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• W2883071342 abstract "In this issue of Immunity, Šestan et al., 2018Šestan M. Marinovic S. Kavazovic I. Cekinovic D. Wueest S. Turk Wensveen T. Brizic I. Jonjic S. Konrad D. Wensveen F.M. Polic B. Virus-induced interferon-γ causes insulin resistance in skeletal muscle and derails glycemic control in obesity.Immunity. 2018; 49 (this issue): 164-177Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar show that viral-induced inflammation leads to insulin resistance in skeletal muscle, followed by compensatory hyperinsulinemia, which promotes the anti-viral effector response of CD8+ T cells. Interestingly, this leads to persistent glucose intolerance and the progression of type 2 diabetes in pre-diabetic animals. In this issue of Immunity, Šestan et al., 2018Šestan M. Marinovic S. Kavazovic I. Cekinovic D. Wueest S. Turk Wensveen T. Brizic I. Jonjic S. Konrad D. Wensveen F.M. Polic B. Virus-induced interferon-γ causes insulin resistance in skeletal muscle and derails glycemic control in obesity.Immunity. 2018; 49 (this issue): 164-177Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar show that viral-induced inflammation leads to insulin resistance in skeletal muscle, followed by compensatory hyperinsulinemia, which promotes the anti-viral effector response of CD8+ T cells. Interestingly, this leads to persistent glucose intolerance and the progression of type 2 diabetes in pre-diabetic animals. Studies over the last three decades have established that obesity is associated with persistent low-grade inflammation that promotes the development of systemic insulin resistance (IR). The links between obesity, inflammation, and IR leading to diabetes remain incompletely understood (Kotas and Medzhitov, 2015Kotas M.E. Medzhitov R. Homeostasis, inflammation, and disease susceptibility.Cell. 2015; 160: 816-827Abstract Full Text Full Text PDF PubMed Scopus (642) Google Scholar). In addition, although obesity-associated IR in the context of pre-diabetes can exist for many years with normal glucose tolerance, the transition from pre-diabetes to type 2 diabetes (T2D) with abnormal glucose tolerance is oftentimes abrupt. Acute events such as infection have been postulated to potentially trigger this transition. In this issue of Immunity, Šestan et al. propose a potential mechanistic pathway by which viral inflammation leads to T2D in pre-diabetic individuals. In a mouse model of viral infection, the authors demonstrated that viral-induced interferon-γ (IFN-γ) caused IR in skeletal muscle by downregulating insulin receptor expression, and that hyperinsulinemia, occurring secondary to skeletal muscle IR, enhanced the anti-viral response of CD8+ T cells (Figure 1). In a secondary finding, the authors also reported that when this compensatory hyperinsulinemia occurred in mice with diet-induced IR, this led to development of prolonged impaired glycemic control. Altogether, these findings suggest a mechanism by which the endocrine and immune systems communicate through both hormones and cytokines to promote anti-viral activity and maintain or influence glucose homeostasis. T2D is characterized by a loss of glycemic control often due to IR of metabolic tissues such as adipose and muscle. The onset of this disease is preceded by a condition known as pre-diabetes, in which IR is observed, but glucose intolerance (GI) has not yet developed, and systemic blood glucose levels remain normal. Šestan et al. highlight that the progression from pre-diabetes to T2D is often abrupt and is believed to be driven by some singular event that results in loss of glycemic control (Mason et al., 2007Mason C.C. Hanson R.L. Knowler W.C. Progression to type 2 diabetes characterized by moderate then rapid glucose increases.Diabetes. 2007; 56: 2054-2061Crossref PubMed Scopus (61) Google Scholar, Tabák et al., 2012Tabák A.G. Herder C. Rathmann W. Brunner E.J. Kivimäki M. Prediabetes: A high-risk state for developing diabetes.Lancet. 2012; 379: 2279-2290Abstract Full Text Full Text PDF PubMed Scopus (1499) Google Scholar). However, it is unknown what events might result in progression to T2D. There is limited epidemiological data that supports the authors’ hypothesis that acute viral infection might push pre-diabetics into T2D (Chen et al., 2012Chen S. Jm de Craen A. Raz Y. Derhovanessian E. Vossen Ctm A. Westendorp Gj R. Pawelec G. Maier A.B. Cytomegalovirus seropositivity is associated with glucose regulation in the oldest old. Results from the Leiden 85-plus Study.Immun. Ageing. 2012; 9: 18Crossref PubMed Scopus (45) Google Scholar). Their hypothesis is further supported by the fact that obesity is associated with systemic low-grade inflammation, characterized by increased “type 1” cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor (TNF), which are also typically produced during response to viral infection (Yamaguchi et al., 2015Yamaguchi K. Nishimura T. Ishiba H. Seko Y. Okajima A. Fujii H. Tochiki N. Umemura A. Moriguchi M. Sumida Y. et al.Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high-fat diet fed mice.Liver Int. 2015; 35: 550-561Crossref PubMed Scopus (36) Google Scholar, Uysal et al., 1997Uysal K.T. Wiesbrock S.M. Marino M.W. Hotamisligil G.S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function.Nature. 1997; 389: 610-614Crossref PubMed Scopus (1902) Google Scholar). In Šestan et al., the authors first demonstrate that respiratory infection in humans resulted in elevated circulating insulin but did not affect plasma glucose concentration. HOMA-IR scores (surrogate measure of insulin resistance) demonstrated a decrease in insulin sensitivity in infected individuals, but the lack of corresponding increase in blood glucose led the authors to question the current prevailing view that decreased insulin sensitivity during infection acts to increase glucose availability to the immune system. In order to test these questions in a direct experimental setting, they infected mice with MCMV, a virus known to infect tissues that are involved in glucose homeostasis. In response to acute infection, infected mice developed increased IR relative to non-infected mice. However, there was no change in glucose tolerance during infection. The authors explain this phenotype by showing that infected mice had increased plasma insulin levels. This evidence supports a model in which IR following infection is compensated for by increased insulin production, thus maintaining normoglycemia. Šestan et al. next investigated whether viral infection could be the event that drives T2D in pre-diabetic animals. To address this, the authors used a mouse model of pre-diabetes in which mice were fed high-fat diet for 6 weeks, after which hepatic IR and increased fasting glucose developed. Importantly, there was no observation of GI or systemic IR at 6 weeks on high-fat diet, mimicking pre-diabetes in humans (Mason et al., 2007Mason C.C. Hanson R.L. Knowler W.C. Progression to type 2 diabetes characterized by moderate then rapid glucose increases.Diabetes. 2007; 56: 2054-2061Crossref PubMed Scopus (61) Google Scholar). Pre-diabetic mice infected with MCMV developed IR and GI. Additionally, the GI was maintained even 3 weeks after infection. However, when different viral infections were used in this model, the prolonged effect on glucose homeostasis was not observed, though the initial loss of glucose control was seen, which leads the reader to question whether this phenomenon is specific to select viruses and not necessarily generalizable. In an attempt to determine whether GI caused by viral infection was preventable, the authors treated mice with the antiviral drug ganciclovir and found that treatment with ganciclovir 1 day after infection inhibited the development of GI in pre-diabetic mice. These data indicate that select viral infections might indeed contribute to the progression of pre-diabetes to T2D. The authors next investigated potential mechanisms by which viral infection might promote a state of IR and GI in pre-diabetic mice. Neutralization of IFN-γ was found to not only increase viral titers in tissues important for glucose homeostasis, but also prevented GI and IR in infected pre-diabetic mice. In order to determine which immune cells were producing IFN-γ in this model, the authors depleted IFN-γ producing immune cell populations by using anti-CD8, anti-CD4, or anti-NK1.1 antibodies with the goal of depleting CD4+ T cells, CD8+ T cells, and NK cells, respectively. It should be noted, however, that in more recent light of immune cell populations, NK1.1 depletion also depletes helper ILC1 cells, which are also potent IFN-γ producers. While the authors attribute this phenotype specifically to NK cells, the contribution of this small subset of cells cannot be ignored, because innate lymphoid cells have been shown to have an important role in the early response to viral infection (Weizman et al., 2017Weizman O.-E. Adams N.M. Schuster I.S. Krishna C. Pritykin Y. Lau C. Degli-Esposti M.A. Leslie C.S. Sun J.C. O’Sullivan T.E. ILC1 Confer Early Host Protection at Initial Sites of Viral Infection.Cell. 2017; 171: 795-808.e12Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). Nonetheless, when NK cell-deficient animals were infected with MCMV, GI and IR were not observed. Furthermore, providing IFN-γ-deficient mice with wild-type NK cells prior to infection led to the development of IR. The authors also used a variant of MCMV that does not activate NK cells, and GI was not observed. Thus, activation of NK cells by MCMV and production of IFN-γ promotes IR and GI and drives the progression of pre-diabetes to T2D. Next, the authors aimed to determine how IFN-γ was inducing IR. Their results