Mark Huising, Ph.D.
Islet Biology and Diabetes, transcriptional control of beta cell differentiation and plasticity of pancreatic islet cell identity.
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. Key to glucose homeostasis are the opposing actions of insulin, which promotes peripheral uptake of glucose, and glucagon, which is a signal to the liver to break down glycogen and release glucose. These hormones are made by beta and alpha cells, respectively, which co-localize in the islets of Langerhans to facilitate the coordinated regulation of their release. The islets also contain somatostatin-producing delta cells, which provide essential negative feedback to both alpha and beta cells. My group studies how the alpha, beta and delta cells within the islet communicate with each other and integrate signals from the central and peripheral nervous system, gastro-intestinal tract, liver, skeletal muscle and adipose tissue. We are only just starting to appreciate the depth and complexity of this intricate network, which contains potential therapeutic targets to treat or even cure diabetes.
One of the family of signals that the Huising lab studies, is named for the stress peptide Corticotropin Releasing Factor, or CRF in short. CRF was originally discovered as the principal hypothalamic factor to initiate the stress response by acting on the pituitary gland. It turns out 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. Urocortin3 (Ucn3), a peptide related to CRF, is abundantly expressed by mature beta cells. We discovered that Ucn3 is co-released with insulin to trigger somatostatin release from neighboring delta cells, which in turn inhibits insulin secretion. In essence, Ucn3 triggers a negative feedback loop that attenuates insulin secretion, provided that glucose levels are successfully reduced. Ucn3 expression also distinguishes mature, functional beta cells from their immature progenitors, which is a trait that is particularly useful to track the differentiation of mature, glucose-responsive beta cells from embryonic or induced pluripotent stem cells. CRF and Ucn3 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 insulin and glucagon output of the pancreas. My group is focused on unraveling the contributions of these local pancreatic CRF family signaling cascades on glucose metabolism in healthy and diabetic individuals.
van der Meulen T, Lee S, Noordeloos E, Donaldson CJ, Adams MW, Noguchi GM, Mawla AM, Huising MO. 2018 Artemether Does Not Turn Alpha Cells into Beta Cells. Cell Metabolism, in press.
van der Meulen T, Mawla AM, DiGruccio MR, Adams MW, Nies V, Dólleman S, Liu S, Ackermann AM, Cáceres E, Hunter AU, Kaestner KH, Donaldson CJ, Huising MO. 2017 Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets. Cell Metabolism, 4:911-926.
Zeng C, Mulas F, Sui Y, Guan T, Miller N, Tan Y, Jin W, Carrano AC, Huising MO, Shirihai OS, Yeo GW, Sander M. 2017 Pseudotemporal ordering of single cells reveals metabolic control of postnatal beta cell proliferation. Cell Metabolism, 5:1160-1175.
Pullen TJ, Huising MO, Rutter GA. 2017 Analysis of purified pancreatic islet beta and alpha cell transcriptomes reveals 11β-hydroxysteroid dehydrogenase (Hsd11b1) as a novel disallowed gene. Frontiers in Genetics 8, 41.
Paglialunga S, Simnett G, Robson H, Hoang M, Pillai R, Arkell AM, Simpson JA, Bonen A, Huising MO, Joseph JW, Holloway GP. 2017 The Rab-GTPase activating protein, TBC1D1, is critical for maintaining normal glucose homeostasis and β-cell mass. Appl. Physiol. Nutr. Metab, 1-9.
Pilbrow AP, Lewis KA, Perrin MH, Sweet WE, Moravec CS, Tang WH, Huising MO, Troughton RW, Cameron VA. 2016 Cardiac CRFR1 Expression Is Elevated in Human Heart Failure and Modulated by Genetic Variation and Alternative Splicing. Endocrinology, 157(12):4865-4874.
DiGruccio MR, Mawla AM, Donaldson CJ, Noguchi GM, Vaughan J, Cowing-Zitron C, van der Meulen T, Huising MO. 2016 Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Molecular Metabolism, 5:449-458.
