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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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Parent-of-origin effect of GRB10 rs933360 on insulin secretion and glucose levels.(A) No significant effect for CIR was observed from the paternally transmitted A-allele. (B) Carriers of the maternally transmitted A-allele showed lower CIR compared to the G-allele. (C) Carriers of the paternally transmitted A-allele had elevated fasting plasma glucose levels, whereas (D) the maternally transmitted A-allele was associated with lower fasting plasma glucose levels. Fin-Swe = Trios from Finland and Sweden, Amish = Amish Family Diabetes Study, Kuopio = Kuopio Offspring Study.
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pgen-1004235-g002: Parent-of-origin effect of GRB10 rs933360 on insulin secretion and glucose levels.(A) No significant effect for CIR was observed from the paternally transmitted A-allele. (B) Carriers of the maternally transmitted A-allele showed lower CIR compared to the G-allele. (C) Carriers of the paternally transmitted A-allele had elevated fasting plasma glucose levels, whereas (D) the maternally transmitted A-allele was associated with lower fasting plasma glucose levels. Fin-Swe = Trios from Finland and Sweden, Amish = Amish Family Diabetes Study, Kuopio = Kuopio Offspring Study.

Mentions: To explore whether GRB10 rs933360 would show a stronger effect on insulin secretion when inherited from either parent, we examined its effect on GSIS in 3,117 non-diabetic individuals from parents-offspring trios from Finland and Sweden [16] and USA [13]. In these families, the maternally transmitted A-allele of rs933360 was associated with reduced GSIS (CIR β = −0.127, p = 0.014; Ins30adjBMI β = −0.125, p = 0.005; Ins30 β = −0.112, p = 0.014; AUCIns β = −0.095, p = 0.016; AUCIns/AUCGluc β = 0.107, p = 0.005) (Figure 2A, B, Table S3B). No significant effect was observed for the paternally transmitted A-allele on GSIS. Surprisingly, the maternally transmitted A-allele was associated with reduced rather than elevated fasting glucose levels (β = −0.139, p = 0.0009). In contrast, the paternally transmitted A-allele was associated with elevated glucose levels (β = 0.102, p = 0.002) (Figure 2C, D, Table S3B). Thereby, the A-allele of rs933360 exerted virtually opposite effects on glucose metabolism if transmitted from the father than the mother. It is very likely that the association with risk or protection from T2D would be missed or diluted in any traditional association study, which does not take the transmission pattern into account.


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)

Parent-of-origin effect of GRB10 rs933360 on insulin secretion and glucose levels.(A) No significant effect for CIR was observed from the paternally transmitted A-allele. (B) Carriers of the maternally transmitted A-allele showed lower CIR compared to the G-allele. (C) Carriers of the paternally transmitted A-allele had elevated fasting plasma glucose levels, whereas (D) the maternally transmitted A-allele was associated with lower fasting plasma glucose levels. Fin-Swe = Trios from Finland and Sweden, Amish = Amish Family Diabetes Study, Kuopio = Kuopio Offspring Study.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1004235-g002: Parent-of-origin effect of GRB10 rs933360 on insulin secretion and glucose levels.(A) No significant effect for CIR was observed from the paternally transmitted A-allele. (B) Carriers of the maternally transmitted A-allele showed lower CIR compared to the G-allele. (C) Carriers of the paternally transmitted A-allele had elevated fasting plasma glucose levels, whereas (D) the maternally transmitted A-allele was associated with lower fasting plasma glucose levels. Fin-Swe = Trios from Finland and Sweden, Amish = Amish Family Diabetes Study, Kuopio = Kuopio Offspring Study.
Mentions: To explore whether GRB10 rs933360 would show a stronger effect on insulin secretion when inherited from either parent, we examined its effect on GSIS in 3,117 non-diabetic individuals from parents-offspring trios from Finland and Sweden [16] and USA [13]. In these families, the maternally transmitted A-allele of rs933360 was associated with reduced GSIS (CIR β = −0.127, p = 0.014; Ins30adjBMI β = −0.125, p = 0.005; Ins30 β = −0.112, p = 0.014; AUCIns β = −0.095, p = 0.016; AUCIns/AUCGluc β = 0.107, p = 0.005) (Figure 2A, B, Table S3B). No significant effect was observed for the paternally transmitted A-allele on GSIS. Surprisingly, the maternally transmitted A-allele was associated with reduced rather than elevated fasting glucose levels (β = −0.139, p = 0.0009). In contrast, the paternally transmitted A-allele was associated with elevated glucose levels (β = 0.102, p = 0.002) (Figure 2C, D, Table S3B). Thereby, the A-allele of rs933360 exerted virtually opposite effects on glucose metabolism if transmitted from the father than the mother. It is very likely that the association with risk or protection from T2D would be missed or diluted in any traditional association study, which does not take the transmission pattern into account.

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