Insulin boost: Definitive speculation

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  • Published: Jan 15, 2013
  • Author: David Bradley
  • Channels: NMR Knowledge Base
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Insulin speculation

How insulin engages its primary binding site on the insulin receptor (Credit: Weiss et al/Nature)

After decades of speculation about exactly how insulin interacts with cells, an international group of scientists (led by NMR pioneer Michael Weiss) has at last demonstrated a mode of action that shows how insulin binds to the cell to allow the cell to transform sugar into energy - and how the insulin molecule then changes shape as a result of this connection.

Insulin, the peptidic hormone made by the pancreas to control blood glucose concentrations, was first identified more than a century ago. Its discovery meant that doctors could understand more clearly diabetes mellitus and so change a once inevitably fatal disease into a manageable, but chronic, condition. Unfortunately, it seems that as consumption of high-calorie, sweetened and fatty foods rises and obesity levels go up, more and more people are likely to develop type 2 diabetes.

International drama

Weiss of Case Western Reserve University School of Medicine in Cleveland, Ohio, and colleagues there and at the University of Chicago and the University of York, UK, suggested that their findings could lead to yet another dramatic improvement for people with the condition.

Until now, scientists have only speculated about exactly how insulin interacts with cells, the international group report their findings in Nature. Insulin is known to be produced by beta cells in the pancreas and as being essential to the regulation of carbohydrate and fat metabolism in the body. The hormone modulates the uptake of glucose from the blood by cells in the liver, skeletal muscles, and fat tissue.

In 1991 the Weiss research group used nuclear magnetic resonance spectroscopy to determine a non-crystallographic structure of insulin and more recently the team has developed a prototype of a form of the hormone that need not be stored in a refrigerator to keep it fresh. The latter development in itself could be a critical breakthrough for those with diabetes in the developing world. The new work builds on the pioneering university of crystallographer Dorothy Hodgkin of the University of Oxford who was the first to successfully solve the hormone' structure in 1969 after decades of work.

"There's been a logjam in our understanding since then," Weiss said. "We hope that we've broken the logjam." He worked with a diverse group of researchers to take on the challenge, among them Mike Lawrence, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, the Chicago and York teams and colleagues at the Institute of Organic Chemistry and Biochemistry in Prague in the Czech Republic.

They knew that cells absorb sugar from food as energy for the body, yet glucose cannot itself penetrate the cell membrane without assistance from insulin. The presence of insulin receptors on the cell surface allows them to bind to the hormone and this provides the mechanism by which glucose can be absorbed. The team used molecular genetics to create structural models of this system - truncated insulin receptor constructs - for testing and structure determination.

"Both insulin and its receptor undergo rearrangement as they interact," Lawrence explains. "A piece of insulin folds out and key pieces within the receptor move to engage the insulin hormone. You might call it a 'molecular handshake.'" The structural study thus confirms the hypothesis of a conformational switch in insulin that is activated upon engagement with the receptor.

Avoiding the needle

Diabetes is commonly treated with multiple daily injections of insulin to help the patient's body control blood glucose levels. Understanding the mechanism of insulin bonding to its receptor and the ensuing conformational mechanics might allow researchers to develop novel analogues of insulin that could replace the injections perhaps with a longer-acting synthetic hormone that might even have oral availability. Weiss explains that it might be possible to target small molecules to the signalling clefts in the receptor rather than requiring the enormous peptide structures of natural or even engineered insulin.

"These findings carry profound implications for diabetes patients," explains Weiss. "This new information increases exponentially the chances that we can develop better treatments - in particular, oral medications instead of syringes, pens or pumps."

"In the next few years, we hope to develop of suite of ultra-stable insulin analogues stable at high temperatures for use by underprivileged patients in the developing world (such as in Bangladesh or Ethiopia) who lack access to refrigeration," Weiss told SpectroscopyNOW. "In the West, such analogue formulations may make possible the safe and convenient use of implanted pumps requiring refill only three times per year. Scientifically, we hope in the coming decade to solve the structure of the intact receptor with and without bound insulin so as to decipher the structural mechanisms of signal propagation. This may in turn make possible small molecule drugs for oral therapy, dispensing with the need for needles or pumps."

Related Links

Nature, 2013, 493, 241–245: "How insulin engages its primary binding site on the insulin receptor"

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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