title: Identification of novel genes for glucose metabolism based upon expression pattern in human islets and effect on insulin secretion and glycemia.
abstract: Normal glucose homeostasis is characterized by appropriate insulin secretion and low HbA1c. Gene expression signatures associated with these two phenotypes could be essential for islet function and pathophysiology of type 2 diabetes (T2D). Herein, we employed a novel approach to identify candidate genes involved in T2D by correlating islet microarray gene expression data (78 donors) with insulin secretion and HbA1c level. The expression of 649 genes (P < 0.05) was correlated with insulin secretion and HbA1c. Of them, five genes (GLR1A, PPP1R1A, PLCDXD3, FAM105A and ENO2) correlated positively with insulin secretion/negatively with HbA1c and one gene (GNG5) correlated negatively with insulin secretion/positively with HbA1c were followed up. The five positively correlated genes have lower expression levels in diabetic islets, whereas GNG5 expression is higher. Exposure of human islets to high glucose for 24 h resulted in up-regulation of GNG5 and PPP1R1A expression, whereas the expression of ENO2 and GLRA1 was down-regulated. No effect was seen on the expression of FAM105A and PLCXD3. siRNA silencing in INS-1 832/13 cells showed reduction in insulin secretion for PPP1R1A, PLXCD3, ENO2, FAM105A and GNG5 but not GLRA1. Although no SNP in these gene loci passed the genome-wide significance for association with T2D in DIAGRAM+ database, four SNPs influenced gene expression in cis in human islets. In conclusion, we identified and confirmed PPP1R1A, FAM105A, ENO2, PLCDX3 and GNG5 as potential regulators of islet function. We provide a list of candidate genes as a resource for exploring their role in the pathogenesis of T2D.
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden jalal.taneera@med.lu.se.
authors.forename: Jalal
authors.initials: J
authors.lastname: Taneera
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden.
authors.forename: Joao
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Atac
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden.
authors.forename: Emilia
authors.initials: E
authors.lastname: Ottosson-Laakso
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden Department of Cell Physiology and Metabolism, Université de Genève, University Medical Centre, 1 rue Michel-Servet, Geneva 4 1211, Switzerland.
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Skåne University Hospital, Lund University, 205 02 Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D005947:Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; C517652:hemoglobin A1c protein, human