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A single species of fly, Drosophila melanogaster, has been the subject of scientific research for more than one hundred years. Why does this tiny insect merit such intense scrutiny? Drosophila's importance as a research organism began with its short life cycle, ability to reproduce in large numbers, and easy-to-see mutant phenotypes. Over time, laboratory investigation revealed surprising similarities between flies and other animals at the level of genes, gene networks, cell interactions, physiology, immunity, and behavior. Like humans, flies learn and remember, fight microbial infection, and slow down as they age. Scientists use Drosophila to investigate complex biological activities in a simple but intact living system. Fly research provides answers to some of the most challenging questions in biology and biomedicine, including how cells transmit signals and form ordered structures, how we can interpret the wealth of human genome data now available, and how we can develop effective treatments for cancer, diabetes, and neurodegenerative diseases. Written by a leader in the Drosophila research community, First in Fly celebrates key insights uncovered by investigators using this model organism. Stephanie Elizabeth Mohr draws on these \"first in fly\" findings to introduce fundamental biological concepts gained over the last century and explore how research in the common fruit fly has expanded our understanding of human health and disease.-- Provided by publisher

Advances in molecular biology and toxicology are paving the way for major improvements in the evaluation of the hazards posed by the large number of chemicals found at low levels in the environment. The National Research Council was asked by the U.S. Environmental Protection Agency to review the state of the science and create a far-reaching vision for the future of toxicity testing. The book finds that developing, improving, and validating new laboratory tools based on recent scientific advances could significantly improve our ability to understand the hazards and risks posed by chemicals. This new knowledge would lead to much more informed environmental regulations and dramatically reduce the need for animal testing because the new tests would be based on human cells and cell components. Substantial scientific efforts and resources will be required to leverage these new technologies to realize the vision, but the result will be a more efficient, informative and less costly system for assessing the hazards posed by industrial chemicals and pesticides.

Glucose Metabolism In Vivo in Four Commonly Used Inbred Mouse Strains Eric D. Berglund 1 , Candice Y. Li 1 2 , Greg Poffenberger 3 , Julio E. Ayala 1 2 , Patrick T. Fueger 4 , Shannon E. Willis 3 , Marybeth M. Jewell 3 , Alvin C. Powers 1 3 5 and David H. Wasserman 1 2 1 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 2 Vanderbilt University–NIH Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, Tennessee 3 Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, Tennessee 4 Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 5 VA Tennessee Valley Healthcare System, Nashville, Tennessee Corresponding author: Eric Berglund, eric.d.berglund{at}vanderbilt.edu Abstract OBJECTIVE —To characterize differences in whole-body glucose metabolism between commonly used inbred mouse strains. RESEARCH DESIGN AND METHODS —Hyperinsulinemic-euglycemic (∼8.5 mmol/l) and -hypoglycemic (∼3.0 mmol/l) clamps were done in catheterized, 5-h-fasted mice to assess insulin action and hypoglycemic counter-regulatory responsiveness. Hyperglycemic clamps (∼15 mmol/l) were done to assess insulin secretion and compared with results in perifused islets. RESULTS —Insulin action and hypoglycemic counter-regulatory and insulin secretory phenotypes varied considerably in four inbred mouse strains. In vivo insulin secretion was greatest in 129X1/Sv mice, but the counter-regulatory response to hypoglycemia was blunted. FVB/N mice in vivo showed no increase in glucose-stimulated insulin secretion, relative hepatic insulin resistance, and the highest counter-regulatory response to hypoglycemia. In DBA/2 mice, insulin action was lowest among the strains, and islets isolated had the greatest glucose-stimulated insulin secretion in vitro. In C57BL/6 mice, in vivo physiological responses to hyperinsulinemia at euglycemia and hypoglycemia were intermediate relative to other strains. Insulin secretion by C57BL/6 mice was similar to that in other strains in contrast to the blunted glucose-stimulated insulin secretion from isolated islets. CONCLUSIONS —Strain-dependent differences exist in four inbred mouse strains frequently used for genetic manipulation and study of glucose metabolism. These results are important for selecting inbred mice to study glucose metabolism and for interpreting and designing experiments. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 8 April 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 3, 2008. Received November 15, 2007. DIABETES

