GALNT2 Expression Is Reduced in Patients with Type 2 Diabetes: Possible Role of Hyperglycemia

PLOS ONE, Dec 2019

Impaired insulin action plays a major role in the pathogenesis of type 2 diabetes, a chronic metabolic disorder which imposes a tremendous burden to morbidity and mortality worldwide. Unraveling the molecular mechanisms underlying insulin resistance would improve setting up preventive and treatment strategies of type 2 diabetes. Down-regulation of GALNT2, an UDPN-acetyl-alpha-D-galactosamine polypeptideN-acetylgalactosaminyltransferase-2 (ppGalNAc-T2), causes impaired insulin signaling and action in cultured human liver cells. In addition, GALNT2 mRNA levels are down-regulated in liver of spontaneously insulin resistant, diabetic Goto-Kakizaki rats. To investigate the role of GALNT2 in human hyperglycemia, we measured GALNT2 mRNA expression levels in peripheral whole blood cells of 84 non-obese and 46 obese non-diabetic individuals as well as of 98 obese patients with type 2 diabetes. We also measured GALNT2 mRNA expression in human U937 cells cultured under different glucose concentrations. In vivo studies indicated that GALNT2 mRNA levels were significantly reduced from non obese control to obese non diabetic and to obese diabetic individuals (p<0.001). In vitro studies showed that GALNT2 mRNA levels was reduced in U937 cells exposed to high glucose concentrations (i.e. 25 mmol/l glucose) as compared to cells exposed to low glucose concentration (i.e. 5.5 mmol/l glucose +19.5 mmol/l mannitol). In conclusion, our data indicate that GALNT2 is down-regulated in patients with type 2 diabetes and suggest that this association is, at least partly, secondary to hyperglycemia. Further studies are needed to understand whether GALNT2 down-regulation plays a pathogenic role in maintaining and/or aggravating the metabolic abnormalities of diabetic milieu.

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GALNT2 Expression Is Reduced in Patients with Type 2 Diabetes: Possible Role of Hyperglycemia

et al. (2013) GALNT2 Expression Is Reduced in Patients with Type 2 Diabetes: Possible Role of Hyperglycemia. PLoS ONE 8(7): e70159. doi:10.1371/journal.pone.0070159 GALNT2 Expression Is Reduced in Patients with Type 2 Diabetes: Possible Role of Hyperglycemia Antonella Marucci 0 Lazzaro di Mauro 0 Claudia Menzaghi 0 Sabrina Prudente 0 Davide Mangiacotti 0 Grazia Fini 0 Giuseppe Lotti 0 Vincenzo Trischitta 0 Rosa Di Paola 0 Kathrin Maedler, University of Bremen, Germany 0 1 Research Unit of Diabetes and Endocrine Diseases, IRCCS ''Casa Sollievo della Sofferenza'' , San Giovanni Rotondo , Italy , 2 Blood Bank IRCCS ''Casa Sollievo della Sofferenza'' , San Giovanni Rotondo, Italy, 3 CSS-Mendel, Rome , Italy , 4 Department of Experimental Medicine, Sapienza University , Rome , Italy Impaired insulin action plays a major role in the pathogenesis of type 2 diabetes, a chronic metabolic disorder which imposes a tremendous burden to morbidity and mortality worldwide. Unraveling the molecular mechanisms underlying insulin resistance would improve setting up preventive and treatment strategies of type 2 diabetes. Down-regulation of GALNT2, an UDPN-acetyl-alpha-D-galactosamine polypeptideN-acetylgalactosaminyltransferase-2 (ppGalNAc-T2), causes impaired insulin signaling and action in cultured human liver cells. In addition, GALNT2 mRNA levels are down-regulated in liver of spontaneously insulin resistant, diabetic Goto-Kakizaki rats. To investigate the role of GALNT2 in human hyperglycemia, we measured GALNT2 mRNA expression levels in peripheral whole blood cells of 84 non-obese and 46 obese non-diabetic individuals as well as of 98 obese patients with type 2 diabetes. We also measured GALNT2 mRNA expression in human U937 cells cultured under different glucose concentrations. In vivo studies indicated that GALNT2 mRNA levels were significantly reduced from non obese control to obese non diabetic and to obese diabetic individuals (p,0.001). In vitro studies showed that GALNT2 mRNA levels was reduced in U937 cells exposed to high glucose concentrations (i.e. 25 mmol/l glucose) as compared to cells exposed to low glucose concentration (i.e. 5.5 mmol/l glucose +19.5 mmol/l mannitol). In conclusion, our data indicate that GALNT2 is down-regulated in patients with type 2 diabetes and suggest that this association is, at least partly, secondary to hyperglycemia. Further studies are needed to understand whether GALNT2 down-regulation plays a pathogenic role in maintaining and/or aggravating the metabolic abnormalities of diabetic milieu. - Funding: This research was supported by Italian Ministry of Health Grants: RC2011 RC2012 RC2013 (R.D.P.), RC2011 (C.M.), RC2011 (S.P.), RC2011 (V.T.); and Fondazione Roma Sostegno alla ricerca scientifica biomedica 2008 (V.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. Type 2 diabetes is a chronic metabolic disorder imposing a tremendous burden to morbidity and mortality worldwide [1]. Impaired insulin action (i.e. insulin resistance, mainly in liver and skeletal muscle) plays a major role in the pathogenesis of type 2 diabetes [2,3]. Thus, unraveling the molecular mechanisms underlying insulin resistance would improve setting up preventive and treatment strategies of type 2 diabetes. We have recently reported that GALNT2, an UDPN-acetyl-alpha-D-galactosamine polypeptideN-acetylgalactosaminyltransferase-2 (ppGalNAc-T2), modulates the expression of ENPP1, an inhibitor of insulin receptor signaling, thus becoming a new potential modulator of cellular insulin action [4]. In addition, GALNT2 mRNA levels has been reported to be down-regulated in liver of spontaneously insulin resistant, diabetic Goto-Kakizaki rats as compared to control normoglycemic animals [5], thus strongly suggesting that GALNT2 has a role on insulin sensitivity and glucose homeostasis in rodents. In order to get some insights about the role of GALNT2 expression in typical conditions of human insulin resistance and hyperglycemia, we measured GALNT2 mRNA expression in peripheral whole blood cells (PWBC) of non-obese and nondiabetic individuals, obese non-diabetic insulin resistant individuals and patients with type 2 diabetes. We also investigated the effect of in vitro high glucose concentration on GALNT2 expression in human cultured cells in order to address the biology underlying the expression changes we did observe in human studies. GALNT2 mRNA Expression in Humans GALNT2 expression levels were measured in PWBC of 84 non-obese non-diabetic individuals, 46 obese non-diabetic individuals and 98 obese patients with type 2 diabetes. Salient clinical features of study subjects are shown in Table 1. Patients with type 2 diabetes were older than non-obese non-diabetic (p,0.001) as well as than obese non-d (...truncated)


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Antonella Marucci, Lazzaro di Mauro, Claudia Menzaghi, Sabrina Prudente, Davide Mangiacotti, Grazia Fini, Giuseppe Lotti, Vincenzo Trischitta, Rosa Di Paola. GALNT2 Expression Is Reduced in Patients with Type 2 Diabetes: Possible Role of Hyperglycemia, PLOS ONE, 2013, Volume 8, Issue 7, DOI: 10.1371/journal.pone.0070159