Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells.

Diabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estrogens, specifically 17-beta estradiol, in the maintenance of pancreatic beta cell health; however, the mechanisms underlying this protection are still unknown. To elucidate these potential mechanisms, we used a pancreatic beta cell line (BTC6) and a mouse model of hyperglycemia-induced atherosclerosis, the ApoE-/-:Ins2+/Akita mouse, exhibiting sexual dimorphism in glucose regulation. In this study we hypothesize that 17-beta estradiol protects pancreatic beta cells by modulating the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. We observed that ovariectomized female and male ApoE-/-:Ins2+/Akita mice show significantly increased expression of apoptotic UPR markers. Sham operated female and ovariectomized female ApoE-/-:Ins2+/Akita mice supplemented with exogenous 17-beta estradiol increased the expression of adaptive UPR markers compared to non-supplemented ovariectomized female ApoE-/-:Ins2+/Akita mice. These findings were consistent to what was observed in cultured BTC6 cells, suggesting that 17-beta estradiol may protect pancreatic beta cells by repressing the apoptotic UPR and enhancing the adaptive UPR activation in response to pancreatic ER stress.

Insight into genetic, biological, and environmental determinants of sexual-dimorphism in type 2 diabetes and glucose-related traits.

There is growing evidence that sex and gender differences play an important role in risk and pathophysiology of type 2 diabetes (T2D). Men develop T2D earlier than women, even though there is more obesity in young women than men. This difference in T2D prevalence is attenuated after the menopause. However, not all women are equally protected against T2D before the menopause, and gestational diabetes represents an important risk factor for future T2D. Biological mechanisms underlying sex and gender differences on T2D physiopathology are not yet fully understood. Sex hormones affect behavior and biological changes, and can have implications on lifestyle; thus, both sex-specific environmental and biological risk factors interact within a complex network to explain the differences in T2D risk and physiopathology in men and women. In addition, lifetime hormone fluctuations and body changes due to reproductive factors are generally more dramatic in women than men (ovarian cycle, pregnancy, and menopause). Progress in genetic studies and rodent models have significantly advanced our understanding of the biological pathways involved in the physiopathology of T2D. However, evidence of the sex-specific effects on genetic factors involved in T2D is still limited, and this gap of knowledge is even more important when investigating sex-specific differences during the life course. In this narrative review, we will focus on the current state of knowledge on the sex-specific effects of genetic factors associated with T2D over a lifetime, as well as the biological effects of these different hormonal stages on T2D risk. We will also discuss how biological insights from rodent models complement the genetic insights into the sex-dimorphism effects on T2D. Finally, we will suggest future directions to cover the knowledge gaps.

Investigating the protective effects of estrogen on ß-cell health and the progression of hyperglycemia-induced atherosclerosis.

Sex differences in the prevalence and development of diabetes and associated cardiometabolic complications are well established. The objective of this study was to analyze the effects of estrogen on the maintenance of ß-cell health/function and atherosclerosis progression, using a mouse model of hyperglycemia-induced atherosclerosis, the ApoE-/-:Ins2+/Akita mouse. ApoE-/-:Ins2+/Akita mice exhibit sexual dimorphism in the control of blood glucose levels. Male ApoE-/-:Ins2+/Akita mice are chronically hyperglycemic due to a significant reduction in pancreatic ß-cell mass. Female mice are only transiently hyperglycemic, maintain ß-cell mass, and blood glucose levels normalize at 35 ± 1 days of age. To determine the effects of estrogen on pancreatic ß-cell health and function, ovariectomies and estrogen supplementation experiments were performed, and pancreatic health and atherosclerosis were assessed at various time points. Ovariectomized ApoE-/-:Ins2+/Akita mice developed chronic hyperglycemia with significantly reduced ß-cell mass. To determine whether the observed effects on ovariectomized ApoE-/-:Ins2+/Akita mice were due to a lack of estrogens, slow-releasing estradiol pellets were inserted subcutaneously. Ovariectomized ApoE-/-:Ins2+/Akita mice treated with exogenous estradiol showed normalized blood glucose levels and maintained ß-cell mass. Exogenous estradiol significantly reduced atherosclerosis in both ovariectomized female and male ApoE-/-:Ins2+/Akita mice relative to controls. Together, these findings suggest that estradiol confers significant protection to pancreatic ß-cell health and can directly and indirectly slow the progression of atherosclerosis.NEW & NOTEWORTHY This study examines the effect(s) of estrogen on ß cell and cardiometabolic health/function in a novel mouse model of hyperglycemia-induced atherosclerosis (ApoE-/-:Ins2+/Akita). Using a combination of estrogen deprivation (ovariectomy) and supplementation strategies, we quantify effects on glucose homeostasis and atherogenesis. Our results clearly show a protective role for estrogen on pancreatic ß-cell health and function and glucose homeostasis. Furthermore, estrogen supplementation dramatically reduces atherosclerosis progression in both male and female mice.