Humans have a long history of using animal models to learn about ourselves. The first records of animal model usage date back to ancient Greece. In the fifth century BCE, Alcmaeon of Croton observed connections between the brain and sensory organs in dogs. A couple of centuries later, Aristotle studied embryo growth in chicks. Since then, animal models have played an indispensable role in biomedical research, leading to many of the biggest medical breakthroughs. William Harvey, founder of modern physiology, discovered blood circulation in the early 1600s after studying the anatomy of several species of animals. Surgeon Frederick Banting and his student Charles Best found that injections of pancreatic cell extracts relieved diabetic symptoms in dogs, leading to the discovery of insulin in the 1920s. The Salk and Sabin polio vaccine was developed based on more than 40 years of experiments using monkey, rat, and mouse models, leading to a successful double-blind trial on 1.8 million children in 1954.

Regeneration of the Pancreas in Adult Zebrafish Jennifer B. Moss 1 , Punita Koustubhan 2 , Melanie Greenman 1 , Michael J. Parsons 4 , Ingrid Walter 3 and Larry G. Moss 1 1 Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina; 2 Tufts Center for Regenerative and Developmental Biology, Tufts University, Medford, Massachusetts; 3 Department of Pathobiology, Institute of Anatomy, University of Veterinary Medicine, Vienna, Austria; 4 Department of Surgery, Johns Hopkins University, Baltimore, Maryland. Corresponding author: Jennifer B. Moss, jennifer.b.moss{at}duke.edu . Abstract OBJECTIVE Regenerating organs in diverse biological systems have provided clues to processes that can be harnessed to repair damaged tissue. Adult mammalian β-cells have a limited capacity to regenerate, resulting in diabetes and lifelong reliance on insulin. Zebrafish have been used as a model for the regeneration of many organs. We demonstrate the regeneration of adult zebrafish pancreatic β-cells. This nonmammalian model can be used to define pathways for islet-cell regeneration in humans. RESEARCH DESIGN AND METHODS Adult transgenic zebrafish were injected with a single high dose of streptozotocin or metronidazole and anesthetized at 3, 7, or 14 days or pancreatectomized. Blood glucose measurements were determined and gut sections were analyzed using specific endocrine, exocrine, and duct cell markers as well as markers for dividing cells. RESULTS Zebrafish recovered rapidly without the need for insulin injections, and normoglycemia was attained within 2 weeks. Although few proliferating cells were present in vehicles, ablation caused islet destruction and a striking increase of proliferating cells, some of which were Pdx1 positive. Dividing cells were primarily associated with affected islets and ducts but, with the exception of surgical partial pancreatectomy, were not extensively β-cells. CONCLUSIONS The ability of the zebrafish to regenerate a functional pancreas using chemical, genetic, and surgical approaches enabled us to identify patterns of cell proliferation in islets and ducts. Further study of the origin and contribution of proliferating cells in reestablishing islet function could provide strategies for treating human diseases. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received May 9, 2008. Accepted May 14, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

Activation of Estrogen Receptor Is Crucial for Resveratrol-Stimulating Muscular Glucose Uptake via Both Insulin-Dependent and -Independent Pathways Jen-Ying Deng 1 , Po-Shiuan Hsieh 1 , Jiung-Pang Huang 1 , Long-Sheng Lu 3 and Li-Man Hung 1 1 Department of Life Science and Center for Healthy and Aging Research, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan 2 Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan 3 Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan Corresponding author: Li-Man Hung, lisahung{at}mail.cgu.edu.tw Abstract OBJECTIVE —Estradiol (E 2 ) is known to modulate insulin sensitivity and, consequently, glucose homeostasis. Resveratrol (RSV), an agonist of estrogen receptor (ER), has exerted antihyperglycemic effects in streptozotocin-induced type 1 diabetic rats in our previous study and was also shown to improve insulin resistance in other reports. However, it remains unknown whether activation of ER is involved in the metabolic effects of RSV via insulin-dependent and -independent mechanisms. RESEARCH DESIGN AND METHODS —Male Sprague-Dawley rats were given a high cholesterol–fructose (HCF) diet for 15 weeks and were treated with RSV for either 15 days or 15 weeks. RESULTS —Here, we show that RSV shifts the metabolic characteristics of rats on an HCF diet toward those of rats on a standard diet. RSV treatment increased insulin-stimulated whole-body glucose uptake and steady-state glucose uptake of soleus muscle and liver in HCF-fed rats as well as enhanced membrane trafficking activity of GLUT4 and increased phosphorylation of insulin receptor in insulin-resistant soleus muscles. Interestingly, the phosphorylated ER level in insulin-resistant soleus muscle was significantly elevated in rats with RSV treatment in both basal and euglycemic-hyperinsulinemic conditions. RSV exerted an insulin-like stimulatory effect on isolated soleus muscle, epididymal fat and hepatic tissue, and C2C12 myotubes. The RSV-stimulated glucose uptake in C2C12 myotubes was dependent on extracellular signal–related kinase/p38 (early phase, 1 h) and p38/phosphoinositide 3-kinase (late phase, 14 h) activation. Inhibition of ER abrogated RSV-induced glucose uptake in both early and late phases. CONCLUSIONS —Collectively, these results indicate that ER is a key regulator in RSV-stimulating insulin-dependent and -independent glucose uptake, which might account for the protective effects of RSV on diet-induced insulin resistance syndrome. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 21 April 2008. J.-Y.D. and P.-S.H. contributed equally to this article. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 11, 2008. Received December 13, 2007. DIABETES

