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Medha Sharma Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi, India

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Yamini Yadav Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi, India

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Chinmoy Sankar Dey Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, New Delhi, India

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Insulin signaling cascade in peripheral insulin-sensitive tissues regulates whole-body glucose metabolism. Any deregulation in this pathway leads to insulin resistance, ultimately leading to metabolic diseases like type 1 diabetes, type 2 diabetes, and obesity. Insulin signaling in the brain has also been studied for many decades and associated with many primary functions like maintenance of synaptic plasticity, regulation of cognition, and circadian rhythm. Importantly, neuronal insulin signaling has also been associated with the regulation of neuronal glucose uptake. Any impairment in neuronal insulin signaling affecting neuronal glucose uptake has been associated with neurodegenerative disorders like Alzheimer’s disease, the process now being termed as type 3 diabetes. Since the criticality lies in proper signaling cascade, determining important points of deregulation is important. In this review, we have discussed some critical points of such deregulation, dividing them into two classes of enzymes: kinases and phosphatases. We have highlighted their individual roles in neuronal insulin signaling, along with their possible implications in neuronal insulin resistance. Future strategies targeting these nodes in neuronal insulin signaling might be helpful in exploring potential therapeutic opportunities to overcome neuronal insulin resistance and related neurodegenerative diseases.

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Christy M Gliniak Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

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Line Pedersen Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

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Philipp E Scherer Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

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The prevalence of obesity is increasing exponentially across the globe. The lack of effective treatment options for long-term weight loss has magnified the enormity of this problem. Studies continue to demonstrate that adipose tissue holds a biological memory, one of the most important determinant of long-term weight maintenance. This phenomenon is consistent with the metabolically dynamic role of adipose tissue: it adapts and expands to store for excess energy and serves as an endocrine organ capable of synthesizing a number of biologically active molecules that regulate metabolic homeostasis. An important component of the plasticity of adipose tissue is the extracellular matrix, essential for structural support, mechanical stability, cell signaling and function. Chronic obesity upends a delicate balance of extracellular matrix synthesis and degradation, and the ECM accumulates in such a way that prevents the plasticity and function of the diverse cell types in adipose tissue. A series of maladaptive responses among the cells in adipose tissue leads to inflammation and fibrosis, major mechanisms that explain the link between obesity and insulin resistance, risk of type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Adipose tissue fibrosis persists after weight loss and further enhances adipose tissue dysfunction if weight is regained. Here, we highlight the current knowledge of the cellular events governing adipose tissue ECM remodeling during the development of obesity. Our goal is to delineate the relationship more clearly between adipose tissue ECM and metabolic disease, an important step toward better defining the pathophysiology of dysfunctional adipose tissue.

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Russell T Turner Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon, USA

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Kenneth A Philbrick Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Carmen P Wong Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Adam J Branscum Biostatistics Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA

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Urszula T Iwaniec Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon, USA
Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon, USA

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Absence of leptin confers metabolic dysfunction resulting in morbid obesity. Bone growth and maturation are also impaired. Partial leptin resistance is more common than leptin deficiency and, when induced by feeding mice a high fat diet, often has a negative effect on bone. Here, we used a genetic model to investigate the skeletal effects of partial and total leptin resistance in mice. This was accomplished by comparing the skeletal phenotypes of 17-week-old female C57Bl6/J wild-type (WT) mice, partial leptin receptor-deficient (db/+) mice and leptin receptor-deficient (db/db) mice (n = 7–8/group), all fed a standard diet. Compared to WT mice, db/db mice were dramatically heavier and hyperleptinemic. These mice were also hypogonadal, hyperglycemic, osteopenic and had lower serum levels of bone turnover markers, osteocalcin and C-terminal telopeptide of type I collagen (CTX). Compared to WT mice, db/+ mice were 14% heavier, had 149% more abdominal white adipose tissue, and were mildly hyperglycemic. db/+ mice did not differ from WT mice in uterine weight or serum levels of markers of bone turnover, although there was a trend for lower osteocalcin. At the bone microarchitectural level, db/+ mice differed from WT mice in having more massive femurs and a trend (P = 0.072) for larger vertebrae. These findings suggest that db/+ mice fed a normal mouse diet compensate for partial leptin resistance by increasing white adipose tissue mass which results in higher leptin levels. Our findings suggest that db/+ mice are a useful diet-independent model for studying the effects of partial leptin resistance on the skeleton.

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Seokwon Jo Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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Emilyn U Alejandro Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

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The metabolic health trajectory of an individual is shaped as early as prepregnancy, during pregnancy, and lactation period. Both maternal nutrition and metabolic health status are critical factors in the programming of offspring toward an increased propensity to developing type 2 diabetes in adulthood. Pancreatic beta-cells, part of the endocrine islets, which are nutrient-sensitive tissues important for glucose metabolism, are primed early in life (the first 1000 days in humans) with limited plasticity later in life. This suggests the high importance of the developmental window of programming in utero and early in life. This review will focus on how changes to the maternal milieu increase offspring’s susceptibility to diabetes through changes in pancreatic beta-cell mass and function and discuss potential mechanisms by which placental-driven nutrient availability, hormones, exosomes, and immune alterations that may impact beta-cell development in utero, thereby affecting susceptibility to type 2 diabetes in adulthood.

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Takanaga Shirai Institute of Health and Sport Sciences, University of Tsukuba, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan
Research Fellow of Japan Society for Promotion Science, Chiyoda-ku, Tokyo, Japan
Department of Human Sciences, Kanagawa University, Rokkakubashi, Kanagawa-ku, Yokohama-shi, Kanagawa, Japan

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Tomohiro Iwata Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan

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Kazuki Uemichi Research Fellow of Japan Society for Promotion Science, Chiyoda-ku, Tokyo, Japan
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan

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Riku Tanimura Research Fellow of Japan Society for Promotion Science, Chiyoda-ku, Tokyo, Japan
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan

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Ryoto Iwai Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan

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Tohru Takemasa Institute of Health and Sport Sciences, University of Tsukuba, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan

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Graphical abstract

Abstract

Calorie restriction (CR) is a widely recognized dietary approach with beneficial impacts on the entire body, including enhancements in oxidative metabolism and life span extension, while maintaining nutritional balance and calorie intake. However, CR leads to reductions in skeletal muscle and fat mass due to decreased food intake. Consequently, CR significantly modifies the metabolic profile of the entire body and its tissues. The observed benefits in skeletal muscle during CR may be attributed to CR-induced signaling mediators or significant changes in blood profiles associated with CR that regulate homeostasis maintenance. This study aimed to examine the mammalian target of rapamycin signaling and mitochondrial function of skeletal muscle from mice that undergone 8 weeks of CR and cells cultured in their serum to determine whether changes in blood secreted factors during CR affect skeletal muscle cells. C57BL6/J male mice were used. For 8 weeks, these were subjected to ad libitum (AL) or 40% CR. C2C12 myotubes were subsequently treated with media containing 10% mouse serum from AL or CR for 24 h. The results indicated that 8 weeks of CR decreased muscle mass and protein synthesis response compared with the AL group. Interestingly, myotubes conditioned with CR serum exhibited an elevation in the protein synthesis response compared with those treated with AL serum. Furthermore, mitochondrial function was enhanced in both CR mice and cells treated with CR serum. These findings suggest that while CR decreases the protein synthesis response, secretory factors present in the blood during CR can activate protein synthesis and promote mitochondrial function.

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Emily J King Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
Central Clinical School, Monash University, Melbourne, Victoria, Australia

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Simon T Bond Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
Central Clinical School, Monash University, Melbourne, Victoria, Australia
Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Australia

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Christine Yang Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia

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Yingying Liu Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia

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Anna C Calkin Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
Central Clinical School, Monash University, Melbourne, Victoria, Australia
Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Australia

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Darren C Henstridge Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
School of Health Sciences, University of Tasmania, Launceston, Tasmania, Australia

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Brian G Drew Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia
Central Clinical School, Monash University, Melbourne, Victoria, Australia
Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Australia

