Glucagon fibrils: NMR looks at insulin counterpart

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  • Published: Aug 15, 2019
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Glucagon fibrils: NMR looks at insulin counterpart

Fibrilisation

Nuclear magnetic resonance (NMR) spectroscopy has revealed to scientists at Massachusetts Institute of Technology (MIT) how glucagon the hormonal counterpart to insulin has a structure unlike other known amyloid fibrils. The discovery might one day lead to an alternative way to control Type 1 diabetes. Image courtesy of the researchers

Nuclear magnetic resonance (NMR) spectroscopy has revealed to scientists at Massachusetts Institute of Technology (MIT) how glucagon the hormonal counterpart to insulin has a structure unlike other known amyloid fibrils. The discovery might one day lead to an alternative way to control Type 1 diabetes.

People with Type 1 diabetes can only control their blood glucose levels through regular monitoring of concentrations and injection of the hormone insulin. Insulin modulates the absorption of glucose from the bloodstream. Conversely, should a person with the condition lapse into a coma because of severe hypoglycemia, they might be revived with an injection of the counterpoint hormone to insulin, which is known as glucagon. The form of glucagon given to patients comes as a powder and has to be dissolved in liquid prior to injection. If it is stored as a solution it forms aggregates called amyloid fibrils, which are of no use to the patient. However, the new study opens up the possibility of make a stable form of the hormone that does not aggregate in this way simply by altering its amino acid sequence slightly.

Putting stable on the table

“Insulin in solution is stable for many weeks, and the goal is to achieve the same solution stability with glucagon,” explains MIT's Mei Hong. He points out that “Peptide fibrillization is a problem that the pharmaceutical industry has been working for many years to solve.”

Hong has previously studied the structures of other amyloid peptides, including one that binds to metals such as zinc. It was already known that glucagon exists in the alpha helical form in the body and that this structure binds tightly to its receptor on liver cells. The binding process triggers a sequence of reactions that ultimately releases glucose back into the bloodstream. Now, in work funded by pharmaceutical company Merck Sharp and Dohme and the National Institutes of Health, the team has shown that glucagon fibrils comprise stacked beta sheets in which the peptides run antiparallel to each other, unlike other fibrils.

New sequence

“All thermodynamically stable amyloid fibrils known so far are parallel packed beta sheets,” Hong explains. “A stable antiparallel beta strand amyloid structure has never been seen before.” One reason that these glucagon fibrils are particularly stable is that neighbouring side chains interact to form so-called "steric zippers". If the amino acid sequence were change to preclude the formation of steric zippers but not interfere with binding to the liver receptors it might be possible to form a solution-stable form of glucagon that could used without worrying about preparing it immediately prior to injection and the additional inconvenience and delay that causes in treating patients with hypoglycaemia.

Related Links

Nature Struct Mol Biol 2019, online: "The peptide hormone glucagon forms amyloid fibrils with two coexisting ß-strand conformations"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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