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Developmental biology - The Hormone Insulin|
Insulin can go viral
"Our research may help open up a new field that we might call microbial endocrinology. We show that these viral insulin-like peptides can act on human and rodent cells. With the very large number of microbial peptides to which we are exposed, there is a novel window for host-microbe interactions. We hope that studying these processes will help us to better understand the role of microbes in human disease."
"Indeed, the discovery of the viral insulin-like hormones raises the question of what their role might be in diabetes, as well as autoimmune disease, cancer and other metabolic conditions," says C. Ronald Kahn, MD, Joslin's chief academic officer and senior author on the paper.
By analyzing large public research databases that hold viral genomic sequences, Emrah Altindis, PhD and his colleagues at Joslin found that various viruses can produce peptides that are similar in whole or in part to 16 human hormones and regulatory proteins.
"What really caught our attention were four viruses that had insulin-like sequences," says Kahn. Viruses known to infect fish. The Joslin team collaborated with Richard DiMarchi, professor of chemistry at Indiana University, as his lab chemically synthesized viral insulin-like peptides (VILPs), to find out if they could also be active in mammals.
Experimenting in mouse and human cells, the scientists proved VILPs can indeed bind with human insulin receptors and those of a closely related hormone called IGF-1 (insulin-like growth factor 1) — both critical proteins stimulating cells to grow through absorbtion of glucose. Also, peptides associated with these proteins can stimulate all signaling pathways inside cells which are also stimulated by human insulin and IGF-1. Mice injected with these viral peptides exhibited lower levels of blood glucose, another sign of insulin action. Moreover, database analysis found the human intestine is already exposed to these same viruses.
"These viruses are definitely known to infect fish and amphibians, but they are not known to infect humans. However, it's possible that humans get exposed to them when eating fish. Nobody has checked directly checked whether, under some conditions the viruses, could either infect cells or be at least partly absorbed through the intestines."
Scientists will now broaden their search for other viruses that produce human-like hormones as there are thought to be more than 300,000 viruses that can be carried in mammals, and only 7,500 or so of these (about 2.5%) have been sequenced.
"This research also opens up a new aspect to study in type 1 diabetes and autoimmunity," Kahn adds. "It may be that these or similar microbial insulin-like molecules are an environmental trigger to start the autoimmune reaction in type 1 diabetes." A similar question applies to type 2 diabetes and obesity. When the body fails to respond properly to insulin, could viral peptides be contributing to insulin resistance? And these, or similar viruses, might also be a factor in certain human cancers.
"If these viruses are inside the gut, could the VILPs they produce stimulate growth of gut cells into polyps or tumors of the gut? Or if they're absorbed or become infectious, could they infect any organ in the body?"
Analyzing such viral peptides may eventually help drug companies to design new forms of synthesized human insulins.
Although there has been tremendous progress in understanding hormone action and its relationship to human physiology and disease, there has been no comprehensive approach to search the viral genome for the presence of human-like hormones. Here, using a bioinformatics approach, we have identified 16 different human peptide hormones/growth factors, including four insulin/insulin growth factor (IGF)1-like peptides (VILPs) that have homologous sequences in viruses. When these VILPs were chemically synthesized, the resulting peptides could bind to human and murine insulin and IGF1 receptors, stimulate postreceptor signaling, increase glucose uptake, and activate proliferation of cells. Injection of VILPs into mice can significantly lower the blood glucose. Thus, VILPs are members of the insulin superfamily and first characterized viral hormones.
Viruses are the most abundant biological entities and carry a wide variety of genetic material, including the ability to encode host-like proteins. Here we show that viruses carry sequences with significant homology to several human peptide hormones including insulin, insulin-like growth factors (IGF)-1 and -2, FGF-19 and -21, endothelin-1, inhibin, adiponectin, and resistin. Among the strongest homologies were those for four viral insulin/IGF-1–like peptides (VILPs), each encoded by a different member of the family Iridoviridae. VILPs show up to 50% homology to human insulin/IGF-1, contain all critical cysteine residues, and are predicted to form similar 3D structures. Chemically synthesized VILPs can bind to human and murine IGF-1/insulin receptors and stimulate receptor autophosphorylation and downstream signaling. VILPs can also increase glucose uptake in adipocytes and stimulate the proliferation of fibroblasts, and injection of VILPs into mice significantly lowers blood glucose. Transfection of mouse hepatocytes with DNA encoding a VILP also stimulates insulin/IGF-1 signaling and DNA synthesis. Human microbiome studies reveal the presence of these Iridoviridae in blood and fecal samples. Thus, VILPs are members of the insulin/IGF superfamily with the ability to be active on human and rodent cells, raising the possibility for a potential role of VILPs in human disease. Furthermore, since only 2% of viruses have been sequenced, this study raises the potential for discovery of other viral hormones which, along with known virally encoded growth factors, may modify human health and disease.
Authors: Joslin's Weikang Cai, Masaji Sakaguchi, Wang Guoxiao and Hui Pan also contributed to the research. Other coauthors included Fa Zhang, Fa Liu, Richard DiMarchi and Vasily Gelfanov of Indiana University in Bloomington; and Pierre De Meyts of de Duve Institute in Brussels, Belgium.
Lead funding was from the National Institutes of Health and the Iacocca Family Foundation.
About Joslin Diabetes Center
Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is an independent, non-profit institution affiliated with Harvard Medical School, and one of only 11 NIH-designated Diabetes Research Centers in the U.S. For more information, visit http://www.joslin.org or follow @joslindiabetes
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Insulin is a protein-based hormone that is made by the beta cells of the pancreas. Most people know that insulin is the hormone that helps put glucose into body cells for use as fuel. Without insulin, cells don't have enough biochemical energy and must use other nutrients in order to function.
Without insulin, life-threatening complications occur due to high blood sugar levels.
Image credit: Diabetes Library