Proteomic Analysis of Restored Insulin Production and Trafficking in Obese Diabetic Mouse Pancreatic Islets following Euglycemia

Taewook Kang, Brandon B. Boland, Cristina Alarcon, Joseph S. Grimsby, Christopher J. Rhodes, Martin R. Larsen*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

For the treatment of patients with prediabetes or diabetes, clinical evidence has emerged that β-cell function can be restored by glucose-lowering therapeutic strategies. However, little is known about the molecular mechanisms underlying this functional adaptive behavior of the pancreatic β-cell. This study examines the dynamic changes in protein expression and phosphorylation state associated with (pro)insulin production and secretory pathway function mediated by euglycemia to induce β-cell rest in obese/diabetic db/db islet β-cells. Unbiased quantitative profiling of the protein expression and phosphorylation events that occur upon β-cell adaption during the transition from hyperglycemia to euglycemia was assessed in isolated pancreatic islets from obese diabetic db/db and wild-type (WT) mice using quantitative proteomics and phosphoproteomics together with bioinformatics analysis. Dynamic changes in the expression and phosphorylation of proteins associated with pancreatic β-cell (pro)insulin production and complementary regulated-secretory pathway regulation were observed in obese diabetic db/db islets in a hyperglycemic environment, relative to WT mouse islets in a normal euglycemic environment, that resolved when isolated db/db islets were exposed to euglycemia for 12 h in vitro. By similarly treating WT islets in parallel, the effects of tissue culture could be mostly eliminated and only those changes associated with resolution by euglycemia were assessed. Among such regulated protein phosphorylation-dependent signaling events were those associated with COPII-coated vesicle-dependent ER exit, ER-to-Golgi trafficking, clathrin-coat disassembly, and a particular association for the luminal Golgi protein kinase, FAM20C, in control of distal secretory pathway trafficking, sorting, and granule biogenesis. Protein expression and especially phosphorylation play key roles in the regulation of (pro)insulin production, correlative secretory pathway trafficking, and the restoration of β-cell secretory capacity in the adaptive functional β-cell response to metabolic demand, especially that mediated by glucose.

OriginalsprogEngelsk
TidsskriftJournal of Proteome Research
Vol/bind18
Udgave nummer9
Sider (fra-til)3245-3258
ISSN1535-3893
DOI
StatusUdgivet - 6. sep. 2019

Fingeraftryk

Obese Mice
Phosphorylation
Islets of Langerhans
Insulin
Proteins
Glucose
Tissue culture
Clathrin
COP-Coated Vesicles
Bioinformatics
Medical problems
Sorting
Protein Kinases
Prediabetic State
Restoration
Proteomics
Association reactions
Computational Biology
Hyperglycemia

Citer dette

Kang, Taewook ; Boland, Brandon B. ; Alarcon, Cristina ; Grimsby, Joseph S. ; Rhodes, Christopher J. ; Larsen, Martin R. / Proteomic Analysis of Restored Insulin Production and Trafficking in Obese Diabetic Mouse Pancreatic Islets following Euglycemia. I: Journal of Proteome Research. 2019 ; Bind 18, Nr. 9. s. 3245-3258.
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abstract = "For the treatment of patients with prediabetes or diabetes, clinical evidence has emerged that β-cell function can be restored by glucose-lowering therapeutic strategies. However, little is known about the molecular mechanisms underlying this functional adaptive behavior of the pancreatic β-cell. This study examines the dynamic changes in protein expression and phosphorylation state associated with (pro)insulin production and secretory pathway function mediated by euglycemia to induce β-cell rest in obese/diabetic db/db islet β-cells. Unbiased quantitative profiling of the protein expression and phosphorylation events that occur upon β-cell adaption during the transition from hyperglycemia to euglycemia was assessed in isolated pancreatic islets from obese diabetic db/db and wild-type (WT) mice using quantitative proteomics and phosphoproteomics together with bioinformatics analysis. Dynamic changes in the expression and phosphorylation of proteins associated with pancreatic β-cell (pro)insulin production and complementary regulated-secretory pathway regulation were observed in obese diabetic db/db islets in a hyperglycemic environment, relative to WT mouse islets in a normal euglycemic environment, that resolved when isolated db/db islets were exposed to euglycemia for 12 h in vitro. By similarly treating WT islets in parallel, the effects of tissue culture could be mostly eliminated and only those changes associated with resolution by euglycemia were assessed. Among such regulated protein phosphorylation-dependent signaling events were those associated with COPII-coated vesicle-dependent ER exit, ER-to-Golgi trafficking, clathrin-coat disassembly, and a particular association for the luminal Golgi protein kinase, FAM20C, in control of distal secretory pathway trafficking, sorting, and granule biogenesis. Protein expression and especially phosphorylation play key roles in the regulation of (pro)insulin production, correlative secretory pathway trafficking, and the restoration of β-cell secretory capacity in the adaptive functional β-cell response to metabolic demand, especially that mediated by glucose.",
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author = "Taewook Kang and Boland, {Brandon B.} and Cristina Alarcon and Grimsby, {Joseph S.} and Rhodes, {Christopher J.} and Larsen, {Martin R.}",
year = "2019",
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Proteomic Analysis of Restored Insulin Production and Trafficking in Obese Diabetic Mouse Pancreatic Islets following Euglycemia. / Kang, Taewook; Boland, Brandon B.; Alarcon, Cristina; Grimsby, Joseph S.; Rhodes, Christopher J.; Larsen, Martin R.

