Persons with latent autoimmune diabetes in adults express higher dipeptidyl peptidase-4 activity compared to persons with type 2 and type 1 diabetes

Published:September 21, 2016DOI:https://doi.org/10.1016/j.diabres.2016.09.013

      Highlights

      • Difference in DPP-4 activity exists between persons with T1, T2 diabetes and LADA.
      • Dipeptidyl peptidase-4 activity is highest in persons with latent autoimmune diabetes in adults.
      • Dipeptidyl peptidase-4 activity correlates with glutamic acid autoantibody.
      • Dipeptidyl peptidase-4 inhibitors might be considered in treatment of autoimmune diabetes.

      Abstract

      Aims

      We aimed to determine serum dipeptidyl peptidase-4 (DPP-4) activity in a group of persons with latent autoimmune diabetes in adults (LADA) and to compare it with persons with type 1, type 2 diabetes and healthy controls.

      Methods

      DPP-4 activity measurement was performed in 67 persons (21 with type 1, 26 type 2 and 19 with LADA) and 13 healthy age and gender matched controls.

      Results

      Persons with LADA showed highest DPP-4 activity among the study groups (32.71 ± 3.55 vs 25.37 ± 2.84 vs 18.57 ± 2.54 vs 18.57 ± 2.61 U/L p < 0.001). Mean glutamic acid autoantibody in persons with LADA was 164.32 ± 86.28 IU/mL. It correlated with DPP-4 activity (r = 0.484, p = 0.013). Furthermore, DPP-4 activity correlated with waist circumference (r = 0.279, p = 0.034) and glycated haemoglobin A1c (r = 0.483, p < 0.001), as well as with LDL cholesterol (r = 0.854, p < 0.001) and total daily insulin dose (r = 0.397, p = 0.001). In the multinomial regression analysis DPP-4 activity remained associated with both LADA (prevalence ratio 1.058 (1.012–1.287), p = 0.001) and type 1 diabetes (prevalence ratio 1.506 (1.335–1.765), p < 0.001) while it did not show an association with type 2 diabetes (prevalence ratio 0.942 (0.713–1.988), p = 0.564).

      Conclusions

      Persons with LADA express higher DPP-4 activity compared to persons with both type 1 and type 2 diabetes. The possible pathophysiological role of DPP-4 in the LADA pathogenesis needs to be further evaluated.

