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Studies carried out by scientists at Helmholtz Zentrum München and the German Center for Diabetes Research (DZD), have found that a genetic variant of the gene DUSP8 can increase the risk for type 2 diabetes (T2D) in men, by impairing how the brain responds to the hormone insulin. “Carriers of a genetic variant of the gene DUSP8 were shown to have a moderately increased risk for type 2 diabetes …” said Sonja C. Schriever, PhD, lead author of the study, which is published in The Journal of Clinical Investigation, “… but the functional importance of Dusp8 for the etiology of the disease remained unknown.” The team’s studies in mice and in humans are reported in a paper titled, “Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity.”

Insulin is a pancreatic hormone that controls 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 subsequent impairment of the cellular response downstream to the insulin receptor. This phenomenon, termed insulin resistance, is a major hallmark of type 2 diabetes, but to date hasn’t yet been fully understood.

The brain thus plays a major role in controlling our blood glucose levels, and in type 2 diabetics this brain control of glucose metabolism is often dysfunctional. However, the genetic basis for this phenomenon has so far remained elusive, the authors wrote. Recent genome-wide association studies (GWAS) have identified a dual-specificity phosphatase (DUSP) gene known as DUSP8, as a risk gene for T2D. And work using genetic models has also revealed “ … potentially important roles of DUSPs in the regulation of pathophysiological signaling with relevance to human diseases including cancer, diabetes, inflammatory, and neurodegenerative disorders.”

The team’s newly reported studies have helped to unravel how the protein Dusp8 regulates glucose tolerance and insulin sensitivity. Initial mouse studies showed that knocking out Dusp8 exacerbated high-fat diet (HFD)-induced glucose intolerance, but specifically in male animals, not in females. “ .. male Dusp8 KO [knockout] mice exposed to HFD showed an impairment of glucose homeostasis in a glucose tolerance test,” the team wrote. “In a pyruvate tolerance test (PTT), we found increased baseline glucose levels after overnight fasting and impaired glucose clearance in HFD-fed Dusp8 KO males. An insulin tolerance test (ITT) revealed a decrease in insulin sensitivity in obese Dusp8 KO males.” Further studies demonstrated that Dusp8 has a regulatory effect on inflammatory processes in the hypothalamus and on the hypothalamic-pituitary-adrenal (HPA) axis.

The research results indicated that the protein appears to protect against hyperactivation of inflammatory signaling and impaired insulin sensitivity in the hypothalamus. 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 together aggravated insulin sensitivity. “ … these data suggest impaired insulin sensitivity instead of insulin secretory problems in HFD-fed Dusp8 KO males,” they wrote. “Mechanistically, we found impaired hypothalamic–pituitary–adrenal (HPA) axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling.” And while female mice that lacked Dusp8 put on weight and body fat when fed a HFD, neither glucose tolerance nor insulin sensitivity were affected by Dusp8 knockout in HFD-fed female mice.

The sex-specific role of murine Dusp8 was consistent with data from functional magnetic resonance imaging (fMRI) in human volunteers, which revealed reduced hypothalamic insulin sensitivity in male but not female carriers of the DUSP8 type 2 diabetes risk variant. “In a small but well-characterized cohort, we were able to show that homozygous male carriers of the minor frequency risk allele for DUSP8 have impaired hypothalamic insulin sensitivity,” the scientists stated. “The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with fMRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men.” The team acknowledged that the reasons for the sex-specificity remain elusive. However, they suggested, “ … the absence of effects on glucocorticoid action or hypothalamic inflammation in female Dusp8 KO mice may entail direct effects of sex hormones such as estradiol on HPA axis circuitry or peripheral glucoregulatory organs.”

“By combining cellular models, Dusp8 loss- and gain-of-function mice and 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,” commented co-senior author Paul Pfluger, PhD.

“Overall, our findings resonate with the emerging consensus that sex as a biological variable has to be a special focus in murine models and human studies,” the authors concluded. Schriever further stated, “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.”

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.

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