastolic function of Cameroonians with type 2 diabetes

Cardiovascular disease is the most prevalent cause of morbidity and mortality in diabetic populations. Safe beverages of medicinal plants contribute as a strategy for the prevention and management of these complications. We investigated the effects of a drink mixture of Hibiscus sabdariffa and Stevia rebaudiana extracts on diastolic function in a group of type 2 diabetes patients. We carried out a non-randomized open-label, one-arm clinical trial. Patients with type 2 diabetes and glycated hemoglobin < 8% were included. Each participant consumed 425 mL of a standardized drink every morning after breakfast over a period of 8 weeks. The effects on the E/A ratio (Mitral peak velocity of early filling E/Mitral peak velocity of last filling A) and lipid profile were determined. We included 20 patients (13 women and 7 men) with a median age of 59 years [56–63.5] and type 2 diabetes of a duration of 8 years [3.25–11.5]. Transthoracic ultrasound at baseline showed 12 patients with diastolic dysfunction. After the 8 weeks intervention, lipid profile parameters improved significantly: triglycerides decreased by 45.58% ( P = 0.008), LDL-cholesterol by 21% ( P = 0.018) and HDL-cholesterol increased by 29.26% ( P < 0.001). Generally, there was an insignificant increase in E/A ratio after intervention, from 0.68 [0.55–1.00] to 0.80 [0.70–0.97], P = 0.937. However, patients with diastolic dysfunction at baseline showed a significant increase in the E/A ratio from 0.60 [0.50–0.69] to 0.70 [0.60–0.95] corresponding to a variation of 16.7% ( P = 0.016). We did not find any significant side effects and the drink was judged to be quite palatable in 18/20 patients. A drink associating Hibiscus sabdariffa with Stevia rebaudiana has beneficial effects on the diastolic function of type 2 diabetes patients and also on their lipid profile.

Platelet activity and hypercoagulation in type 2 diabetes

BackgroundA strong correlation exists between type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), with CVD and the presence of atherosclerosis being the prevailing cause of morbidity and mortality in diabetic populations. T2DM is accompanied by various coagulopathies, including anomalous clot formation or amyloid fibrin(ogen), the presence of dysregulated inflammatory molecules. Platelets are intimately involved in thrombus formation and particularly vulnerable to inflammatory cytokines.MethodsThe aim of this current study was therefore to assess whole blood (hyper)coagulability, platelet ultrastructure and receptor expression, as well as the levels of IL-1β, IL-6, IL-8 and sP-selectin in healthy and diabetic individuals. Platelet morphology was assessed through scanning electron microscopy (SEM), while assessment of GPIIb/IIIa receptor expression was performed with confocal microscopy and flow cytometry with the addition of FITC-PAC-1 and CD41-PE antibodies. IL-1β, IL-6 and IL-8 and sP-selectin levels were assessed using a multiplex assay.ResultsIn T2DM there is significant upregulation of circulating inflammatory markers, hypercoagulation and platelet activation, with increased GPIIb/IIIa receptor expression, as seen with flow cytometry and confocal microscopy. Analyses showed that these receptors were additionally shed onto microparticles, which was confirmed with SEM.ConclusionsCumulatively, this provides mechanistic evidence that pathological states of platelets together with amyloid fibrin(ogen) in T2DM, might underpin an increased risk for cardiovascular events.

Proteostasis in epicardial versus subcutaneous adipose tissue in heart failure subjects with and without diabetes

