Summary
To clarify whether GAD-ab are associated with diabetic autonomic neuropathy and/or complement fixing antibodies against sympathetic ganglia, adrenal medulla, and vagus nerve, we examined 133 diabetic patients (95 with IDDM). GAD-ab were determined by a radioligand binding assay using in vitro expression of recombinant GAD-65 whereas sympathetic ganglia antibodies, adrenal medulla antibodies, vagus nerve, and ICA were evaluated by indirect immunofluorescence assays. Autonomic nerve function was evaluated by objective tests (heart rate reactions to deep breathing and to tilt). In the total material of 133 patients, GAD-ab were detected in 36 patients, all of whom had IDDM. The frequency of GADab was similar (38%) in IDDM patients with and without signs of autonomic neuropathy (21 of 55 vs 15 of 40). In addition, there were no significant associations between GAD-ab and autonomic nerve antibodies; GAD-ab were detected in 9 of 21 (43%) of patients with and in 27 of 112 (24%) of patients without sympathetic ganglia antibodies, in 5 of 15 (33%) of patients with and 31 of 118 (26%) without adrenal medulla antibodies, and in 5 of 15 (33%) with and 31 of 118 (26%) of patients without vagus nerve antibodies. The frequency of ICA, however, was significantly increased in patients with sympathetic ganglia antibodies compared with those without sympathetic ganglia antibodies (10 of 21 [48%] vs 21 of 112 [19%]; p<0.01). In conclusion, GAD-ab were neither associated with disturbed autonomic nerve function nor with antibodies against autonomic nerve structures.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- GAD:
-
Glutamic acid decarboxylase
- ab:
-
antibodies
- ICA:
-
islet cell antibodies
- CF-ADM:
-
complement-fixing adrenal medulla antibodies
- CF-SG:
-
complement-fixing sympathetic ganglia antibodies
- CF-V:
-
complement-fixing vagal nerve antibodies
- IDDM:
-
insulin-dependent diabetes mellitus
- NIDDM:
-
non-insulin-dependent diabetes mellitus
- JDF:
-
Juvenile Diabetes Foundation
References
Bækkeskov S, Aanstoot H-J, Christgau S et al. (1990) Identification of the 64 K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature (Lond) 347: 151–156
Bækkeskov S, Nielsen JH, Marner B, Bilde T, Ludvigsson J, Lernmark Å (1982) Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature (Lond) 298: 167–169
Bækkeskov S, Landin M, Kristensen JK et al. (1987) Antibodies to a 64 000 Mr human islet cell antigen precede the clinical onset of insulin dependent diabetes. J Clin Invest 79: 926–934
Srikanta S, Ganda OP, Gleason RE, Jackson RA, Soeldner JS, Eisenbarth GS (1984) Pre-type 1 diabetes. Linear loss beta cell response to intravenous glucose. Diabetes 33: 717–720
Landin-Olsson M, Karlsson A, Dahlquist G, Blom L, Lernmark Å, Sundkvist G (1989) Islet cell and other organ-specific autoantibodies in all children developing type 1 (insulin-dependent) diabetes mellitus in Sweden during one year and in matched controls. Diabetologia 32: 387–395
Kolb H, Dannehl K, Grüneklee D et al. (1988) Prospective analysis of islet cell antibodies in children with type 1 (insulin-dependent) diabetes. Diabetologia 31: 189–194
Wallensteen M, Dahlquist G, Persson B et al. (1988) Factors influencing the magnitude, duration, and rate of fall of B-cell function in type 1 (insulin-dependent) diabetes children followed for two years from their clinical diagnosis. Diabetologia 31: 664–669
Peig M, Gomis R, Ercilla G, Casamitjana R, Bottazzo GF, Pujol-Borell R (1989) Correlation between residual β-cell function and islet cell antibodies in newly diagnosed type 1 diabetes. Follow up study. Diabetes 38: 1396–1401
Christie MR, Daneman D, Champagne P, Delovitch TL (1990) Persistence of serum antibodies to 64,000-Mr islet cell protein after onset of type 1 diabetes. Diabetes 39: 653–656
