Effect of a common variant of the PCSK2 gene on reduced insulin secretion

Jonsson, Anna; Isomaa, Bo; Tuomi, Tiinamaija; Eriksson, Johan G.; Groop, Leif; Lyssenko, Valeriya

doi:10.1007/s00125-012-2728-5

Cited by 17 publications

(15 citation statements)

References 29 publications

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“…A significant difference in the allele frequency distribution of a simple CA tandem-repeat DNA polymorphism (STRP) in intron 2 of PCSK2 has been reported in a case-control study of T2DM patients and normal controls in a Japanese population 26 ( Table 5 ). Jonssan et al recently reported that the C allele of PCSK2 rs2208203 in intron 2 was associated with reduced insulin secretion measured as the corrected insulin response as well as disposition index 40 . The variant was also associated with lower fasting glucagon levels in non-diabetic individuals with FPG over 5.5 mmol/l 40 ( Table 5 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population

Chang

Chiu

Sheu

et al. 2015

Sci Rep

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Proprotein convertase subtilisin/kexin type 2 (PCSK2) is a prohormone processing enzyme involved in insulin and glucagon biosynthesis. We previously found the genetic polymorphism of PCSK2 on chromosome 20 was responsible for the linkage peak of several glucose homeostasis parameters. The aim of this study is to investigate the association between genetic variants of PCSK2 and glucose homeostasis parameters and incident diabetes. Total 1142 Chinese participants were recruited from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family study, and 759 participants were followed up for 5 years. Ten SNPs of the PCSK2 gene were genotyped. Variants of rs6044695 and rs2284912 were associated with fasting plasma glucose, and variants of rs2269023 were associated with fasting plasma glucose and 1-hour plasma glucose during OGTT. Haplotypes of rs4814605/rs1078199 were associated with fasting plasma insulin levels and HOMA-IR. Haplotypes of rs890609/rs2269023 were also associated with fasting plasma glucose, fasting insulin and HOMA-IR. In the longitudinal study, we found individuals carrying TA/AA genotypes of rs6044695 or TC/CC genotypes of rs2284912 had lower incidence of diabetes during the 5-year follow-up. Our results indicated that PCSK2 gene polymorphisms are associated with pleiotropic effects on various traits of glucose homeostasis and incident diabetes.

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Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population

Chang

Chiu

Sheu

et al. 2015

Sci Rep

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“…We also investigated the expression of genes related to metabolic and immune functions. Ins1 was decreased in 8-day BBdp rats, while expression of Pcsk2, a proprotein convertase that participates in both insulin and glucagon production, was upregulated (Jonsson et al 2012) (Fig. 4A); Pcsk1 was unchanged.…”

Section: Journal Of Endocrinologymentioning

confidence: 99%

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Crookshank

Serrano

Wang

et al. 2018

Journal of Endocrinology

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It is unknown whether there is a gene signature in pancreas which is associated with type 1 diabetes (T1D). We performed partial pancreatectomies on 30 day preinsulitic, diabetes-prone BioBreeding (BBdp) rats to prospectively identify factors involved in early prediabetes. Microarrays of the biopsies revealed downregulation of ER stress, metabolism and apoptosis. Based on these results, additional investigations compared gene expression in control (BBc) and BBdp rats age ~8, 30 and 60 days using RT-qPCR. Neonates had increased ER stress gene expression in pancreas. This was associated with decreased insulin, cleaved caspase-3 and Ins1 whereas Gcg and Pcsk2 were increased. The increase in ER stress was not sustained at 30 days and decreased by 60 days. In parallel, the liver gene profile showed a similar signature in neonates but with an early decrease of the unfolded protein response (UPR) at 30 days. This suggested that changes in the liver precede those in the pancreas. Tnf and Il1b expression was increased in BBdp pancreas in association with increased caspase-1, cleaved caspase-3 and decreased proinsulin area. Glucagon area was increased in both 30 day and 60 day BBdp rats. Increased co-localization of BIP and proinsulin was observed at 60 days in the pancreas, suggesting insulin-related ER dysfunction. We propose that dysregulated metabolism leads to ER stress in neonatal rats long before insulitis, creating a microenvironment in both pancreas and liver that promotes autoimmunity.

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“…Therefore, they may regulate growth hormone and downstream hormone production, including IGF1 and possibly also insulin. Pcsk2 was reported to be involved in processing insulin, glucagon, somatostatin, and amylin (43)(44)(45). Here, we show for the first time that IGF1 is significantly reduced when Pcsk2 is depleted.…”

Section: Continuous and Time-specific Genetic Regulation Of Igf1 In Dmentioning

confidence: 49%

Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1

Yuan

Gatti

Krier

et al. 2014

The Journals of Gerontology: Series A

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We previously reported that insulin-like growth factor 1 (IGF1) was involved in coregulating female sexual maturation and longevity. To understand the underlying genetic mechanisms, based on the strain survey assays of development and aging traits, we crossed two mouse strains, KK/HIJ and PL/J, and produced 307 female F2 mice. We observed the age of vaginal patency (AVP) and the life span of these females. We also measured circulating IGF1 level at 7, 16, 24, 52, and 76 weeks. IGF1 level at 7 weeks significantly correlated with AVP. IGF1 levels at ages of 52 and 76 weeks negatively correlated with longevity (p ≤ .05). A gene mapping study found 22, 4 ,and 3 quantitative trait loci for IGF1, AVP, and life span, respectively. Importantly, the colocalization of IGF1, AVP, and life span quantitative trait loci in the distal region of chromosome 2 suggests this locus carries gene(s) that could regulate IGF1, AVP, and life span. In this region, proprotein convertase subtilisin/kexin type 2 has been found to be associated with female sexual maturation in a human genome-wide association study. We verified the roles of proprotein convertase subtilisin/kexin type 2 in regulating IGF1 and AVP by showing that depletion of proprotein convertase subtilisin/kexin type 2 significantly reduced IGF1 and delayed AVP in mice, suggesting that it also might be involved in the regulation of aging.Key Words: Female sexual maturation-Life span-Genetics-Mouse-Pcsk2. Decision Editor: Rafael de Cabo, PhDThe evolutionary theory of aging predicts the existence of pleiotropic genes that mediate female sexual maturation (FSM) and life span (1,2). Several lines of evidence support this hypothesis. In the invertebrates, researchers found that allowing only older female Drosophila to reproduce resulted in decreased female fecundity and increased life span in later generations (3,4). In wild mammalian species, ranging from mice to elephants show that the later the initial age of reproduction, the longer the life span (5). The tradeoff holds within species as well. For example, opossums living on a predator-free island in Virginia matured later and aged more slowly than opossums on the "more dangerous" mainland (6). Mice trapped in the wild had delayed FSM and greater female reproduction life span and longevity compared with laboratory mice (7,8). However, the underlying genetic and molecular mechanisms have yet to be clarified.Our previous studies systematically measured age of FSM and longevity in more than 30 mouse inbred strains (9,10). The age of

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Effect of a common variant of the PCSK2 gene on reduced insulin secretion

Cited by 17 publications

References 29 publications

Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population

Genetic polymorphisms of PCSK2 are associated with glucose homeostasis and progression to type 2 diabetes in a Chinese population

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1

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