Diabetic patients exhibit a reduction in β cells, which secrete insulin to help regulate glucose homeostasis; however, little is known about the factors that regulate proliferation of these cells in human pancreas. Access to primary human β cells is limited and a challenge for both functional studies and drug discovery progress. We previously reported the generation of a human β cell line (EndoC-βH1) that was generated from human fetal pancreas by targeted oncogenesis followed by in vivo cell differentiation in mice. EndoC-βH1 cells display many functional properties of adult β cells, including expression of β cell markers and insulin secretion following glucose stimulation; however, unlike primary β cells, EndoC-βH1 cells continuously proliferate. Here, we devised a strategy to generate conditionally immortalized human β cell lines based on Cre-mediated excision of the immortalizing transgenes. The resulting cell line (EndoC-βH2) could be massively amplified in vitro. After expansion, transgenes were efficiently excised upon
Raphaël Scharfmann, Severine Pechberty, Yasmine Hazhouz, Manon von Bülow, Emilie Bricout-Neveu, Maud Grenier-Godard, Fanny Guez, Latif Rachdi, Matthias Lohmann, Paul Czernichow, Philippe Ravassard
Insulin signaling in osteoblasts has been shown recently to contribute to whole-body glucose homeostasis in animals fed a normal diet; however, it is unknown whether bone contributes to the insulin resistance that develops in animals challenged by a high-fat diet (HFD). Here, we evaluated the consequences of osteoblast-specific overexpression of or loss of insulin receptor in HFD-fed mice. We determined that the severity of glucose intolerance and insulin resistance that mice develop when fed a HFD is in part a consequence of osteoblast-dependent insulin resistance. Insulin resistance in osteoblasts led to a decrease in circulating levels of the active form of osteocalcin, thereby decreasing insulin sensitivity in skeletal muscle. Insulin resistance developed in osteoblasts as the result of increased levels of free saturated fatty acids, which promote insulin receptor ubiquitination and subsequent degradation. Together, these results underscore the involvement of bone, among other tissues, in the disruption of whole-body glucose homeostasis resulting from a HFD and the involvement of insulin and osteocalcin cross-talk in glucose intolerance. Furthermore, our data indicate that insulin resistance develops in bone as the result of lipotoxicity-associated loss of insulin receptors.
Jianwen Wei, Mathieu Ferron, Christopher J. Clarke, Yusuf A. Hannun, Hongfeng Jiang, William S. Blaner, Gerard Karsenty
Central congenital hypothyroidism (CCH) is more prevalent in children born to women
with hyperthyroidism during pregnancy, suggesting a role for thyroid hormone (TH) in
the development of central thyroid regulation. Using the zebrafish embryo as a model
for thyroid axis development, we have characterized the ontogeny of negative feedback
regulation of thyrotrope function and examined the effect of excess TH on thyrotrope
development. We found that thyroid-stimulating hormone β subunit
Ksenia N. Tonyushkina, Meng-Chieh Shen, Theresa Ortiz-Toro, Rolf O. Karlstrom
Pancreatic β cell dysfunction is pathognomonic of type 2 diabetes mellitus (T2DM) and is driven by environmental and genetic factors. β cell responses to glucose and to incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are altered in the disease state. While rodent β cells act as a coordinated syncytium to drive insulin release, this property is unexplored in human islets. In situ imaging approaches were therefore used to monitor in real time the islet dynamics underlying hormone release. We found that GLP-1 and GIP recruit a highly coordinated subnetwork of β cells that are targeted by lipotoxicity to suppress insulin secretion. Donor BMI was negatively correlated with subpopulation responses to GLP-1, suggesting that this action of incretin contributes to functional β cell mass in vivo. Conversely, exposure of mice to a high-fat diet unveiled a role for incretin in maintaining coordinated islet activity, supporting the existence of species-specific strategies to maintain normoglycemia. These findings demonstrate that β cell connectedness is an inherent property of human islets that is likely to influence incretin-potentiated insulin secretion and may be perturbed by diabetogenic insults to disrupt glucose homeostasis in humans.
David J. Hodson, Ryan K. Mitchell, Elisa A. Bellomo, Gao Sun, Laurent Vinet, Paolo Meda, Daliang Li, Wen-Hong Li, Marco Bugliani, Piero Marchetti, Domenico Bosco, Lorenzo Piemonti, Paul Johnson, Stephen J. Hughes, Guy A. Rutter
Amélie Bonnefond, Anne Raimondo, Fanny Stutzmann, Maya Ghoussaini, Shwetha Ramachandrappa, David C. Bersten, Emmanuelle Durand, Vincent Vatin, Beverley Balkau, Olivier Lantieri, Violeta Raverdy, François Pattou, Wim Van Hul, Luc Van Gaal, Daniel J. Peet, Jacques Weill, Jennifer L. Miller, Fritz Horber, Anthony P. Goldstone, Daniel J. Driscoll, John B. Bruning, David Meyre, Murray L. Whitelaw, Philippe Froguel
Misfolding of exportable proteins can trigger endocrinopathies. For example, misfolding of insulin can result in autosomal dominant mutant
Jordan Wright, Xiaofan Wang, Leena Haataja, Aaron P. Kellogg, Jaemin Lee, Ming Liu, Peter Arvan
The osteoblast-derived hormone osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly,
Franck Oury, Mathieu Ferron, Wang Huizhen, Cyrille Confavreux, Lin Xu, Julie Lacombe, Prashanth Srinivas, Alexandre Chamouni, Francesca Lugani, Herve Lejeune, T. Rajendra Kumar, Ingrid Plotton, Gerard Karsenty
To explore the physiological functions of endothelin-2 (ET-2), we generated gene-targeted mouse models. Global
Inik Chang, Alexa N. Bramall, Amy Greenstein Baynash, Amir Rattner, Dinesh Rakheja, Martin Post, Stephen Joza, Colin McKerlie, Duncan J. Stewart, Roderick R. McInnes, Masashi Yanagisawa
Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3′-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary- and astrocyte-specific
Tatiana L. Fonseca, Mayrin Correa-Medina, Maira P.O. Campos, Gabor Wittmann, Joao P. Werneck-de-Castro, Rafael Arrojo e Drigo, Magda Mora-Garzon, Cintia Bagne Ueta, Alejandro Caicedo, Csaba Fekete, Balazs Gereben, Ronald M. Lechan, Antonio C. Bianco
Type 2 diabetes (T2D) has emerged as a major threat to human health in most parts of the world. Therapeutic strategies aimed at improving pancreatic β cell function are predicted to prove beneficial for the treatment of T2D. In the present study, we demonstrate that drug-mediated, chronic, and selective activation of β cell Gq signaling greatly improve β cell function and glucose homeostasis in mice. These beneficial metabolic effects were accompanied by the enhanced expression of many genes critical for β cell function, maintenance, and differentiation. By employing a combination of in vivo and in vitro approaches, we identified a novel β cell pathway through which receptor-activated Gq leads to the sequential activation of ERK1/2 and IRS2 signaling, thus triggering a series of events that greatly improve β cell function. Importantly, we found that chronic stimulation of a designer Gq-coupled receptor selectively expressed in β cells prevented both streptozotocin-induced diabetes and the metabolic deficits associated with the consumption of a high-fat diet in mice. Since β cells are endowed with numerous receptors that mediate their cellular effects via activation of Gq-type G proteins, our findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors.
Shalini Jain, Inigo Ruiz de Azua, Huiyan Lu, Morris F. White, Jean-Marc Guettier, Jürgen Wess