Onset of insulin-dependent diabetes mellitus after interferon-alfa therapy for hairy cell leukaemia

Guerci, A.; Guerci, Bruno; Lévy-Marchal, Claire; Ongagna, Jean-Claude; Ziegler, O.; Candiloros, H.; Guerci, O; Drouin, P

doi:10.1016/s0140-6736(94)90276-3

Cited by 64 publications

(27 citation statements)

References 5 publications

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“…Thus, undesirable effects of long term treatment with IFN-␤ to counteract other diseases (like chronic hepatitis or multiple sclerosis) cannot be ruled out. In this regard, it has been reported that long term therapeutic use of type I IFNs induces autoimmunity (50 -52) as well as the appearance of type 1 diabetes after treatment with type I IFNs (53)(54)(55), supporting the hypothesis that both IFN-␣ and IFN-␤ might lead to diabetes mellitus.…”

Section: Discussionmentioning

confidence: 89%

Evidence from Transgenic Mice That Interferon-β May Be Involved in the Onset of Diabetes Mellitus

Pelegrin¹,

Devedjian²,

Costa

et al. 1998

Journal of Biological Chemistry

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A number of cytokines have been shown to alter the function of pancreatic ␤-cells and thus might be involved in the development of type 1 diabetes. Interferon-␤ (IFN-␤) expression is induced in epithelial cells by several viruses, and it has been detected in islets of type 1 diabetic patients. Here we show that treatment of isolated mouse islets with this cytokine was able to alter insulin secretion in vitro. To study whether IFN-␤ alters ␤-cell function in vivo and leads to diabetes, we have developed transgenic mice (C57BL6/SJL) expressing IFN-␤ in ␤-cells. These mice showed functional alterations in islets and impaired glucose-stimulated insulin secretion. Transgenic animals presented mild hyperglycemia, hypoinsulinemia, hypertriglyceridemia, and altered glucose tolerance test, all features of a prediabetic state. However, they developed overt diabetes, with lymphocytic infiltration of the islets, when treated with low doses of streptozotocin, which did not induce diabetes in control mice. In addition, about 9% of the transgenic mice obtained from the N3 back-cross to outbred albino CD-1 mice spontaneously developed severe hyperglycemia and hypoinsulinemia and showed mononuclear infiltration of the islets. These results suggest that IFN-␤ may be involved in the onset of type 1 diabetes when combined with either an additional factor or a susceptible genetic background.

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Section: Discussionmentioning

confidence: 89%

Evidence from Transgenic Mice That Interferon-β May Be Involved in the Onset of Diabetes Mellitus

Pelegrin¹,

Devedjian²,

Costa

et al. 1998

Journal of Biological Chemistry

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“…IFNs play important antiviral, antitumor, and immunomodulatory functions (43), yet can elicit and mediate pathologic scenarios (44). IFN has long been linked to pancreatic dysfunction in humans via elevated IFN expression in pancreatic tissues of patients with type 1 diabetes mellitus (45,46) and induction of pancreatitis (47)(48)(49) and diabetogenic effects (50,51) by pharmaceutical IFN used for treatment of tumors or viral infections. In addition, experiments in mouse models demonstrated that transgenic expression of IFN in β cells leads to…”

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confidence: 99%

Type I interferons mediate pancreatic toxicities of PERK inhibition

Yu¹,

Zhao²,

Gui³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERKdeficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas-specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors.T umor microenvironment-associated deficit in oxygen and nutrients activate numerous pathways that aid cancer and tumor stroma cells by increasing their ability to survive, withstand anticancer therapies, and ultimately select for more aggressive and viable clones capable of metastasizing (1). Activation of the unfolded protein response (UPR) plays a central role in these processes (2). Three branches of this response include stimulation of activating transcription factor-6 and activation of two kinases, inositol requiring enzyme 1α/β and the eukaryotic translation initiation factor 2-alpha kinase 3 [also termed double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase, or pancreatic endoplasmic reticulum kinase (PERK)]. The latter kinase contributes to phosphorylation of the eukaryotic translation initiation factor 2-alpha and controls the rate of global translation and noncanonical induction of specific proteins that help cope with stress (reviewed in ref. 2).Among three main UPR pathways, signaling through PERK has received the most attention for its central role in cancer (3-6). Genetic studies have demonstrated that PERK is essential in supporting tumor growth and progression via diverse mechanisms, including stimulation of angiogenesis (7-12), potential effects on antitumor immunity (13,14), and direct increase in cancer cell viability by altering its metabolic status (15), promoting survival autophagy (16-18), and induction of prosurvival microRNAs (19). Accordingly, development of novel, potent, and selective PERK inhibitors as a means to treat cancers has been proposed (20, 21). Several PERK inhibitors have shown promising results in various preclinical tumor models (22-24). Furthermore, some of these inhibitors can protect against the prion-...

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“…For example, higher levels of IFN-␣ mRNA and protein were detected in the pancreata of T1D patients than in pancreata of nondiabetic patients (9,10). IFN-␣ treatment of patients with tumors or viral hepatitis is associated with an increased incidence of T1D (11,12). Over-expression of IFN-␣ on ␤ cells induced T1D in non-autoimmune-prone C57BL/6 mice (13).…”

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confidence: 99%