Metformin, lipids and atherosclerosis prevention

Purpose of review: We provide an overview of recent publications that extend clinically relevant knowledge relating to metformin's effects on lipids and atherosclerotic vascular disease and/or provide insights into the drug's mechanisms of action on the heart and vasculature. Recent findings: We focus on original research in humans or in human tissues. Several recently completed randomized clinical trials have reported effects of metformin on surrogate measures of atherosclerotic vascular disease, including carotid–intima media thickness, vascular reactivity and calcification in people with Type 1 (T1D) and Type 2 (T2D) diabetes as well as nondiabetic dysglycaemia. In addition, observational studies have provided novel insights into the mechanisms of metformin's effects on carotid plaque, monocytes/macrophages, vascular smooth muscle and endothelial cells, including via 5’-adenosine monophosphate-activated protein kinase (AMPK) activation. Summary: Recent trials based on surrogate outcome measures have provided further data suggesting protective effects of metformin against vascular disease in youth and adults with Type 1 diabetes, as well as in adults with prediabetes and Type 2 diabetes. In parallel, human tissue and cell studies have provided new insights into pleiotropic effects of metformin and suggest novel drug targets. As metformin is an inexpensive agent with an established safety profile, larger scale clinical trials based on hard clinical outcomes [cardiovascular disease (CVD) events] are now indicated

Is it time to repair a fairly fast SAAB convertible? Testing an evidence-based mnemonic for the secondary prevention of cardiovascular disease

OBJECTIVES: Optimising secondary prevention of cardiovascular disease has the greatest potential to reduce recurrent events, yet despite major guidelines there are ongoing treatment gaps. FFSAABC (Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers and Clopidogrel) is one mnemonic previously adopted to assist clinicians in remembering medications for use in secondary prevention. The aim of this narrative review is to examine the current evidence base for medications recommended for patients with established cardiovascular disease and the current applicability of this, or a revised mnemonic for their use. STUDY DESIGN: Randomised controlled trials and systematic reviews were sought examining Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers or Clopidogrel vs placebo in secondary prevention. The emerging evidence base for other contemporary therapies including the P2Y12 inhibitors (ticagrelor and prasugrel) and aldosterone antagonists was also reviewed. RESULTS: Definitive evidence supports the use of statins, aspirin, angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, and P2Y12 antagonists (clopidogrel, ticagrelor or prasugrel) for the secondary prevention of cardiovascular disease. Aldosterone antagonists have strong evidence in the presence of systolic heart failure. There is a weaker evidence base for the routine use of omega-3 fatty acid supplementation although this therapy carries minimal harms. Fenofibrate reduces cardiovascular events in dyslipidaemic patients, with additional benefits in patients with diabetes. CONCLUSIONS: Mnemonic upgrading from a Fairly Fast SAAB Convertible to a Fairly Fast SA2A2B (Fish oils, Fibrate, Statin, Antiplatelets (Aspirin+Other), ACE/ARB, Aldosterone Antagonist, Beta-blocker) may help to ensure patients receive best practice evidence-based pharmacotherapies for the secondary prevention of cardiovascular disease

Prevalence of Health-Risk Behaviours Among Indigenous Australians With Diabetes: A Review

Aboriginal and Torres Strait Islander Australians are at high risk of Type 2 diabetes and its complications. Optimal lifestyle choices can improve health outcomes. A thematic review of original research publications related to smoking, nutrition, alcohol intake, physical activity and emotional wellness in Aboriginal and Torres Strait Islander Australians with diabetes was performed. Overall, 7118 English-language publications were identified by search engines (PubMed, CINAHL, Scopus, Medline-Web of Science, and Google Scholar) with search terms Indigenous Australians OR Aboriginal and Torres Strait Islanders AND diabetes AND lifestyle OR smoking OR nutrition OR alcohol OR physical activity OR emotional wellbeing and their common synonyms. After review of abstracts and publication reference lists, 36 articles met inclusion criteria and were reviewed. In general, the self-reported health-related behaviours of Aboriginal and Torres Strait Islander Australian adults with diabetes, which is predominantly Type 2 diabetes, was suboptimal. An important clinical challenge in diabetes care is to sustainably reduce smoking, improve nutrition (including alcohol use), increase physical activity, reduce sedentary time, and improve emotional wellbeing, which should lead to reduced rates of diabetes complications. Regular assessments and multi-stakeholder input, including individuals, communities, clinical, health policy, societal and government inputs and partnerships, are desirable to facilitate closing the gap in health between Aboriginal and Torres Strait Islander and non-Indigenous Australians