Background The pharmaceutical industry is in the midst of a productivity crisis and rates of translation from bench to bedside are dismal. Patients are being let down by the current system of drug discovery; of the several 1000 diseases that affect humans, only a minority have any approved treatments and many of these cause adverse reactions in humans. A predominant reason for the poor rate of translation from bench to bedside is generally held to be the failure of preclinical animal models to predict clinical efficacy and safety. Attempts to explain this failure have focused on problems of internal validity in preclinical animal studies (e.g. poor study design, lack of measures to control bias). However there has been less discussion of another key factor that influences translation, namely the external validity of preclinical animal models. Review of problems of external validity External validity is the extent to which research findings derived in one setting, population or species can be reliably applied to other settings, populations and species. This paper argues that the reliable translation of findings from animals to humans will only occur if preclinical animal studies are both internally and externally valid. We review several key aspects that impact external validity in preclinical animal research, including unrepresentative animal samples, the inability of animal models to mimic the complexity of human conditions, the poor applicability of animal models to clinical settings and animal–human species differences. We suggest that while some problems of external validity can be overcome by improving animal models, the problem of species differences can never be overcome and will always undermine external validity and the reliable translation of preclinical findings to humans. Conclusion We conclude that preclinical animal models can never be fully valid due to the uncertainties introduced by species differences. We suggest that even if the next several decades were spent improving the internal and external validity of animal models, the clinical relevance of those models would, in the end, only improve to some extent . This is because species differences would continue to make extrapolation from animals to humans unreliable. We suggest that to improve clinical translation and ultimately benefit patients, research should focus instead on human-relevant research methods and technologies.

Type 1 diabetes is an incurable chronic autoimmune disease. Although transplantation of pancreatic islets may serve as a surrogate source of insulin, recipients are subjected to a life of immunosuppression. Interleukin (IL)-21 is necessary for type 1 diabetes in NOD mice. We examined the efficacy of an IL-21-targeted therapy on prevention of diabetes in NOD mice, in combination with syngeneic islet transplantation. In addition, we assessed the role of IL-21 responsiveness in islet allograft rejection in mouse animal models. NOD mice were treated with IL-21R/Fc, an IL-21-neutralizing chimeric protein. This procedure was combined with syngeneic islet transplantation to treat diabetic NOD mice. Survival of allogeneic islet grafts in IL-21R-deficient mice was also assessed. Evidence is provided that IL-21 is continually required by the autoimmune infiltrate, such that insulitis was reduced and reversed and diabetes inhibited by neutralization of IL-21 at a late preclinical stage. Recovery from autoimmune diabetes was achieved by combining neutralization of IL-21 with islet transplantation. Furthermore, IL-21-responsiveness by CD8+ T-cells was sufficient to mediate islet allograft rejection. Neutralization of IL-21 in NOD mice can inhibit diabetes, and when paired with islet transplantation, this therapeutic approach restored normoglycemia. The influence of IL-21 on a graft-mounted immune response was robust, since the absence of IL-21 signaling prevented islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes.