Association of Obesity Risk SNPs in PCSK1 with Insulin Sensitivity and Proinsulin Conversion

Overview

Journal BMC Med Genet

Publisher Biomed Central

Specialty Genetics

Date 2010 Jun 11

PMID 20534142

Citations 29

Authors

Martin Heni

Axel Haupt

Silke A Schafer

Caroline Ketterer

Claus Thamer

Fausto Machicao

Norbert Stefan

Harald Staiger

Hans-Ulrich Haring

Andreas Fritsche

Affiliations

Soon will be listed here.

Abstract

Background: Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, beta-cell dysfunction, or glucose intolerance.

Methods: We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp.

Results: The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p >or= 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: p(additive) model <or= 0.009, effect sizes 8/8%, rs6232: pdominant model <or= 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p >or= 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom <or= 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism.

Conclusions: Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis.

Citing Articles

Integrating metabolomics and proteomics to identify novel drug targets for heart failure and atrial fibrillation.

van Vugt M, Finan C, Chopade S, Providencia R, Bezzina C, Asselbergs F Genome Med. 2024; 16(1):120.

PMID: 39434187 PMC: 11492627. DOI: 10.1186/s13073-024-01395-4.

scParser: sparse representation learning for scalable single-cell RNA sequencing data analysis.

Zhao K, So H, Lin Z Genome Biol. 2024; 25(1):223.

PMID: 39152499 PMC: 11328435. DOI: 10.1186/s13059-024-03345-0.

Association of and Allelic Variants with Obesity and Metabolic Syndrome in Mexican Adults.

Velazquez-Roman J, A Angulo-Zamudio U, Leon-Sicairos N, Flores-Villasenor H, Benitez-Baez M, Espinoza-Salomon A Genes (Basel). 2023; 14(9).

PMID: 37761915 PMC: 10531047. DOI: 10.3390/genes14091775.

Association between Genotype and the Glycemic Response to an Oral Glucose Tolerance Test: A Systematic Review.

Bayer S, Reik A, von Hesler L, Hauner H, Holzapfel C Nutrients. 2023; 15(7).

PMID: 37049537 PMC: 10096950. DOI: 10.3390/nu15071695.

LC-MS/MS based detection of circulating proinsulin derived peptides in patients with altered pancreatic beta cell function.

Foreman R, Meek C, Roberts G, George A, Reimann F, Gribble F J Chromatogr B Analyt Technol Biomed Life Sci. 2022; 1211:123482.

PMID: 36242807 PMC: 7614196. DOI: 10.1016/j.jchromb.2022.123482.

References

Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, van Haeften T . Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care. 2000; 23(3):295-301. DOI: 10.2337/diacare.23.3.295. View

Benzinou M, Creemers J, Choquet H, Lobbens S, Dina C, Durand E . Common nonsynonymous variants in PCSK1 confer risk of obesity. Nat Genet. 2008; 40(8):943-5. DOI: 10.1038/ng.177. View

Zhu X, Orci L, Carroll R, Norrbom C, Ravazzola M, Steiner D . Severe block in processing of proinsulin to insulin accompanied by elevation of des-64,65 proinsulin intermediates in islets of mice lacking prohormone convertase 1/3. Proc Natl Acad Sci U S A. 2002; 99(16):10299-304. PMC: 124908. DOI: 10.1073/pnas.162352799. View

Rouille Y, Duguay S, Lund K, Furuta M, Gong Q, Lipkind G . Proteolytic processing mechanisms in the biosynthesis of neuroendocrine peptides: the subtilisin-like proprotein convertases. Front Neuroendocrinol. 1995; 16(4):322-61. DOI: 10.1006/frne.1995.1012. View

Kirchhoff K, Machicao F, Haupt A, Schafer S, Tschritter O, Staiger H . Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia. 2008; 51(4):597-601. DOI: 10.1007/s00125-008-0926-y. View

Jackson R, Creemers J, Farooqi I, Raffin-Sanson M, Varro A, Dockray G . Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J Clin Invest. 2003; 112(10):1550-60. PMC: 259128. DOI: 10.1172/JCI18784. View

Matsuda M, DeFronzo R . Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999; 22(9):1462-70. DOI: 10.2337/diacare.22.9.1462. View

Hager J, Dina C, Francke S, Dubois S, Houari M, Vatin V . A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat Genet. 1998; 20(3):304-8. DOI: 10.1038/3123. View

Seidah N, Chretien M . Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides. Brain Res. 2000; 848(1-2):45-62. DOI: 10.1016/s0006-8993(99)01909-5. View

10.

Fujinami A, Ohta K, Obayashi H, Fukui M, Hasegawa G, Nakamura N . Serum brain-derived neurotrophic factor in patients with type 2 diabetes mellitus: Relationship to glucose metabolism and biomarkers of insulin resistance. Clin Biochem. 2008; 41(10-11):812-7. DOI: 10.1016/j.clinbiochem.2008.03.003. View

11.

Khatib A, Siegfried G, Chretien M, Metrakos P, Seidah N . Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy. Am J Pathol. 2002; 160(6):1921-35. PMC: 1850825. DOI: 10.1016/S0002-9440(10)61140-6. View

12.

Jackson R, Creemers J, Ohagi S, Raffin-Sanson M, Sanders L, Montague C . Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet. 1997; 16(3):303-6. DOI: 10.1038/ng0797-303. View

13.

Farooqi I, Volders K, Stanhope R, Heuschkel R, White A, Lank E . Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. J Clin Endocrinol Metab. 2007; 92(9):3369-73. DOI: 10.1210/jc.2007-0687. View

14.

Mykkanen L, Haffner S, Hales C, Ronnemaa T, Laakso M . The relation of proinsulin, insulin, and proinsulin-to-insulin ratio to insulin sensitivity and acute insulin response in normoglycemic subjects. Diabetes. 1997; 46(12):1990-5. DOI: 10.2337/diab.46.12.1990. View

15.

Seidah N, Mayer G, Zaid A, Rousselet E, Nassoury N, Poirier S . The activation and physiological functions of the proprotein convertases. Int J Biochem Cell Biol. 2008; 40(6-7):1111-25. DOI: 10.1016/j.biocel.2008.01.030. View

16.

Bell C, Benzinou M, Siddiq A, Lecoeur C, Dina C, Lemainque A . Genome-wide linkage analysis for severe obesity in french caucasians finds significant susceptibility locus on chromosome 19q. Diabetes. 2004; 53(7):1857-65. DOI: 10.2337/diabetes.53.7.1857. View

17.

Frayling T, Timpson N, Weedon M, Zeggini E, Freathy R, Lindgren C . A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007; 316(5826):889-94. PMC: 2646098. DOI: 10.1126/science.1141634. View

18.

Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K . Identification and characterization of metabolically benign obesity in humans. Arch Intern Med. 2008; 168(15):1609-16. DOI: 10.1001/archinte.168.15.1609. View

19.

Steiner D . The proprotein convertases. Curr Opin Chem Biol. 1998; 2(1):31-9. DOI: 10.1016/s1367-5931(98)80033-1. View

20.

Chagnon Y, Rice T, Perusse L, Borecki I, Lacaille M, Pare C . Genomic scan for genes affecting body composition before and after training in Caucasians from HERITAGE. J Appl Physiol (1985). 2001; 90(5):1777-87. DOI: 10.1152/jappl.2001.90.5.1777. View