The complementary roles of iron and estrogen in menopausal differences in cardiometabolic outcomes.

Biological hormonal changes are frequently cited as an explanatory factor of sex and menopause differences in cardiometabolic diseases (CMD) and its associated risk factors. However, iron metabolism which varies between sexes and among women of different reproductive stages could also play a role. Recent evidence suggest that iron may contribute to CMD risk by modulating oxidative stress pathways and inflammatory responses, offering insights into the mechanistic interplay between iron and CMD development. In the current review, we provide a critical appraisal of the existing evidence on sex and menopausal differences in CMD, discuss the pitfall of current estrogen hypothesis as sole explanation, and the emerging role of iron in CMD as complementary pathway. Prior to menopause, body iron stores are lower in females as compared to males, but the increase during and after menopause, is tandem with an increased CMD risk. Importantly, basic science experiments show that an increased iron status is related to the development of type 2 diabetes (T2D), and different cardiovascular diseases (CVD). While epidemiological studies have consistently reported associations between heme iron intake and some iron biomarkers such as ferritin and transferrin saturation with the risk of T2D, the evidence regarding their connection to CVD remains controversial. We delve into the factors contributing to this inconsistency, and the limitation of relying on observational evidence, as it does not necessarily imply causation. In conclusion, we provide recommendations for future studies on evaluating the potential role of iron in elucidating the sex and menopausal differences observed in CMD.

Effect of Bedtime Melatonin Administration in Patients with Type 2 Diabetes: A Triple-Blind, Placebo-Controlled, Randomized Trial.

Melatonin is widely available as over the counter product. Despite promising effects of melatonin supplementation on glycemic control, there is a significant heterogeneity between studies. The current study aimed at determining the effect of melatonin on fasting blood glucose (FBG), insulin resistance/sensitivity indices, glycosylated hemoglobin A1c (HbA1c), and high sensitivity C-reactive protein (hs-CRP) among type 2 diabetes mellitus (T2D) population during 8 weeks in a randomized, triple-blind, placebo-controlled trial. Thirty four subjects with the mean age ± standard deviation of 57.74 ± 8.57 years and 36 subjects with the mean age of 57.61 ± 9.11 years were allocated to 6 mg nightly melatonin and placebo groups, respectively. Melatonin and placebo groups were matched by age, gender, body mass index, and duration of diabetes. Also, there was no significant difference in laboratory findings except for HbA1c, which was lower in the placebo group (7.00 ± 0.89% vs 7.60 ± 1.47%, P=0.042). After trial completion, the increase of serum levels of melatonin was greater in the intervention than the placebo group (3.38 ± 1.33 vs 0.94 ± 1.28 ng/L, P=0.192). Moreover, compared to placebo group, among melatonin users, homeostasis model assessment of insulin resistance (HOMA1-IR) tended to be unfavorable at the end of follow-up [-0.51 (-1.76-0.81) vs. 0.28 (-1.24-1.74), P=0.20]; the similar trend was also shown for insulin sensitivity index (HOMA1-S) [2.33 (-3.59-12.46) vs. -2.33 (-10.61-9.16), P=0.148]. No differences were observed in FBG, HbA1C, and hs-CRP changes between the trial groups. The current study did not support the improving effect of melatonin on glucose homeostasis.