      Keywords

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      References

        • American Diabetes Association
        Diagnosis and classification of diabetes mellitus.
        Diabetes Care. 2010; 33: S62-S69
        • Bluestone J.A.
        • Herold K.
        • Eisenbarth G.
        Genetics, pathogenesis and clinical interventions in type 1 diabetes.
        Nature. 2010; 464: 1293-1300
        • Bellgrau D.
        • Eisenbarth G.S.
        Immunobiology of autoimmunity.
        in: Eisenbarth G.S. Endocrine and organ specific autoimmunity. RG Landes, Austin (TX)1999: 1-18
        • Fourlanos S.
        • Dotta F.
        • Greenbaum C.J.
        • Palmer J.P.
        • Rolandsson O.
        • Colman P.G.
        • et al.
        Latent autoimmune diabetes in adults (LADA) should be less latent.
        Diabetologia. 2005; 48: 2206-2212
        • Borg H.
        • Gottsater A.
        • Fernlund P.
        • Sundkvist G.
        A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in persons with adult-onset diabetes.
        Diabetes. 2002; 51: 1754-1762
        • Falorni A.
        • Brozzetti A.
        Diabetes-related antibodies in adult diabetic persons.
        Best Pract Res Clin Endocrinol Metab. 2005; 19: 119-133
        • Brophy S.
        • Yderstraede K.
        • Mauricio D.
        • Hunter S.
        • Hawa M.
        • Pozzilli P.
        • et al.
        Time to insulin initiation cannot be used in defining latent autoimmune diabetes in adults.
        Diabetes Care. 2008; 31: 439-441
        • Davis T.M.E.
        • Wright A.D.
        • Mehta Z.M.
        • Cull C.A.
        • Stratton I.M.
        • Bottazzo G.F.
        • et al.
        Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and the relationship with metabolic control (UKPDS 70).
        Diabetologia. 2005; 48: 695-702
        • Cakirca M.
        • Karatoprak C.
        • Zorlu M.
        • Ksikac M.
        • Kanat M.
        • Cikrikcioglu M.A.
        • et al.
        Effect of vildagliptin add-on treatment to metformin on plasma asymmetric dimethylarginine in type 2 diabetes mellitus persons.
        Drug Des Devel Ther. 2014; 8: 239-243
        • Takeda Y.
        • Fujita Y.
        • Honjo J.
        • Yanagimachi T.
        • Sakagami H.
        • Takiyama Y.
        • et al.
        Reduction of both β cell death and α cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice.
        Diabetologia. 2012; 55: 404-412
        • D’Alessio D.A.
        • Denney A.M.
        • Hermiller L.M.
        • Prigeon R.L.
        • Martin J.M.
        • tharp W.G.
        • et al.
        Treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin improves fasting islet-cell function in subjects with type 2 diabetes.
        J Clin Endocrinol Metab. 2009; 94: 81-88
        • Foley J.E.
        • Bunck M.C.
        • Moller-Goede D.L.
        • Poelma M.
        • Nijpels G.
        • Eekhoff E.M.
        • et al.
        β Cell function following 1 year vildagliptin or placebo treatment and after 12 week washout in drug-naive persons with type 2 diabetes and mild hyperglycaemia: a randomised controlled trial.
        Diabetologia. 2011; 54: 1985-1991
        • Utzschneider K.M.
        • Tong J.
        • Montgomery B.
        • Udayasankar J.
        • Gerchman F.
        • Marcovina S.M.
        • et al.
        The dipeptidyl peptidase-4 inhibitor vildagliptin improves β-cell function and insulin sensitivity in subjects with impaired fasting glucose.
        Diabetes Care. 2008; 31: 108-113
        • Shah P.
        • Ardestani A.
        • Dharmadhikari G.
        • Laue S.
        • Schumann D.M.
        • Kerr-Conte J.
        • et al.
        The DPP-4 inhibitor linagliptin restores β-cell function and survival in human isolated islets through GLP-1 stabilization.
        J Clin Endocrinol Metab. 2013; 98: E1163-E1172
        • Tian L.
        • Gao J.
        • Hao J.
        • Zhang Y.
        • Yi H.
        • O’Brien T.D.
        • et al.
        Reversal of new-onset diabetes through modulating inflammation and stimulating β-cell replication in nonobese diabetic mice by a dipeptidyl peptidase IV inhibitor.
        Endocrinology. 2010; 151: 3049-3060
        • Jelsing J.
        • Vrang N.
        • van Witteloostuijn S.B.
        • Mark M.
        • Klein T.
        The DPP4 inhibitor linagliptin delays the onset of diabetes and preserves β-cell mass in non-obese diabetic mice.
        J Endocrinol. 2012; 214: 381-387
        • Varga T.
        • Firneisz G.
        • Nagy G.
        • Somogyi A.
        Elevated serum dipeptidyl peptidase-4 activity in type 1 diabetes mellitus: a direct comparison.
        Orv Hetil. 2010; 151: 899-902
        • Zhao Y.
        • Yang L.
        • Xiang Y.
        • Huang G.
        • Long Z.
        • Li X.
        • et al.
        Dipeptidyl peptidase 4 inhibitor sitagliptin maintains β-cell function in persons with recent-onset latent autoimmune diabetes in adults: one year prospective study.
        J Clin Endocrinol Metab. 2014; 99 ([Epub 2014 Jan 16]): E80-E876https://doi.org/10.1210/jc.2013-3633
        • Sacks D.B.M.
        • Arnold M.
        • Bakris G.L.
        • Bruns D.E.
        • et al.
        Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus.
        Diabetes Care. 2011; 34: e61-e99
        • Duvnjak L.
        • Blaslov K.
        • Perković M.N.
        • Ćuća J.K.
        Dipeptidyl peptidase-4 activity might be a link between tumour necrosis factor alpha and insulin resistance in type 1 diabetes.
        Endocrine. 2016; 53: 453-458
        • Sell H.
        • Blüher M.
        • Klöting N.
        • Schlich R.
        • Willems M.
        • Ruppe F.
        • et al.
        Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro.
        Diabetes Care. 2013; 36 ([PMID: 24130353]): 4083-4090https://doi.org/10.2337/dc13-0496
        • Röhrborn D.
        • Eckel J.
        • Sell H.
        Shedding of dipeptidyl peptidase 4 is mediated by metalloproteases and up-regulated by hypoxia in human adipocytes and smooth muscle cells.
        FEBS Lett. 2014; 588 ([November 3, Epub 2014 Sep 12. PMID: 25217834]): 3870-3877https://doi.org/10.1016/j.febslet.2014.08.029
        • Lambeir A.M.
        • Durinx C.
        • Scharpé S.
        • De Meester I.
        Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV.
        Crit Rev Clin Lab Sci. 2003; 40 ([PMID: 12892317]): 209-294
        • Varga T.
        • Somogyi A.
        • Barna G.
        • Wichmann B.
        • Nagy G.
        • Rácz K.
        • et al.
        Higher serum DPP-4 enzyme activity and decreased lymphocyte CD26 expression in type 1 diabetes.
        Pathol Oncol Res. 2011; 17 ([PMID: 23817599]): 925-930https://doi.org/10.1515/jpem-2013-0122
        • Iwabuchi A.
        • Kamoda T.
        • Saito M.
        • Nozue H.
        • Izumi I.
        • Hirano T.
        • et al.
        Serum dipeptidyl peptidase 4 activity in children with type 1 diabetes mellitus.
        J Pediatr Endocrinol Metab. 2013; 26: 1093-1097
        • Firneisz G.
        • Varga T.
        • Lengyel G.
        • Fehér J.
        • Ghyczy D.
        • Wichmann B.
        • et al.
        Serum dipeptidyl peptidase-4 activity in insulin resistant persons with non-alcoholic fatty liver disease: a novel liver disease biomarker.
        PLoS ONE. 2010; 5: e12226https://doi.org/10.1371/journal.pone.0012226
        • Morimoto C.
        • Schlossman S.F.
        The structure and function of CD26 in the T-cell immune response.
        Immunol Rev. 1998; 161: 55-70
        • Johansen O.E.
        • Boehm B.O.
        • Grill V.
        • Torjesen P.A.
        • Bhattacharya S.
        • Patel S.
        • et al.
        C-peptide levels in latent autoimmune diabetes in adults treated with linagliptin vs glimepiride: exploratory results from a 2-year double-blind randomized controlled study.
        Endocr Rev. 2012; 33: SUN-LB1