PKR inhibitors suppress endoplasmic reticulum stress and subdue glucolipotoxicitymediated impairment of insulin secretion in pancreatic beta cells
PKR inhibitors suppress endoplasmic reticulum stress and subdue glucolipotoxicitymediated impairment of insulin secretion in pancreatic beta cells
Type 2 diabetes mellitus is characterized by insulin resistance and hypersecretion of insulin from the pancreas to compensatefor decreased insulin sensitivity in the peripheral tissues. In later stages of the disease insulin-secreting beta cell degeneration commencesand patients require insulin replacement therapy in order to accomplish proper regulation of their blood glucose. Endoplasmicreticulum (ER) stress in the beta cells is one of the factors contributing to this detrimental effect. Protein kinase R (PKR) is a cellularstress kinase activated by ER stress and contributing to degeneration of pancreatic islets. In order to determine whether inhibition ofPKR activation by specific small molecule inhibitors of PKR ameliorates pancreatic insulin secretion capacity, we treated beta cells withtwo imidazole/oxindole-derived inhibitors of PKR kinase, imoxin (C16) and 2-aminopurine (2-AP), in the presence of ER stress. Ourresults demonstrate that PKR inhibition suppresses tunicamycin-mediated ER stress without altering the insulin production capacityof the cells. Palmitic acid-mediated suppression of insulin secretion, however, was subdued significantly by PKR inhibitor treatmentthrough an ER stress-related mechanism. We suggest that PKR inhibitor treatment may be used to increase the insulin secretion capacityof the pancreas in later stages of diabetes.
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- Åkerfeldt MC, Howes J, Chan JY, Stevens VA, Boubenna N et al.
(2008). Cytokine-induced β-cell death is independent of
endoplasmic reticulum stress signaling. Diabetes 57: 3034-
3044.
- Barlow J, Jensen VH, Jastroch M, Affourtit C (2016). Palmitateinduced impairment of glucose-stimulated insulin secretion
precedes mitochondrial dysfunction in mouse pancreatic islets.
Biochemical Journal 473: 487-496.
- Carpentier KS, Esparo NM, Child SJ, Geballe AP (2016). A single
amino acid dictates protein kinase R susceptibility to unrelated
viral antagonists. PLoS Pathogens 12: e1005966.
- Carvalho-Filho M, Carvalho B, Oliveira A, Guadagnini D, Ueno M et
al. (2012). Double-stranded RNA-activated protein kinase is a
key modulator of insulin sensitivity in physiological conditions
and in obesity in mice. Endocrinology 153: 5261-5274.
- Cnop M, Ladriere L, Hekerman P, Ortis F, Cardozo AK et al. (2007).
Selective inhibition of eukaryotic translation initiation factor 2α
dephosphorylation potentiates fatty acid-induced endoplasmic
reticulum stress and causes pancreatic β-cell dysfunction and
apoptosis. Journal of Biological Chemistry 282: 3989-3997.
- Cnop M, Welsh N, Jonas JC, Jörns A, Lenzen S et al. (2005).
Mechanisms of pancreatic β-cell death in type 1 and type
2 diabetes: many differences, few similarities. Diabetes 54:
S97-S107.
- Cunha DA, Hekerman P, Ladrière L, Bazarra-Castro A, Ortis F et
al. (2008). Initiation and execution of lipotoxic ER stress in
pancreatic β-cells. Journal of Cell Science 121: 2308-2318.
- Drong A, Lindgren C, McCarthy M (2012). The genetic and epigenetic
basis of type 2 diabetes and obesity. Clinical Pharmacology &
Therapeutics 92: 707-715.
- Engin F, Nguyen T, Yermalovich A, Hotamisligil GS (2014). Aberrant
islet unfolded protein response in type 2 diabetes. Scientific
Reports 4: 4054.
- Garcia M, Meurs E, Esteban M (2007). The dsRNA protein kinase
PKR: virus and cell control. Biochimie 89: 799-811.
- Gil J, Esteban M (2000). Induction of apoptosis by the dsRNAdependent protein kinase (PKR): mechanism of action.
Apoptosis 5: 107-114.
- Guo W, Wong S, Xie W, Lei T (2007). Palmitate modulates
intracellular signaling, induces endoplasmic reticulum stress,
and causes apoptosis in mouse 3T3-L1 and rat primary
preadipocytes. American Journal of Physiology-Endocrinology
and Metabolism 293: E576-E586.
- Gwiazda KS, Yang TLB, Lin Y, Johnson JD (2009). Effects of palmitate
on ER and cytosolic Ca2+ homeostasis in β-cells. American
Journal of Physiology-Endocrinology and Metabolism 296:
E690-E701.
- Hotamisligil G (2009). Inflammation and endoplasmic reticulum
stress in obesity and diabetes. International Journal of Obesity
32: S52.
- Hotamisligil GS (2010). Endoplasmic reticulum stress and the
inflammatory basis of metabolic disease. Cell 140: 900-917.
