Top

Open Access 17-04-2024 | Insulins | Original Article

GALNT2 expression is associated with glucose control and serum metabolites in patients with type 2 diabetes

Authors: Vincenzo Trischitta, Alessandra Antonucci, Claudia Menzaghi, Antonella Marucci, Rosa Di Paola

Abstract

Aims

Aim of this study was to investigate in type 2 diabetes whether expression level of GALNT2, a positive modulator of insulin sensitivity, is associated with a metabolic signature.

Methods

Five different metabolite families, including acylcarnitines, aminoacids, biogenic amines, phospholipids and sphingolipids were investigated in fasting serum of 70 patients with type 2 diabetes, by targeted metabolomics. GALNT2 expression levels were measured in peripheral white blood cells by RT-PCR. The association between GALNT2 expression and serum metabolites was assessed using false discovery rate followed by stepwise selection and, finally, multivariate model including several clinical parameters as confounders. The association between GALNT2 expression and the same clinical parameters was also investigated.

Results

GALNT2 expression was independently correlated with HbA1c levels (P value = 0.0052), a finding that is the likely consequence of the role of GALNT2 on insulin sensitivity. GALNT2 expression was also independently associated with serum levels of the aminoacid glycine (P value = 0.014) and two biogenic amines phenylethylamine (P value = 0.0065) and taurine (P value = 0.0011). The association of GALNT2 expression with HbA1c was not mediated by these three metabolites.

Conclusions

Our data indicate that in type 2 diabetes the expression of GALNT2 is associated with several serum metabolites. This association needs to be further investigated to understand in depth its role in mediating the effect of GALNT2 on insulin sensitivity, glucose control and other clinical features in people with diabetes.

Available only for authorised users

Reaven GM (1988) Banting lecture 1988: role of insulin resistance in human disease. Diabetes 37(12):1595–607. https://doi.org/10.2337/diab.37.12.1595CrossRefPubMed

Wilson PW, D’Agostino RB, Parise H, Sullivan L, Meigs JB (2005) Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 112(20):3066–3072. https://doi.org/10.1161/CIRCULATIONAHA.105.539528CrossRefPubMed

WHO (2017) Noncommunicable diseases, progress monitor

Schjoldager KT, Narimatsu Y, Joshi HJ, Clausen H (2020) Global view of human protein glycosylation pathways and functions. Nat Rev Mol Cell Biol 21(12):729–749. https://doi.org/10.1038/s41580-020-00294-xCrossRefPubMed

Steentoft C, Vakhrushev SY, Joshi HJ et al (2013) Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology. EMBO J 32(10):1478–1488. https://doi.org/10.1038/emboj.2013.79CrossRefPubMedPubMedCentral

Antonucci A, Marucci A, Trischitta V, Di Paola R (2022) Role of GALNT2 on insulin sensitivity, lipid metabolism and fat homeostasis. Int J Mol Sci 23(2):1. https://doi.org/10.3390/ijms23020929CrossRef

Marucci A, Cozzolino F, Dimatteo C et al (2013) Role of GALNT2 in the modulation of ENPP1 expression, and insulin signaling and action GALNT2: a novel modulator of insulin signaling. BBA Mol Cell Res 1833(6):1388–1395. https://doi.org/10.1016/j.bbamcr.2013.02.032CrossRef

Marucci A, Antonucci A, De Bonis C et al (2019) GALNT2 as a novel modulator of adipogenesis and adipocyte insulin signaling. Int J Obes (Lond) 43(12):2448–2457. https://doi.org/10.1038/s41366-019-0367-3CrossRefPubMed

Roberts F, Zhu D, Farquharson C, Macrae VE (2019) ENPP1 in the regulation of mineralization and beyond. Trends Biochem Sci 44(7):616–628. https://doi.org/10.1016/j.tibs.2019.01.010CrossRefPubMed

10.

Maddux BA, Sbraccia P, Kumakura S et al (1995) Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature 373(6513):448–451. https://doi.org/10.1038/373448a0CrossRefPubMed

11.

Maddux BA, Goldfine ID (2000) Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Diabetes 49(1):13–19. https://doi.org/10.2337/diabetes.49.1.13CrossRefPubMed

12.

Maddux BA, Chang YN, Accili D, McGuinness OP, Youngren JF, Goldfine ID (2006) Overexpression of the insulin receptor inhibitor PC-1/ENPP1 induces insulin resistance and hyperglycemia. Am J Physiol Endocrinol Metab 290(4):E746–E749. https://doi.org/10.1152/ajpendo.00298.2005CrossRefPubMed

13.

Di Paola R, Caporarello N, Marucci A et al (2011) ENPP1 affects insulin action and secretion: evidences from in vitro studies. PLoS ONE 6(5):e19462. https://doi.org/10.1371/journal.pone.0019462CrossRefPubMedPubMedCentral

14.

Dimatteo C, Marucci A, Palazzo A et al (2013) Role of somatomedin-B-like domains on ENPP1 inhibition of insulin signaling. Biochim Biophys Acta 1833(3):552–558. https://doi.org/10.1016/j.bbamcr.2012.10.017CrossRefPubMed

15.

