Clayton Foundation Laboratories for Peptide Biology
Mark Huising studies the actions of Corticotropin Releasing Factor and Urocortins in the pancreas, with the aim of finding novel therapeutic strategies to treat and potentially cure diabetes.
One in twelve Americans suffers from diabetes1 and the incidence of diabetes will continue to increase with an estimated one in three adult Americans currently suffering from pre-diabetes and expected to develop frank diabetes in the foreseeable future. Moreover, the medical costs associated with diabetes are currently estimated at 174 billion annually1, and are forecast to rise progressively. Type 2 diabetes, which occurs when the insulin-producing beta cells of the pancreas can no longer keep up with the increased demand for and decreased sensitivity to insulin, is the most prevalent form of the disease and is often associated with overweight or obesity. A smaller but significant number of diabetic patients has type 1 diabetes, which often manifests at an early age when the body loses the ability to make insulin as a result of an autoimmune assault on the beta cells of the pancreas. Despite all the advances of modern medicine, a diagnosis of diabetes is still a major risk factor in the development of macro- and microvascular complications including cardiac failure, kidney problems and lower limb amputations, and people with diagnosed diabetes are twice as likely to die compared to people of similar age without diabetes1. This illustrates the dire need for new therapies to combat, cure and prevent diabetes.
Proper control of glucose metabolism is essential to thrive. Consequently our bodies have evolved sophisticated and subtle yet remarkably effective ways to maintain tight blood glucose control over the course of many decades. These include a tight and interconnected network of signaling molecules, some of which act within the pancreas while others signal to and from the brain, liver, skeletal muscle, gastro-intestinal tract and adipose tissue. We are only just starting to appreciate the depth and complexity of this intricate network, which stands to contain tantalizing clues for potential therapeutic targets to treat or even cure diabetes.
This is aptly illustrated by the emerging beneficial potential of the stress peptide Corticotropin Releasing Factor, CRF in short, on key aspects of islet biology. CRF was originally discovered as the principal hypothalamic factor to initiate the stress response by acting on the pituitary gland. Recently, we demonstrated that the insulin-producing beta cells of the pancreas can respond directly to CRF with increased insulin secretion, increased beta cell proliferation and reduced beta cell death in the face of pro-inflammatory insults, which is a promising set of beneficial characteristics united in a single molecule. Urocortin 3, a peptide related to CRF, is abundantly expressed by mature beta cells and makes important contributions to the regulation of insulin secretion and glucose metabolism. Furthermore, we observe that Urocortin 3 expression distinguishes mature, functional endocrine cells generated from human embryonic stem cells from their immature progenitors. CRF and Urocortin 3 are just two examples of signaling molecules whose direct actions on the pancreas add a novel layer of complexity to the intricate network of signaling molecules that in concert governs beta cell mass and endocrine output of the pancreas. Our group is focused on unraveling the contributions of these local pancreatic CRF family signaling cascades on glucose metabolism.
1 Source: National Diabetes Fact Sheet, Centers for Disease Control, Atlanta, GA. (http://www.cdc.gov/diabetes/pubs/factsheet11.htm)
- B.Sc./M.Sc. in Biology, Wageningen University, The Netherlands
- Ph.D. in Biology, Radboud University Nijmegen, The Netherlands
Awards and Honors
- Recipient of a five-year Career Development Award from the Juvenile Diabetes Research Foundation (JDRF).
- Recipient of a two-year Research Grant from the Juvenile Diabetes Research Foundation (JDRF) to study the salutary actions of Urocortins on functional beta cell mass.
- Recipient of the 2011 Novo Nordisk Award for Endocrinology for important contributions to the field of human growth, diabetes mellitus, osteoporosis and medical technology assessment.
- Recipient of a multi-year award from the Leona M. & Harry B. Helmsley Charitable Trust.
- Recipient of the Endocrine Scholars Award 2007, awarded by the US Endocrine Society for Outstanding Achievements in Basic Endocrine Research.
