ADA 2021: The future of insulin at 100

Professor Michael Weiss

A better future for people with diabetes through ultra rapid, ultra stable, and glucose-responsive insulins will require a focused and collective “moon landing” approach.

In a special ADA 2021 session celebrating 100 years of insulin, presenters acknowledged major advances since insulin was first developed in 1920 but also looked forward to more innovation.

Professor Michael Weiss, director of chemical biology and biotherapeutics for the Indiana University Precision Health Initiative, told the session that device driven protein engineering was the new field of discovery.

“The brilliant engineering successes in making CGM and ever more precise pumps with microfluidics holds the promise essentially of normal control of blood glucose but current insulin formulations are not as good as the engineering,” he said.

There needed to be an escape from the Catch-22 situation where engineers made devices to fit current insulins and protein chemists made insulins compatible with existing devices.

“Device drive protein engineering is the next step to achieve hyper-rapid insulins that in the closed loop systems or artificial pancreases will match the speed and precision of normal beta cell pancreatic insulin releases into the portal circulation.”

Moon landing

He said the transformative goal, before a cure for diabetes, was to make the perfect insulins for the perfect devices – and that would require less work optimising different products in isolation and more collaborative effort.

“Think about it like the moon landing challenge … achieved in 1969. We want a moon landing where we can combine these ultra rapid, ultra stable, glucose responsive features into the perfect insulin for patients, all in the same hypothetical future product,” he said.

Professor Weiss said that until recently, researchers had been unable to answer difficult questions such as ‘why does insulin lose its activity at room temperature’ or ‘how does it bind to the receptor’.

But the cryogenic electron microscopy (cryo-EM) revolution has now transformed the structural understanding of how insulin works.

“And so here we believe will be the secret to create, in the next decade, the truly glucose responsive insulins that don’t need polymers or matrices or microneedles to have glucose-dependent delivery, but the molecule itself would be intrinsically sensitive to the concentration of glucose such as that when the blood glucose goes down, the insulin would turn itself off.”

“Now imagine you had a closed loop system that achieved a time in range that we are happy about – say 75% – and you use a glucose responsive insulin in the reservoir of the pump, surely we can then combine the safety provided by the CGM and the control algorithm in the system together with the intrinsic smart characteristics of the insulin to give another layer of control. And perhaps we can achieve a time in range of 95% with that 5% being predominantly small hyperglycaemic excursions and not hypoglycemia with all its attendant unpleasant feelings and potential risks of loss of consciousness or convulsions.”

“It’s really the anxiety of hypoglycaemia that for many patients and also for many physicians limits our attempts to achieve lower HbA1c – the tight glycaemic control that can delay or prevent long term complications.”

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