demonstrated that IFN-γ mediated its effects on IR independent of macrophages, adipocytes, and hepatocytes. However, IFN-γ specifically induced IR in skeletal muscle. Infection resulted in decreased phosphorylation of AKT (pAKT) kinase in myocytes, indicating decreased insulin signaling, and was found to be an IFN-γ-dependent effect. Furthermore, glucose uptake in muscle was decreased after infection, while visceral adipose tissue (VAT) glucose uptake was not affected. The mechanism of IFN-γ driving IR in skeletal muscle cells hinted at a decrease in insulin signaling upstream of AKT, because decreased pAKT was accompanied by unchanged total AKT. The authors saw a decrease in insulin receptor transcription in muscle following LCMV or MCMV infection, and this effect was lost in IFN-γ-deficient mice. Interestingly, decreased insulin receptor transcription was still observed 3 weeks following infection. This observation led the authors to conclude that decreased insulin receptor transcription in myocytes could be the cause of long-term IR and subsequent GI observed in infected pre-diabetic mice. To determine the physiological relevance of IFN-γ induced IR, the authors hypothesized that insulin might act as a costimulatory signal to CD8+ T cells, because CD8+ T cells are highly dependent on CD28 co-stimulation, and both insulin and CD28 signal through the AKT pathway. They found that treatment of CD8+ T cells with insulin induced downstream signaling detectable by immunoblot and promoted cytokine and granzyme B production, especially when the insulin stimulation was combined with anti-CD28 treatment. To investigate this phenomenon outside the complex environment of obesity, the authors injected long-acting basal insulin daily to induce constant hyperinsulinemia and infected mice with MCMV. One week following infection, they observed increased CD8+ effector cell function and cytokine production in mice receiving daily insulin injections, indicating that insulin promotes anti-viral CD8+ T cell response. When insulin signaling was removed from the mouse by ablation of pancreatic beta cells, CD8+ T cell response against MCMV was reduced. Finally, the authors deleted IFN-γ receptor specifically on myocytes, infected the mice with MCMV, and observed a reduction in viral-specific CD8+ T cells and cytokine production. Together, these data combine to propose a mechanism by which viral infection increases local IFN-γ concentrations at sites of viral replication, inducing downregulation of the insulin receptor, resulting in hyperinsulinemia locally, resulting in stimulation of a CD8+ T cell anti-viral responses. These findings are presented in the context of viral-infection induced inflammation; however, these findings may also be applicable to other settings of inflammation, particularly obesity-associated inflammation. One question is whether these findings negate the possibility that systemic IR in response to infection-induced inflammation might improve immunity by enhancing nutrient availability to fuel activated immune cells. Indeed, both mechanisms might occur, as T cells activated in limited glucose conditions have decreased ability to produce pro-inflammatory cytokines at glucose concentrations in which problems with cell viability and proliferation are not apparent (Jacobs et al., 2008Jacobs S.R. Herman C.E. Maciver N.J. Wofford J.A. Wieman H.L. Hammen J.J. Rathmell J.C. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways.J. Immunol. 2008; 180: 4476-4486Crossref PubMed Scopus (553) Google Scholar). This mechanism presented by Šestan et al. illustrates an important communication between the endocrine system and the immune system to promote immunity without compromising glucose homeostasis, and demonstrates that viral infection in pre-diabetic individuals might be the insult that results in progression to T2D. These findings are presented in a mouse model. If replicable in human studies, this observation could influence how we provide care to pre-diabetic patients with common viral infections that do not usually warrant treatment, but might “interfere” with glucose tolerance. Virus-Induced Interferon-γ Causes Insulin Resistance in Skeletal Muscle and Derails Glycemic Control in ObesityŠestan et al.ImmunityJune 26, 2018In BriefIt is unknown how viral infections contribute to the progression of type 2 diabetes. Šestan and colleagues demonstrate that virus-induced interferon-γ increases muscle insulin resistance, which drives hyperinsulinemia to keep euglycemia and to boost anti-viral CD8+ T cell responses. This mechanism in obese subjects with hepatic IR derails glycemic control. Full-Text PDF Open Archive" @default.
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• W2883071342 title "Viral Infection “Interferes” with Glucose Tolerance" @default.
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