Short-term CFTR inhibition reduces islet area in C57BL/6 mice

Dawood Khan, Ryan Kelsey, Rashmi R Maheshwari, Virginia M Stone, Annie Hasib, Fiona Manderson Koivula, Aoife Watson, Stephen Harkin, Nigel Irwin, James A Shaw, Neville McClenaghan, Viktória Venglovecz, Attila Ébert, Malin Flodstrom-Tullberg, Michael G White, Catriona Kelly

Research output: Contribution to journalArticle

Abstract

Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. Loss of beta cell area, even without overt diabetes or pancreatitis is consistently observed. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. CFTR was inhibited in C57BL/6 mice via 8-day intraperitoneal injection of CFTRinh172. Animals had a 7-day washout period before measures of hormone concentration or islet function were performed. Short-term CFTR inhibition increased blood glucose concentrations over the course of the study. However, glucose tolerance remained normal without insulin resistance. CFTR inhibition caused marked reductions in islet size and in beta cell and non-beta cell area within the islet, which resulted from loss of islet cell size rather than islet cell number. Significant reductions in plasma insulin concentrations and pancreatic insulin content were also observed in CFTR-inhibited animals. Temporary CFTR inhibition had little long-term impact on glucose-stimulated, or GLP-1 potentiated insulin secretion. CFTR inhibition has a rapid impact on islet area and insulin concentrations. However, islet cell number is maintained and insulin secretion is unaffected suggesting that early administration of therapies aimed at sustaining beta cell mass may be useful in slowing the onset of CFRD.
LanguageEnglish
Article number11244
Number of pages11
JournalScientific Reports
Volume9
Issue number1
Early online date2 Aug 2019
DOIs
Publication statusE-pub ahead of print - 2 Aug 2019

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Inbred C57BL Mouse
Insulin
Islets of Langerhans
Cystic Fibrosis
Cell Count
Glucose
Glucagon-Like Peptide 1
Secondary Prevention
Intraperitoneal Injections
Cell Size
Pancreatitis
Lung Diseases
Insulin Resistance
Blood Glucose
Hormones
Mortality

Cite this

Khan, Dawood ; Kelsey, Ryan ; Maheshwari, Rashmi R ; Stone, Virginia M ; Hasib, Annie ; Manderson Koivula, Fiona ; Watson, Aoife ; Harkin, Stephen ; Irwin, Nigel ; Shaw, James A ; McClenaghan, Neville ; Venglovecz, Viktória ; Ébert, Attila ; Flodstrom-Tullberg, Malin ; White, Michael G ; Kelly, Catriona. / Short-term CFTR inhibition reduces islet area in C57BL/6 mice. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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abstract = "Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. Loss of beta cell area, even without overt diabetes or pancreatitis is consistently observed. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. CFTR was inhibited in C57BL/6 mice via 8-day intraperitoneal injection of CFTRinh172. Animals had a 7-day washout period before measures of hormone concentration or islet function were performed. Short-term CFTR inhibition increased blood glucose concentrations over the course of the study. However, glucose tolerance remained normal without insulin resistance. CFTR inhibition caused marked reductions in islet size and in beta cell and non-beta cell area within the islet, which resulted from loss of islet cell size rather than islet cell number. Significant reductions in plasma insulin concentrations and pancreatic insulin content were also observed in CFTR-inhibited animals. Temporary CFTR inhibition had little long-term impact on glucose-stimulated, or GLP-1 potentiated insulin secretion. CFTR inhibition has a rapid impact on islet area and insulin concentrations. However, islet cell number is maintained and insulin secretion is unaffected suggesting that early administration of therapies aimed at sustaining beta cell mass may be useful in slowing the onset of CFRD.",
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Khan, D, Kelsey, R, Maheshwari, RR, Stone, VM, Hasib, A, Manderson Koivula, F, Watson, A, Harkin, S, Irwin, N, Shaw, JA, McClenaghan, N, Venglovecz, V, Ébert, A, Flodstrom-Tullberg, M, White, MG & Kelly, C 2019, 'Short-term CFTR inhibition reduces islet area in C57BL/6 mice', Scientific Reports, vol. 9, no. 1, 11244. https://doi.org/10.1038/s41598-019-47745-w

Short-term CFTR inhibition reduces islet area in C57BL/6 mice. / Khan, Dawood; Kelsey, Ryan; Maheshwari, Rashmi R; Stone, Virginia M; Hasib, Annie; Manderson Koivula, Fiona; Watson, Aoife; Harkin, Stephen; Irwin, Nigel; Shaw, James A; McClenaghan, Neville; Venglovecz, Viktória; Ébert, Attila; Flodstrom-Tullberg, Malin; White, Michael G; Kelly, Catriona.

In: Scientific Reports, Vol. 9, No. 1, 11244, 02.08.2019.

Research output: Contribution to journalArticle

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AU - Khan, Dawood

AU - Kelsey, Ryan

AU - Maheshwari, Rashmi R

AU - Stone, Virginia M

AU - Hasib, Annie

AU - Manderson Koivula, Fiona

AU - Watson, Aoife

AU - Harkin, Stephen

AU - Irwin, Nigel

AU - Shaw, James A

AU - McClenaghan, Neville

AU - Venglovecz, Viktória

AU - Ébert, Attila

AU - Flodstrom-Tullberg, Malin

AU - White, Michael G

AU - Kelly, Catriona

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N2 - Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. Loss of beta cell area, even without overt diabetes or pancreatitis is consistently observed. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. CFTR was inhibited in C57BL/6 mice via 8-day intraperitoneal injection of CFTRinh172. Animals had a 7-day washout period before measures of hormone concentration or islet function were performed. Short-term CFTR inhibition increased blood glucose concentrations over the course of the study. However, glucose tolerance remained normal without insulin resistance. CFTR inhibition caused marked reductions in islet size and in beta cell and non-beta cell area within the islet, which resulted from loss of islet cell size rather than islet cell number. Significant reductions in plasma insulin concentrations and pancreatic insulin content were also observed in CFTR-inhibited animals. Temporary CFTR inhibition had little long-term impact on glucose-stimulated, or GLP-1 potentiated insulin secretion. CFTR inhibition has a rapid impact on islet area and insulin concentrations. However, islet cell number is maintained and insulin secretion is unaffected suggesting that early administration of therapies aimed at sustaining beta cell mass may be useful in slowing the onset of CFRD.

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