- Ingrand S, Barrier L, Lafay-Chebassier C, Fauconneau B, Page G, et
al. (2007). The oxindole/imidazole derivative C16 reduces in
vivo brain PKR activation. FEBS Letters 581: 4473-4478.
- Kharroubi I, Ladrière L, Cardozo AK, Dogusan Z, Cnop M et al.
(2004). Free fatty acids and cytokines induce pancreatic β-cell
apoptosis by different mechanisms: role of nuclear factor-κB
and endoplasmic reticulum stress. Endocrinology 145: 5087-
5096.
- Lakshmanan AP, Harima M, Suzuki K, Soetikno V, Nagata M et al.
(2013). The hyperglycemia stimulated myocardial endoplasmic
reticulum (ER) stress contributes to diabetic cardiomyopathy
in the transgenic non-obese type 2 diabetic rats: a differential
role of unfolded protein response (UPR) signaling proteins.
International Journal of Biochemistry & Cell Biology 45: 438-
447.
- Laybutt D, Preston A, Åkerfeldt M, Kench J, Busch A et al. (2007).
Endoplasmic reticulum stress contributes to beta cell apoptosis
in type 2 diabetes. Diabetologia 50: 752-763.
- Liu X, Zeng X, Chen X, Luo R, Li L et al. (2019). Oleic acid protects
insulin-secreting INS-1E cells against palmitic acid-induced
lipotoxicity along with an amelioration of ER stress. Endocrine
2019: 1-13.
- Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M et al. (2007).
The endoplasmic reticulum in pancreatic beta cells of type 2
diabetes patients. Diabetologia 50: 2486-2494.
- Marciniak SJ, Ron D (2006). Endoplasmic reticulum stress signaling
in disease. Physiological Reviews 86: 1133-1149.
- Nakamura T, Arduini A, Baccaro B, Furuhashi M, Hotamisligil GS
(2014). Small-molecule inhibitors of PKR improve glucose
homeostasis in obese diabetic mice. Diabetes 63: 526-534.
- Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G et al. (2010).
Double-stranded RNA-dependent protein kinase links
pathogen sensing with stress and metabolic homeostasis. Cell
140: 338-348.
- Özcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN et al. (2004).
Endoplasmic reticulum stress links obesity, insulin action, and
type 2 diabetes. Science 306: 457-461.
- Peters KR (2013). Liraglutide for the treatment of type 2 diabetes: a
clinical update. American Journal of Therapeutics 20: 178-188.
- Poitout V, Amyot J, Semache M, Zarrouki B, Hagman D et al. (2010).
Glucolipotoxicity of the pancreatic beta cell. Biochimica et
Biophysica Acta-Molecular and Cell Biology of Lipids 1801:
289-298.
- Raskin P, Allen E, Hollander P, Lewin A, Gabbay RA et al. (2005).
Initiating insulin therapy in type 2 diabetes: a comparison of
biphasic and basal insulin analogs. Diabetes Care 28: 260-265.
- Rothenburg S, Seo EJ, Gibbs JS, Dever TE, Dittmar K (2009). Rapid
evolution of protein kinase PKR alters sensitivity to viral
inhibitors. Nature Structural & Molecular Biology 16: 63.
- Song B, Scheuner D, Ron D, Pennathur S, Kaufman RJ (2008). Chop
deletion reduces oxidative stress, improves β cell function, and
promotes cell survival in multiple mouse models of diabetes.
Journal of Clinical Investigation 118: 3378-3389.
- Srinivasan S, Ohsugi M, Liu Z, Fatrai S, Bernal-Mizrachi E et al.
(2005). Endoplasmic reticulum stress–induced apoptosis
is partly mediated by reduced insulin signaling through
phosphatidylinositol 3-kinase/Akt and increased glycogen
synthase kinase-3β in mouse insulinoma cells. Diabetes 54:
968-975.
- Tibaldi J (2007). Actions of insulin beyond glycemic control: a
perspective on insulin detemir. Advances in Therapy 24: 868-
882.
- Tibaldi J, Rakel R (2007). Why, when and how to initiate insulin
therapy in patients with type 2 diabetes. International Journal
of Clinical Practice 61: 633-644.
- Udumula MP, Babu MS, Bhat A, Dhar I, Sriram D et al. (2017).
High glucose impairs insulin signaling via activation of PKR
pathway in L6 muscle cells. Biochemical and Biophysical
Research Communications 486: 645-651.
- Watanabe T, Imamura T, Hiasa Y (2018). Roles of protein kinase R
in cancer: potential as a therapeutic target. Cancer Science 109:
919-925.
- Whiting DR, Guariguata L, Weil C, Shaw J (2011). IDF diabetes
atlas: global estimates of the prevalence of diabetes for 2011
and 2030. Diabetes Research and Clinical Practice 94: 311-321.
- Youssef OA, Safran SA, Nakamura T, Nix DA, Hotamisligil GS et al.
(2015). Potential role for snoRNAs in PKR activation during
metabolic stress. Proceedings of the National Academy of
Sciences of the USA 112: 5023-5028.