To the best of our knowledge, the present study was the first to examine sex-related differences in myocardial glucose metabolism in individuals having different degrees of glucose tolerance. We found that deterioration in glucose homeostasis from normal glucose tolerance to prediabetes to T2DM was associated with a greater impairment in myocardial glucose metabolic rate, assessed using dynamic PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp, in women than men without coronary heart disease. Notably, as compared with women with NGT, those with prediabetes exhibited a 35% decrease (P = 0.04) in insulin-stimulated myocardial glucose metabolism and women with T2DM a 74% decrease (P = 0.006), respectively. Conversely, as compared with men with NGT, only men with T2DM exhibited a 40% reduction in myocardial glucose uptake (P = 0.004), while no significant difference was observed between men with NGT and prediabetes.
Additionally, we found that prediabetic and T2DM women exhibited greater relative differences in whole-body insulin-stimulated glucose disposal, than prediabetic and diabetic men when compared with their NGT counterparts. These findings confirm and extend the notion that deterioration of glucose homeostasis in women is associated with a worsening in insulin sensitivity as compared with men (11, 14, 33). In keeping with the present data, a previous study reported a greater impairment in insulin sensitivity assessed by euglycemic hyperinsulinemic clamp in women with prediabetes than men when compared with their NGT counterparts (14). Accordingly, other studies have examined sex-related differences in insulin sensitivity using indices derived from oral glucose tolerance test (OGTT) in individuals having different degree of glucose tolerance showing that sex advantage in glucose metabolism seen in women with NGT vanished in T2DM (11, 33).
Growing evidence has shown that women with T2DM have a considerably higher diabetes-related relative risk for the incident of major CV events and mortality, including a 44% higher relative risk for coronary heart disease event, as compared with men (5–10). We found a significant reduction in myocardial glucose metabolic rate in women with T2DM than male counterparts. An impairment in insulin-stimulated myocardial glucose metabolism in women with T2DM may indicate an early stage of myocardial energy disarrangement and reduced cardiac mechano-energetic performance (22, 23). Indeed, lower myocardial glucose metabolic rate has been associated with a worse CV risk profile (23), and carotid and coronary atherosclerosis (23, 24, 28). Furthermore, we have previously shown that as compared with men with T2DM, women with T2DM exhibited a higher reduction in cardiac mechano-energetic efficiency, and an increase in left ventricular mass, both being predictors of CV events (12, 26–27, 34). Overall, the higher degree of myocardial insulin resistance observed in women with the altered glucose homeostasis as compared with men may be an early metabolic trigger leading to subsequent maladaptive changes involving cardiac geometry, myocardial mechanical energy efficiency, and coronary atherosclerosis, thus eventually ensuing in excess CV risk in women compared to men when diagnostic threshold of T2DM is reached. Clearly, further studies are warranted to confirm the role of myocardial insulin resistance in the sex-related differences in the development of CVD in T2DM.
The current results should be interpreted within the context of its strengths and limitations. A main strength is the use of gold standard methods to assess myocardial glucose metabolism by cardiac 18F-FDG PET scan combined with euglycemic hyperinsulinemic clamp technique, which allows the valuation of insulin-stimulated myocardial glucose uptake under uniform experimental conditions of euglycemia and physiological hyperinsulinemia (17, 39). Moreover, glucose tolerance was accurately assessed using FPG, 2h post-load glucose levels during an OGTT, and HbA1c according to ADA criteria thus excluding any potential misclassification of participants (29). Additionally, all tests including 18F-FGD PET scan combined with euglycemic hyperinsulinemic clamp were collected by skilled examiners after a standardized training, who were blinded to the clinical data of the study participants.
Nonetheless, the present study also has some limitations. The results are only based on White individuals aging between 30 and 70 years thus limiting the generalizability of the present data to other ethnicities or to older individuals. Additionally, the cross-sectional design of the study precludes causal inferences, and, therefore, no conclusions regarding cause-effect relationships can be made.