RESUMEN
Managing diabetes mellitus is an ongoing concern, especially in the presence of heart failure. Recent reports have drawn attention to adverse cardiovascular events associated with the use of thiazolidinediones, including rosiglitazone (Avandia). In 2011, the U.S. Food and Drug Administration implemented a stringent "restricted access program" for the prescription of Avandia. Other studies, which have revealed increased mortality rates in association with tight glycemic control, raise serious concerns about managing diabetes in heart-failure patients. Herein, we provide a perspective on the management of noninsulin-dependent diabetes in patients with heart failure. We point out that thiazolidinediones exert their major effects through insulin sensitization, which potentiates the action of insulin. A defining feature of insulin resistance is excess fuel supply and restricted rates of substrate utilization by the heart. We postulate that the use of excess insulin and insulin-sensitizing agents can lead to adverse cardiovascular events and contractile dysfunction through an increase of substrate uptake to an insulin-resistant heart that is already flooded with fuel. We include a table of antidiabetic agents and nonpharmacologic interventions aimed at lowering substrate supply, and of the respective clinical trials supporting their safety and efficacy. Although previously contraindicated in patients with heart failure, metformin appears to be both safe and effective therapy for diabetes in those patients. Because metformin reduces gluconeogenesis in the liver, we propose that the management of diabetes in heart-failure patients should target the source, rather than the destination, of excess fuel.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insuficiencia Cardíaca/epidemiología , Hipoglucemiantes/uso terapéutico , Tiazolidinedionas/uso terapéutico , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Comorbilidad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/fisiopatología , Gluconeogénesis/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipoglucemiantes/efectos adversos , Resistencia a la Insulina , Hígado/efectos de los fármacos , Hígado/metabolismo , Miocardio/metabolismo , Medición de Riesgo , Factores de Riesgo , Rosiglitazona , Tiazolidinedionas/efectos adversos , Resultado del TratamientoRESUMEN
The pgsA null Escherichia coli strain, UE54, lacks the major anionic phospholipids phosphatidylglycerol and cardiolipin. Despite these alterations the strain exhibits relatively normal cell division. Analysis of the UE54 phospholipids using negativeion electrospray ionization mass spectrometry resulted in identification of a new anionic phospholipid, N-acylphosphatidylethanolamine. Staining with the fluorescent dye 10-N-nonyl acridine orange revealed anionic phospholipid membrane domains at the septal and polar regions. Making UE54 null in minCDE resulted in budding off of minicells from polar domains. Analysis of lipid composition by mass spectrometry revealed that minicells relative to parent cells were significantly enriched in phosphatidic acid and N-acylphosphatidylethanolamine. Thus despite the absence of cardiolipin, which forms membrane domains at the cell pole and division sites in wild-type cells, the mutant cells still maintain polar/septal localization of anionic phospholipids. These three anionic phospholipids share common physical properties that favor polar/septal domain formation. The findings support the proposed role for anionic phospholipids in organizing amphitropic cell division proteins at specific sites on the membrane surface.