Diabetes and Obesity

Genes that regulate tolerance and beta cell survival in type 1 diabetes

The research project involves analysis of the function of the CDK4 gene in the generation and maintenance of islet cells in the pancreas.  The background to the project is that we identified a novel mutation in the CDK4 gene in the Wanchi (aboriginal word meaning “sick”) mouse strain that was identified through an ENU mutagenesis program. The Wanchi mice develop diabetes by around 8 weeks of age.  Interestingly the onset of diabetes is more rapid in males compared to female animals.  The mutation occurs in the stop codon of CDK4 gene leading to an additional 30 amino acids being added to the c-terminus of the protein.  The development of diabetes is not due to autoimmune attack of the islets, but rather the CDK4 gene appears to play an essential role in the growth and maintenance of pancreatic islet beta cells. 

In this project we would like to understand how the Wanchi allele disrupts CDK4 protein function. We would also like to understand what the target genes that are disrupted in the beta cells if Wanchi mutant mice as this could provide an important insight into the mechanism that govern the homeostasis of islet beta cell mass. In the long term this could help to understand how to grow beta cells to help treat type 1 diabetes in humans.

Investigators: A/Prof Gerard Hoyne, Dr Charmaine  Simeonovic
Contact: Assoc Prof Gerard Hoyne  ghoyne@nd.edu.au

Role of the novel gene fatsin in the regulation of obesity and type 2 diabetes

Diabetes and obesity is growing at an alarming rate throughout the world fuelled by population growth, urbanization, overeating, and physical inactivity. Type 2 diabetes (T2D) is a leading cause of chronic renal failure, adult blindness, limb amputation and a major risk factor for heart disease, stroke and birth defects. Obesity is an important risk factor for the development of T2D and there is evidence for a complex interplay between genetics and environment for both diseases. T2D is caused by a combination of insulin resistance at skeletal muscle, liver and adipose tissues and impaired insulin secretion from pancreatic islets. The disease manifests with impaired glucose tolerance and/or impaired fasting glucose concentrations and frank T2D develops due to beta cell failure. Around 25-30% of Australians have non alcoholic fatty liver disease (NAFLD) that is attributable to being overweight/obese, having T2D and metabolic syndrome. The significance of NAFLD is that it relates most strongly to the risk of T2D and metabolic syndrome and the incidence of cardiovascular disease and cancer that arise in these patients and little is known about the molecular mechanisms that control the disease pathogenesis.

We have identified a mouse strain through an ENU mutagenesis screen that develops obesity with insulin resistance, T2D and metabolic syndrome, hepatic steatosis that progresses to NAFLD when fed a regular diet. The mutation was located to a novel gene on chromosome 8 which we called “Fatsin”. The gene has not been previously implicated in the development of T2D or obesity in either rodents or humans is a nuclear protein that regulates alternative splicing of mRNAs. The availability of the fatso strain will allow us to study the entire disease process of T2D and obesity from “cause to effect”. This information will provide novel insights into the development of T2D and obesity and could open up therapeutic strategies aimed at targeting alternative splicing of key genes responsible for human diseases. Such approaches are already proceeding in cancer and autoimmunity.

The background studies have been performed primarily in mice and we would like to investigate if the Fatsin gene might also be mutated in patients with fatty liver disease and obesity.  This could provide a novel insight into the regulation of this disease in humans.

Investigators: A/Prof Gerard Hoyne, Dr Charmaine  Simeonovic, Dr Leon Adams
Contact:  Assoc Prof Gerard Hoyne  ghoyne@nd.edu.au