Studies of the human pancreas and islets

We are studying the human islet and pancreas using in vitro and in vivo methods and infrastructure our group has established. We are part of the NIH-funded Human Islet Research Network (HIRN). Rodent islets have important similarities and differences (morphology, cell composition, gene expression, glucose-stimulated insulin secretion).

  1. The Integrated Islet Distribution Program answers the call for improved human islet phenotyping and reporting of human islet characteristics in research articles. Brissova M, Niland JC, Cravens J, Olack B, Sowinski J, Evans-Molina C (2019) Diabetologia
  2. Use of human islets to understand islet biology and diabetes: progress, challenges and suggestions. Hart NJ, Powers AC (2019) Diabetologia 62(2): 212-222
  3. Cystic fibrosis-related diabetes is caused by islet loss and inflammation. Hart NJ, Aramandla R, Poffenberger G, Fayolle C, Thames AH, Bautista A, Spigelman AF, Babon JAB, DeNicola ME, Dadi PK, Bush WS, Balamurugan AN, Brissova M, Dai C, Prasad N, Bottino R, Jacobson DA, Drumm ML, Kent SC, MacDonald PE, Powers AC (2018) JCI Insight 3(8)
  4. Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. Dai C, Hang Y, Shostak A, Poffenberger G, Hart N, Prasad N, Phillips N, Levy SE, Greiner DL, Shultz LD, Bottino R, Kim SK, Powers AC (2017) J Clin Invest 127(10): 3835-3844
  5. Human Islets Have Fewer Blood Vessels than Mouse Islets and the Density of Islet Vascular Structures Is Increased in Type 2 Diabetes. Brissova M, Shostak A, Fligner CL, Revetta FL, Washington MK, Powers AC, Hull RL (2015) J Histochem Cytochem 63(8): 637-45
  6. Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles. Kayton NS, Poffenberger G, Henske J, Dai C, Thompson C, Aramandla R, Shostak A, Nicholson W, Brissova M, Bush WS, Powers AC (2015) Am J Physiol Endocrinol Metab 308(7): E592-602
  7. Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets. Dai C, Brissova M, Hang Y, Thompson C, Poffenberger G, Shostak A, Chen Z, Stein R, Powers AC (2012) Diabetologia 55(3): 707-18

How α cell and gene expression are compromised in type 1 diabetes

We are investigating how both α and β cells change in type 1 (T1D) and type 2 (T2D) diabetes. We have found that several functional and molecular features of normal β cells are maintained in the remaining T1D β cells; however, α cells have impaired glucagon secretion and an altered gene expression profile. To elucidate the mechanism of α cell dysfunction, we using a pseudoislet model system.

  1. Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks. Haliyur R, Tong X, Sanyoura M, Shrestha S, Lindner J, Saunders DC, Aramandla R, Poffenberger G, Redick SD, Bottino R, Prasad N, Levy SE, Blind RD, Harlan DM, Philipson LH, Stein RW, Brissova M, Powers AC (2019) J Clin Invest 129(1): 246-251
  2. α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes. Brissova M, Haliyur R, Saunders D, Shrestha S, Dai C, Blodgett DM, Bottino R, Campbell-Thompson M, Aramandla R, Poffenberger G, Lindner J, Pan FC, von Herrath MG, Greiner DL, Shultz LD, Sanyoura M, Philipson LH, Atkinson M, Harlan DM, Levy SE, Prasad N, Stein R, Powers AC (2018) Cell Rep 22(10): 2667-2676

Identification of a human pancreatic β cell-specific marker

We identified a human β cell-specific highly enriched biomarker, Ectonucleoside Triphosphate Diphosphohydrolase-3 (NTPDase3) that is expressed in adult human β cells. We have shown that an NTPDase3 antibody can be used for in vivo live β cell sorting and imaging, for purification of live human β cells, and for in vivo imaging of transplanted human β cells. We are collaborating with several groups to use this marker to better understand human islet biology.

  1. Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis. Saunders DC, Brissova M, Phillips N, Shrestha S, Walker JT, Aramandla R, Poffenberger G, Flaherty DK, Weller KP, Pelletier J, Cooper T, Goff MT, Virostko J, Shostak A, Dean ED, Greiner DL, Shultz LD, Prasad N, Levy SE, Carnahan RH, Dai C, Sévigny J, Powers AC (2019) Cell Metab 29(3): 745-754.e4

How pancreatic islets become so extensively vascularized and innervated

Our group is investigating how the pancreatic islet becomes so extensively vascularized and innervated. We demonstrated that VEGF-A, which is expressed in developing and adult endocrine cells, is a crucial factor in promoting and sustaining intra-islet endothelial cells and hence, the islet vascular network. We also showed that there are crucial interactions and cross-talk between islet endocrine cells and islet endothelial cells that are critical for normal islet function, mass, and glucose-stimulated insulin secretion. We also demonstrated that islet innervation is dependent on signals that promote islet vascularization and that the islet vascular network provides a scaffold for migration of intra-islet nerve fibers.

