OBJECTIVES: 1) To compare serum levels of regenerating islet-derived 1 alpha (Reg1α) proteins in type 1 diabetics, type 2 diabetics and controls and correlate them with their clinical/biochemical parameters.
2) To compare Reg1α levels in diabetics with and without disease complications.
METHODS: In this cross sectional comparative study, ten type 1 diabetics and thirty type 2 diabetics were recruited from Medical department of PNS Shifa hospital, Karachi. Twenty controls were selected from among friends and relatives with non diabetic background. Biochemical parameters like Fasting blood glucose (FBG), Glycosylated Hemoglobin (HbA1c), Total Cholesterol (TC) and Triglycerides (TG) were measured. Serum levels of Reg1α were analyzed using ELISA.
RESULTS: Reg1α protein levels, compared to controls were significantly higher (p <001) in both type 1 and 2 diabetics with increase more discernible in case of type 2. A decrease in the Reg1α levels was observed with increase in the duration of the disease in type 2 diabetes patients. However the levels of the protein remained significantly higher than the controls. Patients with diabetic complications had higher protein levels as compared to diabetics without complications. We observed positive correlation of Reg1α with age at onset of disease in case of type 1 diabetics (p<0.05). Patients with risk factors like high body mass index and smoking had higher protein levels.
CONCLUSION: Reg1α proteins in types 1 and 2 diabetes patients can be used as biological marker for detection of β-cell apoptosis and regeneration independently. It may be used to identify patients with disease complications.
KEY WORDS: Diabetes Mellitus (MeSH); Hemoglobin A, Glycosylated (MeSH); Blood HbA1c protein, human (MeSH); Regenerating Islet-Derived 1 alpha Protein (MeSH), Diabetes complications (MeSH)
Chiang JL, Kirkman MS, Laffel LM, Peters AL, Type 1 Diabetes Sourcebook A. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes care 2014;37(7):2034-54.
Saisho Y. beta-cell dysfunction: Its critical role in prevention and management of type 2 diabetes. World J Diab 2015;6(1):109-24.
Matveyenko AV, Butler PC. Relationship between beta-cell mass and diabetes onset. Diabetes, obesity & metabolism 2008;10 Suppl 4:23-31.
Terazono K, Yamamoto H, Takasawa S, Shiga K, Yonemura Y, Tochino Y, et al. A novel Cgene activated in regenerating islets. J Biol Chem 1988;263(5):2111-4.
Watanabe T, Yonemura Y, Yonekura H, Suzuki Y, Miyashita H, Sugiyama K, et al. Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(9):3589-92.
Zenilman ME, Magnuson TH, Swinson K, Egan J, Perfetti R, Shuldiner AR. Pancreatic thread protein is mitogenic to pancreatic-derived cells in culture. Gastroenterol 1996;110(4):1208-14.
Levine JL, Patel KJ, Zheng Q, Shuldiner AR, Zenilman ME. A recombinant rat regenerating protein is mitogenic to pancreatic derived cells. J Surg Res 2000;89(1):60-5.
Kobayashi S, Akiyama T, Nata K, Abe M, Tajima M, Shervani NJ, et al. Identification of a receptor for reg (regenerating gene) protein, a pancreatic beta-cell regeneration factor. J Biol Chem 2000;275(15):10723-6.
Unno M, Nata K, Noguchi N, Narushima Y, Akiyama T, Ikeda T, et al. Production and characterization of Reg knockout mice: reduced proliferation of pancreatic beta-cells in Reg knockout mice. Diabetes 2002;51 Suppl 3:S478-83.
Bluth M, Mueller CM, Pierre J, Callender G, Kandil E, Viterbo D, et al. Pancreatic regenerating protein I in chronic pancreatitis and aging: implications for new therapeutic approaches to diabetes. Pancreas 2008;37(4):386-95.
Okamoto H. The Reg gene family and Reg proteins: with special attention to the regeneration of pancreatic beta-cells. J Hepatobiliary Pancreat Surg 1999;6(3):254-62.
Calderari S, Irminger JC, Giroix MH, Ehses JA, Gangnerau MN, Coulaud J, et al. Regenerating 1 and 3b gene expression in the pancreas of type 2 diabetic Goto-Kakizaki (GK) rats. PloS one. 2014;9(2):e90045.
