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New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway.
Hsu, SK, Cheng, KC, Mgbeahuruike, MO, Lin, YH, Wu, CY, Wang, HD, Yen, CH, Chiu, CC, Sheu, SJ
International journal of molecular sciences. 2021;(17)
Abstract
Under metabolic stress conditions such as hypoxia and glucose deprivation, an increase in the AMP:ATP ratio activates the AMP-activated protein kinase (AMPK) pathway, resulting in the modulation of cellular metabolism. Metformin, which is widely prescribed for type 2 diabetes mellitus (T2DM) patients, regulates blood sugar by inhibiting hepatic gluconeogenesis and promoting insulin sensitivity to facilitate glucose uptake by cells. At the molecular level, the most well-known mechanism of metformin-mediated cytoprotection is AMPK pathway activation, which modulates metabolism and protects cells from degradation or pathogenic changes, such as those related to aging and diabetic retinopathy (DR). Recently, it has been revealed that metformin acts via AMPK- and non-AMPK-mediated pathways to exert effects beyond those related to diabetes treatment that might prevent aging and ameliorate DR. This review focuses on new insights into the anticancer effects of metformin and its potential modulation of several novel types of nonapoptotic cell death, including ferroptosis, pyroptosis, and necroptosis. In addition, the antimetastatic and immunosuppressive effects of metformin and its hypothesized mechanism are also discussed, highlighting promising cancer prevention strategies for the future.
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Comparison of the effect of glucose-lowering agents on the risk of atrial fibrillation: A network meta-analysis.
Shi, W, Zhang, W, Zhang, D, Ren, G, Wang, P, Gao, L, Chen, H, Ding, C
Heart rhythm. 2021;(7):1090-1096
Abstract
BACKGROUND Diabetes is associated with the progression of atrial fibrillation (AF) and atrial flutter (AFL). However, whether glucose-lowering agents could reduce AF/AFL remains unclear. We hypothesized that different glucose-lowering agents exhibit different characteristic effects on the risk of AF/AFL. OBJECTIVES The goals of this study were to evaluate the effect of different glucose-lowering agents and identify the optimal treatment that can reduce AF/AFL events in patients with diabetes. METHODS We searched PubMed, Embase, and the Cochrane Library from their inception to September 30, 2020. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used in this network meta-analysis. The primary end point of our study was AF or AFL. Only studies that reported AF/AFL as clinical end points with a follow-up period of at least 12 months were included. The results from trials were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The results were pooled using a Bayesian random-effects model. RESULTS Five eligible studies (9 glucose-lowering agents, including thiazolidinedione, metformin, sulfonylurea, insulin, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist [GLP-1RA], sodium-glucose cotransporter 2 inhibitor, alpha-glucosidase inhibitor, and non-sulfonylurea) consisting of 263,583 patients with type 2 diabetes mellitus were included. Based on the pooled results, GLP-1RA significantly reduced AF/AFL events compared with metformin (OR 0.17; 95% CI 0.04-0.61), sulfonylurea (OR 0.23; 95% CI 0.07-0.73), insulin (OR 0.20; 95% CI 0.07-0.86), and non-sulfonylurea (OR 0.18; 95% CI 0.04-0.66). CONCLUSION Compared with other glucose-lowering agents, GLP-1RA could reduce the risk of AF/AFL in patients with diabetes.
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Obesity and Diabetes.
Aras, M, Tchang, BG, Pape, J
The Nursing clinics of North America. 2021;(4):527-541
Abstract
Obesity is the most significant risk factor for the development of diabetes. Both obesity and diabetes rates have continued to increase in tandem and pose increased mortality for patients and increased health care costs for the community. Weight loss of 5% or more of total body weight renders improvements in glycemic control, decreases in the need for diabetes medications, and improved quality of life. Cotreatment of obesity and diabetes requires a comprehensive medical approach that encompasses intensive lifestyle modification including behavioral changes, nutrition, and physical activity, as well as pharmacotherapy and possible surgical management.
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4.
Rationale for the use of metformin and exercise to counteract statin-associated side effects.
Haxhi, J, Thompson, PD
International journal of clinical practice. 2021;(5):e13900
Abstract
INTRODUCTION Statins are the most widely prescribed drugs for lowering low-density lipoprotein cholesterol (LDL-C) and reducing cardiovascular morbidity and mortality. They are usually well-tolerated, but have two main safety concerns: statin-associated muscle symptoms (SAMS) and new-onset type 2 diabetes (NOD). METHODS A PubMed search was carried out using the following key words were used: statins, statin-associated muscle symptoms, statin myalgia, statin-associated diabetes, metformin and statins, exercise and statins. RESULTS Mitochondrial damage and muscle atrophy are likely the central mechanisms producing SAMS, whereas decreased glucose transport, fatty acid oxidation and insulin secretion are likely involved in the development of NOD. Metformin and exercise training share many pathways that could potentially contrast SAMS and NOD. Clinical evidence also supports the combination of statins with metformin and exercise. CONCLUSION This combination appears attractive both from a clinical and an economical viewpoint, since all three therapies are highly cost-effective and their combination could result in diabetes and cardiovascular disease prevention.