  1. Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding. Reinert RB, Cai Q, Hong JY, Plank JL, Aamodt K, Prasad N, Aramandla R, Dai C, Levy SE, Pozzi A, Labosky PA, Wright CV, Brissova M, Powers AC (2014) Development 141(7): 1480-91
  2. Vascular endothelial growth factor-a and islet vascularization are necessary in developing, but not adult, pancreatic islets. Reinert RB, Brissova M, Shostak A, Pan FC, Poffenberger G, Cai Q, Hundemer GL, Kantz J, Thompson CS, Dai C, McGuinness OP, Powers AC (2013) Diabetes 62(12): 4154-64

How islet cells grow, proliferate, differentiate, and regenerate

Human islet cells have limited proliferative or regenerative capacity - we are studying factors that promote both the α- and β- cell function and proliferation. We have discovered two situations in which islet cells proliferate and expand: 1) as part of our studies on islet vascularization, we discovered that increased expression of VEGF-A created a microenvironment is which β cell loss is followed by a robust islet proliferation and regeneration and that this is dependent on the recruitment of macrophages from the bone marrow, 2) we found that interruption of hepatic glucagon signaling generates stimulates α islet cell proliferation.

  1. Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation. Dean ED, Li M, Prasad N, Wisniewski SN, Von Deylen A, Spaeth J, Maddison L, Botros A, Sedgeman LR, Bozadjieva N, Ilkayeva O, Coldren A, Poffenberger G, Shostak A, Semich MC, Aamodt KI, Phillips N, Yan H, Bernal-Mizrachi E, Corbin JD, Vickers KC, Levy SE, Dai C, Newgard C, Gu W, Stein R, Chen W, Powers AC (2017) Cell Metab 25(6): 1362-1373.e5
  2. Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. Dai C, Kayton NS, Shostak A, Poffenberger G, Cyphert HA, Aramandla R, Thompson C, Papagiannis IG, Emfinger C, Shiota M, Stafford JM, Greiner DL, Herrera PL, Shultz LD, Stein R, Powers AC (2016) J Clin Invest 126(5): 1857-70
  3. Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes β cell regeneration. Brissova M, Aamodt K, Brahmachary P, Prasad N, Hong JY, Dai C, Mellati M, Shostak A, Poffenberger G, Aramandla R, Levy SE, Powers AC (2014) Cell Metab 19(3): 498-511

Development of technology to quantify and image the pancreas and islets

Pancreatic islets represent only about 1-2% of pancreas. The small islet mass and the location of the pancreatic islets make it very challenging to assess pancreatic mass in vivo. Our group developed new technologies that allow visualization of pancreatic mass and processes in vivo in rodents. This has provided insight into normal physiology and diabetes. Mice created in our laboratory have been deposited in repositories and are being used by investigators throughout the world.

We are also working with imaging specialists, biomedical engineers, and pediatric endocrinologists to use new MRI modalities to examine the pancreas in individuals with new-onset diabetes. We discovered that the entire pancreas is smaller at the onset of type 1 diabetes.

  1. Pancreas Volume Declines During the First Year After Diagnosis of Type 1 Diabetes and Exhibits Altered Diffusion at Disease Onset. Virostko J, Williams J, Hilmes M, Bowman C, Wright JJ, Du L, Kang H, Russell WE, Powers AC, Moore DJ (2019) Diabetes Care 42(2): 248-257/li>
  2. Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands. Virostko J, Henske J, Vinet L, Lamprianou S, Dai C, Radhika A, Baldwin RM, Ansari MS, Hefti F, Skovronsky D, Kung HF, Herrera PL, Peterson TE, Meda P, Powers AC (2011) Proc Natl Acad Sci U S A 108(51): 20719-24
  3. Bioluminescence imaging in mouse models quantifies beta cell mass in the pancreas and after islet transplantation. Virostko J, Radhika A, Poffenberger G, Chen Z, Brissova M, Gilchrist J, Coleman B, Gannon M, Jansen ED, Powers AC (2010) Mol Imaging Biol 12(1): 42-53

How β cells and islets respond to demands of insulin resistance and obesity

Pancreatic islets respond to the increased demands of insulin resistance by increasing insulin production and secretion; failure of this compensatory response leads to type 2 diabetes (T2D). We are working to understand how islet compensatory responses to insulin resistance and have discovered that key islet-enriched transcription factors play a crucial role in the normal response and in T2D. Importantly, we have found that the response of the human islet is quite different from the rodent islet.

  1. Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. Dai C, Kayton NS, Shostak A, Poffenberger G, Cyphert HA, Aramandla R, Thompson C, Papagiannis IG, Emfinger C, Shiota M, Stafford JM, Greiner DL, Herrera PL, Shultz LD, Stein R, Powers AC (2016) J Clin Invest 126(5): 1857-70
  2. Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice. Kang L, Dai C, Lustig ME, Bonner JS, Mayes WH, Mokshagundam S, James FD, Thompson CS, Lin CT, Perry CG, Anderson EJ, Neufer PD, Wasserman DH, Powers AC (2014) Diabetes 63(11): 3699-710
  3. Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis. Dai C, Brissova M, Reinert RB, Nyman L, Liu EH, Thompson C, Shostak A, Shiota M, Takahashi T, Powers AC (2013) Diabetes 62(12): 4144-53