Tyrosine Kinase Inhibitors and Diabetes: A Novel Treatment Paradigm?

Fountas, Athanasios; Diamantopoulos, Leonidas-Nikolaos; Tsatsoulis, Agathocles

doi:10.1016/j.tem.2015.09.003

Cited by 84 publications

(58 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…And despite the essential function of ABL kinases in development, human patients with CML treated with imatinib (or nilotinib) can tolerate chronic ABL inhibition. Indeed, a multitude of mounting reports document paradoxical cell-sparing effects of tyrosine kinase inhibitory drugs originally developed against cancers (Fountas et al, 2015; Hagerkvist et al, 2007; Han et al, 2009b; Paniagua et al, 2006). Clinical studies and case reports show improved glycemic control and reversal of diabetes in humans treated with imatinib, sunitinib, or dasatanib (Fountas et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, a multitude of mounting reports document paradoxical cell-sparing effects of tyrosine kinase inhibitory drugs originally developed against cancers (Fountas et al, 2015; Hagerkvist et al, 2007; Han et al, 2009b; Paniagua et al, 2006). Clinical studies and case reports show improved glycemic control and reversal of diabetes in humans treated with imatinib, sunitinib, or dasatanib (Fountas et al, 2015). While the cell-sparing mechanism of action of these drugs and their relevant kinase targets is not generally understood, here the cytoprotective basis of one member, imatinib, is clarified.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes

et al. 2017

View full text Add to dashboard Cite

SUMMARY In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)—IRE1α—endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1α’s enzymatic activities, thereby potentiating ER stress-induced apoptosis. During ER stress, cytosolic ABL kinases localize to the ER membrane, where they bind, scaffold, and hyperactivate IRE1α’s RNase. Imatinib—an anti-cancer tyrosine kinase inhibitor—antagonizes the ABL-IRE1α interaction, blunts IRE1α RNase hyperactivity, reduces pancreatic β-cell apoptosis, and reverses type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. A mono-selective kinase inhibitor that allosterically attenuates IRE1α’s RNase—KIRA8—also efficaciously reverses established diabetes in NOD mice by sparing β-cells and preserving their physiological function. Our data support a model wherein ER-stressed β-cells contribute to their own demise during T1D pathogenesis and implicate the ABL-IRE1α axis as a drug target for the treatment of an autoimmune disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Clinical observations of diabetic cancer patients have revealed that TKIs can lower blood glucose despite various growth factor and oncogenic-related targets 2, 3, 5, 29–32 . Understanding off-target effects of existing therapies can mitigate deleterious drug consequences, but it also provides the opportunity to re-task approved drugs 33, 34 .…”

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia

Duggan

Foley

Henriksbo

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Inflammation underpins aspects of insulin resistance and dysglycemia. Microbiota-derived cell wall components such as muropeptides or endotoxin can trigger changes in host immunity and metabolism. Specific peptidoglycan motifs promote metabolic tissue inflammation, lipolysis and insulin resistance via Nucleotide-binding oligomerization domain-containing protein 1 (Nod1). Receptor-interacting serine/threonine-protein kinase 2 (Ripk2) mediates Nod1-induced immunity, but the role of Ripk2 in metabolism is ill-defined. We hypothesized that Ripk2 was required for Nod1-mediated inflammation, lipolysis and dysglycemia. This is relevant because certain tyrosine kinase inhibitors (TKIs) inhibit Ripk2 and there is clinical evidence of TKIs lowering inflammation and blood glucose. Here, we showed that only a subset of TKIs known to inhibit Ripk2 attenuated Nod1 ligand-mediated adipocyte lipolysis. TKIs that inhibit Ripk2 decreased cytokine responses induced by Nod1-activating peptidoglycan, but not endotoxin in both metabolic and immune cells. Pre-treatment of adipocytes or macrophages with the TKI gefitinib inhibited Nod1-induced Cxcl1 and Il-6 secretion. Furthermore, treatment of mice with gefitinib prevented Nod1-induced glucose intolerance in vivo. Ripk2 was required for these effects on inflammation and metabolism, since Nod1-mediated cytokine and blood glucose changes were absent in Ripk2−/− mice. Our data show that specific TKIs used in cancer also inhibit Nod1-Ripk2 immunometabolism responses indicative of metabolic disease.

show abstract

“…Inhibitors of protein tyrosine kinase have been shown to be associated with remission of type 1 and type 2 diabetes (Fountas A et al, 2015). Taken together, these elements point out that TYK2 is a target for study on its association with diabetes.…”

Section: Introductionmentioning

confidence: 93%

Brief Note Polymorphism V362F (rs2304256) of tyrosine kinase 2 is not associated with childhood- or adulthood-onset type 1 diabetes in southern Brazil

Graciolo¹,

Welter²,

Campos³

et al. 2019

Genet. Mol. Res.

View full text Add to dashboard Cite

Type 1 diabetes mellitus (T1D) is considered a polygenic disease that is influenced by environmental factors and autoimmune responses to autoantibodies, resulting in metabolic abnormalities. Tyrosine kinase 2 (TYK2) is involved in type I interferon signaling in beta cells, and TYK2 polymorphism rs2304256 has been associated with T1D. We investigated polymorphism rs2304256 (TYK2) in a case-control study of Euro-Brazilians with T1D manifested during childhood and adulthood. We studied 307 individuals manifesting clinical signs of type 1 diabetes (151 children below 14 years of age and 156 adults with diagnosis after 18 years of age). The control samples consisted of 169 healthy children and 150 healthy adult subjects. T1D groups had inadequate glycemic control because fasting glucose and mean HbA1C concentrations were significantly higher than in the control groups. Real-time PCR with

show abstract

Tyrosine Kinase Inhibitors and Diabetes: A Novel Treatment Paradigm?

Cited by 84 publications

References 83 publications

Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes

Targeting ABL-IRE1α Signaling Spares ER-Stressed Pancreatic β Cells to Reverse Autoimmune Diabetes

Tyrosine kinase inhibitors of Ripk2 attenuate bacterial cell wall-mediated lipolysis, inflammation and dysglycemia

Brief Note Polymorphism V362F (rs2304256) of tyrosine kinase 2 is not associated with childhood- or adulthood-onset type 1 diabetes in southern Brazil

Contact Info

Product

Resources

About