The STATs in cell stress-type responses

In the early 1990's, a new cell signaling pathway was described. This new paradigm, now known as the JAK/STAT pathway, has been extensively investigated in immune-type cells in response to interferons and interleukins. However, recent evidence suggests that the JAK/STAT pathway also mediates diverse cellular responses to various forms of biological stress including hypoxia/reperfusion, endotoxin, ultraviolet light, and hyperosmolarity. The current literature describing the JAK/STAT pathway's role in cellular stress responses has been reviewed herein, but it is clear that our knowledge in this area is far from complete

Multifocal pupillography identifies changes in visual sensitivity according to severity of diabetic retinopathy in type 2 diabetes

PURPOSE. Retinal light sensitivity loss has been shown to occur prior to other signs of retinopathy and may predict the sight-threatening sequelae. A rapid, objective perimetric test could augment diabetes care. We investigated the clinical use of multifocal pupillographic objective perimetry (mfPOP) to identify patients with and without diabetic retinopathy. METHODS. Retinopathy severity was determined using the Early Treatment of Diabetic Retinopathy Study (ETDRS) standard for fundus photography. Pupillary responses were measured from both eyes of 25 adults with none to moderate diabetic retinopathy and 24 agematched controls, using three mfPOP stimulus variants. Multifocal pupillographic objective perimetry stimulus variants tested 44 regions per eye arranged in a five-ring dartboard layout presented within either the central 300 or 600 of fixation. Receiver operator characteristic (ROC) curves were produced from contraction amplitudes and time to peak responses. RESULTS. Regression analysis revealed that mean amplitude deviations were larger with severity of early retinopathy. On average, the longest delays were measured in patients with no retinopathy. The brightest wide-field stimuli produced the highest area under the ROC curve for differentiating eyes with no retinopathy from nonproliferative diabetic retinopathy (NPDR) and from healthy eyes (100 ± 0.0%, mean ± SE). The asymmetry in local delay deviations between eyes tended to produce higher sensitivity and specificity than amplitude deviations. CONCLUSIONS. Asymmetry in local response delays measured by mfPOP may provide useful information regarding the severity of diabetic retinopathy and may have clinical use as a rapid, noninvasive method for identifying functional loss even in the absence of NPDR

Pyridoxamine, an Inhibitor of Advanced Glycation Reactions, Also Inhibits Advanced Lipoxidation Reactions: Mechanism of Action of Pyridoxamine

Maillard or browning reactions lead to formation of advanced glycation end products (AGEs) on protein and contribute to the increase in chemical modification of proteins during aging and in diabetes. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) have proven effective in animal model and clinical studies as inhibitors of AGE formation and development of diabetic complications. We report here that PM also inhibits the chemical modification of proteins during lipid peroxidation (lipoxidation) reactions in vitro, and we show that it traps reactive intermediates formed during lipid peroxidation. In reactions of arachidonate with the model protein RNase, PM prevented modification of lysine residues and formation of the advanced lipoxidation end products (ALEs) N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, malondialdehyde-lysine, and 4-hydroxynonenal-lysine. PM also inhibited lysine modification and formation of ALEs during copper-catalyzed oxidation of low density lipoprotein. Hexanoic acid amide and nonanedioic acid monoamide derivatives of PM were identified as major products formed during oxidation of linoleic acid in the presence of PM. We propose a mechanism for formation of these products from the 9- and 13-oxo-decadienoic acid intermediates formed during peroxidation of linoleic acid. PM, as a potent inhibitor of both AGE and ALE formation, may prove useful for limiting the increased chemical modification of tissue proteins and associated pathology in aging and chronic diseases, including both diabetes and atherosclerosis

