Endocrinology, SBMS, Faculty of Medicine, The University of Queensland, St Lucia, Qld, Australia
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Polycystic ovary syndrome (PCOS) is a common endocrinopathy occurring in reproductive-age women. Hyperandrogenism, polycystic ovaries, chronic anovulation, and metabolic aberrations are the common features in PCOS. Hormonal changes are causing pathological symptoms in women with PCOS. The various hormone alterations in PCOS have been demonstrated. Hormones, such as insulin, growth hormones (GH), ghrelin, LEAP-2, gonadotropin-releasing hormone (GnRH), insulin, the luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio, androgens, and estrogens, are all abnormal in PCOS women. These hormones are related to metabolic disorders, such as diabetes and insulin resistance, overweight and obesity, infertility, and disturbed menstrual cycle in PCOS patients. The pathological changes of these hormones, such as increased insulin, reduced GH, increased ghrelin, and leptin resistance, result in an increased prevalence of diabetes and obesity in PCOS women. A reduced GH, increased LEAP-2 levels, high LH basal, increased LH/FSH ratio, high androgens, and low estrogen are demonstrated in PCOS and linked to infertility. This narrative review aims to clarify the changes of hormone profiles, such as insulin, GH, LH, FSH, androgens, estrogen, progesterone, ghrelin, LEAP-2, asprosin, and subfatin, in PCOS, which may reveal novel targets for better diagnosis and treatment of PCOS.
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Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, Texas, USA
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Department of Cell and Microbiology, Weill Cornell Medical College, New York, New York, USA
Department of Genetics, The University of Texas Anderson Cancer Center, Houston, Texas, USA
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Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, Texas, USA
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Department of Cell and Microbiology, Weill Cornell Medical College, New York, New York, USA
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Metabolic syndrome (MetS) is an increasing global health threat and strong risk factor for type 2 diabetes (T2D). MetS causes both hyperinsulinemia and islet size overexpansion, and pancreatic β-cell failure impacts insulin and proinsulin secretion, mitochondrial density, and cellular identity loss. The low-density lipoprotein receptor knockout (LDLr −/−) model combined with high-fat diet (HFD) has been used to study alterations in multiple organs, but little is known about the changes to β-cell identity resulting from MetS. Osteocalcin (OC), an insulin-sensitizing protein secreted by bone, shows promising impact on β-cell identity and function. LDLr −/− mice at 12 months were fed chow or HFD for 3 months ± 4.5 ng/h OC. Islets were examined by immunofluorescence for alterations in nuclear Nkx6.1 and PDX1 presence, insulin–glucagon colocalization, islet size and %β-cell and islet area by insulin and synaptophysin, and mitochondria fluorescence intensity by Tomm20. Bone mineral density (BMD) and %fat changes were examined by Piximus Dexa scanning. HFD-fed mice showed fasting hyperglycemia by 15 months, increased weight gain, %fat, and fasting serum insulin and proinsulin; concurrent OC treatment mitigated weight increase and showed lower proinsulin-to-insulin ratio, and higher BMD. HFD increased %β and %islet area, while simultaneous OC-treatment with HFD was comparable to chow-fed mice. Significant reductions in nuclear PDX1 and Nkx6.1 expression, increased insulin–glucagon colocalization, and reduction in β-cell mitochondria fluorescence intensity were noted with HFD, but largely prevented with OC administration. OC supplementation here suggests a benefit to β-cell identity in LDLr −/− mice and offers intriguing clinical implications for countering metabolic syndrome.
Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
Diabetes and Nutritional Sciences, King's College London, London, UK
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Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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Sexual dimorphism in energy metabolism is now established and suggested to affect many aspects of metabolic diseases and in particular diabetes and obesity. This is strongly related to sex-based differences in whole-body insulin resistance. Women are more insulin sensitive compared to men, but this metabolic advantage gradually disappears after menopause or when insulin resistance progresses to hyperglycemia and diabetes. In this narrative review, first, we describe the pathophysiology related to insulin resistance and then we present the epidemiological evidence as well as the important biological factors that play a crucial role in sexual dimorphism in insulin sensitivity. We focus particularly on the differences in body fat and muscle mass distribution and function, in inflammation and in sex hormones between males and females. Most importantly, we describe the significant mechanistic differences in insulin sensitivity as well as glucose and lipid metabolism in key metabolic organs: liver, white adipose tissue, and skeletal muscle. Finally, we present the sex-based differences in response to different interventions and discuss important open research questions.
