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1.
Cardiomyocyte mitochondrial dysfunction in diabetes and its contribution in cardiac arrhythmogenesis.
El Hadi, H, Vettor, R, Rossato, M
Mitochondrion. 2019;:6-14
Abstract
Cardiovascular disease is the leading cause of diabetes-related morbidity and mortality. It is widely accepted that heart failure risk is increased in diabetic patients even after adjusting for coronary artery disease and hypertension. Mitochondria are the center of fatty acid (FA) and glucose metabolism and thus are likely to be impacted by impaired metabolism associated with diabetes. Although the cause of this increased heart failure risk is multifactorial, increasing evidence points toward a crucial role for cardiomyocyte mitochondria dysfunction. Altered energy metabolism, defects in mitochondrial dynamics, increased oxidative stress, impaired calcium (Ca2+) handling and mitochondria-induced cell death are observed in mitochondria of diabetic myocardium. In addition, mitochondrial dysfunction appears to contribute substantially to the origin of arrhythmias in diabetic hearts. The current review will describe these mitochondrial abnormalities in cardiomyocytes attempting to provide an overview of underlying mechanisms. Finally, we briefly discuss the potential link between mitochondrial malfunction and arrhythmogenesis.
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Does diabetes prevention translate into reduced long-term vascular complications of diabetes?
Nathan, DM, Bennett, PH, Crandall, JP, Edelstein, SL, Goldberg, RB, Kahn, SE, Knowler, WC, Mather, KJ, Mudaliar, S, Orchard, TJ, et al
Diabetologia. 2019;(8):1319-1328
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Abstract
The global epidemic of type 2 diabetes has prompted numerous studies and public health efforts to reduce its development. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose tolerance. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant outcome, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention.
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Myocardial Ischemia and Diabetes Mellitus: Role of Oxidative Stress in the Connection between Cardiac Metabolism and Coronary Blood Flow.
Severino, P, D'Amato, A, Netti, L, Pucci, M, Infusino, F, Maestrini, V, Mancone, M, Fedele, F
Journal of diabetes research. 2019;:9489826
Abstract
Ischemic heart disease (IHD) has several risk factors, among which diabetes mellitus represents one of the most important. In diabetic patients, the pathophysiology of myocardial ischemia remains unclear yet: some have atherosclerotic plaque which obstructs coronary blood flow, others show myocardial ischemia due to coronary microvascular dysfunction in the absence of plaques in epicardial vessels. In the cross-talk between myocardial metabolism and coronary blood flow (CBF), ion channels have a main role, and, in diabetic patients, they are involved in the pathophysiology of IHD. The exposition to the different cardiovascular risk factors and the ischemic condition determine an imbalance of the redox state, defined as oxidative stress, which shows itself with oxidant accumulation and antioxidant deficiency. In particular, several products of myocardial metabolism, belonging to oxidative stress, may influence ion channel function, altering their capacity to modulate CBF, in response to myocardial metabolism, and predisposing to myocardial ischemia. For this reason, considering the role of oxidative and ion channels in the pathophysiology of myocardial ischemia, it is allowed to consider new therapeutic perspectives in the treatment of IHD.
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Rationale for the Early Use of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Type 2 Diabetes.
Handelsman, Y
Advances in therapy. 2019;(10):2567-2586
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Abstract
Diabetes-related complications including cardiovascular disease, heart failure (HF), chronic kidney disease, retinopathy, and neuropathy are associated with a high burden of disease. Early initiation of glucose-lowering therapy in patients with type 2 diabetes to achieve glycemic control is important for reduction of not only microvascular risk but also of CV (cardiovascular) risk. Clinical studies have indicated that early achievement of glycemic targets is likely to have the greatest effect on preventing microvascular and macrovascular complications. In addition to improvements in glycemic control and CV risk factors, CV outcomes trials (CVOTs) of empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS), and dapagliflozin (DECLARE-TIMI 58) showed significant glucose-independent reductions in the risk of major adverse CV events and/or hospitalization for HF, as well as reductions in the risk of kidney disease progression, versus placebo. These CVOTs and a renal outcomes study of canagliflozin (CREDENCE) support the early initiation of sodium-glucose cotransporter (SGLT)-2 inhibitors to potentially provide the most benefit toward glycemic control and CV and renal risk. Thus, current treatment recommendations include the early addition of SGLT-2 inhibitor therapy, not only in patients with established CVD, HF, and/or CKD but also in the general population of patients with T2D.Funding: AstraZeneca.
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Effects of sodium-glucose cotransporter (SGLT) inhibitors in addition to insulin therapy on glucose control and safety outcomes in adults with type 1 diabetes: A meta-analysis of randomized controlled trials.