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5.
Natural-derived compounds and their mechanisms in potential autosomal dominant polycystic kidney disease (ADPKD) treatment.
Mahendran, R, Lim, SK, Ong, KC, Chua, KH, Chai, HC
Clinical and experimental nephrology. 2021;(11):1163-1172
Abstract
BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic kidney disorder that impairs renal functions progressively leading to kidney failure. The disease affects between 1:400 and 1:1000 ratio of the people worldwide. It is caused by the mutated PKD1 and PKD2 genes which encode for the defective polycystins. Polycystins mimic the receptor protein or protein channel and mediate aberrant cell signaling that causes cystic development in the renal parenchyma. The cystic development is driven by the increased cyclic AMP stimulating fluid secretion and infinite cell growth. In recent years, natural product-derived small molecules or drugs targeting specific signaling pathways have caught attention in the drug discovery discipline. The advantages of natural products over synthetic drugs enthusiast researchers to utilize the medicinal benefits in various diseases including ADPKD. CONCLUSION Overall, this review discusses some of the previously studied and reported natural products and their mechanisms of action which may potentially be redirected into ADPKD.
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Could the use of butyric acid have a positive effect on microbiota and treatment of type 2 diabetes?
Stachowska, E, Wiśniewska, M, Dzieżyc, A, Bohatyrewicz, A
European review for medical and pharmacological sciences. 2021;(13):4570-4578
Abstract
OBJECTIVE This review focuses on the role of butyrate as one of the key metabolites of gut microbiota. Butyrate along with other short-chain fatty acids, acetate and propionate, is one of the most important regulators of human metabolism. In this review, we discuss how changes in gut microbiota triggered by type 2 diabetes mellitus and its treatment (e.g., metformin) affect butyrate synthesis, how to increase butyrate production and whether there is robust evidence for the positive effects of sodium butyrate in the treatment of diabetes mellitus. MATERIALS AND METHODS Literature review was conducted by all authors. Studies published until 27/03/2020 were included. Search words were: ("butyric acid" OR "butyrate") AND ("type 2 diabetes "OR "T2DM"). The articles selected for the study were not chosen in a systematic manner, so the evidence may not be comprehensive. RESULTS Butyrate was found to effectively reduce inflammation and plays a prominent role in the function of the intestinal barrier. To date the use of sodium butyrate in the treatment of patients with T2DM is not very popular. Meanwhile, butyric acid can beneficially modulate intestinal functions, counteracting the negative effects of the disease as well as the drugs used to treat diabetes. CONCLUSIONS T2DM is a widespread chronic disease. Understanding role of microbiota in type 2 diabetes and the mechanisms connecting T2DM and alterations in gut microbiota could be the key to improved treatment of T2DM.
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Noninsulin Diabetes Therapies in Older Adults.
Tekin, Z, Zimmerman, RS
Clinics in geriatric medicine. 2020;(3):385-394
Abstract
Diabetes risk increases with age due to changes in β-cell function and increased insulin resistance and is one of the most common chronic medical conditions in the elderly. Diabetes management in this population requires a multidisciplinary, patient-centric approach due to wide heterogeneity in patients' health and functional capacities. Meticulous assessment of each patient before formulating a regimen and thorough patient education are keys to success in achieving glycemic goals, which should be individualized. Lifestyle modification is recommended for every patient.
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Osmolar-gap in the setting of metformin-associated lactic acidosis: Case report and a literature review highlighting an apparently unusual association.
Elshafei, MN, Alamin, M, Mohamed, MFH
Medicine. 2020;(41):e22492
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Abstract
RATIONALE Metformin-associated lactic acidosis (MALA) is a rare adverse effect that has significant morbidity and mortality. MALA is a high anion gap (AG), nonosmolar acidosis. Associated osmolar-gap (OG) is rarely reported, so finding an OG may make the diagnosis of MALA challenging. PATIENT CONCERNS Forty-five years' old type II diabetic patient on metformin presented to emergency with a two-day history of vomiting, watery diarrhea, and mild abdominal discomfort. On examinations, he looked dehydrated. Investigation revealed acute kidney injury (AKI) with a high lactic acid (LA) level of 24 mmol/L, pH of 6.8, AG of 40, and an OG of 20 mOsm/kg DIAGNOSES The presence of an OG made the diagnosis challenging; the history was negative for alcohol, osmolar substance, or illicit drug ingestion or use. The toxicology screen was negative. After ruling out plausible causes of AG and OG, MALA was deemed the likely reason for his presentation likely precipitated by dehydration and AKI. INTERVENTIONS He underwent two sessions of hemodialysis, afterward managed with fluid hydration. OUTCOMES On day 3, he was in the polyuric phase suggestive of acute tubular necrosis. His serum creatinine improved afterward with improved acidosis; after 8 days, he was discharged in stable condition. LESSONS MALA is a rare side effect of metformin therapy. Acute kidney injury is a known precipitant of MALA. In our review, we highlight the association of MALA and the presence of an OG. We believe that treating physicians should be aware of this relationship to avoid delaying or overlooking such an important diagnosis.