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Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow, UK
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The integral role of the hypothalamic–pituitary–gonadal axis in reproductive processes makes it a prime therapeutic target. By inhibiting sex steroid synthesis, gonadotropin-releasing hormone (GnRH) analogues are used in the management of cancers, benign neoplasms, infertility and gender dysphoria. However, the wide application of these therapeutics raises concerns regarding the unintended effects upon the cardiovascular system. In males with prostate cancer, GnRH analogues when used as an androgen deprivation therapy appear to increase the risk of cardiovascular disease, which is the leading cause of death in this population. Therefore, due to the utilisation of GnRH analogues across the lifespan and gender spectrum, this relationship merits discussion. Existing data suggest an association between GnRH analogues and major adverse cardiovascular events in males. Conversely, females receiving GnRH analogues for breast cancer treatment appear to be at an increased risk of developing hypertension. In this narrative review, we describe the uses of GnRH analogues in adults, adolescents and children. We discuss whether sex plays a role in the cardiovascular effects of GnRH analogues and explore the significance of sex hormone receptors in the vasculature. We also consider confounding factors such as malignancy, advanced age and infertility.
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The solute carrier (SLC) family is a large group of membrane transport proteins. Their dysfunction plays an important role in the pathogenesis of thyroid cancer. The most well-known SLC is the sodium-iodide symporter (NIS), also known as sodium/iodide co-transporter or solute carrier family 5 member 5 (SLC5A5) in thyroid cancer. The dysregulation of NIS in thyroid cancer is well documented. The role of NIS in the uptake of iodide is critical in the treatment of thyroid cancer, radioactive iodide (RAI) therapy in particular. In addition to NIS, other SLC members may affect the autophagy, proliferation, and apoptosis of thyroid cancer cells, indicating that an alteration in SLC members may affect different cellular events in the evolution of thyroid cancer. The expression of the SLC members may impact the uptake of chemicals by the thyroid, suggesting that targeting SLC members may be a promising therapeutic strategy in thyroid cancer.
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The Diabetes Institute, Ohio University, Athens, Ohio, USA
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The Diabetes Institute, Ohio University, Athens, Ohio, USA
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The Diabetes Institute, Ohio University, Athens, Ohio, USA
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Studies in humans and mice have determined that distinct subpopulations of adipocytes reside even within individual adipose tissue depots. Previously, our lab defined three white adipocyte subpopulations with stable and unique gene expression profiles, which were termed type 1, 2, and 3 adipocytes, respectively. Our previous studies demonstrated that type 2 adipocytes were highly responsive to the inflammatory cytokine, tumor necrosis factor alpha (TNFα). This study extends these findings to investigate the role of type 2 adipocytes in obesity. We found that treatment with TNFα increased lipolysis specifically in type 2 adipocytes, at least in part, through the reduction of fat-specific protein 27 (FSP27) expression. To assess the physiological role of lipolysis from this adipocyte subpopulation, a type2Ad-hFSP27tg mouse model was generated by overexpressing human FSP27 specifically in type 2 adipocytes. Glucose and insulin tolerance test analysis showed that male type2Ad-hFSP27tg mice on 60% high-fat diet exhibited improved glucose tolerance and insulin sensitivity, with no change in body weight compared to controls. These metabolic changes may, at least in part, be explained by the reduced lipolysis rate in the visceral fat of type2Ad-hFSP27tg mice. Although FSP27 overexpression in primary type 2 adipocytes was sufficient to acutely reduce TNFα-induced apoptosis in vitro, it failed to reduce macrophage infiltration in obesity in vivo. Taken together, these results strongly suggest that type 2 adipocytes contribute to the regulation of lipolysis and could serve as a potential therapeutic target for obesity-associated insulin resistance.