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Type 2 diabetes mellitus (T2DM), a condition characterised by insulin resistance (IR) and skeletal muscle mitochondrial abnormalities, is a leading cause of death in developed societies. Much work has postulated that improving pathways linked to mitochondrial health, including autophagy, may be a potential avenue to prevent or treat T2DM. Given the recent data indicating a role for tripartite motif-containing 28 (TRIM28) in autophagy and mitochondrial pathways, we investigated whether muscle-specific deletion of TRIM28 might impact on obesity, glucose tolerance, and IR in mice. We studied two different muscle-specific (MCK-cre and ACTA1-cre-ERT2) TRIM28 knockout models, which were phenotyped during and after being fed a chow or high-fat diet (HFD). Whilst muscle-specific deletion of TRIM28 in both models demonstrated alterations in markers of mitochondrial activity and autophagy in skeletal muscle, we did not observe major impacts on the majority of metabolic measures in these mice. Specifically, we demonstrate that deletion of TRIM28 in skeletal muscle of mice during (MCK-cre) or post-development (ACTA1-cre-ERT2) does not prevent HFD-induced obesity or glucose intolerance. These findings are consistent with those reported previously in relation to autophagy and mitochondria in other cell types, and thus warrant further study into the biological role TRIM28 has in relation to mitochondrial function.

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Leonardo Matta Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany
Institute for Diabetes and Cancer, Helmholtz Center Munich, Munich, Germany

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Cinthia Breves Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Luiz Fonte Boa Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Aina Eiras Domingos Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Caroline C Faria Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
UMR9019 CNRS, Université Paris-Saclay, Institut Gustave Roussy, Villejuif, France

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Itanna Souza Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Niedson Correia Lima-Junior Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Anna Paola Trindade Rocha Josué de Castro Institute of Nutrition, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Bianca M Gregório Urogenital Research Unit, State University of Rio de Janeiro, Rio de Janeiro, Brazil

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Denise Pires Carvalho Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Andrea C F Ferreira Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Josué de Castro Institute of Nutrition, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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José Hamilton Matheus Nascimento Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Leonardo Maciel NUMPEX, Duque de Caxias Campus, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Rodrigo S Fortunato Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Estrogen deficiency is a well-known hallmark of menopause and is associated with oxidative stress and metabolic dysfunction. Quercetin (Q), a flavonoid found in fruits and vegetables, has demonstrated anti-inflammatory effects in experimental models of metabolic disorders. In this study, we aimed to investigate the effects of quercetin on retroperitoneal white adipose tissue (rWAT) redox homeostasis and systemic metabolic parameters in ovariectomized (OVX) rats. Female Wistar rats at 3 months old were divided into the following experimental groups: sham-operated treated with vehicle (DMSO 10% + PBS – 1 mL/kg); OVX (vehicle treated) and OVX-Q (25 mg/kg) – via oral gavage, daily for 5 weeks. Q did not prevent weight gain but improved glucose tolerance and blood cholesterol profile, and attenuated uterine atrophy in OVX rats. Furthermore, Q had a protective effect on rWAT, once the OVX-Q group presented lower oxidative stress levels, and reduced levels of the pro-inflammatory cytokine tumor necrosis factor alpha, compared to the OVX group. Q improved antioxidant enzyme activities such as superoxide dismutase and catalase and decreased reactive oxygen species production, in OVX-Q rats. It was followed by increased levels of total thiol content and lower lipid peroxidation. Moreover, Q reduced senescent-related genes p16INK4a and p19ARF expression which were higher in the OVX group. In conclusion, quercetin supplementation improved redox homeostasis and reduced senescence-related markers, and inflammation in rWAT, which was reflected in preserved systemic metabolic health parameters in OVX rats. These findings suggest that quercetin may have therapeutic potential for the management of metabolic disorders associated with menopause-induced estrogen deficiency.

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Neil Tanday Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland

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Aimee Coulter-Parkhill Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland

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R Charlotte Moffett Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland

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Karthick Suruli Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland

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Vaibhav Dubey Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland

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Peter R Flatt Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland

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Nigel Irwin Diabetes Research Centre, Ulster University, Coleraine, Londonderry, Northern Ireland