Khetarpal SA, Schjoldager KT, Christoffersen C et al (2016) Loss of function of GALNT2 lowers high-density lipoproteins in humans, nonhuman primates, and rodents. Cell Metab 24(2):234–245. https://doi.org/10.1016/j.cmet.2016.07.012CrossRefPubMedPubMedCentral

16.

Kathiresan S, Melander O, Guiducci C et al (2008) Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 40(2):189–197. https://doi.org/10.1038/ng.75CrossRefPubMedPubMedCentral

17.

Lee YH, Nair S, Rousseau E et al (2005) Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes. Diabetologia 48(9):1776–1783. https://doi.org/10.1007/s00125-005-1867-3CrossRefPubMedPubMedCentral

18.

Li X, Zhang Y, Zhang M, Wang Y (2020) GALNT2 regulates ANGPTL3 cleavage in cells and in vivo of mice. Sci Rep 10(1):1–9. https://doi.org/10.1038/s41598-020-73388-3CrossRef

19.

Schjoldager KTBG, Vester-Christensen MB, Bennett EP et al (2010) O-glycosylation modulates proprotein convertase activation of angiopoietin-like protein 3: possible role of polypeptide GalNAc-transferase-2 in regulation of concentrations of plasma lipids. J Biol Chem 285(47):36293–36303. https://doi.org/10.1074/jbc.M110.156950CrossRefPubMedPubMedCentral

20.

Willer CJ, Sanna S, Jackson AU et al (2008) Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40(2):161–169. https://doi.org/10.1038/ng.76CrossRefPubMedPubMedCentral

21.

Willer CJ, Mohlke KL (2012) Finding genes and variants for lipid levels after genome-wide association analysis. Curr Opin Lipidol 23(2):98–103. https://doi.org/10.1097/MOL.0b013e328350fad2CrossRefPubMedPubMedCentral

22.

Teslovich TM, Musunuru K, Smith AV et al (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466(7307):707–713. https://doi.org/10.1038/nature09270CrossRefPubMedPubMedCentral

23.

Roman TS, Marvelle AF, Fogarty MP et al (2015) Multiple hepatic regulatory variants at the GALNT2 GWAS locus associated with high-density lipoprotein cholesterol. Am J Hum Genet 97(6):801–815. https://doi.org/10.1016/j.ajhg.2015.10.016CrossRefPubMedPubMedCentral

24.

Marucci A, di Mauro L, Menzaghi C et al (2013) GALNT2 expression is reduced in patients with Type 2 diabetes: possible role of hyperglycemia. PLoS ONE 8(7):e70159. https://doi.org/10.1371/journal.pone.0070159CrossRefPubMedPubMedCentral

25.

Almon RR, DuBois DC, Lai W, Xue B, Nie J, Jusko WJ (2009) Gene expression analysis of hepatic roles in cause and development of diabetes in Goto-Kakizaki rats. J Endocrinol 200(3):331–346. https://doi.org/10.1677/JOE-08-0404CrossRefPubMed

26.

Zilmer M, Edmondson AC, Khetarpal SA et al (2020) Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function. Brain 143(4):1114–1126. https://doi.org/10.1093/brain/awaa063CrossRefPubMedPubMedCentral

27.

Chen J, Guan L, Liu H, Liu Q, Fan P, Bai H (2021) GALNT2 gene variant rs4846914 is associated with insulin and insulin resistance depending on BMI in PCOS patients: a case-control study. Reprod Sci 28(4):1122–1132. https://doi.org/10.1007/s43032-020-00380-7CrossRefPubMed

28.

Yang Q, Vijayakumar A, Kahn BB (2018) Metabolites as regulators of insulin sensitivity and metabolism. Nat Rev Mol Cell Biol 19(10):654–672. https://doi.org/10.1038/s41580-018-0044-8CrossRefPubMedPubMedCentral

29.

Scarale MG, Mastroianno M, Prehn C et al (2022) Circulating metabolites associate with and improve the prediction of all-cause mortality in type 2 diabetes. Diabetes 71(6):1363–1370. https://doi.org/10.2337/db22-0095CrossRefPubMed

30.

Vandesompele J, De Preter K, Pattyn F et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. https://doi.org/10.1186/gb-2002-3-7-research0034CrossRefPubMedPubMedCentral

31.

Bennett DA (2001) How can I deal with missing data in my study? Aust N Z J Public Health 25(5):464–469CrossRefPubMed

32.

Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B (Methodol) 57(1):289–300. https://doi.org/10.1111/j.2517-6161.1995.tb02031.xCrossRef

33.

Thalacker-Mercer AE, Ingram KH, Guo F, Ilkayeva O, Newgard CB, Garvey WT (2014) BMI, RQ, diabetes, and sex affect the relationships between amino acids and clamp measures of insulin action in humans. Diabetes 63(2):791–800. https://doi.org/10.2337/db13-0396CrossRefPubMedPubMedCentral

34.

