Sex Differences in the Progression of Diabetes‐associated Cardiac Pathology

Abstract

Type 2 Diabetes Mellitus (T2DM) is a major contributor to cardiovascular disease (CVD). We hypothesized that there are significant sex‐related differences in the progression of T2DM‐induced cardiac pathology in pre‐menopausal diabetic female rats and age‐matched diabetic male rats. These differences were assessed in 3 study groups: ZDF male rats (ZDF‐M) and lean female rats (L‐F) on Purina 5008 diet, and ZDF female (ZDF‐F) rats on Research Diets D12468 (to induce T2DM) from the age of 6‐20 weeks. ZDF‐M went from having a ~26 fold higher fasting plasma insulin (INS) than L‐F at 9‐weeks, to <2 fold at 20‐weeks (p<0.05). In contrast, in ZDF‐F, INS was ~ 64 fold higher than L‐F at 15‐weeks and was still ~50 fold higher than L‐F and ~21 fold higher than ZDF‐M at 20‐weeks (p<0.05). Hyperglycemia was lower in ZDF‐F than ZDF‐M at all ages, but ZDF‐F had lower plasma HDL and higher LDL levels and higher % body fat and lower % lean muscle mass (as determined by EchoMRI) compared to ZDF‐M and L‐F (p<0.05). Cardiac echocardiography showed heart rate was significantly different among all three groups with ZDF‐F being greatest and ZDF‐M lowest. However, only ZDF‐M displayed cardiac diastolic dysfunction, indicated by dilatory remodeling, increased isovolumic relaxation time, increased late diastolic filling (A) and decreased E/A and E'/A' ratios. ZDF‐M had the highest 24‐hr urine clearance of Na+, K+, glucose and protein (p<0.05).ConclusionT2DM had different effects on ZDF‐F and ZDF‐M. ZDF‐F had a quicker loss of lean muscle mass and HDL despite longer hyperinsulinemic stage of T2DM, whereas ZDF‐M had higher HDL, but worse cardiac dysfunction.Funding: LSME, UM‐Columbia (LP), NIH 1R01HL118376‐01(LP), R01HL112998 (CAE).