Research provides hope for type 1 diabetes ‘cure’

Early stages of ‘world-leading’ clinical research have demonstrated the regeneration of insulin in pancreatic stem cells can replace the need for round-the-clock injections for people living with type 1 diabetes.
 
The recently published paper, led by researchers from the Baker Heart and Diabetes Institute, has shown that newly made insulin cells can respond to glucose and produce insulin within 48 hours, following stimulation with two enhancer of zeste homolog 2 (EZH2) small molecule inhibitors currently approved in the US by the Food and Drug Administration (FDA) for rare cancers: GSK126 and tazemetostat.
 
The inhibitors have been shown to rapidly return insulin production in pancreatic cells destroyed in patients with type 1 diabetes.
 
Professor Sam El-Osta, Head of the Baker Institute’s Epigenetics in Human Health and Disease Program and supervisor at Monash University’s Department of Diabetes, led the research and told newsGP the aim is to eventually develop available treatments to restore insulin production in people living with type 1 diabetes.
 
But while the long-term plan is that following clinical trials the TGA would approve a drug to go on the market for GPs to prescribe to people who are insulin dependent, ‘we’re nowhere near that yet’.
 
‘The work is definitely proof of concept, but it is using human material, and we’ve shown a restoration of insulin synthesis and production in pancreatic stem cells,’ Professor El-Osta said.

‘What we’re able to do is use FDA-approved drugs that are currently used in human clinical trials for other conditions. The drugs were not necessarily designed for diabetes, but by using one of two different drugs that belong to the same class of enzymes that we’re inhibiting, we showed in insulin-dependent people that we’re able to convert one of the key enzymes that’s responsible for pancreatic stem cell capacity.
 
‘And by restoring the pancreatic stem cell capacity, we also are able to influence insulin expression.’

Professor El-Osta said the results harness people’s remaining pancreatic cells to increase insulin production, meaning it could potentially modify the cause of diabetes and eliminate the need for regular insulin injections in some people living with type 1.

‘From our point of view, this holds the potential to become the first disease-modifying treatment for type 1 diabetes by facilitating glucose-responsive insulin production … and could potentially lead to the development of a regenerative strategy,’ he said.
 
The study used pancreatic cells from child and adult donors with type 1 diabetes and from non-diabetics, to investigate the reactivation of pancreatic progenitor cells by assessing the small molecule inhibitors GSK126 and tazemetostat for regenerative beta cell capacity.
 
The results demonstrated how insulin-producing cells that are destroyed in people with type 1 diabetes can be regenerated into glucose-sensing and functionally secreting insulin cells. Forty-eight hours of stimulation with the small molecule inhibitors was sufficient to restore insulin production from damaged pancreatic cells.
 
RACGP Specific Interests Diabetes Chair Dr Gary Deed believes that while the research is still in early stages, it shows promise.
 
‘It’s a little “pie in the sky stuff” and just at pre-clinical stage so currently not very relevant to GPs,’ he said.
 
‘But this reflects world-leading, high-quality Australian diabetes research that shows advances in type 1 diabetes are progressing and hopefully we may see a “cure” in the near future.’
 
Beta cell replacement is a central requirement for the treatment of insulin-dependent diabetes, the authors state, with the type of endocrine cell found in pancreatic islets that synthesise, store and release insulin.
 
In people with type 1 diabetes, T-cells of the immune system selectively destroy the insulin-producing beta cells which leads to a lifelong dependence on insulin. Therefore, the authors highlight ‘an urgent need to identify novel therapies’ that stimulate beta cell growth and induce beta cell function. 
 
It is estimated more than 8.4 million people worldwide live with type 1 diabetes, with numbers expected to significantly increase by 2040. In Australia, around 134,000 people are currently living with type 1 diabetes, with many diagnosed as children.
 
The study authors believe their new therapeutic approach of awakening insulin-producing cells is viable in those aged 7–61 years.
 
Current pharmaceutical options for diabetes treatment help control blood glucose levels but do not prevent or reverse the destruction of insulin-secreting cells.
 
While the new potential treatment is still some time away from being available for management of type 1 diabetes, Professor El-Osta said for GPs it’s a matter of ‘watch this space’ and the next step is to investigate the novel regenerative approach in a pre-clinical model. 

‘There is some excitement and promise regarding these compounds, and we have a current animal study which should be completed in the next two years, [when] we will have the toxicology results, but also the results towards the regenerative capacity in small animal models of diabetes,’ he said.

‘We’ll also have the results of whether they’re able to influence stem cell production in the pancreas, as well as influence the expression of the beta cell which is the only cell in the body that is able to produce insulin.
 
‘And of course, ultimately whether the cells can then produce independently despite diabetes, whether these cells can produce insulin in response to the pharmacological inhibitors.’
 
With a key part of the research to maintain trajectory to find a cure for type 1 diabetes, the authors conclude that while ‘other factors involved in regulating progenitor expansion will need to be considered’, they propose that ‘the specialised chromatin structures assembled for methylation-dependent silencing will need to be overcome to restore or revert precursor capacity’.
 
‘This reawakening might be achieved in resistant exocrine cells by inhibiting EZH2 dependent silencing to regain the ability of beta-like cells to produce insulin,’ they state.
 
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EZH2 insulin dependence insulin production pancreas function type 1 diabetes