Lu, J, Tang, L, Meng, H, Zhao, J, Liang, Y
Diabetes/metabolism research and reviews. 2019;(7):e3169
Abstract
Sodium-glucose cotransporter (SGLT) inhibitors added to insulin therapy have been proposed as treatment strategy for type 1 diabetes (T1D). We thus conducted a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of this combination in T1D. We searched the PubMed, EMBASE, and Cochrane Library databases and ClinicalTrials.gov for RCTs. Statistical analyses were performed using STATA 15. Ten eligible placebo-controlled trials involving 5961 patients were included. Compared with placebo, SGLT inhibitors were associated with a reduction in HbA1c of -0.39% (95% CI, -0.43 to -0.36), an improved mean amplitude of glucose excursion (MAGE) of -14.81 mg/dL (95% CI, -19.08 to -10.54), and a reduction in body weight of -3.47% (95% CI, -3.78 to -3.16), as well as no increased relative risk of hypoglycaemia (1.01; 95% CI, 0.99-1.02) or severe hypoglycaemia (0.91; 95% CI, 0.77-1.07). SGLT inhibitors decreased fasting plasma glucose and insulin requirement but increased the risk of genital infection (3.57; 95% CI, 2.97-4.29) and diabetic ketoacidosis (3.11; 95% CI, 2.11-4.58). However, the very low dose empagliflozin (2.5 mg) did not increase the risk of diabetic ketoacidosis (risk ratio [RR] 0.67; 95% CI, 0.11-3.95). SGLT inhibitors had no effect on overall adverse events, urinary tract infection, or bone fracture but slightly increased the risk of serious adverse events (1.35; 95% CI, 1.16-1.58), severe adverse events (1.84; 95% CI, 1.20-2.84), adverse events leading to discontinuation (1.50; 95% CI, 1.22-1.84), drug-related adverse events (1.78; 95% CI, 1.44-2.19), and diarrhoea (1.54; 95% CI, 1.15-2.05). Although adverse events exist, the available data provide evidence that the combination of SGLT inhibitors with basal insulin treatment is beneficial in patients with T1D.
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Global trends in diabetes complications: a review of current evidence.
Harding, JL, Pavkov, ME, Magliano, DJ, Shaw, JE, Gregg, EW
Diabetologia. 2019;(1):3-16
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Abstract
In recent decades, large increases in diabetes prevalence have been demonstrated in virtually all regions of the world. The increase in the number of people with diabetes or with a longer duration of diabetes is likely to alter the disease profile in many populations around the globe, particularly due to a higher incidence of diabetes-specific complications, such as kidney failure and peripheral arterial disease. The epidemiology of other conditions frequently associated with diabetes, including infections and cardiovascular disease, may also change, with direct effects on quality of life, demands on health services and economic costs. The current understanding of the international burden of and variation in diabetes-related complications is poor. The available data suggest that rates of myocardial infarction, stroke and amputation are decreasing among people with diabetes, in parallel with declining mortality. However, these data predominantly come from studies in only a few high-income countries. Trends in other complications of diabetes, such as end-stage renal disease, retinopathy and cancer, are less well explored. In this review, we synthesise data from population-based studies on trends in diabetes complications, with the objectives of: (1) characterising recent and long-term trends in diabetes-related complications; (2) describing regional variation in the excess risk of complications, where possible; and (3) identifying and prioritising gaps for future surveillance and study.
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Body Weight Considerations in the Management of Type 2 Diabetes.
Apovian, CM, Okemah, J, O'Neil, PM
Advances in therapy. 2019;(1):44-58
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Obesity is one of the main risk factors for type 2 diabetes (T2D), representing a major worldwide health crisis. Modest weight-loss (≥ 5% but < 10%) can minimize and reduce diabetes-associated complications, and significant weight-loss can potentially resolve disease. Treatment guidelines recommend that intensive lifestyle interventions, pharmacologic therapy, and/or metabolic surgery be considered as options for patients with T2D and obesity. The benefits and risks of such interventions should be evaluated in the context of their weight-loss potential, ability to sustain weight change, side effect profile, and costs. Antihyperglycemia therapies have considerable effects on patient weight, prompting careful consideration of weight-loss or weight-neutral therapies for patients with T2D who also have obesity. Metformin, sodium glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), α-glucosidase inhibitors, and amylin mimetics promote weight-loss. Dipeptidyl peptidase-4 inhibitors and fixed-ratio insulin/GLP-1 RA combination therapies (IDegLira, iGlarLixi) appear to be weight-neutral. Thiazolidinediones, insulin secretagogues (sulfonylureas, meglitinides), and insulins are associated with weight gain. Sulfonylureas are additionally associated with a higher risk of serious hypoglycemia from hyperinsulinemia, making them less suitable for the treatment of patients who are overweight or have obesity. Patients are often overtitrated on basal insulin, resulting in an increased risk of hypoglycemia and weight gain without achieving glycemic goals. Given these observations, the effects of antihyperglycemia agents on weight should be considered when individualizing T2D therapy.Funding: Sanofi US, Inc.
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Tannins and vascular complications of Diabetes: An update.
