title: Sex, sex steroids, and diabetic cardiomyopathy: making the case for experimental focus.
abstract: More than three decades ago, the Framingham study revealed that cardiovascular risk is elevated for all diabetics and that this jeopardy is substantially accentuated for women in particular. Numerous studies have subsequently documented worsened cardiac outcomes for women. Given that estrogen and insulin exert major regulatory effects through common intracellular signaling pathways prominent in maintenance of cardiomyocyte function, a sex-hormone:diabetic-disease interaction is plausible. Underlying aspects of female cardiovascular pathophysiology that exaggerate cardiovascular diabetic risk may be identified, including increased vulnerability to coronary microvascular disease, age-dependent impairment of insulin-sensitivity, and differential susceptibility to hyperglycemia. Since Framingham, considerable progress has been made in the development of experimental models of diabetic disease states, including a diversity of genetic rodent models. Ample evidence indicates that animal models of both type 1 and 2 diabetes variably recapitulate aspects of diabetic cardiomyopathy including diastolic and systolic dysfunction, and cardiac structural pathology including fibrosis, loss of compliance, and in some instances ventricular hypertrophy. Perplexingly, little of this work has explored the relevance and mechanisms of sexual dimorphism in diabetic cardiomyopathy. Only a small number of experimental studies have addressed this question, yet the prospects for gaining important mechanistic insights from further experimental enquiry are considerable. The case for experimental interrogation of sex differences, and of sex steroid influences in the aetiology of diabetic cardiomyopathy, is particularly compelling-providing incentive for future investigation with ultimate therapeutic potential.
authors.affiliation: Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia;
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Reichelt
authors.forename: Kimberley M
authors.initials: KM
authors.lastname: Mellor
authors.forename: James R
authors.initials: JR
authors.lastname: Bell
authors.forename: Chanchal
authors.initials: C
authors.lastname: Chandramouli
authors.forename: John P
authors.initials: JP
authors.lastname: Headrick
authors.forename: Lea M D
authors.initials: LM
authors.lastname: Delbridge
mesh_terms: D000818:Animals; D058065:Diabetic Cardiomyopathies / Q000150:complications* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006801:Humans; D008955:Models, Cardiovascular; D012107:Research Design; D012737:Sex Factors; D018487:Ventricular Dysfunction, Left / Q000150:complications* / Q000378:metabolism*; D016387:Women's Health
chemical_list: D012739:Gonadal Steroid Hormones
keywords: cardiac; contractility; diabetes; gender; hypertrophy; insulin-sensitivity; sex