Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes

Min Joo Kim, Mi Na Kim, Se Hee Min, Dong Sik Ham, Ji Won Kim, Kun Ho Yoon, Kyong Soo Park, Hye Seung Jung

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: We have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets and mice through induction of ER chaperone BIP. Therefore, we investigated if PI would have the same effects in a diabetic condition as well. Methods: GSK2606414 was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. To generate a mouse model of type 2 diabetes mellitus (DM), male C57BL/6J mice were fed with high-fat diet and injected with streptozotocin. Several doses (6–16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. Results: High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40 nM which decreased PERK phosphorylation by 40% significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain and prominent hyperglycemia were induced, PI at 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. Conclusion: PI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM.

Original languageEnglish
Pages (from-to)87-91
Number of pages5
JournalMetabolism: Clinical and Experimental
Volume97
DOIs
StatePublished - 1 Aug 2019

Fingerprint

Type 2 Diabetes Mellitus
Insulin
Glucose
glimepiride
Palmitates
Hyperglycemia
Blood Glucose
Phosphorylation
Physiological Stress
High Fat Diet
Streptozocin
Islets of Langerhans
Inbred C57BL Mouse
Weight Gain
Insulin Resistance
Pancreas
Body Weight
Calcium
Phenotype
Weights and Measures

Keywords

  • Glucose-stimulated insulin secretion
  • PERK
  • PERK inhibitor
  • Type 2 diabetes mellitus

Cite this

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title = "Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes",
abstract = "Background: We have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets and mice through induction of ER chaperone BIP. Therefore, we investigated if PI would have the same effects in a diabetic condition as well. Methods: GSK2606414 was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. To generate a mouse model of type 2 diabetes mellitus (DM), male C57BL/6J mice were fed with high-fat diet and injected with streptozotocin. Several doses (6–16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. Results: High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40 nM which decreased PERK phosphorylation by 40{\%} significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain and prominent hyperglycemia were induced, PI at 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. Conclusion: PI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM.",
keywords = "Glucose-stimulated insulin secretion, PERK, PERK inhibitor, Type 2 diabetes mellitus",
author = "Kim, {Min Joo} and Kim, {Mi Na} and Min, {Se Hee} and Ham, {Dong Sik} and Kim, {Ji Won} and Yoon, {Kun Ho} and Park, {Kyong Soo} and Jung, {Hye Seung}",
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Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes. / Kim, Min Joo; Kim, Mi Na; Min, Se Hee; Ham, Dong Sik; Kim, Ji Won; Yoon, Kun Ho; Park, Kyong Soo; Jung, Hye Seung.

In: Metabolism: Clinical and Experimental, Vol. 97, 01.08.2019, p. 87-91.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes

AU - Kim, Min Joo

AU - Kim, Mi Na

AU - Min, Se Hee

AU - Ham, Dong Sik

AU - Kim, Ji Won

AU - Yoon, Kun Ho

AU - Park, Kyong Soo

AU - Jung, Hye Seung

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Background: We have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets and mice through induction of ER chaperone BIP. Therefore, we investigated if PI would have the same effects in a diabetic condition as well. Methods: GSK2606414 was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. To generate a mouse model of type 2 diabetes mellitus (DM), male C57BL/6J mice were fed with high-fat diet and injected with streptozotocin. Several doses (6–16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. Results: High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40 nM which decreased PERK phosphorylation by 40% significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain and prominent hyperglycemia were induced, PI at 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. Conclusion: PI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM.

AB - Background: We have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets and mice through induction of ER chaperone BIP. Therefore, we investigated if PI would have the same effects in a diabetic condition as well. Methods: GSK2606414 was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. To generate a mouse model of type 2 diabetes mellitus (DM), male C57BL/6J mice were fed with high-fat diet and injected with streptozotocin. Several doses (6–16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. Results: High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40 nM which decreased PERK phosphorylation by 40% significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain and prominent hyperglycemia were induced, PI at 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. Conclusion: PI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM.

KW - Glucose-stimulated insulin secretion

KW - PERK

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