Department of Neurobiology, Physiology and Behavior
Department of Physiology and Membrane Biology, School of Medicine
ONE IN TWELVE AMERICANS suffers from diabetes. 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. Type 2 diabetes (T2D), 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 also rising number of around 1 million people in the US has Type 1 diabetes (T1D), which is driven by the progressive loss of the insulin-producing beta cells as a consequence of autoimmunity for which no cure exists. Despite all the advances of modern medicine and ever more sophisticated technology to monitor and control blood glucose, diabetes is still a major risk factor in the development of macro- and microvascular complications including cardiac failure and lower limb amputations. This illustrates the dire need for new therapies to combat, cure and prevent diabetes. We are at an important moment in time in diabetes research with the promise of stem cell derived beta cells, exciting new insight into the potential of beta cell neogenesis from a variety of endogenous precursors and the potential for target discovery through comprehensive interrogation of the epigenome and transcriptome by deep sequencing.
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.
Department and Center Affiliations
CBS Grad Group Affiliations
Specialties / Focus
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
Integrated Genetics and Genomics
- Genomics, Proteomics and Metabolomics
- Gene Regulation
- American Diabetes Association
- The Endocrine Society
- The American Association for the Advancement of Science
- The Islet Society
- 2006 Ph.D. Comparative Neuroendocrinology and Immunology Radboud University Nijmegen, The Netherlands
- 2000 M.Sc. Biology Wageningen University, The Netherlands
The Somatostatin-Secreting Pancreatic d Cell in Health and Disease. Rorsman P, Huising MO. Nature Reviews in Endocrinology 2018 Jul;14(7):404-414. doi: https://doi.org/10.1038/s41574-018-0020-6. PMID: 29773871
Artemether Does Not Turn α Cells into β Cell van der Meulen T, Lee S, Noordeloos E, Donaldson CJ, Adams MW, Noguchi GM, Mawla AM, Huising MO. Cell Metab. 2018 Jan 9;27(1):218-225.e4. doi: http://dx.doi.org/10.1016/j.cmet.2017.10.002. PMID: 29103923
Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets. van der Meulen T, Mawla AM, DiGruccio MR, Adams MW, Nies V, Dólleman S, Liu S, Ackermann AM, Cáceres E, Hunter AE, Kaestner KH, Donaldson CJ, Huising MO. Cell Metab. 2017 Apr 4;25(4):911-926.e6. doi:10.1016/j.cmet.2017.03.017. PMID: 28380380
Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal β Cell Proliferation. Zeng C, Mulas F, Sui Y, Guan T, Miller N, Tan Y, Liu F, Jin W, Carrano AC, Huising MO, Shirihai OS, Yeo GW, Sander M. Cell Metab. 2017 May 2;25(5):1160-1175.e11. doi: 10.1016/j.cmet.2017.04.014. PMID: 28467932.
CRISPR/Cas9 microinjection in oocytes disables pancreas development in sheep. Vilarino M, Rashid ST, Suchy FP, McNabb BR, van der Meulen T, Fine EJ, Ahsan S, Mursaliyev N, Sebastiano V, Diab SS, Huising MO, Nakauchi H, Ross PJ. Sci Rep. 2017 Dec 12;7(1):17472. doi: 10.1038/s41598-017-17805-0.
Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. DiGruccio MR, Mawla AM, Donaldson CJ, Noguchi GM, Vaughan J, Cowing-Zitron C, van der Meulen T, Huising MO. Molecular Metabolism, 5:449-458. PMID: 27408771.
Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. van der Meulen T, Donaldson CJ, Cáceres E, Hunter AE, Cowing-Zitron C, Pound LD, Adams MW, Zembrzycki A, Grove KL, Huising MO. Nat Med. 2015 Jun 15. doi: 10.1038/nm.3872. PMID: 26076035
Tuning to the right signal. Huising MO. Diabetologia. 2015 Jun;58(6):1146-8. doi: 10.1007/s00125-015-3567-y. PMID: 25810040
Role of transcription factors in the transdifferentiation of pancreatic islet cells. van der Meulen T, Huising MO. J Mol Endocrinol. 2015 Apr;54(2):R103-17. doi: 10.1530/JME-14-0290. Review. PMID: 25791577
Data-driven synthesis of proteolysis-resistant peptide hormones. Prothiwa M, Syed I, Huising MO, van der Meulen T, Donaldson CJ, Trauger SA, Kahn BB, Saghatelian A. J Am Chem Soc. 2014 Dec 24;136(51):17710-3. doi: 10.1021/ja5065735. PMID: 25496053
CRFR1 activation protects against cytokine-induced β-cell death. Blaabjerg L, Christensen GL, Matsumoto M, van der Meulen T, Huising MO, Billestrup N, Vale WW. J Mol Endocrinol. 2014 Dec;53(3):417-27. doi: 10.1530/JME-14-0056. PMID: 25324488
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. Benner C, van der Meulen T, Cacéres E, Tigyi K, Donaldson CJ, Huising MO. BMC Genomics. 2014 Jul 22;15:620. doi: 10.1186/1471-2164-15-620. PMID: 25051960
TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Riera CE, Huising MO, Follett P, Leblanc M, Halloran J, Van Andel R, de Magalhaes Filho CD, Merkwirth C, Dillin A. Cell. 2014 May 22;157(5):1023-36. doi: 10.1016/j.cell.2014.03.051. PMID: 24855942
Maturation of stem cell-derived beta-cells guided by the expression of urocortin 3. van der Meulen T, Huising MO. Rev Diabet Stud. 2014 Spring;11(1):115-32. doi: 10.1900/RDS.2014.11.115. PMID: 25148370
Urocortin 3 marks mature human primary and embryonic stem cell-derived pancreatic alpha and beta cells. van der Meulen T, Xie R, Kelly OG, Vale WW, Sander M, Huising MO. PLoS One. 2012;7(12):e52181. doi: 10.1371/journal.pone.0052181. PMID: 23251699
Glucocorticoids differentially regulate the expression of CRFR1 and CRFR2α in MIN6 insulinoma cells and rodent islets. Huising MO, Pilbrow AP, Matsumoto M, van der Meulen T, Park H, Vaughan JM, Lee S, Vale WW. Endocrinology. 2011 Jan;152(1):138-50. doi: 10.1210/en.2010-0791. PMID: 21106875
CRFR1 is expressed on pancreatic beta cells, promotes beta cell proliferation, and potentiates insulin secretion in a glucose-dependent manner. Huising MO, van der Meulen T, Vaughan JM, Matsumoto M, Donaldson CJ, Park H, Billestrup N, Vale WW. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):912-7. doi: 10.1073/pnas.0913610107. PMID: 20080775
Residues of corticotropin releasing factor-binding protein (CRF-BP) that selectively abrogate binding to CRF but not to urocortin 1. Huising MO, Vaughan JM, Shah SH, Grillot KL, Donaldson CJ, Rivier J, Flik G, Vale WW. J Biol Chem. 2008 Apr 4;283(14):8902-12. doi: 10.1074/jbc.M709904200. PMID: 18234674
Two divergent leptin paralogues in zebrafish (Danio rerio) that originate early in teleostean evolution. Gorissen M, Bernier NJ, Nabuurs SB, Flik G, Huising MO. J Endocrinol. 2009 Jun;201(3):329-39. doi: 10.1677/JOE-09-0034. PMID: 19293295
Phylogeny and evolution of class-I helical cytokines. Huising MO, Kruiswijk CP, Flik G. J Endocrinol. 2006 Apr;189(1):1-25. PMID: 16614377
Molecular evolution of CXC chemokines: extant CXC chemokines originate from the CNS. Huising MO, Stet RJ, Kruiswijk CP, Savelkoul HF, Lidy Verburg-van Kemenade BM. Trends Immunol. 2003 Jun;24(6):307-13. PMID: 12810106