Topic of an Editorial in: Molecular Metabolism (Tong and Mauvais-Jarvis, 5:433-434).
van der Meulen T, Donaldson CJ, Caceres E, Hunter AE, Cowing-Zitron C, Pound LD, Adams MW, Zembrzycki A, Grove KL, Huising MO. 2015 Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion, Nature Medicine, 21(7):769-776.
Topic of an Editors Choice in: Science Signaling (W. Wong).
Hogan MF, Ravnskjaer K, Matsumura S, Huising MO, Hull RL, Kahn SE, Montminy M. 2015 Hepatic insulin resistance following chronic activation of the CREB coactivator CRTC2, J Biol. Chem. 290(43):25997-26006.
Huising MO. 2015 Tuning to the right signal. Diabetologia 58(6):1146-1148.
van der Meulen T and Huising MO. 2015 Role of transcription factors in the transdifferentiation of pancreatic islet cells. Journal of Molecular Endocrinology 54(2):R103-117.
Prothiwa M, Syed I, Huising MO, van der Meulen T, Donaldson CJ, Trauger SA, Kahn BB, Saghatelian A. 2014 Data-driven synthesis of proteolysis-resistant peptide hormones, J Am Chem Soc 136(51):17710-17713.
Blaabjerg L Christensen GL, Matsumoto M, Huising MO, van der Meulen T, Billestrup N, Vale WW. 2014 CRFR1 activation protects against cytokine-induced beta cell death, Journal of Molecular Endocrinology 53(3):417-427.
Benner C, van der Meulen T, Caceres E, Tigyi K, Donaldson CJ, Huising MO. 2014 The transcriptional landscape of mouse beta cells compared to human beta cells reveals notable species differences in long non-coding RNA and protein-coding gene expression, BMC Genomics 15(1):620.
van der Meulen T, Huising MO. 2014 Maturation of Stem Cell-Derived Beta cells Guided by the Expression of Urocortin 3, The Review of Diabetic Studies, 11(1):115-132.
Reira CE, Huising MO, Follet P, Leblanc M, Van Andel R, de Maghalaes Filho CD, Merkwirth C, Dillin A. 2014 TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling, Cell 157, 1023-1036.
Topic of a Preview in: Cell (Steculorum and Bruning, 157:1004-1006).
Manuel R, Metz JR, Flik G, Vale WW, Huising MO. 2014 Corticotropin-releasing factor-binding protein (CRF-BP) inhibits CRF- and urotensin-I-mediated activation of CRF receptor-1 and -2 in common carp. General and Comp. Endocrinology 24;202C:69-75.
Jensen MV, Haldeman JM, Zhang H, Lu D, Huising MO, Vale WW, Hohmeier HE, Rosenberg P, Newgard CB 2013 Control of Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion. J Biol Chem 9;288(32):23128-40).
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.
Gorissen M, Bernier NJ, Manuel R, de Gelder S, Metz JR, Huising MO, Flik G. 2012 Recombinant human leptin attenuates stress axis activity in common carp (Cyprinus carpio L.). General and Comp. Endocrinology 178(1):75-81.
Huising MO, Pilbrow A, Matsumoto M, 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.
Featured in the Wall Street Journal
- Dutch Zoology Award (2006) from the Royal Dutch Zoological Society
- Endocrine Scholars Award (2007) from The Endocrine Society
- Novo Nordisk Award for Endocrinology (2011) from the Dutch Endocrine Society
- Career Development Award (2013) from the Juvenile Diabetes Research Foundation
- Helmsley Award (2015) from the Endocrine Society and the Helmsley Charitable Trust
- Individual Biomedical Research Award (2015) from the Hartwell Foundation
- Nominated for the Helmholtz Young Investigator Diabetes Award (2016)
- Neurobiology, Physiology and Behavior
- Physiology and Membrane Biology
- American Diabetes Association
- The Endocrine Society
- The American Association for the Advancement of Science
Biochemistry, Molecular, Cellular and Developmental Biology
- Genomics, Proteomics and Metabolomics
- Differentiation, Morphogenesis and Wound Healing
- Developmental Biology
- Gene Regulation
- Molecular Physiology
- Stem Cell Biology
Molecular, Cellular, and Integrative Physiology
- Comparative Physiology
- Metabolic Physiology
- Cellular Physiology
- Molecular Physiology
- Systemic Physiology