Metabolic Disease

Endogenous Interleukin-22 is critical in regulating homeostasis of metabolic tissue. To avoid adverse effects associated with IL-22 therapy, the lab’s developed IL-22-fusion biologics that are targeted to metabolic tissue. The aim of these projects is focussed on de-risking IL-22 therapeutics and assessing its efficacy in improving metabolic outcomes, including effects of lipid accumulation and liver fibrosis

On-going Projects

  • Exogenous IL-22 improves hyperglycaemia

    Discovery: Exogenous IL-22 treatment in preclinical models of diabetes and obesity, normalised hyperglycaemia. IL-22 reduced oxidative stress and endoplasmic reticulum stress in pancreatic beta cells, allowing the secretion of high quality insulin. Published Nature Medicine, 2014

  • Targeted-IL-22 therapy for Fatty Liver Disease

    Discovery: The cytokine Interleukin-22 (IL-22) is an efficient inhibitor of cellular stress which reduced hepatic and pancreatic inflammation, improved glucose intolerance and insulin resistance and significantly reduced hepatic lipid accumulation. Whilst drugs in the NASH pipeline target only one of the specific pathways critical in NASH pathology, our engineered targeted IL-22-biologics (PCT-EU/AU/US; WO2010/096930A1), target multiple pathways in NASH with the potential to exert a profound effect in NASH treatment. Partly published, Nature Comms, 2024.

  • Endogenous role of IL-22RA1 in metabolic disease

    Discovery: Interleukin-22 receptor (IL-22RA1) is highly expressed on pancreatic beta and alpha cells and hepatocytes. Tissue specific IL-22RA1-knockout animals (beta cell knockouts, alpha cell knockouts and hepatocyte knockouts) have highlighted the importance of endogenous IL-22 (published, Nature Comms, 2024).

Publications

Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis.

Sajiir H, Wong KY, Müller A, Keshvari S, Burr L, Aiello E, Mezza T, Giaccari A, Sebastiani G, Dotta F, Ramm GA, Macdonald GA, McGuckin MA, Prins JB, Hasnain SZ. Nat Commun. 2024 May 29;15(1):4527.

Effect of different volumes of interval training and continuous exercise on interleukin-22 in adults with metabolic syndrome: A randomized trial.

Ramos, JS, Dalleck, LC, Stennett, RC, Mielke, GI, Keating, SE, Murray L, Hasnain, SZ, Fassett, RG, McGuckin M, Croci I, Coombes JS. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2020. 13, pp. 2443-2453

Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress.

Hasnain SZ, Borg DJ, Harcourt BE, Tong H, Sheng YH, Ng CP, Das I, Wang R, Chen AC, Loudovaris T, Kay TW, Thomas HE, Whitehead JP, Forbes JM, Prins JB, McGuckin MA. Nature Medicine. (2014)20;(12): 1417‐26.

Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis

Sajiir H, Keshvari S, Wong KY, Borg DJ, Steyn FJ, Fercher C, Taylor K, Taylor B, Barnard RT, Müller A, Moniruzzaman M, Miller G, Wang R, Fotheringham A, Schreiber V, Sheng YH, Hancock JL, Loo D, Burr L, Huynh T, Lockett J, Ramm GA, Macdonald GA, Prins JB, McGuckin MA, Hasnain SZ. Nat Commun. 2024 May 29;15(1):4528.

A Cost-Effective Three-Dimensional Culture Platform Functionally Mimics the Adipose Tissue Microenvironment Surrounding the Kidney.

Shen K, Vesey DA, Hasnain SZ, Zhao K, Wang H, Johnson DW, Saunders N, Burgess M, Gobe GC. Biochem Biophys Res Commun. 2020. 12;522(3):736-742.

Rationally Designed Dendritic Silica Nanoparticles for Oral Delivery of Exenatide.

Abeer MM, Meka AK, Pujara N, Kumeria T, Strounina E, Nunes R, Costa A, Sarmento B, Hasnain SZ, Ross BP, Popat A. Pharmaceutics. 2019 Aug 19;11(8).

Perinatal exposure to high dietary advanced glycation end products in transgenic NOD8.3 mice leads to pancreatic beta cell dysfunction.

Borg, D.J, Yap, F.Y.T, Keshvari, S, Simmons, D.G, Gallo, L.A, Fotheringham, A.K, Zhuang, A, Slattery, R.M, Hasnain SZ, Coughlan, M.T, Kantharidis, P, Forbes, J.M. Islets. Jan 2 ;10( 1) : 10 - 24 . doi : 10. 1080/19382014.2017.1405189.

The effect of interleukin-22 treatment on autoimmune diabetes in the NOD mouse.

Borg, D.J, W ang, R, Murray, L, Tong, H, Steptoe, R.J, McGuckin, M.A, Hasnain SZ. Diabetologia (2017). 60; 11: 2256-2261.

Fibre Intake Is Independently Associated with Increased Circulating Interleukin-22 in Individuals with Metabolic Syndrome.

Torquati L, Coombes JS, Murray L, Hasnain SZ, Mallard AR, McGuckin MA, Fassett RG, Croci I, Ramos JS. Nutrients. (2019);11(4). pii: E815. doi: 10.3390/nu11040815.

Pre-Diabetes Increases Tuberculosis Disease Severity, While High Body Fat Without Impaired Glucose Tolerance Is Protective.

Sinha R, Ngo MD, Bartlett S, Bielefeldt-Ohmann H, Keshvari S, Hasnain SZ, Donovan ML, Kling JC, Blumenthal A, Chen C, Short KR, Ronacher K.Front. Cell Infect Microbiol. Jul 2021. DOI: 10.3389/fcimb.2021.691823

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes.

Hasnain SZ, Prins JB, McGuckin MA. J Mol Endocrinol. 2016 Feb;56(2):R33-54.