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Meta-analysis on the efficacy and safety of SGLT2 inhibitors and incretin based agents combination therapy vs. SGLT2i alone or add-on to metformin in type 2 diabetes.
Zhou, Y, Geng, Z, Wang, X, Huang, Y, Shen, L, Wang, Y
Diabetes/metabolism research and reviews. 2020;(2):e3223
Abstract
We aimed to determine whether sodium-glucose cotransporter type 2 inhibitors (SGLT2is) and incretin-based agents combination therapy produces more benefits than SGLT2is alone in patients with type 2 diabetes mellitus (T2DM). PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing SGLT2is plus Dipeptidyl-Peptidase 4 inhibitors (SGLT2is/DPP4is) or glucagon like peptide-1 receptor agonists (SGLT2is/GLP-1RAs) against SGLT2is as monotherapy or add-on to metformin in T2DMs. A total of 13 studies with 7350 participants were included. Combination with GLP-1RAs exhibited more HbA1c reduction (WMD: -0.8; 95% CI, -1.14 to -0.45%), weight loss (-1.46; 95% CI, -2.38 to -0.54 kg), and systolic blood pressure (SBP) reduction (-2.88; 95% CI, -4.52 to -1.25 mmHg) versus SGLT2is alone but increased the gastrointestinal disorder risk (RR: 1.68; 95% CI, 1.14-2.47). Combination with DPP4is exhibited an extra effect on HbA1c reduction (-0.47; 95% CI, -0.58 to -0.37%), a neutral effect on weight (0.19; 95% CI, -0.11 to 0.48 kg) and SBP (-0.01; 95% CI, -0.85 to 0.63 mmHg), and ameliorated the genital infections risk (0.73; 95% CI, 0.54-0.97) versus SGLT2is. Meta-regression indicated the hypoglycemic efficacy of SGLT2is/DPP4is is higher in Asians than in other ethnics, and the differences in BMI across ethnic groups may mediate this effect. SGLT2is and incretin-based agents combination therapy is efficacious and safe versus SGLT2is alone in T2DMs. Particularly, combination with GLP-1RAs shows additional benefits to glycemic, weight, and SBP control to a larger extent than DPP4is, while combination with DPP4is ameliorates the risk for genital infection seen with SGLT2is. We highlight the need for individualized treatment related to the selection of this novel combination therapy.
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Type 2 diabetes mellitus management in patients with chronic kidney disease: an update.
Kleinaki, Z, Kapnisi, S, Theodorelou-Charitou, SA, Nikas, IP, Paschou, SA
Hormones (Athens, Greece). 2020;(4):467-476
Abstract
Diabetes mellitus (DM) is a chronic multisystem disease. Diabetic nephropathy (DN) is one of its significant microvascular complications, associated with increased morbidity and mortality. The aim of this article is to review the literature regarding the latest advances in the management of type 2 DM (T2DM) in patients with chronic kidney disease (CKD). We initially refer to the screening guidelines, the diagnostic tests used, the need for novel biomarkers in DN, the recent advances in high-risk patient identification, the recommended glycemic targets, and concerns regarding the accuracy of HbA1c in these patients. Then, a detailed explanation of the appropriate medical management based on evidence from recent trials is presented, analyzed, and discussed. All patients with T2DM should be screened for albuminuria at initial diagnosis and annually thereafter. Proteomics and metabolomics today represent promising diagnostic tools. Optimal glycemic control, with individualized HbA1c targets, is fundamental for reduced onset or delayed progression of DN and microvascular complications, in general. This can be enhanced by lifestyle modifications and pharmacological interventions when needed. Metformin represents the first pharmacological step, with, recently, a broadened indication for patients with impaired renal function. If HbA1c remains above the target in patients with established CKD, SGLT2i or GLP-1 RA are the preferred second-line agents, as introduced in all new guidelines. This change was the result of recent landmark trials that highlighted the superiority of the two aforementioned medication categories in terms of both renal and cardiovascular outcomes.