Islet biology

Group Leader: A/Prof Helen Thomas
Team Members: Dr Prerak Trivedi, Dr Robyn Sutherland, Dr Michaela Waibel, Dr Stuart Mannering, Mr Nick Scott, Ms Victoria Huang, Ms Stacey Fynch, Prof Tom Kay
Collaborators: Dr Chris Burns, Prof Bruce Kemp, Dr Misty Jenkins, Prof Matthias von Herrath

Discovering new applications for approved drugs or those in advanced clinical development is one way to ensure a rapid transition from the laboratory to the clinic. For many of the pathways involved in diabetes pathogenesis, drugs already exist that have been developed for other applications, such as cancer therapy. We have established a pipeline of pre-clinical studies with such drugs, and plan to progress these through to clinical studies in type 1 diabetes. These drugs may also be used together with antigen-specific immunotherapy. We hope to identify regimens that are effective but safe, and which do not have to be administered lifelong. We have tested inhibitors of JAK1/JAK2, the kinases downstream of many cytokine receptors. Our data indicate that JAK inhibitors prevent the migration of immune cells into islets, prevent diabetes in mouse models, and reverse established autoimmune diabetes in non-obese diabetic (NOD) mice. There are many other kinase inhibitors being developed for other indications. We will test these in NOD mice, in collaboration with leaders in kinase biology and pharmaceutical companies.

Group Leader: Dr Helen Thomas
Team Members: Dr Satoru Akazawa, Dr Zia Mollah, Mr Evan Pappas, Ms Leanne Mackin, Mr Justin Kwong, Prof Tom Kay
Collaborators: Prof Joe Trapani, Prof Phil Bird, Dr Tom Brodnicki, Dr Bala Krishnamurthy

The trigger leading to loss of tolerance to self-antigens in genetically predisposed individuals is conventionally thought to follow an environmental event such as viral infection. We have identified an endogenous trigger that can activate the very small number of T cells that recognise islet autoantigens. Granzyme A is a protease implicated in the degradation of intracellular DNA, and we have identified an important role for granzyme A in regulating autoimmunity. Absence of granzyme A accelerates diabetes in NOD mice and results in increased cytosolic DNA that can act as an endogenous signal to stimulate local type I IFN production. This activates the residual autoantigen-specific T cells that have escaped thymic deletion, even in immune tolerant individuals. We will study NOD mouse models and samples from patients with pre-diabetes and established diabetes to understand how granzyme A maintains immune tolerance. These studies will likely lead to a paradigm shift in understanding the triggers of type 1 diabetes, which are currently very poorly understood.

Group Leader: A/Prof Helen Thomas
Team Members: Dr Jingjing Ge, Dr Esteban Gurzov, Mr William Stanley, Dr Sara Litwak
Collaborators:  Prof Andreas Strasser, Dr Sean McGee, Dr Ian Smyth

Type 2 diabetes is an enormous global health problem affecting nearly 350 million individuals world-wide. It occurs as a result of declining beta-cell function in insulin-resistant subjects together with a decrease in beta cell mass. Evidence suggests that loss of beta cell mass is due to apoptosis, with hyperglycaemia as a potential cause. Inhibition of apoptosis may be able to prevent beta cell loss. Increasing functional beta cell mass would reduce insulin requirements, improve glucose control and reduce complications of diabetes. However, drugs to inhibit apoptosis have not been implemented in diabetes.

Using very well characterized mouse models, we were the first to identify that the pro-apoptotic molecules BIM and PUMA are required for glucose-induced apoptosis of islet cells. We have generated exciting results that suggest BIM deficiency protects leptin receptor mutant mice from development of fasting hyperglycaemia and increases beta cell mass. It is unclear whether this is an intrinsic beta cell effect or due to improved insulin sensitivity. We aim to study how BIM contributes to type 2 diabetes development using conditionally targeted mouse models. We will also examine how beta cell mass is increased in BIM-deficient mice.

Group Leader: Dr Esteban Gurzov
Team members: Dr Sara Litwak, Mr William Stanley, A/Prof Helen Thomas
Collaborators: Prof Decio Eizirik

Type 1 diabetes is the result of autoimmune assault against the insulin-producing pancreatic b cells, where chronic local inflammation (insulitis) leads to b cell destruction. T cells and macrophages infiltrate into islets early in type 1 diabetes pathogenesis. These immune cells secrete cytokines that lead to the production of reactive oxygen species (ROS) and T cell invasion and activation. Cytokine signaling pathways are very tightly regulated to prevent excessive signaling. Two molecules that inhibit cytokine signaling include the suppressor of cytokine signaling (SOCS)-1 and T cell protein tyrosine phosphatase (TCPTP). These molecules are expressed in b cells, and their inactivation sensitizes b cells to cytokine signaling. Protein tyrosine phosphatases such as TCPTP are highly susceptible to oxidation by ROS, which occurs during pathological inflammation. The gene for TCPTP, PTPN2, has also been associated with type 1 diabetes in genome-wide association studies, and the genetic susceptibility is linked with reduced expression of TCPTP. ROS-mediated inactivation of TCPTP, together with its reduced expression in genetically susceptible individuals, provides a mechanism by which excessive cytokine signaling in b cells results in increased expression of inflammatory genes (e.g. chemokines) and exacerbated insulitis. In this project we will utilize mice that lack TCPTP or SOCS1 specifically in b cells to test the hypothesis that b cells contribute to their own demise by activating inflammatory signals driven by local ROS and cytokine production.