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 Endocrine Disorders

Maria M Byrne⁴  Jochen HM Prehn¹  Rolf Graf³  Caroline Bonner¹  Syed R Rizvi²  Jasmin Schmid¹  Ma Peyh Kyithar²  Siobhan Bacon² 

[1] Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland;Department of Diabetes, Mater Misericordiae University Hospital, Dublin 7, Ireland;Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland;Department of Endocrinology, Mater Misericordiae University Hospital, 30 Eccles Street, Dublin 7, Ireland

关键词: Regenerating gene 1A (reg1A);    Pancreatic stone protein (PSP);    Type 1 diabetes;    Beta-Cell;    Serum biomarker;    Apoptosis;    Maturity onset diabetes of the young (MODY);   

Others  :  1086366
DOI  :  10.1186/1472-6823-12-13

 received in 2012-01-11, accepted in 2012-06-30,  发布年份 2012

【 摘 要 】

Background

Mutations in the transcription factor hepatocyte nuclear factor-1-alpha (HNF1A) result in the commonest type of maturity onset diabetes of the young (MODY). HNF1A-MODY carriers have reduced pancreatic beta cell mass, partially due to an increased rate of apoptosis. To date, it has not been possible to determine when apoptosis is occurring in HNF1A-MODY.We have recently demonstrated that beta cell apoptosis stimulates the expression of the pancreatic stone protein/regenerating (PSP/reg) gene in surviving neighbour cells, and that PSP/reg1A protein is subsequently secreted from these cells. The objective of this study was to determine whether serum levels of PSP/reg1A are elevated during disease progression in HNF1A-MODY carriers, and whether it may provide information regarding the onset of beta-cell apoptosis.

Methods

We analysed serum PSP/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY), and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed.

Results

PSP/reg1A serum levels were significantly elevated in HNF1A-MODY (n = 37) subjects compared to controls (n = 60) (median = 12.50 ng/ml, IQR = 10.61-17.87 ng/ml versus median = 10.72 ng/ml, IQR = 8.94-12.54 ng/ml, p = 0.0008). PSP/reg1A correlated negatively with insulin levels during OGTT, (rho = −0.40, p = 0.02). Interestingly we noted a significant positive correlation of PSP/reg1A with age of the HNF1A-MODY carriers (rho = 0.40 p = 0.02) with an age of 25 years separating carriers with low and high PSP/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP/reg1A compared to controls, however this was independent of the duration of diabetes.

Conclusion

Our data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25 years and over. PSP/reg1A may be developed as a serum marker to detect increased beta-cell apoptosis, or its therapeutic response.