BackgroundCardiovascular diseases (CVDs) are leading cause of death and primary cause of morbidity and mortality in diabetic population. Epicardial adipose tissue (EAT) covers the heart's surface and is a source of biomolecules regulating heart and blood vessel physiology. The protective activation of the unfolded protein response (UPR) and autophagy allows the cardiomyocyte reticular network to restore energy and/or nutrient homeostasis and to avoid cell death. However, an excessive or prolonged UPR activation can trigger cell death. UPR activation is an early event of diabetic cardiomyopathies and deregulated autophagy is associated with CVDs. ResultsAn upregulation of UPR markers (glucose-regulated protein 78 KDa, glucose-regulated protein 94 KDa, inositol-requiring enzyme 1α, protein kinase RNA-like ER kinase and CCAAT/−enhancer-binding protein homologous protein (CHOP) gene) in EAT compared to subcutaneous adipose tissue (SAT), was observed as well as the UPR-related apoptosis marker caspase-4/procaspase-4 ratio but not in CHOP protein levels. Additionally, levels of ubiquitin and ubiquitinated proteins were decreased in EAT. Moreover, upregulation of autophagy markers (5′ adenosine monophosphate-activated protein kinase, mechanistic target of rapamycin, Beclin 1, microtubule-associated protein light chain 3-II, lysosome-associated membrane protein 2, and PTEN-induced putative kinase 1) was observed, as well as an increase in the apoptotic Bim but not the ratio between Bim and the anti-apoptotic Bcl-2 in EAT. Diabetic patients show alterations in UPR activation markers but not in autophagy or apoptosis markers. ConclusionUPR and autophagy are increased in EAT compared to SAT, opening doors to the identification of early biomarkers for cardiomyopathies and novel therapeutic targets.

Estimated Glomerular Filtration Rate, Proteinuria, and Risk of Cardiovascular Diseases and All-cause Mortality in Diabetic Population: a Community-based Cohort Study

Data about associations between estimated glomerular filtration rate (eGFR) and proteinuria with cardiovascular diseases (CVDs) and all-cause mortality among diabetic population is less described. We aimed to describe these associations in Chinese diabetic population, and investigate the difference between sexes. The study was based on 8,301 diabetic participants in the Kailuan study, who was free of CVDs at baseline. We used Cox proportional hazard models to examine the associations of eGFR and proteinuria with CVDs and all-cause mortality. A stratified analysis by gender was performed. During a median follow-up of 8.05 years, 917 deaths and 813 incident CVDs occurred. Adjusted for all potential confounders, eGFR was associated with all-cause mortality, but not associated with incidence of CVDs. Compared to those with eGFR ≥ 90 ml/min/1.73 m2, Participants with eGFR <45 ml/min/1.73 m2 had 1.50 fold higher risk of all-cause mortality. Adjusted for all potential confounders, proteinuria was associated with risk of both CVDs and all-cause mortality. Additionally, the risk of all-cause mortality by proteinuria was greater in women than that in men. Both lower eGFR and proteinuria are independent risk factors for all-cause mortality in the Chinese diabetic population. Proteinuria conferred excessive risk for CVDs, and especially in women.

Abstract 9777: Dietary Phosphatidylcholine and Risk of All-cause and Cardiovascular-specific Mortality Among Women and Men With Type 2 Diabetes

Introduction: The trimethylamine-containing nutrient phosphatidylcholine is the major dietary source for gut microbiota metabolite trimethylamine-N-oxide, which has been related to cardiovascular diseases (CVD) and mortality. We recently found higher dietary phosphatidylcholine intake was associated with an increased risk of diabetes. No study has analyzed whether phosphatidylcholine intake is related to all-cause and CVD mortality in diabetic patients, who have a higher risk of CVD and premature mortality than the general population. Methods: In total, we included 10061 women and 3668 men with type 2 diabetes in the Nurses’ Health Study and Health Professionals Follow-up Study, respectively. Dietary intakes and potential confounders were assessed with regularly administered questionnaires. Results: We documented 2427 all-cause and 807 CVD deaths during up to 30-year follow-up. After multivariate adjustment for potential confounders, including age, smoking, body mass index, physical activity, dietary intakes and duration of diabetes, higher phosphatidylcholine intake was associated with an increased risk of all-cause and CVD mortality. The pooled relative risk comparing top to bottom quartiles of phosphatidylcholine intake was 1.22 (95%CI, 1.07-1.39; P for trend across quartiles=0.003) for all-cause mortality and 1.33 (1.04-1.69; P for trend=0.03) for CVD mortality. Conclusions: These data indicate that higher phosphatidylcholine consumption is associated with higher all-cause and CVD mortality in diabetic population, independent of other risk factors. Our findings suggest dietary modulation may be a potential interventional strategy to reduce mortality related to gut microbiota metabolites.