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The present study examines differences in metabolic and pancreatic islet adaptative responses following streptozotocin (STZ) and hydrocortisone (HC) administration in male and female transgenic GluCreERT2/Rosa26-eYFP mice. Mice received five daily doses of STZ (50 mg/kg, i.p.) or 10 daily doses of HC (70 mg/kg, i.p.), with parameters assessed on day 11. STZ-induced hyperglycaemia was evident in both sexes, alongside impaired glucose tolerance and reduced insulin concentrations. HC also had similar metabolic effects in male and female mice resulting in classical increases of circulating insulin indicative of insulin resistance. Control male mice had larger pancreatic islets than females and displayed a greater reduction of islet and beta-cell area in response to STZ insult. In addition, female STZ mice had lower levels of beta-cell apoptosis than male counterparts. Following HC administration, female mouse islets contained a greater proportion of alpha cells when compared to males. All HC mice presented with relatively comparable increases in beta- and alpha-cell turnover rates, with female mice being slightly more susceptible to HC-induced beta-cell apoptosis. Interestingly, healthy control female mice had inherently increased alpha-to-beta-cell transdifferentiation rates, which was decreased by HC treatment. The number of glucagon-positive alpha cells altering their lineage to insulin-positive beta cells was increased in male, but not female, STZ mice. Taken together, although there was no obvious sex-specific alteration of metabolic profile in STZ or HC mice, subtle differences in pancreatic islet morphology emphasises the impact of sex hormones on islets and importance of taking care when interpreting observations between males and females.

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James Cantley Division of Systems Medicine, School of Medicine, University of Dundee, UK

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Vincent Poitout Montreal Diabetes Research Center, Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada
Department of Medicine, Université de Montréal, Montréal, QC, Canada

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Rebecca L Hull-Meichle Research and Development Service, VA Puget Sound Health Care System, Seattle, Washington, USA
Department of Medicine, University of Washington, Seattle, Washington, USA

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The year 2023 marks 100 years since publication of the first report of a hyperglycemic factor in pancreatic extracts which C P Kimball and John R Murlin named glucagon (from GLUCose AGONist). Glucagon has a range of profound effects on metabolism including, but not limited to, stimulation of hepatic glucose production. Dysregulation of glucagon secretion is a key feature of both major forms of diabetes, leading to the concept that diabetes is a bihormonal disorder. Still, the work to fully understand the production and biological effects of glucagon has proceeded at a slower pace compared to that of insulin. A recent resurgence of interest in the islet alpha (α) cell, the predominant site of glucagon production, has been facilitated in part by technological innovations. This work has led to significant developments in the field, from defining how alpha cells develop and how glucagon secretion from pancreatic alpha cells is regulated to determining the role of glucagon in metabolic homeostasis and the progression of both major forms of diabetes. In addition, glucagon is considered to be a promising target for diabetes therapy, with many new potential applications arising from research in this field. This collection of reviews, led by Guest Editors James Cantley, Vincent Poitout and Rebecca Hull-Meichle, is intended to capture the field’s current understanding of glucagon and alpha cell biology, as well stimulate additional interest and research on this important hormone.

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Marilyn B Renfree School of BioSciences, The University of Melbourne, Melbourne, Victoria, Australia

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Geoff Shaw School of BioSciences, The University of Melbourne, Melbourne, Victoria, Australia

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Since the discovery in 1968 that dihydrotestosterone (DHT) is a major mediator of androgen action, a convincing body of evidence has accumulated to indicate that the major pathway of DHT formation is the 5α-reduction of circulating testosterone in androgen target tissues. However, we now know that DHT can also be formed in peripheral tissues by the oxidation of 5α-androstane-3α,17β-diol (adiol). This pathway is responsible for the formation of the male phenotype. We discuss the serendipitous discovery in the tammar wallaby of an alternate pathway by which adiol is formed in the testes, secreted into plasma and converted in peripheral tissues to DHT. This alternate pathway is responsible for virilisation of the urogenital system in this species and is present in the testes at the onset of male puberty of all mammals studied so far. This is the first clear-cut function for steroid 5α-reductase 1 in males. Unexpectedly, the discovery of this pathway in this Australian marsupial has had a major impact in understanding the pathophysiology of aberrant virilisation in female newborns. Overactivity of the alternate pathway appears to explain virilisation in congenital adrenal hyperplasia CAH, in X-linked 46,XY disorders of sex development. It also appears to be important in polycystic ovarian syndrome (PCOS) since PCOS ovaries have enhanced the expression of genes and proteins of the alternate pathway. It is now clear that normal male development in marsupials, rodents and humans requires the action of both the classic and the alternate (backdoor) pathways.

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