Autophagy deficiency in β cells blunts incretininduced suppression of glucagon release from α cells

Min Joo Kim, Ok Kyong Choi, Kyung Sil Chae, Hakmo Lee, Sung Soo Chung, Dong Sik Ham, Ji Won Kim, Kun Ho Yoon, Kyong Soo Park, Hye Seung Jung

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet β cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male β cell-specific Atg7 knockout (Atg7 Δβ cell ) mice and wild-type mice were administered vildagliptin for 12 weeks. Vildagliptin treatment improved glucose intolerance and hypoinsulinemia; however, it failed to suppress serum glucagon levels after glucose loading in the Atg7 Δβ cell mice. Ex vivo glucose-induced glucagon suppression was also blunted in the islets from vildagliptin-treated Atg7 Δb cell mice. The α cell mass was not affected by β cell autophagy deficiency or vildagliptin. However, glucagon mRNA expression was significantly increased by vildagliptin in the autophagy-deficient islets, and was significantly reduced by vildagliptin in wild-type islets. Pancreatic glucagon contents were not in agreement with the changes in mRNA expression, suggesting a dysregulation in glucagon translation and secretion. In vitro studies revealed that glucose-stimulated cAMP production was impaired in the autophagy-deficient islets exposed to exendin-4. Taken together, the results suggest that the constitutive autophagy in β cells could regulate incretin-induced glucagon expression and release in α cells, and that cAMP may play a role in this process.

Original languageEnglish
JournalIslets
Volume7
Issue number5
DOIs
StatePublished - 1 Jan 2015

Fingerprint

Autophagy
Glucagon
Incretins
Glucose
Type 2 Diabetes Mellitus
Messenger RNA
Glucose Intolerance
Islets of Langerhans
vildagliptin
Insulin
Serum

Keywords

  • A cell
  • Autophagy
  • Dipeptidyl-peptidase IV inhibitors
  • Glucagon
  • Incretins
  • Vildagliptin

Cite this

Kim, Min Joo ; Choi, Ok Kyong ; Chae, Kyung Sil ; Lee, Hakmo ; Chung, Sung Soo ; Ham, Dong Sik ; Kim, Ji Won ; Yoon, Kun Ho ; Park, Kyong Soo ; Jung, Hye Seung. / Autophagy deficiency in β cells blunts incretininduced suppression of glucagon release from α cells. In: Islets. 2015 ; Vol. 7, No. 5.
@article{a16053c8b8d748459f5e740d9a7ecf01,
title = "Autophagy deficiency in β cells blunts incretininduced suppression of glucagon release from α cells",
abstract = "Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet β cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male β cell-specific Atg7 knockout (Atg7 Δβ cell ) mice and wild-type mice were administered vildagliptin for 12 weeks. Vildagliptin treatment improved glucose intolerance and hypoinsulinemia; however, it failed to suppress serum glucagon levels after glucose loading in the Atg7 Δβ cell mice. Ex vivo glucose-induced glucagon suppression was also blunted in the islets from vildagliptin-treated Atg7 Δb cell mice. The α cell mass was not affected by β cell autophagy deficiency or vildagliptin. However, glucagon mRNA expression was significantly increased by vildagliptin in the autophagy-deficient islets, and was significantly reduced by vildagliptin in wild-type islets. Pancreatic glucagon contents were not in agreement with the changes in mRNA expression, suggesting a dysregulation in glucagon translation and secretion. In vitro studies revealed that glucose-stimulated cAMP production was impaired in the autophagy-deficient islets exposed to exendin-4. Taken together, the results suggest that the constitutive autophagy in β cells could regulate incretin-induced glucagon expression and release in α cells, and that cAMP may play a role in this process.",
keywords = "A cell, Autophagy, Dipeptidyl-peptidase IV inhibitors, Glucagon, Incretins, Vildagliptin",
author = "Kim, {Min Joo} and Choi, {Ok Kyong} and Chae, {Kyung Sil} and Hakmo Lee and Chung, {Sung Soo} and Ham, {Dong Sik} and Kim, {Ji Won} and Yoon, {Kun Ho} and Park, {Kyong Soo} and Jung, {Hye Seung}",
year = "2015",
month = "1",
day = "1",
doi = "10.1080/19382014.2015.1129096",
language = "English",
volume = "7",
journal = "Islets",
issn = "1938-2014",
publisher = "Landes Bioscience",
number = "5",

}

Autophagy deficiency in β cells blunts incretininduced suppression of glucagon release from α cells. / Kim, Min Joo; Choi, Ok Kyong; Chae, Kyung Sil; Lee, Hakmo; Chung, Sung Soo; Ham, Dong Sik; Kim, Ji Won; Yoon, Kun Ho; Park, Kyong Soo; Jung, Hye Seung.

