- A recent study explored whether a molecule unrelated to insulin could perform the same role as insulin.
- Using cryo-electron microscopy, the researchers identified a small non-insulin-related protein that can activate the human insulin receptor.
- This finding paves the way for the future development of an insulin-mimicking oral pill to replace daily insulin injections for people with diabetes.
When food is broken down in the gut, glucose is released into the bloodstream. In response, the pancreas secretes the hormone insulin, which “instructs” the fat, muscle, and liver cells to take up glucose.
Globally, an estimated 8.4 million people are living with type 1 diabetes (T1D), a condition in which the body does not produce the hormone insulin or makes very little of it. Without insulin, glucose remains in the blood and cells lack the energy needed to maintain life.
People with type 1 diabetes (and some with type 2 diabetes) need to receive insulin to control their blood glucose levels and energy absorption. Most commonly, insulin is injected using either a syringe, insulin pen, or insulin pump. This has several limitations to this method, including:
- injection pain
- discomfort for people with needle phobia
- possible non-compliance with injection routine
- risk of lipodystrophy (abnormal distribution of fat)
Now, researchers at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia, in collaboration with researchers at Lilly, have identified a protein that mimics the role of insulin, potentially paving the way for the development of an oral pill to replace insulin injections.
Their findings were recently published in Nature Communications.
The road to developing an insulin pill
The obstacle to oral insulin administration is the fact that insulin is a protein that is digested in the stomach before it reaches the bloodstream.
For insulin to work, it must get past the stomach and into the bloodstream still intact, to be transported to the insulin receptors on fat, muscle, and liver cells.
In recent years, there have been many research efforts to overcome this challenge.
For example, in a 2019 study, an MIT-led research team developed an ingestible, self-orienting capsule containing a small needle that could inject insulin directly into the stomach wall.
Other researchers have focused on insulin mimetics — molecules that mimic insulin’s ability to activate the human insulin receptor, which in turn, triggers blood glucose uptake. Yet this is not an easy feat.
Peter R. Flatt, Ph.D., professor of biological and biomedical sciences at Ulster University, explained to Medical News Today that, “insulin […] has a complex structure which has defeated chemists trying to make a small molecule mimetic that can be taken orally.”
Daniel J. Leahy, Ph.D., professor of molecular biosciences at the University of Texas at Austin, noted to MNT:
“It has been difficult to make an insulin-supplanting pill as insulin is a protein that would be digested in the gut, and any insulin-mimicking ‘pill’ would have to survive being digested as well as be absorbed into the bloodstream.
In addition, recent breakthroughs in cryo-electron microscopy (cryo-EM), a technique for determining the 3D shape of biomolecules, have enabled researchers to visualize complicated molecules like insulin in great detail.
Cryo-EM involves flash-freezing solutions of biomolecules and then bombarding them with electrons to produce magnified images of individual molecules. Using cryo-EM, researchers are able to generate 3D images of the insulin receptor and observe how insulin and other molecules alter its shape.
Novel technology sheds light on insulin receptors
When insulin interacts with the human insulin receptor present in fat, muscle, and liver cells, it induces a structural change in the receptor.
Nicholas Kirk, Ph.D., study first author and senior research officer at WEHI, described the interaction between insulin and the receptor as being “like a hand bringing a pair of tongs together.”
Certain peptides (short chains of amino acids linked together by peptide bonds) are known to interact with the insulin receptor in a similar manner to insulin.
The researchers used cryo-EM to examine the interaction between these peptides and the insulin receptor at a molecular level.
They found that a specific peptide consisting of a chain of 33 amino acids can bind to and activate the insulin receptor in a similar manner to insulin.
Implications for new insulin receptor activators
The researchers are hopeful that their findings will illuminate pathways for the development of novel activators of the human insulin receptor, which could be used for the treatment of diabetes.
“The designed molecule is a protein (33 aa ‘peptide’) so doesn’t solve the ‘get past the gut’ problem needed for a successful pill but does provide proof of principle of their strategy and demonstrates that if a gut-stable [or] absorbable molecule with their design features can be made it will be effective.”
– Daniel J. Leahy, Ph.D., professor of molecular biosciences
If a gut-stable activator of the insulin receptor were to be found, this would likely lead to the development of an oral pill for type 1 diabetes.
The ability to manage type 1 diabetes using a pill rather than injections would signify an improvement in the quality of life for people living with the condition.
Pills would also have the added benefit of easier storage compared to insulin vials, which must be kept at low temperatures according to guidelines.
When could an insulin pill become available?
Despite the positive implications of the insulin-mimicking molecule, more rigorous studies are still needed before an insulin pill could be made available to the general public.
“It’s still a long road that will require further research, but it’s exciting to know that our discovery opens the door for oral treatments for type 1 diabetes,” Dr. Kirk said in a news release.
Although therapeutic outcomes from this study are distant, the existence of oral semaglutide on the market is proof that injectable drugs can be successfully converted to oral pill form.
Until recently, glucagon-like peptide-1 (GLP-1) receptor agonists — which are used to treat type 2 diabetes — were all available in injection form.
A randomized, double-blind, phase 3a trial (the PIONEER 4 study) showed that the efficacy of the pill form of the GLP-1 drug semaglutide is comparable to that of the injectable form.
Now, oral semaglutide (trade name: Rybelsus) is approved by the FDA for the treatment of type 2 diabetes, and patients who are unable or unwilling to manage their condition using injections have a viable treatment alternative.
Source: Read Full Article