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

Chang, Tien-Jyun; Chiu, Yen‐Feng; Sheu, Wayne Huey‐Herng; Shih, KC; Hwu, Chii‐Min; Quertermous, Thomas; Jou, Yuh–Shan; Kuo, Shan-Shan; Chang, Yi‐Cheng; Chuang, Lee‐Ming

doi:10.1038/srep14380

Cited by 22 publications

(15 citation statements)

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“…Global KO Fasting hypoglycaemia, lowered IPGTT glycemia, lack mature glucagon, αand δ-cell hyperplasia, elevated des-31, 32 proinsulin and intact proinsulin [35][36][37][38] Cpe Global KO Obesity, hyperglycaemia, neurological defects, hyperleptinemia 39,40 Cpe HbA1c. 25 Further intronic SNPs have been tied to increased T2D risk (rs2021785), 22 lowered T2D risk 24 and no T2D risk, despite associations with elevated area under the curve of plasma insulin and glucose during OGTT 24 (Table 1).…”

Section: Pcsk2mentioning

confidence: 99%

Islet prohormone processing in health and disease

Chen

Taylor

Verchere

2018

Diabetes Obesity Metabolism

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Biosynthesis of peptide hormones by pancreatic islet endocrine cells is a tightly orchestrated process that is critical for metabolic homeostasis. Like neuroendocrine peptides, insulin and other islet hormones are first synthesized as larger precursor molecules that are processed to their mature secreted products through a series of proteolytic cleavages, mediated by the prohormone convertases Pc1/3 and Pc2, and carboxypeptidase E. Additional posttranslational modifications including C-terminal amidation of the β-cell peptide islet amyloid polypeptide (IAPP) by peptidyl-glycine α-amidating monooxygenase (Pam) may also occur. Genome-wide association studies (GWAS) have showed genetic linkage of these processing enzymes to obesity, β-cell dysfunction, and type 2 diabetes (T2D), pointing to their important roles in metabolism and blood glucose regulation. In both type 1 diabetes (T1D) and T2D, and in the face of metabolic or inflammatory stresses, islet prohormone processing may become impaired; indeed elevated proinsulin:insulin (PI:I) ratios are a hallmark of the β-cell dysfunction in T2D. Recent studies suggest that genetic or acquired defects in proIAPP processing may lead to the production and secretion of incompletely processed forms of proIAPP that could contribute to T2D pathogenesis, and additionally that impaired processing of both PI and proIAPP may be characteristic of β-cell dysfunction in T1D. In islet α-cells, the prohormone proglucagon is normally processed to bioactive glucagon by Pc2 but may express Pc1/3 under certain conditions leading to production of GLP-1(7-36 ). A better understanding of how β-cell processing of PI and proIAPP, as well as α-cell processing of proglucagon, are impacted by genetic susceptibility and in the face of diabetogenic stresses, may lead to new therapeutic approaches for improving islet function in diabetes.

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Section: Pcsk2mentioning

confidence: 99%

Islet prohormone processing in health and disease

Chen

Taylor

Verchere

2018

Diabetes Obesity Metabolism

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“…While intronic PCSK2 variants are present at minor allele frequencies (MAF) of up to 8% [16], exonic variants are extremely rare in the outbred population. Fourteen putative missense variants were identified in the NHLBI Exome Sequencing Project (ESP), T2D-Genes, and 1000Genomes phase 1 databases (C18G, R47S, E52K, A77D, R81C, D123N, N221D, P244Q, A267T, A385V, R430W, M525V, T569I, and Q595L).…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have found both positive and negative associations between intronic variants in PCSK2 and increased T2D risk [13, 14, 16–18]. Since coding variants in PCSK2 are very rare in outbred populations, no information exists on whether variants confer a loss or gain of function for this enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…Work in a Chinese population confirmed association between rs2021785 and T2D risk, and a study in a Japanese population also found clear association between an intronic PCSK2 microsatellite and diabetes risk [13, 14]. In a longitudinal study, Chang et al [16] found that individuals carrying certain intronic PCSK2 variants (rs6044695 and rs2284912) had a lower incidence of diabetes during a 5-year follow-up, suggesting a protective effect of these particular variants (or linked genes). The repeated association between PCSK2 variants and diabetes risk, either positive or negative, in a variety of human populations suggests that differences in PC2 activity, potentially affecting peptide hormone cleavage and thus glycemic control, may represent an important factor in the progression to T2D.…”

Section: Introductionmentioning

confidence: 99%

“…Increasing evidence from genome-wide association studies suggests that at least 9 common variants in the gene encoding human PC2, PCSK2, are associated with diabetes risk and related traits in human populations ([13–15]; summarized in [16]). The PCSK2 intronic variant rs2208203 was associated with lower fasting glucagon levels, as well as reduced insulin secretion, in a Scandinavian population [17].…”

Section: Introductionmentioning

confidence: 99%

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Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population

Winters

Ramos‐Molina

Jarvela

et al. 2017

Diabetes Research and Clinical Practice

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Aims In humans, noncoding variants of PCSK2, the gene encoding prohormone convertase 2 (PC2), have been previously associated with risk for and age of onset of type 2 diabetes (T2D). The aims of this study were to identify coding variants in PCSK2; to determine their possible association with glucose handling; and to determine functional outcomes for coding variants in biochemical studies. Methods Exome-wide genotyping was performed on 1725 Old Order Amish (OOA) subjects. PCSK2 coding variants were tested for association with diabetes-related phenotypes. In vitro analyses using transfected human PC2-encoding constructs were performed to determine the impact of each mutation on PC2 activity. Results We identified 10 rare missense coding variants in PCSK2 in various genomic databases. R430W (rs200711626) is greatly enriched in the OOA population (MAF 4.3%). This variant is almost twice as common (MAF 7.4%) in OOA individuals with T2D as in OOA individuals with normal or with normal/impaired glucose tolerance (MAF 3.9% and 2.9%, respectively; p= 0.25 and p=0.10). In vitro experiments revealed a broadening of the pH optimum for the R430W variant, which may result in increased activity against PCSK2 substrates. Conclusions Although the association of the R430W variation with T2D in the OOA population did not reach significance, based upon the broadened pH profile of R430W PC2, we speculate that the presence of this substitution may result in altered processing of PCSK2 substrates, ultimately leading to increased conversion to diabetes.

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Hippocampal changes in mice lacking an active prohormone convertase 2

DeVera

Yang

et al. 2020

Hippocampus

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Prohormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2‐null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2‐null state may affect the function of the hippocampus. In this study, adult PC2‐null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2‐null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field‐excitatory postsynaptic potentials (EPSP), long‐term potentiation (LTP), and paired‐pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2‐null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2‐null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2‐null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2‐null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2‐null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2‐null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.

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

Cited by 22 publications

References 50 publications

Islet prohormone processing in health and disease

Islet prohormone processing in health and disease

Functional analysis of PCSK2 coding variants: A founder effect in the Old Order Amish population

Hippocampal changes in mice lacking an active prohormone convertase 2

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