PhD in Diabetes - Islet Biology Group
Job No:
G88
Location:
Darlinghurst, Sydney
Supervisor: A/Prof Ross Laybutt
The current epidemic of type 2 diabetes represents a major global health problem, with over 7% of the Australians suffering the disease. While there is a well-established relationship between obesity and insulin resistance, the majority of overweight individuals do not develop type 2 diabetes because their pancreatic b-cells compensate with enhanced insulin secretion. It is the failure of b-cell compensation that is fundamental to the development of diabetes. The b-cell is a highly specialised cell with a unique metabolic profile and differentiation specifically geared towards making these cells able to sense fluctuations in circulating glucose levels and secrete insulin accordingly. We propose that in susceptible individuals, a gradual rise in blood glucose (hyperglycaemia) and lipid levels resulting from increasing obesity and insulin resistance leads to a loss of the unique expression pattern of genes necessary for appropriate insulin secretion. This exacerbates hyperglycaemia, which causes further b-cell dedifferentiation and eventually the death of b-cells by apoptosis. Our group has recently found evidence in several models of diabetes that supports this hypothesis. We have identified and are investigating novel candidate genes that link hyperglycaemia to the development of impaired b-cell function. Furthermore, we are investigating endoplasmic reticulum (ER) stress as a potential mechanism for b-cell destruction in type 1 and type 2 diabetes. We are using in vivo and in vitro systems to investigate the following hypotheses important for our understanding of b-cell failure and progression to diabetes:
- The loss of b-cell phenotype (dedifferentiation) underlies the loss of insulin secretory function in type 2 diabetes.
- Hyperglycaemia plays a critical role regulating the progression to b-cell dedifferentiation.
- The overexpression of key candidate gene products play an integral role linking hyperglycaemia to the loss of b-cell differentiation and secretion.
- ER stress is necessary and contributes to b-cell death in type 1 and type 2 diabetes.
Identifying the mechanisms of b-cell failure in diabetes is of critical importance considering that the incidence of newly diagnosed diabetes is growing to epidemic proportions. Our studies will make a major contribution to our understanding of why b-cells fail in diabetes and aim to provide novel therapeutic targets in the treatment of diabetes.
Recent Publications:
Chan JY, Luzuriaga J, Bensellam M, Biden TJ, Laybutt DR. Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in β-cell gene expression and progression to diabetes. Diabetes 62(5):1557-68, 2013.
Chan JY, Biden TJ, Laybutt DR. Cross-talk between the unfolded protein response and nuclear factor-kB signalling pathways regulates cytokine-mediated beta cell death in MIN6 cells and isolated mouse islets. Diabetologia 2012; 55:2999-3009
Achard CS, Laybutt DR. Lipid-induced endoplasmic reticulum stress in liver cells results in two distinct outcomes: adaptation with enhanced insulin signaling or insulin resistance. Endocrinology 153(5): 2164-77, 2012
Åkerfeldt MC, Laybutt DR. Inhibition of Id1 augments insulin secretion and protects against high-fat diet-induced glucose intolerance. Diabetes 2011; 60:2506-2514