Laddha, AP, Kulkarni, YA
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2019;:229-245
Abstract
BACKGROUND Diabetes mellitus is a chronic metabolic disorder associated with persistent increased level of glucose in the blood. According to a report by World Health Organisation (WHO), prevalence of diabetes among adults over 18 years of age had reached to 8.5% in year 2014 which was 4.7% in 1980s. The Prolong increased level of glucose in blood leads to development of microvascular (blindness, nephropathy and neuropathy) and macrovascular (cardiovascular and stroke) degenerative complications because of uncontrolled level of glucose in blood. This also leads to the progression of oxidative stress and affecting metabolic, genetic and haemodynamic system by activation of polyol pathway, protein kinase C pathway, hexosamine pathway and increases advanced glycation end products (AGEs) formation. Diabetes mellitus and its associated complications are one of the major leading causes of mortality worldwide. Various natural products like alkaloids, glycosides, flavonoids, terpenoids and polyphenols are reported for their activity in management of diabetes and its associated diabetic complications. Tannins are systematically studied by many researchers in past few decades for their effect in diabetes and its complications. AIM: The present review was designed to compile the data of tannins and their beneficial effects in the management of diabetic complications. METHOD Literature search was performed using various dataset like pubmed, EBSCO, proQuest Scopus and selected websites including the National Institutes of Health (NIH) and the World Health Organization (WHO). RESULTS Globally, more than 400 natural products have been investigated in diabetes and its complications. Tannins are the polyphenolic compounds present in many medicinal plants and various dietary sources like fruits, nuts, grains, spices and beverages. Various reports have shown that compounds like gallic acid, ellagic acid, catechin, epicatechin and procynidins from medicinal plants play major role in controlling progression of diabetes and its related complications by acting on molecular pathways and key targets involved in progression. Many chemists used above mentioned phyto-constituents as a pharmacophore for the developing new chemical entities having higher therapeutic benefits in management of diabetic complications. CONCLUSION This review focuses on the role of various tannins in prevention and management of diabetic complications like diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and diabetic cardiomyopathy. It will help researchers to find some leads for the development of new cost effective therapy using dietary source for the management of diabetic complications.
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[Sex and gender-specific aspects in prediabetes and diabetes mellitus-clinical recommendations (Update 2019)].
Kautzky-Willer, A, Harreiter, J, Abrahamian, H, Weitgasser, R, Fasching, P, Hoppichler, F, Lechleitner, M
Wiener klinische Wochenschrift. 2019;(Suppl 1):221-228
Abstract
Metabolic diseases dramatically affect the life of men and women from infancy up to old age in different and manifold ways and are a major challenge for the healthcare system. The treating physicians are confronted with the different needs of women and men in the clinical routine. Gender-specific differences affect screening, diagnostic and treatment strategies as well as the development of complications and mortality rates. Impairments in glucose and lipid metabolism, regulation of energy balance and body fat distribution and therefore the associated cardiovascular diseases, are greatly influenced by steroidal and sex hormones. Furthermore, education, income and psychosocial factors play an important role in the development of obesity and diabetes differently in men and women. Males appear to be at greater risk of diabetes at a younger age and at a lower body mass index (BMI) compared to women but women feature a dramatic increase in the risk of diabetes-associated cardiovascular diseases after the menopause. The estimated future years of life lost owing to diabetes is somewhat higher in women than men, with a higher increase in vascular complications in women but a higher increase of cancer deaths in men. In women prediabetes or diabetes are more distinctly associated with a higher number of vascular risk factors, such as inflammatory parameters, unfavorable changes in coagulation and higher blood pressure. Women with prediabetes and diabetes have a much higher relative risk for vascular diseases. Women are more often morbidly obese and less physically active but may have an even greater benefit in health and life expectation from increased physical activity than men. In weight loss studies men often showed a higher weight loss than women; however, diabetes prevention is similarly effective in men and women with prediabetes with a risk reduction of nearly 40%. Nevertheless, a long-term reduction in all cause and cardiovascular mortality was so far only observed in women. Men predominantly feature increased fasting blood glucose levels, women often show impaired glucose tolerance. A history of gestational diabetes or polycystic ovary syndrome (PCOS) as well as increased androgen levels in women and the presence of erectile dysfunction or decreased testosterone levels in men are important sex-specific risk factors for the development of diabetes. Many studies showed that women with diabetes reach their target values for HbA1c, blood pressure and low-density lipoprotein (LDL)-cholesterol less often than their male counterparts, although the reasons are unclear. Furthermore, sex differences in the effects, pharmacokinetics and side effects of pharmacological treatment should be taken more into consideration.
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Aerobic exercise can modulate the underlying mechanisms involved in the development of diabetic complications.
Yaribeygi, H, Butler, AE, Sahebkar, A
Journal of cellular physiology. 2019;(8):12508-12515
Abstract
Diabetes mellitus is a highly prevalent metabolic disorder that affects many molecular pathways, causing a shift from a physiologic to a pathophysiologic state. Alterations in the molecular pathways promote diabetic complications and, thus, many medical and nonmedical therapies have been directed at preventing these complications. Despite the beneficial effects on moderating glycemic control, medical therapies may also have unfavorable side effects. This makes nonmedical therapeutic approaches more attractive due to lower pharmacological side effects of these strategies compared to medical agents. Aerobic exercise is now considered as a major nonmedical strategy that can promote beneficial and protective effects to counteract the development of diabetic complications via attenuation of the major molecular mechanisms involved in diabetes.