Synthetic hinge could hold key to revolutionary 'smart' insulin therapy


Date:
August 2, 2021
Source:
Indiana University School of Medicine
Summary:
For people with diabetes who are insulin dependent, glycemic
control is a full-time job. But what if their medication could do
the work for them - - an insulin whose activity in the bloodstream
responds to the blood glucose levels and adjusts accordingly? A
new invention could lead to just that.



FULL STORY ==========================================================================
For people with diabetes who are insulin dependent, glycemic control is
a full- time job. But what if their medication could do the work for
them -- an insulin whose activity in the bloodstream responds to the
blood glucose levels and adjusts accordingly? An invention from Indiana University School of Medicine Distinguished Professor Michael A. Weiss,
MD, PhD, could lead to just that.


==========================================================================
In a breakthrough study published in the peer-reviewed journal PNAS, Weiss
and his team describe the use of a synthetic "switch" that can be opened
or closed using a simple sugar sensor. The study was in part collaborative
with Thermalin, Inc., a small biotech company that Weiss began in 2008.

Their concept exploits a natural mechanism, designated the "protective
hinge," that is built into vertebrate insulins. The protective hinge
is a natural structural feature that evolved more than half a billion
years ago to keep the hormone stable in its closed state but foldable
and functional in its open state.

"The reason a glucose-responsive insulin is important is that the
biggest barrier to the effective use of insulin, especially in Type 1
diabetes, is the fear of the consequences of blood sugar going too low,"
said Weiss, who is also the Chair of the Department of Biochemistry and Molecular Biology.

Immediate consequences of severely low blood sugar (hypoglycemia) can
include delirium, convulsions or loss of consciousness, and repeated
episodes of severe hypoglycemia can cause cognitive decline. On the other
hand, chronic high blood sugar (hyperglycemia) can lead to blindness,
stroke or amputation. Staying in the desired blood glucose range is a
delicate balance that insulin-dependent diabetics face every day.

But Weiss said that he envisions a future when people do not have to
choose to risk their long-term health to protect themselves from the
immediate dangers of severe hypoglycemia.



==========================================================================
"The promise of this kind of 'smart' insulin is that it would
transform diabetes care, so people wouldn't have to worry anymore,"
said Weiss. "With our invention, we envision that when the blood sugar
goes low, the hinge would close. But there will be much work to do to
translate our proof of principle to an FDA-approved product." In the
100 years since the discovery of insulin, its use as a treatment for
diabetes has gone through many significant changes. C. Ronald Kahn, MD,
chief academic officer at the Joslin Diabetes Center at Harvard Medical
School, said that glucose-responsive insulin could be the next.

"In the recent study from the Weiss laboratory appearing in PNAS,
we see an example of the next exciting phase of insulin development,
namely development of an insulin analogue which through chemical
modification can sense the level of sugar present in the blood," said
Kahn. "While the current analogue has been designed to sense fructose,
it seems likely that this same approach can be used to develop analogues
to sense glucose. Whether these can be sensitive enough to be modulated
by changes within the physiological range remains to be determined,
but if so, this would be an important new tool in the management of
diabetes." Other types of glucose-responsive insulins are being developed elsewhere. What makes Weiss' invention unique is its simplicity. The
synthetic hinge exploits naturally occurring processes and introduces
fewer external or artificial elements compared to other approaches.

While their study uses fructose as model (representative of a
monosaccharide like glucose), it proves that Weiss' synthetic hinge
concept works. His team is already working on glucose-responsive
insulin candidates that open and close at the desired high and low
glucose thresholds, which are respectively 70 to 180 milligrams per
deciliter. By replacing the fructose sensor with glucose sensors,
a revolutionary insulin therapy may be closer than we think.

The above referenced study is titled "Insertion of a synthetic switch
into insulin provides metabolite-dependent regulation of hormone-receptor activation." Contributing authors include Yen-Shan Chen, PhD, Yanwu Yang,
PhD, Balamurugan Dhayalan, PhD, Mark A. Jarosinski, PhD, and Deepak
Chatterjee, PhD, from Indiana University; Nelson B. Phillips, PhD, from
Case Western Reserve University; Yule Liu, PhD, Laurie Broadwater, PhD,
Thomas Hattier, PhD, and M.

Dodson Michael, PhD, from Thermalin, Inc; and Michael C. Lawrence from
the University of Melbourne.

This work is supported in part by grants from the JDRF, the Leona M. and
Harry B. Helmsley Charitable Trust, and the National Institutes of Health
(R01 DK040949 and R01 DK127761).

========================================================================== Story Source: Materials provided by
Indiana_University_School_of_Medicine. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Yen-Shan Chen, Jeremy Gleaton, Yanwu Yang, Balamurugan Dhayalan,
Nelson
B. Phillips, Yule Liu, Laurie Broadwater, Mark A. Jarosinski,
Deepak Chatterjee, Michael C. Lawrence, Thomas Hattier, M. Dodson
Michael, Michael A. Weiss. Insertion of a synthetic switch into
insulin provides metabolite-dependent regulation of hormone-receptor
activation.

Proceedings of the National Academy of Sciences, 2021; 118 (30):
e2103518118 DOI: 10.1073/pnas.2103518118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210802160640.htm

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