Islet biology

Our research is focused on preventing pancreatic beta cell destruction to preserve beta cell mass in diabetes. We have identified pathways of beta cell death in type 1 and 2 diabetes. We aim to understand how different effector mechanisms participate in diabetes development, and how they can be prevented. The pathogenesis of type 1 and 2 diabetes is complex, with immune abnormalities in type 1 and insulin resistance in type 2 diabetes. However, beta cell deficiencies are required for both diseases, and this is the focus of the Islet Biology Laboratory. We are testing whether blocking cell death pathways activated by high glucose concentrations in beta cells can prevent type 2 diabetes. In type 1 diabetes, we study the interaction between the immune system and beta cells. In particular, we are interested in preventing beta cell killing by CD8+ T cells and understanding how blocking cytokines with JAK inhibitors prevents type 1 diabetes. Our work is being applied to humans through the transplantation of human islets from organ donors to reverse diabetes and in a clinical trial to test the JAK inhibitor baricitinib in participants with newly-diagnosed type 1 diabetes.

Research Themes

Molecular changes induced by JAK inhibitors in type 1 diabetes

JAK inhibitors potentially have direct beneficial effects on both pancreatic beta cells and immune cells by affecting the signalling from several cytokine receptors. Using samples from the BANDIT trial, we will investigate immune mechanisms by which baricitinib impacts T1D and evaluate the impact of baricitinib on T1D-associated immune responses. We will do this using phenotypic and genomic analyses of islet antigen-specific T cells in trial participants. Tetramer-based magnetic bead enrichment of T cells will be used to phenotype cells by flow cytometry. Simultaneous cell surface protein and transcriptome analysis (CITE-seq) will be performed to identify gene signatures in antigen-specific T cells. Complementary studies will be done in NOD mice after treatment with JAK inhibitors in combination with antigen-specific tolerance. Our studies are important for design of future human studies for robust, drug-free prevention of T1D.

Group leaders: Prof Helen Thomas, Dr Bala Krishnamurthy
Team members: Prof Tom Kay, A/Prof Stuart Mannering, Dr Gaurang Jhala, Dr Davis McCarthy, Dr Naiara Bediaga, Dr Christina Azodi, Tara Catterall, Dr Sara Litwak, Dr Michelle So

Defining the role of interferons in autoimmune diabetes

Cytokines, including interferons, play important roles in the autoimmune T cell responses against beta cells. Interferons have been implicated in the pathogenesis of type 1 diabetes. Interferons induce a transcriptional signature in the islets and promote immune cell activation and survival in humans and mouse models of type 1 diabetes. We hypothesise that interferons create an environment conducive to the breakdown of immune tolerance. We are studying whether interferons have overlapping roles in the pathogenesis of diabetes using NOD mice with deficiency in all three of the interferon receptors, made using CRISPR. By studying the action of interferons on beta cells and on immune cells (including T cells and antigen presenting cells) within the islet, we aim to better understand the role of this cytokine family in antigen-specific immune responses.

Group Leaders: Prof Helen Thomas, Prof Tom Kay and Dr Tom Brodnicki
Team Members: Dr Bala Krishnamurthy, Dr Gaurang Jhala, Mr Evan Pappas, Ms Stacey Fynch, Mr David de George, Dr Tingting Ge, Dr Prerak Trivedi

Islet biology in human type 1 diabetes

While a lot is known about the pathogenesis of type 1 diabetes in NOD mice, much less is known of human type 1 diabetes. The Tom Mandel Islet Transplant Program occasionally receives pancreata from organ donors with type 1 diabetes and it is of enormous value to study these. In 2008, we were fortunate to isolate islets from a donor who had type 1 diabetes for only three years. Pancreas sections from this donor reveal infiltrated islets. We expanded and sorted CD4+ and CD8+ T cell clones from the islets and have these as well as islet RNA frozen for future characterization. We will use this and future specimens of this nature to study beta cell biology and immune phenotype of type 1 diabetes in humans.

Group Leaders: Prof Helen Thomas, Prof Tom Kay, A/Prof Stuart Mannering
Team Members: Dr Bala Krishnamurthy, Dr Tom Loudovaris, Dr Pushpak Bhattacharjee, Lina Mariana

Intracellular pathways of beta-cell death in type 2 diabetes

In type 2 diabetes evidence suggests that loss of beta-cell mass is due to apoptosis, and hyperglycaemia has been suggested as a potential cause of beta-cell death. We showed that beta cell apoptosis induced by high glucose concentrations occurs through activation of the pro-apoptotic BH3-only proteins BIM and PUMA. To test whether blocking BIM is able to prevent islet cell death in vivo, we generated leptin receptor deficient db/db mice that lack BIM. These mice have larger islets than wild-type db/db mice and improved glycaemic control, suggesting that protection of beta cells from apoptosis may reduce type 2 diabetes. We aim to study db/db mice with beta cell-specific deletion of BIM. We also aim to identify genes regulated in the islets from BIM-deficient db/db mice that might control their expansion in type 2 diabetes. These studies may identify mechanisms of beta cell expansion resulting in new therapeutic strategies targeting the beta cells.

