Insulin-mimicking molecule could be made into an oral pill

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The researchers identified a protein unrelated to insulin, which could lead to the development of an oral pill that mimics insulin. Sergio Marcos/Stocky
  • A recent study explored whether a molecule unrelated to insulin could play the same role as insulin.
  • Using cryoelectron microscopy, the researchers identified a small non-insulin related protein that can activate the human insulin receptor..
  • This finding paves the way for future development of an insulin-mimicking oral pill to replace daily insulin injections for people with diabetes.

When food is broken down in the intestine, glucose is released into the bloodstream. In response, the pancreas secretes the hormone insulin, which “instructs” fat, muscle, and liver cells to take up glucose.

Globally, it is estimated 8.4 million people live with type 1 diabetes (T1D), a condition in which the body does not produce the hormone insulin or produces very little. Without insulin, glucose remains in the blood and cells lack the energy needed to sustain life.

People with type 1 diabetes (and some with type 2 diabetes) need to take insulin to control their blood glucose levels and energy uptake. Insulin is usually injected using 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 the 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 Lilly researchers, 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 obstacle to oral administration of insulin is the fact that insulin is a protein that is digested in the stomach before reaching the bloodstream.

For insulin to work, it must pass through the stomach and reach the bloodstream intact, to be transported to insulin receptors in fat, muscle, and liver cells.

In recent years, there have been many research efforts to overcome this challenge.

For example, in a study 2019An 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 glucose uptake into the blood. However, this is not an easy feat.

Peter R FlattPh.D., professor of biological and biomedical sciences at the University of Ulster, explained to today’s medical news that, “insulin […] it has a complex structure that has defeated chemists trying to make a small molecule mimetic that can be taken orally.”

Daniel J LeahyPh.D., a professor of molecular biosciences at the University of Texas at Austin, told MNT:

“It has been difficult to make an insulin replacement pill, since insulin is a protein that is digested in the intestine, and any ‘pill’ that mimics insulin would have to survive digestion and be absorbed into the bloodstream.

Additionally, recent advances in cryo-electron microscopy (cryo-EM)a technique for determining the 3D shape of biomolecules, has allowed researchers to visualize complicated molecules like insulin in great detail.

Cryo-EM involves snap-freezing solutions of biomolecules and then bombarding them with electrons to produce magnified images of individual molecules. Using cryo-EM, researchers can generate 3D images of the insulin receptor and watch how insulin and other molecules alter its shape.

When insulin interacts with the human insulin receptor present in fat, muscle, and liver cells, it induces a structural change in the receptor.

Nicholas KirkPh.D., first author of the study and senior research director at WEHI, described the interaction between insulin and the receptor as “like a hand putting a pair of pliers together.”

Certain peptides (short chains of amino acids linked by peptide bonds) are known to interact with the insulin receptor in a similar way to insulin.

The researchers used cryo-EM to examine the interaction between these peptides and the insulin receptor at the 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 way to insulin.

The researchers are hopeful that their findings will illuminate pathways for the development of new human insulin receptor activators, which could be used for the treatment of diabetes.

“The designed molecule is a protein (33 aa ‘peptide’), so it does not solve the ‘going through the gut’ problem necessary for a successful pill, but it does provide proof of principle for their strategy and demonstrates that if a gut stable [or] absorbable molecule with its design characteristics can be made that will be effective”.

– Daniel J. Leahy, Ph.D., professor of molecular biosciences

If a stable intestinal activator of the insulin receptor were found, this would likely lead to the development of an oral pill for type 1 diabetes.

The ability to control type 1 diabetes using a pill instead of injections would mean an improvement in the quality of life for people living with the condition.

The pills would also have the added benefit of easier storage compared to insulin vials, which must be kept at low temperatures according to guidelines.

Despite the positive implications of the insulin-mimicking molecule, more rigorous studies are still needed before an insulin pill can be made available to the general public.

“It’s still a long way to go that will require more research, but it’s exciting to know that our discovery opens the door to oral treatments for type 1 diabetes,” Dr. Kirk said in a Press release.

Although the therapeutic results of this study are distant, the existence of oral semaglutide on the market is proof that injectable drugs can be successfully converted into oral pills.

Until recently, glucagon-like peptide-1 (GLP-1) receptor agonists, which are used to treat type 2 diabetes, were available in injection form.

A randomized, double-blind, phase 3a trial (the PIONEER STUDIO 4) showed that the efficacy of the pill form of the drug GLP-1 semaglutide is comparable to that of the injectable form.

Oral semaglutide (trade name: Rybelsus) is now FDA-approved for the treatment of type 2 diabetes, and patients who cannot or do not want to control their condition through injections have a viable treatment alternative.

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