A drug that has already been used in the treatment of rare hereditary disorders may provide a relief for people with type 2 diabetes, proposed Australian researchers.
In people with type 2 diabetes, the insulin-producing cells (beta cells) in pancreas are less efficient in making insulin and the body develops a condition known as insulin-resistance. Insulin works by channeling glucose (sugar) from the blood to the cells, and in people with diabetes, high blood sugar content is extremely damaging to blood vessels and organs.
The researchers, Kim Cheng, Kenneth Ho and Jenny Gunton at the Garvan Institute of Medical Research, in Sydney found that reduced expression of the HIF-1 alpha gene in beta cells that causes reduction in protein production, explained the compromised ability of the pancreas in producing insulin in people with type 2 diabetes.
They also found that administering the drug - already used for a rare inherited disorder - increased levels of HIF-1 alpha protein and might improve insulin production.
Dr Gunton said, We believe that HIF-1 alpha is a key player, effectively orchestrating many events in the cell that eventually start to shut down insulin secretion.
The HIF-1 alpha is a transcription factor that controls how genes are expressed or transcribed, she said, and this specific transcription factor influences many genes to regulate glucose uptake and metabolism in the pancreas.
Low levels of the transcription factors results in less energy in the beta cells.
Beta cells secrete insulin when they detect an increase in their own energy. When they can't 'see' glucose, as rising energy, they don't secrete insulin, said Dr Gunton.
The significance of HIF-1 alpha was tested and confirmed by the scientists through a number of methods.
They first genetically engineered mice without HIF-1 alpha gene in beta cells and this group of mice was mildly glucose intolerant - their blood sugar contents were higher than usual.
The animal findings were then replicated in cultured islets revealing reduced levels of HIF-1 alpha protein.
They then fed genetically engineered and normal mice a high fat saturated diet to make them grow fat and trigger insulin resistance. Glucose contents quickly became lesser as beta cells are induced to work harder to maintain normal sugar contents.
All the mice were then given the drug to increase the HIF-1 alpha protein. The results showed glucose contents improved in the 'normal' mice even though they resumed their high fat diet.
As for the mice without HIF-1 alpha gene in their beta cells, the drug triggered no such effect.
Dr Gunton is confident the beta cell HIF-1 alpha is required for the drug to influence glucose tolerance.
She said, Once we'd established that, we did a new study treating the 'normal' mice for six months to establish the drug's safety over the longer-term.
We did not detect side effects and the mice developed better glucose tolerance.
The same results were observed in mice of completely different genetic lineage. In patients with type-2 diabetes who were given the drug, it resulted in normalized gene expression or 'restored function', said Dr Gunton.
Since the drug has a completely different mode of action from any drugs currently used for the treatment of type 2 diabetes, Dr Gunton says, it offers the potential of combined therapy.
The fact that the drug is already approved by the therapeutic Goods Administration in Australia and the US Food and Drug Administration is an excellent first step.
The scientists have designed a potential trial and currently are seeking for fund support.