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A central role for GRB10 in regulation of islet function in man.

Prokopenko I, Poon W, Mägi R, Prasad B R, Salehi SA, Almgren P, Osmark P, Bouatia-Naji N, Wierup N, Fall T, Stančáková A, Barker A, Lagou V, Osmond C, Xie W, Lahti J, Jackson AU, Cheng YC, Liu J, O'Connell JR, Blomstedt PA, Fadista J, Alkayyali S, Dayeh T, Ahlqvist E, Taneera J, Lecoeur C, Kumar A, Hansson O, Hansson K, Voight BF, Kang HM, Levy-Marchal C, Vatin V, Palotie A, Syvänen AC, Mari A, Weedon MN, Loos RJ, Ong KK, Nilsson P, Isomaa B, Tuomi T, Wareham NJ, Stumvoll M, Widen E, Lakka TA, Langenberg C, Tönjes A, Rauramaa R, Kuusisto J, Frayling TM, Froguel P, Walker M, Eriksson JG, Ling C, Kovacs P, Ingelsson E, McCarthy MI, Shuldiner AR, Silver KD, Laakso M, Groop L, Lyssenko V - PLoS Genet. (2014)

Bottom Line: GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion.Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis.The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

View Article: PubMed Central - PubMed

Affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, United Kingdom.

ABSTRACT
Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

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Effects of disrupted GRB10 through knock-down on islet function.(A) Disrupted GRB10 in INS-1 rat β-cells markedly reduced glucose-stimulated insulin secretion. (B) GRB10 knock-down showed reduced glucose-stimulated insulin secretion at 20 mM glucose and glucagon secretion at 1 mM glucose in human pancreatic islets (Ninsulin = 7, Nglucagon = 6 donors of human pancreatic islets; 3–6 measurements in each experiment for each donor). (C) GRB10 knock-down resulted in a reduction of insulin and glucagon mRNA expression (N = 3 donors of human pancreatic islets; 3 measurements in each experiment for each donor). * p<0.05; ** p<0.01, *** p<0.001. Error bars denote SEM.
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pgen-1004235-g004: Effects of disrupted GRB10 through knock-down on islet function.(A) Disrupted GRB10 in INS-1 rat β-cells markedly reduced glucose-stimulated insulin secretion. (B) GRB10 knock-down showed reduced glucose-stimulated insulin secretion at 20 mM glucose and glucagon secretion at 1 mM glucose in human pancreatic islets (Ninsulin = 7, Nglucagon = 6 donors of human pancreatic islets; 3–6 measurements in each experiment for each donor). (C) GRB10 knock-down resulted in a reduction of insulin and glucagon mRNA expression (N = 3 donors of human pancreatic islets; 3 measurements in each experiment for each donor). * p<0.05; ** p<0.01, *** p<0.001. Error bars denote SEM.

Mentions: To gain insight into the mechanisms by which GRB10 influences pancreatic β- and α-cell function, we disrupted Grb10 expression in rat insulinoma INS-1 cells by siRNA and in human islets by shRNA achieved by lentiviral transfection. There was a clear reduction in GSIS after siRNA-disruption of Grb10 in the INS-1 cell line lacking glucagon (Figure 4A). In human pancreatic islets, decreased GRB10 expression resulted in a reduction of both insulin and glucagon secretion and expression (Figure 4B, C). In addition, GRB10 knock-down was also associated with a decrease in forskolin- and K+-stimulated glucagon secretion (Figure S8A).


A central role for GRB10 in regulation of islet function in man.

Prokopenko I, Poon W, Mägi R, Prasad B R, Salehi SA, Almgren P, Osmark P, Bouatia-Naji N, Wierup N, Fall T, Stančáková A, Barker A, Lagou V, Osmond C, Xie W, Lahti J, Jackson AU, Cheng YC, Liu J, O'Connell JR, Blomstedt PA, Fadista J, Alkayyali S, Dayeh T, Ahlqvist E, Taneera J, Lecoeur C, Kumar A, Hansson O, Hansson K, Voight BF, Kang HM, Levy-Marchal C, Vatin V, Palotie A, Syvänen AC, Mari A, Weedon MN, Loos RJ, Ong KK, Nilsson P, Isomaa B, Tuomi T, Wareham NJ, Stumvoll M, Widen E, Lakka TA, Langenberg C, Tönjes A, Rauramaa R, Kuusisto J, Frayling TM, Froguel P, Walker M, Eriksson JG, Ling C, Kovacs P, Ingelsson E, McCarthy MI, Shuldiner AR, Silver KD, Laakso M, Groop L, Lyssenko V - PLoS Genet. (2014)

Effects of disrupted GRB10 through knock-down on islet function.(A) Disrupted GRB10 in INS-1 rat β-cells markedly reduced glucose-stimulated insulin secretion. (B) GRB10 knock-down showed reduced glucose-stimulated insulin secretion at 20 mM glucose and glucagon secretion at 1 mM glucose in human pancreatic islets (Ninsulin = 7, Nglucagon = 6 donors of human pancreatic islets; 3–6 measurements in each experiment for each donor). (C) GRB10 knock-down resulted in a reduction of insulin and glucagon mRNA expression (N = 3 donors of human pancreatic islets; 3 measurements in each experiment for each donor). * p<0.05; ** p<0.01, *** p<0.001. Error bars denote SEM.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3974640&req=5

pgen-1004235-g004: Effects of disrupted GRB10 through knock-down on islet function.(A) Disrupted GRB10 in INS-1 rat β-cells markedly reduced glucose-stimulated insulin secretion. (B) GRB10 knock-down showed reduced glucose-stimulated insulin secretion at 20 mM glucose and glucagon secretion at 1 mM glucose in human pancreatic islets (Ninsulin = 7, Nglucagon = 6 donors of human pancreatic islets; 3–6 measurements in each experiment for each donor). (C) GRB10 knock-down resulted in a reduction of insulin and glucagon mRNA expression (N = 3 donors of human pancreatic islets; 3 measurements in each experiment for each donor). * p<0.05; ** p<0.01, *** p<0.001. Error bars denote SEM.
Mentions: To gain insight into the mechanisms by which GRB10 influences pancreatic β- and α-cell function, we disrupted Grb10 expression in rat insulinoma INS-1 cells by siRNA and in human islets by shRNA achieved by lentiviral transfection. There was a clear reduction in GSIS after siRNA-disruption of Grb10 in the INS-1 cell line lacking glucagon (Figure 4A). In human pancreatic islets, decreased GRB10 expression resulted in a reduction of both insulin and glucagon secretion and expression (Figure 4B, C). In addition, GRB10 knock-down was also associated with a decrease in forskolin- and K+-stimulated glucagon secretion (Figure S8A).

Bottom Line: GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion.Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis.The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

View Article: PubMed Central - PubMed

Affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, United Kingdom.

ABSTRACT
Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

Show MeSH
Related in: MedlinePlus