Sex Differences in Type‐2 Diabetes: Implications for Caveolin‐3 Regulated Mitochondrial Function
Authors: Zemljic‐Harpf Alice E , Ronquillo Antoinette , Dhanani Mehul , Leem Joseph S. , Thio Marianne P. , Alas Basheer F. , Kim So Yeon , Schilling Jan M. , Roth David M. , Patel Hemal H. 
Published: June 2021

IntroductionFemale diabetic patients have worse cardiovascular disease outcomes when compared to diabetic males. The underlying molecular mechanism responsible for this sex‐specific disease progression is still unclear. Caveolins are ubiquitously expressed membrane localized signaling platforms that regulate cardiac stress responses. Cardiac specific overexpression of caveolin‐3 (Cav3 OE) was shown to protect the heart from stressors such as ischemia or pressure‐overload.HypothesisSince we previously reported beneficial effects of cardiac specific Cav3 OE during cardiac stress adaptation, we tested the rationale that diabetic Cav3 OE female mice may be protected from diabetes‐induced mitochondrial dysfunction.Methods11–14‐month (m)‐old male and female Cav3 OE mice and transgene negative littermates (Tg‐neg) were injected with a single dose of streptozotocin (non‐fasted 75mg/kg i.p.) or citrate buffer and either placed on a 60% kcal high‐fat diet (HFD, TD 6414) to induce diabetes or placed on a 4% kcal low fat diet (LFD, TD 7001) as control. Food intake was monitored weekly and body weight assessed in two‐week intervals. Glucose tolerance testing (GTT) was performed 4 month‐post diabetes induction. 5m post diabetes induction, cardiac function was determined by echocardiography. Animals were sacrificed 6m post HFD and cardiac tissues harvested for ultrastructural analysis and high‐resolution respirometry on left ventricular free wall.ResultsHFD induced similar weight gain in mid‐age male and female Cav3 OE and Tg‐neg mice. In both sexes and genotypes GTT showed a comparable increase in glucose levels 4m post HFD. No differences in cardiac contractility (%EF) or diastolic function (E/A, and E′/A′), were detected between the four groups 5m post HFD. We identified cardiac hypertrophy with preserved systolic and diastolic function in male and female Tg‐neg mice on HFD while male and female Cav3OE mice did not show cardiac hypertrophy. Swollen cristae and diffuse mitochondrial inner and outer membrane structures were found in male and female Tg‐neg mice on HFD, but in Cav3 OE mice mitochondrial ultrastructure was preserved in both sexes. Mitochondrial function was preserved in all male T2DM hearts while reduced oxygen consumption was found in female Tg‐neg T2DM but not in female Cav3 OE T2DM.ConclusionWe show for the first time that mid‐age diabetic female mice present mitochondrial dysfunction earlier than male diabetic animals and Cav3 OE protects females from cardiac hypertrophy and mitochondrial dysfunction. The findings here mimic the clinical phenomenon that female diabetic patients show worsened cardiovascular outcomes. Therefore, Cav3 may present a novel target to protect the female heart from diabetes induced metabolic injury.Support or Funding InformationNational Institutes of Health (HL091071, AG052722) and the Veterans Administration (BX001963) to HHPThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.