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Physiology and Pharmacology, Western University, London, Ontario, Canada
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Insulin resistance contributes to the development of various diseases, including type 2 diabetes and gestational diabetes. Even though gestational diabetes is specific to pregnancy, it can result in long-term glucose intolerance and type 2 diabetes after delivery. Given the substantial health and economic burdens associated with diabetes, it is imperative to better understand the mechanisms leading to insulin resistance and type 2 diabetes so that treatments targeted at reversing symptoms can be developed. Considering that the endocrine cells of the pancreas (islets of Langerhans) largely contribute to the pathogenesis of diabetes (beta-cell insufficiency and dysfunction), the elucidation of the various mechanisms of endocrine cell plasticity is important to understand. By better defining these mechanisms, targeted therapeutics can be developed to reverse symptoms of beta-cell deficiency and insulin resistance in diabetes. Animal models play an important role in better understanding these mechanisms, as techniques for in vivo imaging of endocrine cells in the pancreas are limited. Therefore, this review article will discuss the available rodent models of gestational and type 2 diabetes that are characterized by endocrine cell impairments in the pancreas, discuss the models with a comparison to human diabetes, and explore the potential mechanisms of endocrine cell plasticity that contribute to these phenotypes, as these mechanisms could ultimately be used to reverse blood glucose dysregulation in diabetes.
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
Banting & Best Diabetes Centre, Toronto, Ontario, Canada
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Banting & Best Diabetes Centre, Toronto, Ontario, Canada
Department of Physiology, University of Toronto, Toronto, Ontario, Canada
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Department of Physiology, University of Toronto, Toronto, Ontario, Canada
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Metabolic tests are vital to determine in vivo insulin sensitivity and glucose metabolism in preclinical models, usually rodents. Such tests include glucose tolerance tests, insulin tolerance tests, and glucose clamps. Although these tests are not standardized, there are general guidelines for their completion and analysis that are constantly being refined. In this review, we describe metabolic tests in rodents as well as factors to consider when designing and performing these tests.
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We previously reported that Lactobacillus amylovorus KU4 (LKU4) promotes adipocyte browning in mice fed a high-fat diet (HFD mice) in part by remodeling the PPARγ transcription complex. However, the mechanism through which LKU4 enables PPARγ to drive adipocyte browning remains elusive. Here, we report that LKU4 inhibits the expression of PP4C in inguinal white adipose tissue of HFD mice and in insulin-resistant 3T3-L1 adipocytes, which promotes SIRT1-dependent PPARγ deacetylation by activating AMPK, leading to the browning of adipocytes. Consistently, the silencing of PP4C further enhances this pathway. Furthermore, we observed that lactate, a key LKU4 metabolite, reduces insulin-induced PP4C expression and suppresses PP4C inhibition of PPARγ deacetylation and transcriptional activity via AMPK–SIRT1, thereby facilitating the browning of adipocytes. Together, these data demonstrate that LKU4 promotes the AMPK–SIRT1–PPARγ pathway by inhibiting PP4C, thereby facilitating adipocyte browning in HFD mice.
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The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Australia
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Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, UK
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Adverse environmental conditions before birth are known to programme adult metabolic and endocrine phenotypes in several species. However, whether increments in fetal cortisol concentrations of the magnitude commonly seen in these conditions can cause developmental programming remains unknown. Thus, this study investigated the outcome of physiological increases in fetal cortisol concentrations on glucose–insulin dynamics and pituitary–adrenal function in adult sheep. Compared with saline treatment, intravenous fetal cortisol infusion for 5 days in late gestation did not affect birthweight but increased lamb body weight at 1–2 weeks after birth. Adult glucose dynamics, insulin sensitivity and insulin secretion were unaffected by prenatal cortisol overexposure, assessed by glucose tolerance tests, hyperinsulinaemic–euglycaemic clamps and acute insulin administration. In contrast, prenatal cortisol infusion induced adrenal hypo-responsiveness in adulthood with significantly reduced cortisol responses to insulin-induced hypoglycaemia and exogenous adrenocorticotropic hormone (ACTH) administration relative to saline treatment. The area of adrenal cortex expressed as a percentage of the total cross-sectional area of the adult adrenal gland was also lower after prenatal cortisol than saline infusion. In adulthood, basal circulating ACTH but not cortisol concentrations were significantly higher in the cortisol than saline-treated group. The results show that cortisol overexposure before birth programmes pituitary–adrenal development with consequences for adult stress responses. Physiological variations in cortisol concentrations before birth may, therefore, have an important role in determining adult phenotypical diversity and adaptability to environmental challenges.
