Increased myocardial lipid delivery is a determinant of myocardial substrate metabolism and function in animal models of type 2 diabetes (T2DM). Sex also has major effects on myocardial metabolism in the human heart. Our aims were to determine: 1) if sex affects the myocardial metabolic response to lipid lowering in T2DM; 2) altering lipid (fatty acid [FA] or triglyceride) delivery to the heart would lower the elevated myocardial lipid metabolism associated with T2DM; and 3) if decreasing lipid delivery improves diastolic dysfunction in T2DM. To this end, we studied 78 T2DM patients (43 women) with positron emission tomography, echocardiography, and whole body tracer studies before and 3 months after randomization to metformin (MET), metformin+rosiglidazone (ROSI), or metformin+Lovaza (LOV). No treatment main effects were found for myocardial substrate metabolism, partly because men and women often had different responses to a given treatment. In men, MET decreased FA clearance, which was linked to increased plasma FA levels, myocardial FA utilization and oxidation and lower myocardial glucose utilization. In women, ROSI increased FA clearance, thereby decreasing plasma FA levels and myocardial FA utilization. Although LOV did not change triglyceride levels, it improved diastolic function, particularly in men. Group and sex also interacted in determining myocardial glucose uptake. Thus, in T2DM, different therapeutic regimens impact myocardial metabolism and diastolic function in a sex-specific manner. This suggests that sex should be taken into account when designing a patient's diabetes treatment.
[Show abstract][Hide abstract] ABSTRACT: Sex differences in cardiovascular disease and cardiac physiology have been reported in humans as well as in animal models. Premenopausal women have reduced cardiovascular disease compared to men, but the incidence of cardiovascular disease in women increases following menopause. Sex differences in cardiomyocytes likely contribute to the differences in male-female physiology and response to disease. Sex differences in the heart have been noted in electrophysiology, contractility, signaling, metabolism, and cardioprotection. These differences appear to be due, at least in part, to differences in gene and protein expression as well as in post translational protein modifications. This review will focus primarily on estrogen mediated male-female differences in protein expression and signaling pathways in the heart and cardiac cells. It should be emphasized that these basic differences are not intrinsically beneficial or detrimental per se; the difference can be good or bad depending on the context and circumstances.
Biology of Sex Differences 03/2014; 5(1):6. DOI:10.1186/2042-6410-5-6 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In 2008, the US Food and Drug Administration (FDA) issued guidance requiring demonstration of cardiovascular safety for all new glucose-lowering agents intended for the treatment of type 2 diabetes. The main driver for this move was the negative experience that the FDA had encountered with rosiglitazone. This widely prescribed thiazolidinedione had come under intense pressure with publication of an analysis suggesting an increased risk of myocardial infarction. The new FDA stringency stipulated the need for randomized controlled trials involving adequate numbers of participants over sufficiently long exposure and follow-up periods with adjudicated cardiovascular endpoints assessed against specific safety limits. It has been argued that these requirements are perhaps overzealous and run the risk of reducing innovation. Aspects of the pharmaceutical industry are perceived as being increasingly risk-averse within an increasingly competitive diabetes market. Set against these concerns is an opportunity to fill much-needed gaps in knowledge about the cardiovascular risks and benefits of glucose-lowering drugs, both old and new. Five years since the issuance of the FDA guidelines, we assess the operation of the current approval processes. We set the agency’s decision making in a broader context of other major regulatory bodies. Using recent data from trials of saxagliptin, alogliptin, and canagliflozin as examples, alongside the recently announced removal of the prescribing and dispensing restrictions for rosiglitazone, we consider whether the guidelines are functioning as intended.
Pharmaceutical Medicine 06/2014; 28(3):109-117. DOI:10.1007/s40290-014-0053-7
[Show abstract][Hide abstract] ABSTRACT: Background
Women with type 2 diabetes (T2D) are less likely to reach the goals for hemoglobin A1c compared with men, and have higher all-cause mortality. The risk of cardiovascular disease is elevated among both men and women with T2D, however, the risk has declined among men over recent years while it remains stationary in women. Reasons for these sex differences remain unclear, and guidelines for diabetes treatment do not differentiate between sexes. Possible causes for varying outcome include differences in physiology, treatment response, and psychological factors. This review briefly outlines sex differences in hormonal pathophysiology, and thereafter summarizes the literature to date on sex differences in disease course and outcome.
Systematic searches were performed on PubMed using “sex”, “gender”, and various glucose-lowering therapies as keywords. Earlier reviews are summarized and results from individual studies are reported. Reference lists from studies were used to augment the search.
There is an increased risk of missing the diagnosis of T2D when screening women with only fasting plasma glucose instead of with an oral glucose tolerance test. The impact of various risk factors for complications may differ by sex. Efficacy and side effects of some glucose-lowering drugs differ between men and women. Men with T2D appear to suffer more microvascular complications, while women have higher morbidity and mortality in cardiovascular disease and also fare worse psychologically.
Few studies to date have focused on sex differences in T2D. Several questions demand further study, such as whether risk factors and treatment guidelines should be sex-specific. There is a need for clinical trials designed specifically to evaluate sex differences in efficacy and outcome of the available treatments.
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 09/2014; 7:409-20. DOI:10.2147/DMSO.S51301
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