I: Journal of Proteome Research, Bind 18, Nr. 9, 06.09.2019, s. 3245-3258.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Proteomic Analysis of Restored Insulin Production and Trafficking in Obese Diabetic Mouse Pancreatic Islets following Euglycemia

AU - Kang, Taewook

AU - Boland, Brandon B.

AU - Alarcon, Cristina

AU - Grimsby, Joseph S.

AU - Rhodes, Christopher J.

AU - Larsen, Martin R.

PY - 2019/9/6

Y1 - 2019/9/6

N2 - For the treatment of patients with prediabetes or diabetes, clinical evidence has emerged that β-cell function can be restored by glucose-lowering therapeutic strategies. However, little is known about the molecular mechanisms underlying this functional adaptive behavior of the pancreatic β-cell. This study examines the dynamic changes in protein expression and phosphorylation state associated with (pro)insulin production and secretory pathway function mediated by euglycemia to induce β-cell rest in obese/diabetic db/db islet β-cells. Unbiased quantitative profiling of the protein expression and phosphorylation events that occur upon β-cell adaption during the transition from hyperglycemia to euglycemia was assessed in isolated pancreatic islets from obese diabetic db/db and wild-type (WT) mice using quantitative proteomics and phosphoproteomics together with bioinformatics analysis. Dynamic changes in the expression and phosphorylation of proteins associated with pancreatic β-cell (pro)insulin production and complementary regulated-secretory pathway regulation were observed in obese diabetic db/db islets in a hyperglycemic environment, relative to WT mouse islets in a normal euglycemic environment, that resolved when isolated db/db islets were exposed to euglycemia for 12 h in vitro. By similarly treating WT islets in parallel, the effects of tissue culture could be mostly eliminated and only those changes associated with resolution by euglycemia were assessed. Among such regulated protein phosphorylation-dependent signaling events were those associated with COPII-coated vesicle-dependent ER exit, ER-to-Golgi trafficking, clathrin-coat disassembly, and a particular association for the luminal Golgi protein kinase, FAM20C, in control of distal secretory pathway trafficking, sorting, and granule biogenesis. Protein expression and especially phosphorylation play key roles in the regulation of (pro)insulin production, correlative secretory pathway trafficking, and the restoration of β-cell secretory capacity in the adaptive functional β-cell response to metabolic demand, especially that mediated by glucose.

AB - For the treatment of patients with prediabetes or diabetes, clinical evidence has emerged that β-cell function can be restored by glucose-lowering therapeutic strategies. However, little is known about the molecular mechanisms underlying this functional adaptive behavior of the pancreatic β-cell. This study examines the dynamic changes in protein expression and phosphorylation state associated with (pro)insulin production and secretory pathway function mediated by euglycemia to induce β-cell rest in obese/diabetic db/db islet β-cells. Unbiased quantitative profiling of the protein expression and phosphorylation events that occur upon β-cell adaption during the transition from hyperglycemia to euglycemia was assessed in isolated pancreatic islets from obese diabetic db/db and wild-type (WT) mice using quantitative proteomics and phosphoproteomics together with bioinformatics analysis. Dynamic changes in the expression and phosphorylation of proteins associated with pancreatic β-cell (pro)insulin production and complementary regulated-secretory pathway regulation were observed in obese diabetic db/db islets in a hyperglycemic environment, relative to WT mouse islets in a normal euglycemic environment, that resolved when isolated db/db islets were exposed to euglycemia for 12 h in vitro. By similarly treating WT islets in parallel, the effects of tissue culture could be mostly eliminated and only those changes associated with resolution by euglycemia were assessed. Among such regulated protein phosphorylation-dependent signaling events were those associated with COPII-coated vesicle-dependent ER exit, ER-to-Golgi trafficking, clathrin-coat disassembly, and a particular association for the luminal Golgi protein kinase, FAM20C, in control of distal secretory pathway trafficking, sorting, and granule biogenesis. Protein expression and especially phosphorylation play key roles in the regulation of (pro)insulin production, correlative secretory pathway trafficking, and the restoration of β-cell secretory capacity in the adaptive functional β-cell response to metabolic demand, especially that mediated by glucose.

KW - d b/d b

KW - ER homeostasis

KW - ER-to-Golgi trafficking

KW - euglycemia

KW - insulin

KW - insulin biosynthesis

KW - mass spectrometry

KW - obesity

KW - pancreatic islet β-cell

KW - phosphoproteomics

KW - secretory pathway

KW - translation

KW - type 2 diabetes

KW - β-cell rest

U2 - 10.1021/acs.jproteome.9b00160

DO - 10.1021/acs.jproteome.9b00160

M3 - Journal article

C2 - 31317746

AN - SCOPUS:85071716081

VL - 18

SP - 3245

EP - 3258

JO - Journal of Proteome Research

JF - Journal of Proteome Research

SN - 1535-3893

IS - 9

ER -