'Eating machine' helps ID insulin activity

Diabetes researchers at Sydney's Garvan Institute have identified a gene that plays a key role in cellular sensitivity to insulin -- and which could be a target for anti-obesity drugs.

Dr Juan Molero told the recent ComBio 2003 conference in Melbourne that his team had developed a knockout mouse lacking the C-Cbl gene. It's a hot, lean eating machine, with a resting metabolic rate 30 per cent higher than its littermates.

The transgenic mouse burns glucose so rapidly that its body temperature is a full degree higher than normal. Although it eats prodigiously, it has very low reserves of body fat, and 35 per cent less brown fat, the energy store that chilled mammals use to generate body heat by shivering.

The Garvan has patented its discovery. Molero says that, despite its normal role in downregulating energy metabolism, C-Cbl does not appear to be essential for the normal activity of insulin throughout the body, making it a promising target for the treatment of non-insulin dependent diabetes and obesity.

Molero says it's not yet known in which tissues C-Cbl is normally active, and its mode of action is unclear, but it may down-regulate the synthesis of ATP in mitochondria.

To identify the tissues in which C-Cbl is active, the Garvan team is experimenting with a novel technique developed in-house, which uses electroporation and antisense DNA to produce localised, tissue-specific gene knockouts in normal mice,

The DNA is injected into the target tissue, which is then zapped with an electrical charge to make the cell membranes permeable so they take up the DNA, silencing the gene.