A gatekeeper against insulin resistance in the brain

Date:
August 21, 2020
Source:
Deutsches Zentrum fuer Diabetesforschung DZD
Summary:
The brain plays a major role in controlling our blood glucose
levels. In type 2 diabetes this glucose metabolism brain control
is often dysfunctional. A group of scientists has now shown that
in men a genetic variant of the gene DUSP8 can increase the risk
for T2D by impairing our brain response to the hormone insulin.



FULL STORY ==========================================================================
The brain plays a major role in controlling our blood glucose
levels. In type 2 diabetics this glucose metabolism brain control is
often dysfunctional. Genetic components for this phenomenon have so far remained elusive. A group of scientists at Helmholtz Zentrum Mu"nchen
and the German Center for Diabetes Research (DZD) have now shown in the
Journal of Clinical Investigations that in men a genetic variant of the
gene DUSP8 can increase the risk for type 2 diabetes by impairing our
brain response to the hormone insulin.


========================================================================== Insulin is a pancreatic hormone that controls our blood sugar
levels. Insulin not only stimulates the uptake of glucose from blood
into peripheral tissues, it also acts on the brain, specifically the hypothalamus, to control glucose and energy metabolism. In obese subjects, insulin loses some of its activity due to the activation of inflammatory signaling and a subsequent impairment of the cellular response downstream
to the insulin receptor. This phenomenon, termed insulin resistance,
is a major hallmark in the development of type 2 diabetes, but to date
not yet fully understood. Recent genome-wide association studies (GWAS) identified DUSP8 as type 2 diabetes risk gene. Now, scientists have investigated how the protein Dusp8 (dual-specificity phosphatase 8),
which is encoded by the DUSP8 gene, regulates glucose tolerance and
insulin sensitivity.

Genetic variant of the DUSP8 gene increases risk of type 2 diabetes
"Carriers of a genetic variant of the gene DUSP8 were shown to have
a moderately increased risk for type 2 diabetes, but the functional
importance of Dusp8 for the etiology of the disease remained unknown,"
explains Dr. Sonja C.

Schriever, lead author of the study. "By combining cellular models,
Dusp8 loss- and gain-of-function mice and functional magnetic resonance
imaging (fMRI) of humans with genetic variants in the gene DUSP8,
we now exposed a specific role of the protein Dusp8 as a gatekeeper
for systemic glucose tolerance and hypothalamic insulin sensitivity,"
adds colleague and senior author Prof. Dr.

Paul Pfluger. Within the framework of the German Center for
Diabetes Research (DZD), both scientists formed a team of biologists, epidemiologists and clinicians that was able to unravel the molecular mechanisms that link Dusp8 with the development of type 2 diabetes.

Protein Dusp8 has regulatory effects on hypothalamic insulin sensitivity
The protein Dusp8 has a regulatory effect on inflammatory processes in
the hypothalamus and on the hypothalamic-pituitary-adrenal (HPA) axis. It
seems to protect the organism against hyper-activation of inflammatory signaling and impaired insulin sensitivity in the hypothalamus. The
scientists could show that the deletion of the Dusp8 gene in male but not
in female mice increased hypothalamic inflammation, impaired HPA axis
feedback and increased basal stress hormone levels, which all together aggravated the insulin sensitivity.

The sex-specific role of murine Dusp8 was consistent with fMRI data in
human volunteers that revealed reduced hypothalamic insulin sensitivity
in male but not female carriers of the DUSP8 type 2 diabetes risk variant.

"Unraveling the multi-systemic processes that drive the impaired
hypothalamic insulin sensitivity in the mouse models was an important
step to understand the mechanistic underpinnings of the type 2 diabetes
risk gene DUSP8," concludes Schriever. In future studies, the researchers
want to investigate the effect of central insulin action and the DUSP8
type 2 diabetes risk variant on the hypothalamic-pituitary-adrenal axis
in human subjects with or without T2D.


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


========================================================================== Journal Reference:
1. Sonja C. Schriever, Dhiraj G. Kabra, Katrin Pfuhlmann, Peter
Baumann,
Emily V. Baumgart, Joachim Nagler, Fabian Seebacher, Luke Harrison,
Martin Irmler, Stephanie Kullmann, Felipe Corre^a-da-Silva, Florian
Giesert, Ruchi Jain, Hannah Schug, Julien Castel, Sarah Martinez,
Moya Wu, Hans-Ulrich Ha"ring, Martin Hrabe de Angelis, Johannes
Beckers, Timo D. Mu"ller, Kerstin Stemmer, Wolfgang Wurst, Jan
Rozman, Rube'n Nogueiras, Meri De Angelis, Jeffery D. Molkentin,
Natalie Krahmer, Chun- Xia Yi, Mathias V. Schmidt, Serge Luquet,
Martin Heni, Matthias H.

Tschoep, Paul T. Pfluger. Type 2 diabetes risk gene Dusp8 regulates
hypothalamic Jnk signaling and insulin sensitivity. Journal of
Clinical Investigation, 2020; DOI: 10.1172/JCI136363 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200821094817.htm

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