Intake of Vegetables, Legumes, and Fruit, and Risk for All-Cause, Cardiovascular, and Cancer Mortality in a European Diabetic Population

We examined the associations of intake of vegetables, legumes and fruit with all-cause and cause-specific mortality in a population with prevalent diabetes in Europe. A cohort of 10,449 participants with self-reported diabetes within the European Prospective Investigation into Cancer and Nutrition study was followed for a mean of 9 y. Intakes of vegetables, legumes, and fruit were assessed at baseline between 1992 and 2000 using validated country-specific questionnaires. A total of 1346 deaths occurred. Multivariate relative risks (RR) for all-cause mortality were estimated in Cox regression models and RR for cause-specific mortality were derived in a competing risk model. An increment in intake of total vegetables, legumes, and fruit of 80 g/d was associated with a RR of death from all causes of 0.94 [95% CI 0.90–0.98]. Analyzed separately, vegetables and legumes were associated with a significantly reduced risk, whereas nonsignificant inverse associations for fruit intake were observed. Cardiovascular disease (CVD) mortality and mortality due to non-CVD/non-cancer causes were significantly inversely associated with intake of total vegetables, legumes, and fruit (RR 0.88 [95% CI 0.81–0.95] and 0.90 [0.82–0.99], respectively) but not cancer mortality (1.08 [0.99–1.17]). Intake of vegetables, legumes, and fruit was associated with reduced risks of all-cause and CVD mortality in a diabetic population. The findings support the current state of evidence from general population studies that the protective potential of vegetable and fruit intake is larger for CVD than for cancer and suggest that diabetes patients may benefit from a diet high in vegetables and fruits.

Management of hyperglycaemic emergencies in the tropics

Diabetic ketoacidosis (DKA) and hyperglycaemic hyperosmolar state are the two most serious acute metabolic complications of diabetes even if managed properly. These disorders can occur in both types 1 and 2 diabetes, and remain an important cause of morbidity and mortality in diabetic populations especially, in the developing countries. Intravenous insulin and fluid replacement are the mainstays of therapy, with careful monitoring of potassium levels. Bicarbonate therapy is rarely needed. Infection, omission of insulin, and other precipitating factors should be treated. This review is intended to discuss some of the advances in the management of hyperglycaemic emergencies and also to highlight some of the peculiarities of the management of hyperglycaemic emergency in our setting if we are going to be able to improve outcome significantly.

Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of Ca 2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme

Diabetic cardiomyopathy contributes to high morbidity and mortality in diabetic populations. It is manifested by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including oxidative stress. This study was designed to examine the effect of cardiac overexpression of the heavy metal scavenger metallothionein (MT) on cardiac contractile function, intracellular Ca 2+ cycling proteins, stress-activated signaling molecules and the myosin heavy chain (MHC) isozyme in diabetes. Adult male wild-type (FVB) and MT transgenic mice were made diabetic by a single injection of streptozotocin (STZ). Contractile properties were evaluated in cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR 90), maximal velocity of shortening/relengthening (±dL/dt) and intracellular Ca 2+ fluorescence. Diabetes significantly depressed PS, ±dL/dt, prolonged TPS, TR 90 and intracellular Ca 2+ clearing, elevated resting intracellular Ca 2+, reduced caffeine-induced sarcoplasmic reticulum Ca 2+ release and dampened stress tolerance at high stimulus frequencies. MT itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunctions. Diabetes enhanced expression of the AT 1 receptor, phospholamban, the p47 phox NADPH oxidase subunit and poly(ADP-ribose) polymerase (PARP), depressed the level of SERCA2a, Na +-Ca 2+ exchanger and triggered a β-MHC isozyme switch. All of these STZ-induced alterations with the exception of depressed SERCA2a and enhanced phospholamban were reconciled by MT. Collectively, these data suggest a beneficial effect of MT in the therapeutics of diabetic cardiomyopathy, possibly through a mechanism related to NADPH oxidase, PARP and MHC isozyme switch.