Newgard CB, An J, Bain JR et al (2009) A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9(4):311–326. https://doi.org/10.1016/j.cmet.2009.02.002CrossRefPubMedPubMedCentral

35.

Palmer ND, Stevens RD, Antinozzi PA et al (2015) Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study. J Clin Endocrinol Metab 100(3):E463–E468. https://doi.org/10.1210/jc.2014-2357CrossRefPubMed

36.

Floegel A, Stefan N, Yu Z et al (2013) Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. Diabetes 62(2):639–648. https://doi.org/10.2337/db12-0495CrossRefPubMedPubMedCentral

37.

Guasch-Ferré M, Hruby A, Toledo E et al (2016) Metabolomics in prediabetes and diabetes: a systematic review and meta-analysis. Diabetes Care 39(5):833–846. https://doi.org/10.2337/dc15-2251CrossRefPubMedPubMedCentral

38.

Felig P, Marliss E, Cahill GF (1969) Plasma amino acid levels and insulin secretion in obesity. N Engl J Med 281(15):811–816. https://doi.org/10.1056/NEJM196910092811503CrossRefPubMed

39.

Wang-Sattler R, Yu Z, Herder C et al (2012) Novel biomarkers for pre-diabetes identified by metabolomics. Mol Syst Biol 8:615. https://doi.org/10.1038/msb.2012.43CrossRefPubMedPubMedCentral

40.

Wang TJ, Larson MG, Vasan RS et al (2011) Metabolite profiles and the risk of developing diabetes. Nat Med 17(4):448–453. https://doi.org/10.1038/nm.2307CrossRefPubMedPubMedCentral

41.

Ferrannini E, Natali A, Camastra S et al (2013) Early metabolic markers of the development of dysglycemia and type 2 diabetes and their physiological significance. Diabetes 62(5):1730–1737. https://doi.org/10.2337/db12-0707CrossRefPubMedPubMedCentral

42.

Sun S, He D, Luo C et al (2021) Metabolic syndrome and its components are associated with altered amino acid profile in chinese han population. Front Endocrinol (Lausanne) 12:795044. https://doi.org/10.3389/fendo.2021.795044CrossRefPubMed

43.

Sak D, Erdenen F, Müderrisoglu C et al (2019) The relationship between plasma taurine levels and diabetic complications in patients with type 2 diabetes mellitus. Biomolecules 9(3):1. https://doi.org/10.3390/biom9030096CrossRef

44.

De Luca G, Calpona PR, Caponetti A et al (2001) Taurine and osmoregulation: platelet taurine content, uptake, and release in type 2 diabetic patients. Metabolism 50(1):60–64. https://doi.org/10.1053/meta.2001.19432CrossRefPubMed

45.

Rosa FT, Freitas EC, Deminice R, Jordão AA, Marchini JS (2014) Oxidative stress and inflammation in obesity after taurine supplementation: a double-blind, placebo-controlled study. Eur J Nutr 53(3):823–830. https://doi.org/10.1007/s00394-013-0586-7CrossRefPubMed

46.

Lee MY, Cheong SH, Chang KJ, Choi MJ, Kim SK (2003) Effect of the obesity index on plasma taurine levels in Korean female adolescents. Adv Exp Med Biol 526:285–290. https://doi.org/10.1007/978-1-4615-0077-3_36CrossRefPubMed

47.

Tsuboyama-Kasaoka N, Shozawa C, Sano K et al (2006) Taurine (2-aminoethanesulfonic acid) deficiency creates a vicious circle promoting obesity. Endocrinology 147(7):3276–3284. https://doi.org/10.1210/en.2005-1007CrossRefPubMed

48.

Zhai L, Xiao H, Lin C et al (2023) Gut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome. Nat Commun 14(1):4986. https://doi.org/10.1038/s41467-023-40552-yCrossRefPubMedPubMedCentral

49.

Long SE, Jacobson MH, Wang Y et al (2022) Longitudinal associations of pre-pregnancy BMI and gestational weight gain with maternal urinary metabolites: an NYU CHES study. Int J Obes (Lond) 46(7):1332–1340. https://doi.org/10.1038/s41366-022-01116-0CrossRefPubMed

50.

Võsa U, Claringbould A, Westra HJ et al (2021) Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat Genet 53(9):1300–1310. https://doi.org/10.1038/s41588-021-00913-zCrossRefPubMedPubMedCentral

51.

Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612. https://doi.org/10.7326/0003-4819-150-9-200905050-00006CrossRefPubMedPubMedCentral

Title: GALNT2 expression is associated with glucose control and serum metabolites in patients with type 2 diabetes
Authors: Vincenzo Trischitta
Alessandra Antonucci
Claudia Menzaghi
Antonella Marucci
Rosa Di Paola
Publication date: 17-04-2024
Publisher: Springer Milan
Keywords: Insulins
Insulins
Type 2 Diabetes
Published in: Acta Diabetologica
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-024-02280-7

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com