Genetics of Type 2 Diabetes
Genetics of Type 2 Diabetes (collaboration)
Dr Lois Balmer; Dr Sof Andrikopoulos; Austin Hospital, Melbourne
This Silver Stain gel represents a new method to discover protein(s) binding to DNA. We have developed this assay that allows proteins in a band of interest to be isolated, identified and further characterisation performed. The arrow above indicates a protein that may control the Nnt gene after glucose challenge.
Several years of research led to us identifying the Nicotinamide Nucleotide Transhydrogenase (Nnt) gene as being important in a mouse model of type 2 diabetes (T2D). Nnt plays an important role in controlling insulin secretion from the pancreatic β cells. Dr Lois Balmer has been investigating what controls the Nnt gene and has identified a single DNA change (polymorphism) that is the likely culprit. She will define how this sequence difference impairs glucose tolerance in mice with a "normal" (Wild Type) promoter sequence. By performing specialised genetic engineering, she has demonstrated that replacement of a single DNA "letter" affects the amount of Nnt produced after glucose stimulation.
We have developed a new method to identify proteins that interact with DNA. Lois is now in the process of identifying proteins that bind to this specific part of the Nnt gene. This is important as such proteins could be made by other genes important in T2D. Currently we are awaiting the identification of a protein band seen in the Wild Type sequence but not in the mutated sequence. Lois has also sequenced the Nnt gene of the DBA/2 mouse. She will use this sequence to make an antibody against Nnt (in collaboration with Kathy Davern and the Monoclonal Antibody Facility) which we can use in further studies.
Gene-Environment Interactions in Type 2 Diabetes
Type 2 Diabetes is increasing throughout the developing world, and it poses an even greater problem in other countries as they adopt a more Western lifestyle. For example, India is now recognized as the "world capital" of diabetes, as it has the most number of people affected by this disease.
The "Western diet" (together with reduced exercise) is driving the present epidemic of obesity and type 2 diabetes (T2D). Gene-environment interactions are causing this problem, but identifying these genes in humans is notoriously difficult, due to many factors, not least of which is controlling the environmental variables under study.
If we can define the genes which respond to "Western diet" by causing obesity-related diabetes ("Diabesity") we may be able to design therapeutic or prevention strategies which can prevent diabetes. Alternatively, we may be able to replace specific dietary elements which will not trigger the action of these genes.
To our knowledge, we are the only group in the world performing such gene-by-environment studies. We will address the issue of gene-diet interactions in diabesity by addressing two questions using amenable mouse models:
- What genes contribute to diet-induced metabolic changes
We will study the different effects of diet on various metabolic and physiological parameters in two well defined mouse strains (C57BL/6 and DBA/2). Any relevant changes will be defined for further testing using a special resource: BXD inbred strains. This is a rapid way to map and identify genes of interest.
- Can we modify diet to prevent obesity in genetically prone individuals? What gene controls this effect?
One particular mouse strain (NZO) develops obesity and some features of type 2 diabetes when raised on a "standard" diet. By altering components of the diet we will test for reduction in weight gain and T2D traits in these mice. Genes controlling relevant traits can be mapped and identified by analysing the 'children' of NZO mice to C57BL/6.
These studies will yield the following outcomes:
- Identification in obese and normal mice of traits affected by dietary modifications
- Identification and study of genes controlling these traits in "normal" mice
- Study of genes controlling these traits in obesity-prone mice.