Akiyama T, Takasawa S, Nata K, Kobayashi S, Abe M, Shervani NJ, et al. Activation of Reg gene, a gene for insulin-producing beta -cell regeneration: poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(1):48-53.
Gurr W, Yavari R, Wen L, Shaw M, Mora C, Christa L, et al. A Reg family protein is overexpressed in islets from a patient with new-onset type 1 diabetes and acts as T-cell autoantigen in NOD mice. Diabetes 2002;51(2):339-46.
Shervani NJ, Takasawa S, Uchigata Y, Akiyama T, Nakagawa K, Noguchi N, et al. Autoantibodies to REG, a beta-cell regeneration factor, in diabetic patients. Eur J Clin Invest 2004;34(11):752-8.
American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes care. 2010;33 Suppl 1:S62-9.
Astorri E, Guglielmi C, Bombardieri M, Alessandri C, Buzzetti R, Maggi D, et al. Circulating Reg1alpha proteins and autoantibodies to Reg1alpha proteins as biomarkers of beta-cell regeneration and damage in type 1 diabetes. Horm Metab Res 2010;42(13):955-60.
Bacon S, Kyithar MP, Schmid J, Rizvi SR, Bonner C, Graf R, et al. Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward. BMC Endocr Disord 2012;12:13.
Yang J, Li L, Raptis D, Li X, Li F, Chen B, et al. Pancreatic stone protein/regenerating protein (PSP/reg): a novel secreted protein up-regulated in type 2 diabetes mellitus. Endocrine. 2015;48(3):856-62..
Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nature reviews Drug discovery. 2014;13(6):465-76.
Wang X, Bao W, Liu J, Ouyang YY, Wang D, Rong S, et al. Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis. Diabetes care 2013;36(1):166-75.
Yamauchi A, Itaya-Hironaka A, Sakuramoto-Tsuchida S, Takeda M, Yoshimoto K, Miyaoka T, et al. Synergistic Activations of REG Iα and REG Iβ Promoters by IL-6 and Glucocorticoids through JAK/STAT Pathway in Human Pancreatic β Cells. J Diabetes Res 2015;2015:173058.
Bonner C, Bacon S, Concannon CG, Rizvi SR, Baquie M, Farrelly AM, et al. INS-1 cells undergoing caspase-dependent apoptosis enhance the regenerative capacity of neighboring cells. Diabetes 2010;59(11):2799-808.
De Tata V. Age-related impairment of pancreatic Beta-cell function: pathophysiological and cellular mechanisms. Front Endocrinol (Lausanne) 2014;5:138.
Lencioni C, Lupi R, Del Prato S. Beta-cell failure in type 2 diabetes mellitus. Curr Diab Rep 2008;8(3):179-84.
Perfetti R, Egan JM, Zenilman ME, Shuldiner AR. Differential expression of reg-I and reg-II genes during aging in the normal mouse. J Gerontol A Biol Sci Med Sci 1996;51(5):B308-15.
Qiu L, List EO, Kopchick JJ. Differentially expressed proteins in the pancreas of diet-induced diabetic mice. Mol Cell Proteomics 2005;4(9):1311-8.
Keel M, Harter L, Reding T, Sun LK, Hersberger M, Seifert B, et al. Pancreatic stone protein is highly increased during posttraumatic sepsis and activates neutrophil granulocytes. Crit Care Med 2009;37(5):1642-8.
Klein HJ, Csordas A, Falk V, Slankamenac K, Rudiger A, Schonrath F, et al. Pancreatic stone protein predicts postoperative infection in cardiac surgery patients irrespective of cardiopulmonary bypass or surgical technique. PloS one. 2015;10(3):e0120276.
Llewelyn MJ, Berger M, Gregory M, Ramaiah R, Taylor AL, Curdt I, et al. Sepsis biomarkers in unselected patients on admission to intensive or high-dependency care. Crit Care 2013;17(2):R60.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52(1):102-10.
Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 2014;105(2):141-50.
Xie XT, Liu Q, Wu J, Wakui M. Impact of cigarette smoking in type 2 diabetes development. Acta Pharmacologica Sinica. 2009;30(6):784-7.
Scherr A, Graf R, Bain M, Christ-Crain M, Muller B, Tamm M, et al. Pancreatic stone protein predicts positive sputum bacteriology in exacerbations of COPD. Chest 2013;143(2):379-87.
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