In: Islets, Vol. 7, No. 5, 01.01.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Autophagy deficiency in β cells blunts incretininduced suppression of glucagon release from α cells

AU - Kim, Min Joo

AU - Choi, Ok Kyong

AU - Chae, Kyung Sil

AU - Lee, Hakmo

AU - Chung, Sung Soo

AU - Ham, Dong Sik

AU - Kim, Ji Won

AU - Yoon, Kun Ho

AU - Park, Kyong Soo

AU - Jung, Hye Seung

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet β cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male β cell-specific Atg7 knockout (Atg7 Δβ cell ) mice and wild-type mice were administered vildagliptin for 12 weeks. Vildagliptin treatment improved glucose intolerance and hypoinsulinemia; however, it failed to suppress serum glucagon levels after glucose loading in the Atg7 Δβ cell mice. Ex vivo glucose-induced glucagon suppression was also blunted in the islets from vildagliptin-treated Atg7 Δb cell mice. The α cell mass was not affected by β cell autophagy deficiency or vildagliptin. However, glucagon mRNA expression was significantly increased by vildagliptin in the autophagy-deficient islets, and was significantly reduced by vildagliptin in wild-type islets. Pancreatic glucagon contents were not in agreement with the changes in mRNA expression, suggesting a dysregulation in glucagon translation and secretion. In vitro studies revealed that glucose-stimulated cAMP production was impaired in the autophagy-deficient islets exposed to exendin-4. Taken together, the results suggest that the constitutive autophagy in β cells could regulate incretin-induced glucagon expression and release in α cells, and that cAMP may play a role in this process.

AB - Incretin-based therapy such as GLP-1 receptor agonists and DPP-4 inhibitors for type 2 diabetes mellitus is characterized by glucose-dependent insulin secretion and glucose-inhibited glucagon secretion. Recently, autophagy deficiency in islet β cells has been shown to contribute to the pathogenesis of type 2 diabetes mellitus however, with the role of incretin has not been established. To evaluate the role of autophagy in incretin effects, 8-week-old male β cell-specific Atg7 knockout (Atg7 Δβ cell ) mice and wild-type mice were administered vildagliptin for 12 weeks. Vildagliptin treatment improved glucose intolerance and hypoinsulinemia; however, it failed to suppress serum glucagon levels after glucose loading in the Atg7 Δβ cell mice. Ex vivo glucose-induced glucagon suppression was also blunted in the islets from vildagliptin-treated Atg7 Δb cell mice. The α cell mass was not affected by β cell autophagy deficiency or vildagliptin. However, glucagon mRNA expression was significantly increased by vildagliptin in the autophagy-deficient islets, and was significantly reduced by vildagliptin in wild-type islets. Pancreatic glucagon contents were not in agreement with the changes in mRNA expression, suggesting a dysregulation in glucagon translation and secretion. In vitro studies revealed that glucose-stimulated cAMP production was impaired in the autophagy-deficient islets exposed to exendin-4. Taken together, the results suggest that the constitutive autophagy in β cells could regulate incretin-induced glucagon expression and release in α cells, and that cAMP may play a role in this process.

KW - A cell

KW - Autophagy

KW - Dipeptidyl-peptidase IV inhibitors

KW - Glucagon

KW - Incretins

KW - Vildagliptin

UR - http://www.scopus.com/inward/record.url?scp=84964067902&partnerID=8YFLogxK

U2 - 10.1080/19382014.2015.1129096

DO - 10.1080/19382014.2015.1129096

M3 - Article

C2 - 26744903

AN - SCOPUS:84964067902

VL - 7

JO - Islets

JF - Islets

SN - 1938-2014

IS - 5

ER -