Group Leader: Prof Helen Thomas
Team Members: Dr Sara Litwak, Stacey Fynch


Effica Biolabs - a preclinical testing service

Our Preclinical Testing Service was established by members of the Immunology and Diabetes Unit to address the unmet need for a service platform to assist industry and academic labs in testing candidate therapies for type 1 diabetes. Our main goal is to help big pharma and biotech reveal hidden value in their drug pipelines by expanding their indications and accelerating their development of therapies.

For more information, please visit our website:  

Group leaders: Prof Helen Thomas, Dr Tom Brodnicki
Team members: Dr Michalea Waibel, Emma Armitage, Dr Tom Loudovaris, Dr Gaurang Jhala, Dr Sara Litwak, Lina Mariana, Tara Catterall, Evan Pappas

Student Projects


Publication Highlights

  1. Thomas HE, Parker JL, Schreiber RD, Kay TWH. IFN- action on pancreatic beta cells causes class I MHC upregulation but not diabetes. J. Clin. Invest. 102:1249-1257 (1998)
  2. Thomas HE, McKenzie MD, Angstetra E, Campbell PD, Kay TW. Beta cell apoptosis in diabetes. Apoptosis 14:1389-1404 (2009)
  3. O’Connell PJ, Holmes-Walker JD, Goodman D, Hawthorne WJ, Loudovaris T, Gunton JE, Thomas HE, Grey ST, Drogemuller CJ, Ward GM, Torpy DJ, Coates PT, Kay TW, On behalf of the Australian Islet Transplant Consortium. Multicenter Australian Trial of Islet Transplantation: Improving Accessibility and Outcomes. Am. J. Transplant., 13:1850-8 (2013)
  4. Quah HS, Miranda-Hernandez S, Khoo A, Harding A, Fynch S, Elkerbout L, Brodnicki TC, Baxter AG, Kay TWH, Thomas HE*, Graham KL* Deficiency in type I interferon signaling prevents the early interferon-gene signature in pancreatic islets but not type 1 diabetes in non-obese diabetic mice. Diabetes 63:1032-40 (2014)
  5. Trivedi PM, Graham KL, Scott NA, Jenkins MR, Majaw S, Sutherland RM, Fynch S, Lew AM, Burns CJ, Krishnamurthy B, Brodnicki TC, Mannering SI, Kay TW, Thomas HE. Repurposed JAK1/JAK2 inhibitor reverses established autoimmune insulitis in non-obese diabetic mice. Diabetes 66:1650-60 (2017)
  6. Wali JA, Galic S, Tan CYR, Gurzov EN, Frazier AE, Connor T, Ge J, Pappas EG, Stroud D, Varanasi LC, Selck C, Ryan MT, Thorburn DR, Kemp BE, Krishnamurthy B, Kay TWH, McGee SL, Thomas HE. Loss of BIM increases mitochondrial oxygen consumption and lipid oxidation, reduces adiposity and improves insulin sensitivity in mice. Cell Death Differ, 25:217-225 (2018)
  7. Trivedi PM, Fynch S, Kennedy LM, Chee J, Krishnamurthy B, O’Reilly LA, Strasser A, Kay TWH, Thomas HE. Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice. Cell Death Discov. 5:136 (2019)
  8. Sutherland APR, Graham KL, Aston MP, Jhala G, Trivedi P, Catterall T, Fynch S, Kay TWH, Thomas HE. IL-21 regulates SOCS1 expression in autoreactive CD8+ T cells but is not required for acquisition of CTL activity in the islets of non-obese diabetic mice. Sci Rep, 9:15302 (2019)
  9. Ge T, Jhala G, Fynch S, Akazawa S, Litwak S, Pappas EG, Catterall T, Vakil I, Long A, Olson LM, Krishnamurthy B, Kay TW, Thomas HE The JAK1 selective inhibitor ABT 317 blocks signaling through interferon and common gamma chain cytokine receptors to reverse autoimmune diabetes in NOD mice. Front Immmunol. 11:588543 (2020)
  10. Akazawa S, Mackin L, Jhala G, Fynch S, Catterall T, Selck C, Graham KL, Krishnamurthy B, Pappas EG, Kwong C-TJ, Kay TWH, Brodnicki TC, Thomas HE Deficiency of the innate immune adaptor STING promotes autoreactive T-cell expansion in NOD mice. Diabetologia 64:878-889 (2021)