- Recipient of a multi-year fellowship from the Adler Foundation.
- Recipient of the Dutch Zoology Award 2006, awarded by the Royal Dutch Zoological Society for the best thesis in the field of Biology.
- Recipient of the 2004 Annual Publication Prize of the Wageningen Institute of Animal Sciences (WIAS) graduate school.
- VAN DER MEULEN T, XIE R, KELLY OG, VALE WW, SANDER M, HUISING MO. 2012 Urocortin 3 marks mature human primary and embryonic stem cell-derived pancreatic alpha and beta cells. PLoS One 7(12):e52181.
- HUISING MO, PILBROW A, VAN DER MEULEN T, PARK H, DONALDSON CJ, VAUGHAN JM, LEE, SL, VALE WW. 2011 Glucocorticoids differentially regulate the expression of CRFR1 and CRFR2a in MIN6 insulinoma cells and rodent islets. Endocrinology 152(1):138-150.
- GORISSEN M, DE VRIEZE E, FLIK G, HUISING MO. 2011 STAT genes display differential evolutionary rates that correlate with their roles in the endocrine and immune system. Journal of Endocrinology 209(2):175-184.
- HUISING MO, VAN DER MEULEN T, VAUGHAN JM, DONALDSON CJ, PARK H, BILLESTRUP N, VALE WW. 2010 Corticotropin releasing factor receptor 1 (CRFR1) is expressed on pancreatic b cells, promotes b cell proliferation and potentiates insulin secretion in an incretin-like manner. Proceedings of the National Academy of Sciences USA 107(2):912-917.
- GORISSEN M, BERNIER NJ, NABUURS SB, FLIK G, HUISING MO. 2009 Two divergent leptin paralogues in zebrafish (Danio rerio) that originate early in teleostean evolution. Journal of Endocrinology 201(3):329-339.
- HUISING MO, VAUGHAN JM, SHAH SH, GRILLOT KL, DONALDSON CJ, RIVIER J, FLIK G, VALE WW. 2008 Residues of corticotropin releasing factor-binding protein (CRF-BP) that selectively abrogate binding to CRF but not to urocortin 1. Journal of Biological Chemistry 283(14):8902-8912.
- HUISING MO, GEVEN EJW, KRUISWIJK CP, NABUURS SB, STOLTE EH, SPANINGS FAT, VERBURG-VAN KEMENADE BML, FLIK G. 2006 Increased leptin expression in common carp (Cyprinus carpio) after food intake but not after fasting or feeding to satiation. Endocrinology 147(12):5786-5797.
- GORISSEN M, FLIK G, HUISING MO. 2006 Peptides and Proteins regulating food intake: a comparative view. Animal Biology 56(4):447-473.
- HUISING MO, KRUISWIJK CP, FLIK G. 2006 Phylogeny and evolution of class-I helical cytokines. Journal of Endocrinology 189(1):1-25.
- HUISING MO, FLIK G. 2005 The remarkable conservation of corticotropin-releasing hormone (CRH)-binding protein in the Honeybee (Apis mellifera) dates the CRH system to a common ancestor of insects and vertebrates. Endocrinology. 146(5):2165-70.
- HUISING MO, METZ JR, VAN SCHOOTEN C, TAVERNE-THIELE AJ, HERMSEN T, VERBURG-VAN KEMENADE BML, FLIK G. 2004 Structural characterisation of a cyprinid (Cyprinus carpio L.) CRH, CRH-BP and CRH-R1, and the role of these proteins in the acute stress response. Journal of Molecular Endocrinology 32(3):627-648.
- HUISING MO, STET RJ, KRUISWIJK CP, SAVELKOUL HF, VERBURG-VAN KEMENADE BML. 2003 Molecular evolution of CXC chemokines: extant CXC chemokines originate from the CNS. Trends in Immunology 24(6):307-313.
Salk News Releases
- Stress peptide and receptor may have role in diabetes, January 21, 2010