Impact of multimorbidity count on all-cause mortality and glycaemic outcomes in people with type 2 diabetes: a systematic review protocol

Introduction: Type 2 diabetes (T2D) is a leading health priority worldwide. Multimorbidity (MM) is a term describing the co-occurrence of two or more chronic diseases or conditions. The majority of people living with T2D have MM. The relationship between MM and mortality and glycaemia in people with T2D is not clear. Methods and analysis: Medline, Embase, Cumulative Index of Nursing and Allied Health Complete, The Cochrane Library, and SCOPUS will be searched with a prespecified search strategy. The searches will be limited to quantitative empirical studies in English with no restriction on publication date. One reviewer will perform title screening and two review authors will independently screen the abstract and full texts using Covidence software, with disagreements adjudicated by a third reviewer. Data will be extracted using a using a Population, Exposure, Comparator and Outcomes framework. Two reviewers will independently extract data and undertake the risk of bias (quality) assessment. Disagreements will be resolved by consensus. A narrative synthesis of the results will be conducted and meta-analysis considered if appropriate. Quality appraisal will be undertaken using the Newcastle-Ottawa quality assessment scale and the quality of the cumulative evidence of the included studies will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. This protocol was prepared in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines to ensure the quality of our review. Ethics and dissemination: This review will synthesise the existing evidence about the impact of MM on mortality and glycaemic outcomes in people living with T2D and increase our understanding of this subject and will inform future practice and policy. Findings will be disseminated via conference presentations, social media and peer-reviewed publication

Advanced Glycation End Products Acutely Impair Ca2+ Signaling in Bovine Aortic Endothelial Cells

Post-translational modification of proteins in diabetes, including formation of advanced glycation end products (AGEs) are believed to contribute to vascular dysfunction and disease. Impaired function of the endothelium is an early indicator of vascular dysfunction in diabetes and as many endothelial cell processes are dependent upon intracellular [Ca2+] and Ca2+ signalling, the aim of this study was to examine the acute effects of AGEs on Ca2+ signalling in bovine aortic endothelial cells (BAEC). Ca2+ signalling was studied using the fluorescent indicator dye Fura2-AM. AGEs were generated by incubating bovine serum albumin with 0 - 250 mM glucose or glucose-6-phosphate for 0 to 120 days at 37ºC. Under all conditions, the main AGE species generated was carboxymethyl lysine (CML) as assayed using both GC-MS and HPLC. In Ca2+-replete solution, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated the increase in intracellular [Ca2+] caused by ATP (100 µM). In the absence of extracellular Ca2+, exposure of BAEC to AGEs for 5 min caused an elevation in basal [Ca2+] and attenuated subsequent intracellular Ca2+ release caused by ATP, thapsigargin (0.1 µM) and ionomycin (3 µM), but AGEs did not affect extracellular Ca2+ entry induced by the re-addition of Ca2+ to the bathing solution in the presence of any of these agents. The anti-oxidant α-lipoic acid (2 µM) and NAD(P)H oxidase inhibitors apocynin (500 µM) and diphenyleneiodonium (DPI, 1 µM) abolished these effects of AGEs on BAECs, as did the IP3 receptor antagonist xestospongin C (1 µM). In summary, AGEs caused an acute depletion of Ca2+ from the intracellular store in BAECs, such that the Ca2+ signal stimulated by the subsequent application other agents acting upon this store is reduced. The mechanism may involve generation of ROS from NAD(P)H oxidase and possible activation of the IP3 receptor

Serum Apolipoprotein AI and B Are Stronger Biomarkers of Diabetic Retinopathy Than Traditional Lipids

10.2337/dc10-0793Diabetes Care342474-479DICA