【 授权许可】

   
2012 Bacon et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 3.

【 参考文献 】

• [1]Fajans SS, Bell GI, Polonsky KS: Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 2001, 345:971-980.
• [2]Fajans SS, Bell GI: MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care 2011, 34:1878-1884.
• [3]Ellard S, Bellanne-Chantelot C, Hattersley AT: Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 2008, 51:546-553.
• [4]Byrne MM, Sturis J, Menzel S, Yamagata K, Fajans SS, Dronsfield MJ, Bain SC, Hattersley AT, Velho G, Froguel P, et al.: Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes 1996, 45:1503-1510.
• [5]Byrne MM, Sturis J, Clement K, Vionnet N, Pueyo ME, Stoffel M, Takeda J, Passa P, Cohen D, Bell GI, et al.: Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest 1994, 93:1120-1130.
• [6]Pontoglio M, Sreenan S, Roe M, Pugh W, Ostrega D, Doyen A, Pick AJ, Baldwin A, Velho G, Froguel P, et al.: Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. J Clin Invest 1998, 101:2215-2222.
• [7]Wobser H, Dussmann H, Kogel D, Wang H, Reimertz C, Wollheim CB, Byrne MM, Prehn JH: Dominant-negative suppression of HNF-1 alpha results in mitochondrial dysfunction, INS-1 cell apoptosis, and increased sensitivity to ceramide-, but not to high glucose-induced cell death. J Biol Chem 2002, 277:6413-6421.
• [8]Wobser H, Bonner C, Nolan JJ, Byrne MM, Prehn JH: Downregulation of protein kinase B/Akt-1 mediates INS-1 insulinoma cell apoptosis induced by dominant-negative suppression of hepatocyte nuclear factor-1alpha function. Diabetologia 2006, 49:519-526.
• [9]Yamagata K, Nammo T, Moriwaki M, Ihara A, Iizuka K, Yang Q, Satoh T, Li M, Uenaka R, Okita K, et al.: Overexpression of dominant-negative mutant hepatocyte nuclear fctor-1 alpha in pancreatic beta-cells causes abnormal islet architecture with decreased expression of E-cadherin, reduced beta-cell proliferation, and diabetes. Diabetes 2002, 51:114-123.
• [10]Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel MO, Lesage S, Vionnet N, Clement K, Fougerousse F, et al.: Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 1992, 356:162-164.
• [11]Stoffel M, Patel P, Lo YM, Hattersley AT, Lucassen AM, Page R, Bell JI, Bell GI, Turner RC, Wainscoat JS: Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Nat Genet 1992, 2:153-156.
• [12]Cuesta-Munoz AL, Tuomi T, Cobo-Vuilleumier N, Koskela H, Odili S, Stride A, Buettger C, Otonkoski T, Froguel P, Grimsby J, et al.: Clinical heterogeneity in monogenic diabetes caused by mutations in the glucokinase gene (GCK-MODY). Diabetes Care 2010, 33:290-292.
• [13]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, 52:102-110.
• [14]Rehm M, Dussmann H, Janicke RU, Tavare JM, Kogel D, Prehn JH: Single-cell fluorescence resonance energy transfer analysis demonstrates that caspase activation during apoptosis is a rapid process. Role of caspase-3. J Biol Chem 2002, 277:24506-24514.
• [15]Fuchs Y, Steller H: Programmed cell death in animal development and disease. Cell 2011, 147:742-758.
• [16]Bonner C, Bacon S, Concannon CG, Rizvi SR, Baquie M, Farrelly AM, Kilbride SM, Dussmann H, Ward MW, Boulanger CM, et al.: INS-1 cells undergoing caspase-dependent apoptosis enhance the regenerative capacity of neighboring cells. Diabetes 2010, 59:2799-2808.
• [17]Graf R, Schiesser M, Lussi A, Went P, Scheele GA, Bimmler D: Coordinate regulation of secretory stress proteins (PSP/reg, PAP I, PAP II, and PAP III) in the rat exocrine pancreas during experimental acute pancreatitis. J Surg Res 2002, 105:136-144.
• [18]Bimmler D, Angst E, Valeri F, Bain M, Scheele GA, Frick TW, Graf R: Regulation of PSP/reg in rat pancreas: immediate and steady-state adaptation to different diets. Pancreas 1999, 19:255-267.
• [19]Robertson RP, Harmon J, Tran PO, Poitout V: Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 2004, 53(Suppl 1):S119-S124.
• [20]Keel M, Harter L, Reding T, Sun LK, Hersberger M, Seifert B, Bimmler D, Graf R: Pancreatic stone protein is highly increased during posttraumatic sepsis and activates neutrophil granulocytes. Crit Care Med 2009, 37:1642-1648.
• [21]Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT: A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med 2009, 26:437-441.
• [22]Kyithar MP, Bacon S, Pannu KK, Rizvi SR, Colclough K, Ellard S, Byrne MM: Identification of HNF1A-MODY and HNF4A-MODY in Irish families: phenotypic characteristics and therapeutic implications. Diabetes Metab 2011, 37:512-519.
• [23]Teuscher AU, Kendall DM, Smets YF, Leone JP, Sutherland DE, Robertson RP: Successful islet autotransplantation in humans: functional insulin secretory reserve as an estimate of surviving islet cell mass. Diabetes 1998, 47:324-330.
• [24]Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM: Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 2002, 51:2148-2157.
• [25]Evgenov NV, Medarova Z, Dai G, Bonner-Weir S, Moore A: In vivo imaging of islet transplantation. Nat Med 2006, 12:144-148.
• [26]Malaisse WJ: On the track to the beta-cell. Diabetologia 2001, 44:393-406.
• [27]Christofilis MA, Carrere J, Atlan-Gepner C, Zevaco-Mattei C, Thivolet C, Baeza N, Figarella C, Vialettes B: Serum reg protein level is not related to the beta cell destruction/regeneration process during early phases of diabetogenesis in type I diabetes. Eur J Endocrinol 1999, 141:368-373.
• [28]Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC: Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 2005, 48:2221-2228.
• [29]Keenan HA, Sun JK, Levine J, Doria A, Aiello LP, Eisenbarth G, Bonner-Weir S, King GL: Residual insulin production and pancreatic ss-cell turnover after 50 years of diabetes: Joslin Medalist Study. Diabetes 2010, 59:2846-2853.
• [30]Lohr M, Kloppel G: Residual insulin positivity and pancreatic atrophy in relation to duration of chronic type 1 (insulin-dependent) diabetes mellitus and microangiopathy. Diabetologia 1987, 30:757-762.
• [31]Madsbad S, Kehlet H, Hilsted J, Tronier B: Discrepancy between plasma C-peptide and insulin response to oral and intravenous glucose. Diabetes 1983, 32:436-438.
• [32]Tatemichi N, Takahashi C, Hayakawa S, Hayakawa T, Shibata T, Kitagawa M, Sobajima H, Nakae Y: Enzyme immunoassay and characterization of pancreatic stone proteins in human urine. J Clin Lab Anal 1993, 7:365-370.
• [33]Hayakawa T, Naruse S, Kitagawa M, Nakae Y, Harada H, Ochi K, Kuno N, Kurimoto K, Hayakawa S: Pancreatic stone protein and lactoferrin in human pancreatic juice in chronic pancreatitis. Pancreas 1995, 10:137-142.
• [34]Schmiegel W, Burchert M, Kalthoff H, Roeder C, Butzow G, Grimm H, Kremer B, Soehendra N, Schreiber HW, Thiele HG, et al.: Immunochemical characterization and quantitative distribution of pancreatic stone protein in sera and pancreatic secretions in pancreatic disorders. Gastroenterology 1990, 99:1421-1430.
• [35]Jin CX, Hayakawa T, Ko SB, Ishiguro H, Kitagawa M: Pancreatic stone protein/regenerating protein family in pancreatic and gastrointestinal diseases. Intern Med 2011, 50:1507-1516.
• [36]Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, Bertolotto C, Di Mario U, Harlan DM, Perfetti R: Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003, 144:5149-5158.
• [37]Chen D, Liao J, Li N, Zhou C, Liu Q, Wang G, Zhang R, Zhang S, Lin L, Chen K, et al.: A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db/db mice. Proc Natl Acad Sci U S A 2007, 104:943-948.
• [38]DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA, Clement SC, Henry RR, Hodis HN, Kitabchi AE, et al.: Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med 2011, 364:1104-1115.
• [39]Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, Hu Y, Zhou Z, Yan X, Tian H, et al.: Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet 2008, 371:1753-1760.
• [40]Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006, 355:2427-2443.