Gender and biological sex impact the pathogenesis of numerous diseases, including metabolic disorders such as diabetes. In most parts of the world, diabetes is more prevalent in men than in women, ...especially in middle-aged populations. In line with this, considering almost all animal models, males are more likely to develop obesity, insulin resistance and hyperglycaemia than females in response to nutritional challenges. As summarised in this review, it is now obvious that many aspects of energy balance and glucose metabolism are regulated differently in males and females and influence their predisposition to type 2 diabetes. During their reproductive life, women exhibit specificities in energy partitioning as compared with men, with carbohydrate and lipid utilisation as fuel sources that favour energy storage in subcutaneous adipose tissues and preserve them from visceral and ectopic fat accumulation. Insulin sensitivity is higher in women, who are also characterised by higher capacities for insulin secretion and incretin responses than men; although, these sex advantages all disappear when glucose tolerance deteriorates towards diabetes. Clinical and experimental observations evidence the protective actions of endogenous oestrogens, mainly through oestrogen receptor α activation in various tissues, including the brain, the liver, skeletal muscle, adipose tissue and pancreatic beta cells. However, beside sex steroids, underlying mechanisms need to be further investigated, especially the role of sex chromosomes, fetal/neonatal programming and epigenetic modifications. On the path to precision medicine, further deciphering sex-specific traits in energy balance and glucose homeostasis is indeed a priority topic to optimise individual approaches in type 2 diabetes prevention and treatment.
Estrogen receptor alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt ...to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of estrogens.
Due to their cardiovascular protective effect, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent breakthrough therapies for type 2 ...diabetes mellitus (T2DM). In this review article, we discuss the mechanistic and clinical synergies that make the combined use of GLP-1RAs and SGLT2is appealing in patients with T2DM. Overall, the presented cumulative evidence supports the benefits of GLP-1RA plus SGLT2i combination therapy on metabolic-cardiovascular-renal disease in patients with T2DM, with a low hypoglycemia risk. Accordingly, we encourage the adoption of GLP-1RA plus SGLT2i combination therapy in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (i.e., age ≥ 55 years, overweight/obesity, dyslipidemia, hypertension, current tobacco use, left ventricular hypertrophy, and/or proteinuria). Regarding renal effects, the evidence of SGLT2is in preventing kidney failure is more abundant than for GLP-1RAs, which showed a beneficial effect on albuminuria but not on hard kidney endpoints. Hence, in case of persistent albuminuria and/or uncontrolled metabolic risks (i.e., inadequate glycemic control, hypertension, overweight/obesity) on SGLT2i therapy, GLP-1RAs should be considered as the preferential add-on therapy in T2DM patients with chronic kidney disease. Despite the potential clinical benefits of GLP-1RA plus SGLT2i combination therapy in patients with T2DM, several factors may delay this combination to become a common practice soon, such as reimbursement and costs associated with polypharmacy. Altogether, when administering GLP-1RA plus SGLT2i combination therapy, it is important to adopt an individualized approach to therapy taking into account individual preferences, costs and coverage, toxicity profile, consideration of kidney function and glucose-lowering efficacy, desire for weight loss, and comorbidities.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits ...membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2 ⁰) provided selective loss of function of nuclear ERα actions. In ERα-AF2 ⁰, the acceleration of endothelial repair in response to estrogen–dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2 ⁰, whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissue-specific roles.
Purpose of Review
In France, in order to describe the phenotypic characteristics of patients with diabetes hospitalized for coronavirus disease-2019 (COVID-19) and to identify the prognostic factors ...in this specific population, the CORONADO (CORONAvirus and Diabetes Outcomes) study was launched. This review will summarize the key findings from the CORONADO study and put them in perspectives with others studies published on the subject.
Recent Findings
For almost 2 years, the new SARS-CoV-2 (Severe Acute Respiratory Syndrome-CoronaVirus-2), which causes COVID-19, has spread all around the world leading to a pandemic. From the first epidemiological reports, diabetes mellitus has rapidly emerged as a major risk factor associated with severe forms of COVID-19 but few data were available about diabetes characteristics in hospitalized people with COVID-19.
Summary
Between March 10 and April 10, 2020, 2951 patients were included in 68 centers throughout the national territory, including overseas territories. In the CORONADO study, the primary outcome was a composite endpoint combining invasive mechanical ventilation (IMV) and/or death within day 7 (D7). Secondary outcomes included death, IMV, intensive care unit (ICU) admission, and hospital discharge, all considered within D7 and day 28 (D28). The primary outcome occurred in 29.0% participants within D7 following hospital admission. Within D28, the end of the follow-up period, the mortality rate was 20.6%, while 50.2% of patients were discharged. In multivariable analysis, advanced age, microvascular complications, treatment with insulin or statin prior to admission, dyspnea on admission, as well as biological markers reflecting the severity of the infection (high levels of transaminases, leukocytes and CRP, and low platelet levels) were associated with an increased risk of death. Several exploratory analyses were performed to clarify the influence of some parameters such as weight status, sex, type of diabetes, and some routine drugs, including metformin or statins.
Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could ...represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.
