Women with type 1 diabetes (T1D) lose the premenopausal protection from cardiovascular disease (CVD) that non-diabetic (non-DM) women have compared to men, and are also more insulin resistant than non-DM women. Standard CVD risk factors have not been found to adequately predict CVD in the T1D population, but insulin resistance is emerging as a potentially important risk factor. The aim of this study was to determine whether sex hormone levels such as estradiol (E2), total testosterone (TT), and sex-hormone binding globulin (SHBG) explained any of the decreased insulin sensitivity in women with T1D, which could be important in CVD prevention.
This study included 25 premenopausal women 18-45 years of age with a mean ± SD age of 33 ± 8 years who completed a three stage (4, 8 and 40 mU/m2/min) hyperinsulinemic-euglycemic clamp during the luteal phase of the menstrual cycle (T1D n=12 and non-DM n=13). A steady state was achieved during the last 30 minutes of the high insulin infusion stage and mean glucose infusion rate (GIR [mg/kg/FFM/min]) during this time was used as an estimate of the skeletal muscle glucose disposal rate. Sex hormones were compared using unpaired Student t tests between T1D and non-DM participants during each phase of the menstrual cycle and during the morning of the clamp.. Significant differences were explored in multivariable linear regression in which stepwise model selection was used to determine the final model adjusting for age and diabetes status.
In age-adjusted analysis, women with T1D were less than half as insulin sensitive as non-DM women (least squares mean ± SE: 7.5±2.2 vs. 19.0±2.1, respectively, p=0.0014). SHBG was significantly higher in the T1D than the non-DM subjects the morning of the clamp (p<0.0001) and during each phase of the menstrual cycle (p = 0.01). TT was significantly higher in T1D women during the early follicular phase of the menstrual cycle (p=0.02) and was negatively correlated with GIR (r = -0.54, p = 0.04). E2 during the early follicular phase was positively correlated with GIR (r = 0.83, p = 0.01). In multivariable analysis, the difference in the GIR was attenuated by 58%(1-(5.1/12.14)) (least squares mean ± SE: 10.9 ± 1.7 in T1D vs. 16.0 ± 1.5 in non-DM, p = 0.07) after adjusting for age, diabetes status, minutes of vigorous activity, average waist circumference, free estradiol index and testosterone during the early follicular phase of the menstrual cycle In conclusion, the decreased insulin sensitivity observed in premenopausal T1D women with regular menstrual cycles can be mostly explained by lower levels of physical activity, greater central adiposity and differences in sex hormone levels. Most of these factors are modifiable, and so could be important targets in the reduction of CVD.