Discovery could lead to fewer side effects from a diabetes treatment


Date:
March 11, 2022
Source:
University of Pennsylvania School of Medicine
Summary:
A mouse study detailed the differences between the two forms of
the protein PPARgamma, a target of 'glitazone' diabetes drugs,
could cut out weight gain side effects.



FULL STORY ==========================================================================
By uncovering the subtle difference between two varieties of a protein, researchers from the Perelman School of Medicine at the University of Pennsylvania may have discovered how to eliminate the risk of weight gain
from a certain type of diabetes medication. Through this, it's possible
that more patients with diabetes could get more effective treatment from modified thiazolidinediones, which many likely avoid in their current form
due to side effects. These findings were published in Genes & Development.


==========================================================================
"One small, undiscovered difference between the two forms of a
single protein proved to be extremely significant," said study senior
author Mitchell Lazar, MD, PhD,the Willard and Rhoda Ware Professor
in Diabetes and Metabolic Diseases at Penn. "Our findings suggest a
way to improve on the mechanism of action of thiazolidinedione drugs,
which holds promise for eliminating the side effect of weight gain."
The popularity of diabetes drugs called thiazolidinediones, which are
also known as glitazones, has been reduced because of side effects
such as weight gain. They work by activating a fat cell protein called PPARgamma (PPARg). The protein occurs in two forms, PPARg1 and PPARg2,
whose functional differences have been unclear. But when the Penn
researchers examined each form of the protein on its own, they found
that activating just PPARg2 with a thiazolidinedione drug protects mice
from diabetes-like metabolic changes - - without causing weight gain.

Type 2 diabetes is characterized by the progressive dysfunction of the
insulin hormone signaling system in the body, resulting in chronic, high
levels of glucose (sugar) in the blood. This, in turn, contributes to
the hardening of arteries, high blood pressure, heart attacks, strokes,
and other serious diseases. Thought to arise largely due to obesity,
poor diets, and modern sedentary lifestyles, type 2 diabetes has become epidemic in many countries.

The U.S. Centers for Disease Control and Prevention has estimated that,
in the United States alone, about 35 million people, roughly 10 percent
of the population, are living with the disorder.

Thiazolidinediones, which include rosiglitazone (under the brand
name Avandia), were introduced in the 1990s and, for many years, were
widely used as diabetes drugs. They have since become less popular due
to side effects. This has led some researchers to investigate whether
new compounds could be developed that retain these drugs' therapeutic
effects while having fewer side effects.

In their study, Lazar and his team approached this problem by taking a
closer look at thiazolidinediones' target, PPARg, which helps control fat
cell production. The scientists studied two lines of mice: One greatly deficient in one form of the protein, PPARg1, the other greatly deficient
in PPARg2. In the mice, the scientists showed that activating PPARg1 or
PPARg2 with a thiazolidinedione had an anti-diabetic effect in each case, protecting mice from the metabolic harm of a high-fat diet.

However, the researchers discovered that activation of these two forms
has subtly different downstream effects on gene activity. Specifically,
in the PPARg1-deficient mice (in which most of the present PPARg takes the
form of PPARg2), the thiazolidinedione treatment caused no weight gain.

The finding therefore suggests that it may be possible to realize the
benefits of thiazolidinediones without the weight gain side effect,
by activating only PPARg2 and not PPARg1.

"We're now studying in more detail how PPARg1 and PPARg2 work and how
they differ, in the hope of finding ways to selectively activate PPARg2,"
Lazar said.

The research was supported by the American Diabetes Association, the
American Heart Association, Cox Medical Institute, the JPB Foundation,
and the National Institutes of Health.


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


========================================================================== Journal Reference:
1. Wenxiang Hu, Chunjie Jiang, Mindy Kim, Yang Xiao, Hannah J. Richter,
Dongyin Guan, Kun Zhu, Brianna M. Krusen, Arielle N. Roberts,
Jessica Miller, David J. Steger, Mitchell A. Lazar. Isoform-specific
functions of PPARg in gene regulation and metabolism. Genes &
Development, 2022; DOI: 10.1101/gad.349232.121 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220311115313.htm

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