Evidence of Sex Differences in the Endothelin Pathway in Diabetes

Cassandra C. Derella, Jeffrey Thomas, Lawrence C. Layman, Ryan A. Harris

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: The endothelin system has been identified as a key regulator of vascular function and is comprised of two receptors; a constricting A-receptor (ETA R) and dilating B-receptor (ETB R). Sex differences in the ET-1 pathway have been established. Specifically, when compared to men, activation of the ETB R in women results in a favorable dilatory response. In the presence of diabetes; however, the endothelin system in general, is negatively altered. Whether sex differences in the endothelin pathway are observed in type 1 diabetes (T1D), is unknown. Thus, the present investigation sought to test the hypothesis that ETB receptor function is reduced in women with T1D compared to men with T1D. METHODS: Premenopausal women (n=2, HbA1c =10.4±0.8%, age=29±13 years, BMI=29.9±2.8 kg/m2 ) and men (n=4, HbA1c =8.5±1.0%, age=22±3 years, BMI=21.5±2.8 kg/m2 ) with a clinical diagnosis of T1D were recruited to participate. Three microdialysis fibers were inserted into the dermal layer of the right forearm where cutaneous blood flow was measured using laser speckle contrast imaging. Microvascular function was determined by a ten dose incremental perfusion of acetylcholine (Ach; 10-2 -2*103 M). Endothelin receptor function was determined two ways: 1) by a seven dose incremental perfusion of ET-1 (10-20 -10-8 M), and 2) by a seven dose incremental perfusion of ET-1 (10-20 -10-8 M) combined with the selective ETA R antagonist, BQ-123 (750 nM). The dose response area under the curve (AUC) for cutaneous vascular conductance of each fiber was calculated for each individual. RESULTS: Women with T1D had a significantly greater BMI (p=0.026) and HbA1C (p=0.089) compared to men with T1D. The Ach dose response AUC was greater (p=0.135) in women with T1D (753.5±12.7 AU) when compared to men with T1D (691.7±61.1 AU). The ET-1 + BQ-123 dose response AUC tended (p=0.298) to be lower in women with T1D (295.5±14.1 AU) when compared to men with T1D (357.8±98.6 AU). A similar lower response in women was observed for the ET-1 AUC (p=0.102; men: 1411.9±508.9 AU vs women: 821.7±38.5 AU). CONCLUSION: These data suggest that, compared to men with T1D, microvascular function is greater in women, albeit weighing more and having a higher HbA1c . In contrast, preliminary findings indicate that ETB R function may be impaired in women with T1D compared to men with T1D.

Original languageEnglish
JournalFASEB Journal
Volume36
DOIs
StatePublished - May 1 2022
Externally publishedYes

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