Despite a significant pro-inflammatory effect, estrogens protect from the occurrence of high-fat diet-induced insulin resistance and glucose intolerance through the activation of estrogen receptor α.
Estrogens, and in particular 17β-estradiol (E2), play a pivotal role in sexual development and reproduction and are also implicated in a large number of physiological processes, including the ...cardiovascular system. Both acetylcholine-induced and flow-dependent vasodilation are preserved or potentiated by estrogen treatment in both animal models and humans. Indeed, E2 increases the endothelial production of nitric oxide and prostacyclin and prevents early atheroma through endothelial-mediated mechanisms. Furthermore, whereas it prevents endothelial activation, E2 potentiates the ability of several subpopulations of the circulating or resident immune cells to produce proinflammatory cytokines. The balance between these 2 actions could determine the final effect in a given pathophysiological process. E2 also promotes endothelial healing, as well as angiogenesis. Estrogen actions are essentially mediated by 2 molecular targetsestrogen receptor-α (ERα) and ERβ. The analysis of mouse models targeted for ERα or ERβ demonstrated a prominent role of ERα in vascular biology. ERα directly modulates transcription of target genes through 2 activation functions (AFs), AF-1 and AF-2. Interestingly, an AF-1-deficient ERα isoform can be physiologically expressed in the endothelium and appears sufficient to mediate most of the vasculoprotective actions of E2. In contrast, AF-1 is necessary for the E2 actions in reproductive targets. Thus, it appears conceivable to uncouple the vasculoprotective and sexual actions with appropriate selective ER modulators.
17β-Estradiol (E2) regulates estrogen receptor-α (ERα) target gene transcription through the two independent activation functions (AFs), AF1 and AF2, located in the N-terminal and ligand binding ...domain of ERα, respectively. We previously reported that ERα is required for the E2 atheroprotective action as well as for its accelerative action on endothelial healing, but its AF1 function is dispensable. Here, we investigated the role of ERαAF2 in these two major beneficial actions of E2 by electively targeting ERαAF2 (named ERαAF2°). Our results prove four points. (i) Compared with WT ERα, the ability of ERαAF2° to stimulate the C3 complement or the estrogen response element-thymidine kinase promoter in two cell lines was dramatically decreased, confirming the importance of AF2 in the E2-induced transcriptional activity of ERα. (ii) The uterotrophic action of E2 was totally absent in ERαAF2° mice, showing the crucial role of ERαAF2 in E2-induced uterus hyperplasia. (iii) ERαAF2 was dispensable for the accelerative action of E2 on endothelial healing, underlining the functionality of ERαAF2° in vivo. (iv) Finally, the atheroprotective effect of E2 was abrogated in ERαAF2° LDL-r−/− mice. Thus, whereas ERαAF1 and ERαAF2 are both required for the uterotrophic action of E2, we show that only ERαAF2 is necessary for its atheroprotective effect.
Abstract
Dietary lipids can affect metabolic health through gut microbiota-mediated mechanisms, but the influence of lipid-microbiota interaction on liver steatosis is largely unknown. We investigate ...the impact of dietary lipids on human gut microbiota composition and the effects of microbiota-lipid interactions on steatosis in male mice. In humans, low intake of saturated fatty acids (SFA) is associated with increased microbial diversity independent of fiber intake. In mice, poorly absorbed dietary long-chain SFA, particularly stearic acid, induce a shift in bile acid profile and improved metabolism and steatosis. These benefits are dependent on the gut microbiota, as they are transmitted by microbial transfer. Diets enriched in polyunsaturated fatty acids are protective against steatosis but have minor influence on the microbiota. In summary, we find that diets enriched in poorly absorbed long-chain SFA modulate gut microbiota profiles independent of fiber intake, and this interaction is relevant to improve metabolism and decrease liver steatosis.
Diabetes and oral contraception Gourdy, Pierre, MD, PhD
Best Practice & Research Clinical Endocrinology & Metabolism,
02/2013, Letnik:
27, Številka:
1
Journal Article
Recenzirano
The prevalence of diabetes mellitus is increasing dramatically worldwide, resulting in more and more women of reproductive age being affected by either type 1 or type 2 diabetes. Management of ...contraception is a major issue due to the specific risks associated with pregnancy and those potentially induced by hormonal contraceptives in diabetic women. This review emphasizes the urgent need to improve the use of contraception in women with diabetes. There is no consistent evidence that combined oral contraceptives significantly influence the risk of developing diabetes, even in women with a history of gestational diabetes. Furthermore, although data from specific studies remain sparse, no worsening effect has been reported in diabetic women, either in glycemic control or on the course of microvascular complications. Thus, the use of estroprogestive pills is now recognized as a safe and effective option for preconception care of women with uncomplicated diabetes. According to recent guidelines, these contraceptives must be avoided in case of associated cardiovascular risk factors, cardiovascular disease or severe microvascular complications such as nephropathy with proteinuria or active proliferative retinopathy. Prescription of combined hormonal contraception in type 2 diabetic women must also be considered with caution due to a frequent association with obesity and vascular risk factors which increase both thromboembolic and arterial risks. Thanks to their metabolic and vascular safety profile, progestin-only contraceptives, as well as non-hormonal methods, represent alternatives according to patient wishes.
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