The Role of Estrogen in Insulin Resistance: A Review of Clinical and Preclinical Data.

Insulin resistance results when peripheral tissues, including adipose, skeletal muscle, and liver, do not respond appropriately to insulin, causing the ineffective uptake of glucose. This represents a risk factor for the development of type 2 diabetes mellitus. Along with abdominal obesity, hypertension, high levels of triglycerides, and low levels of high-density lipoproteins, insulin resistance is a component of a condition known as the metabolic syndrome, which significantly increases the risk of developing cardiometabolic disorders. Accumulating evidence shows that biological sex has a major influence in the development of cardiometabolic disturbances, with females being more protected than males. This protection appears to be driven by female sex hormones (estrogens), as it tends to disappear with the onset of menopause but can be re-established with hormone replacement therapy. This review evaluates current knowledge on the protective role of estrogens in the relevant pathways associated with insulin resistance. The importance of increasing our understanding of sex as a biological variable in cardiometabolic research to promote the development of more effective preventative strategies is emphasized.

Role of Estrogen in Type 1 and Type 2 Diabetes Mellitus: A Review of Clinical and Preclinical Data.

The incidence and prevalence of diabetes mellitus, and the cardiovascular complications associated with this disease, are rapidly increasing worldwide. Individuals with diabetes have a higher mortality rate due to cardiovascular diseases and a reduced life expectancy compared to those without diabetes. This poses a significant economic burden on health-care systems worldwide, making the diabetes epidemic a global health crisis. Sex differences in the presentation and outcome of diabetes do exist. Premenopausal women are protected from developing diabetes and its cardiovascular complications relative to males and postmenopausal women. However, women with diabetes tend to have a higher mortality as a result of cardiovascular complications than age-matched men. Despite this evidence, preclinical and clinical research looking at sex as a biologic variable in metabolic disorders and their cardiovascular complications is very limited. The aim of this review is to highlight the current knowledge of the potential protective role of estrogens in humans as well as rodent models of diabetes mellitus, and the possible pathways by which this protection is conferred. We stress the importance of increasing knowledge of sex-specific differences to facilitate the development of more targeted prevention strategies.

Preclinical evaluation of a new liposomal formulation of cisplatin, lipoplatin, to treat cisplatin-resistant cervical cancer.

OBJECTIVE: Cisplatin-based chemotherapy has been shown to improve survival in cervical cancer; however, treatment is associated with tumor resistance and significant toxicity. Lipoplatin is a new liposomal formulation of cisplatin, developed to reduce cisplatin toxicity, to improve drug accumulation at tumor sites and to overcome drug resistance. The aim of this study is to analyze the antitumoral activity of lipoplatin against cisplatin-resistant cervical cancer cells and to investigate its mechanism of action. METHODS: The activity and mechanism of action of lipoplatin were studied in the ME-180 cervical cancer cell line and its cisplatin-resistant clone R-ME-180 and HeLa cells using cell proliferation assays, flow cytometry, ELISA assay, cell migration, spheroids and tumor xenograft. RESULTS: We demonstrated that lipoplatin exhibited a potent antitumoral activity on HeLa, ME-180 cells and its cisplatin-resistant clone R-ME-180. Lipoplatin inhibited cell proliferation in a dose-dependent manner and was more active than the reference drug cisplatin in R-ME-180 cells and induced apoptosis, as evaluated by Annexin-V staining and DNA fragmentation, caspases 9 and 3 activation, Bcl-2, and Bcl-xL down-regulation, but Bax up-regulation inhibited thioredoxin reductase (TrxR) enzymatic activity and increased reactive oxygen species (ROS) accumulation; reduced EGFR expression and inhibited both migration and invasion. R-ME-180, but not ME-180 cells, generated three-dimensional (3D)-multicellular spheroids expressing the cancer stem cell marker ALDH. The ability of R-ME-180 cells to form spheroids in vitro and tumors in nude mice was also remarkably decreased by lipoplatin. CONCLUSIONS: Overall, our results suggest that lipoplatin has potential for the treatment of cisplatin-resistant cervical cancer.