Growth receptor binding protein 10 inhibits glucose-stimulated insulin release from pancreatic β-cells associated with suppression of the insulin/insulin-like growth factor-1 signalling pathway.
Growth receptor binding protein 10 (Grb10) is an adaptor protein that interacts with the insulin receptor and insulin-like growth factor (IGF)-1 receptor. Overexpression of Grb10 in muscle cells and adipocytes inhibits insulin signalling, and transgenic mice overexpressing Grb10 exhibit impaired glucose tolerance. However, the roles of Grb10 in β-cells remain unknown. The aim of the present study was to explore the effect of Grb10 on β-cell function. The effects of Grb10 on glucose-stimulated insulin secretion (GSIS) and the insulin/IGF-1 signalling pathway were investigated in rat islets and/or dispersed islet cells with Grb10 overexpresion by adenovirus transfection. Protein expression was detected by western blot analysis. We found that Grb10 was expressed in both human and rat pancreas. Expression of Grb10 was increased in islets isolated from rats fed a high-fat plus high-sugar diet compared with islets isolated from rats fed normal chow diet, as well as in INS 832/13 cells exposed to high levels of glucose (20 mmol/L), palmitate (1 mmol/L) and interleukin-1β (50 U/mL). Overexpression of Grb10 in INS 832/13 cells or rat islets impaired GSIS compared with the respective control (all P < 0.05). Moreover, inhibition of GSIS by Grb10 overexpression was associated with a decrease in insulin- and IGF-1-induced Akt and extracellular signal-regulated kinase 1/2 phosphorylation. The results of the present study demonstrate that Grb10 is an important negative regulator of insulin/IGF-1 signalling in pancreatic β-cells and a potential target to improve β-cell function.
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China; Diabetes Institute, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China.
Ling
L
Li
Xiaowen
X
Li
Yunxia
Y
Zhu
Mingliang
M
Zhang
Dechao
D
Yin
Junxi
J
Lu
Feng
F
Liu
Chen
C
Wang
Weiping
W
Jia
D000818:Animals; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D059305:Diet, High-Fat; D051383:GRB10 Adaptor Protein / Q000096:biosynthesis / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009928:Organ Specificity; D010168:Palmitates / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
D007328:Insulin; D053583:Interleukin-1beta; D010168:Palmitates; C548904:insulin-like growth factor-1, rat; D051383:GRB10 Adaptor Protein; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
Akt; extracellular signal-regulated kinase; growth receptor binding protein 10; insulin secretion