Rowley MJ, Mackay IR, Chen Q-Y, Knowles WJ, Zimmet PZ (1992) Antibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus. Diabetes 41: 548–551
Kaufman DL, Erlander MG, Clare-Salzler M, Atkinson MA, Maclaren NK, Tobin AJ (1992) Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus. J Clin Invest 89: 283–292
Kawasaki E, Moriuchi R, Takino H et al. (1992) Autoantibodies to 64,000-Mr islet cell protein in long-term type 1 (insulin-dependent) diabetic patients. Diabetologia 35: 748–752
Sorenson RL, Garry DG, Brelje TC (1991) Structural and functional considerations of GABA in islets of Langerhans, β-cells and nerves. Diabetes 40: 1365–1374
Duchen LW, Anjorin A, Watkins PJ, Mackay JD (1980) Pathology of autonomic neuropathy in diabetes mellitus. Ann Intern Med 92: 301–303
Guy RJC, Richards F, Edmonds ME, Watkins PJ (1984) Diabetic autonomic neuropathy and iritis: an association suggesting an immunological cause. BMJ 289: 343–345
Gilbey SG, Guy RJC, Jones H, Vergani H, Watkins PJ (1986) Diabetes and autonomic neuropathy: an immunological association? Diabetic Med 3: 241–245
Gilbey SG, Hussain MJ, Watkins PJ, Vergani D (1988) Cell mediated immunity and symptomatic diabetic neuropathy. Diabetic Med 5: 845–848
Brown FM, Kamalesh M, Adri S, Rabinowe SL (1988) Antiadrenal medullary antibodies in IDDM subjects and subjects at high risk of developing IDDM. Diabetes Care 11: 30–33
Brown FM, Brink SJ, Freeman R, Rabinowe SL (1989) Antisympathetic nervous system autoantibodies. Diminished catecholamines with orthostatis. Diabetes 38: 938–941
Rabinowe SL, Brown FM, Watts M, Smith AM (1990) Complement fixing antibodies to sympathetic and parasympathetic tissues in IDDM. Autonomic brake index and heart rate variation. Diabetes Care 13: 1084–1088
Sundkvist G, Lind P, Bergström B, Lilja B, Rabinowe S (1991) Autonomic nervous autoantibodies and autonomic nerve function in type 1 and type 2 diabetic patients. J Intern Med 229: 505–510
Bergström B, Lilja B, Österlin S, Sundkvist G (1990) Autonomic neuropathy in non-insulin dependent (Type 2) diabetes mellitus. Possible influence of obesity. J Intern Med 227: 57–63
Velloso LA, Kämpe O, Hallberg A, Christmanson L, Betsholtz C, Karlsson FA (1993) Demonstration of GAD-65 as the main immunogenic isoform of glutamate decarboxylase in type 1 diabetes and determination of autoantibodies using a radioligand produced by eukaryotic expression. J Clin Invest 91: 2084–2090
Landin-Olsson M, Sundkvist G, Lernmark Å (1987) Prolonged incubation in the two-colour immunofluorescence test increases the prevalence and titres of islet cell antibodies in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30: 327–332
Brown FM, Watts M, Rabinowe SL (1991) Aggregation of subclinical autonomic nervous system dysfunction and auto-antibodies in families with type 1 diabetes. Diabetes 40: 1611–1614
Sundkvist G, Almér L-O, Lilja B (1979) Respiratory influence on heart rate in diabetes mellitus. BMJ 1: 924–925
Sundkvist G, Lilja B, Almér L-O (1980) Abnormal diastolic blood pressure and heart rate reactions to tilting in diabetes mellitus. Diabetologia 19: 433–438
Sundkvist G (1981) Autonomic nervous function in asymptomatic diabetic patients with signs of peripheral neuropathy. Diabetes Care 4: 529–534
Neil HAW, Thompson AV, John S, McCarthy ST, Mann JI (1989) Diabetic autonomic neuropathy: the prevalence of impaired heart rate variability in a geographically defined population. Diabetic Med 6: 20–24
Bergström B, Mattiasson I, Rosén I, Lilja B, Sundkvist G (1989) Platelet sodium and potassium adenosine triphosphatase activity and norepinephrine efflux rate in relation to autonomic and peripheral nerve function in insulin dependent diabetic patients. J Intern Med 225: 185–190
Sundkvist G, Armstrong FM, Bradbury JE et al. (1992) Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. J Diab Comp 6: 123–130
Tuomi T, Zimmet PZ, Rowley MJ, Serjeantson SW, Mackay IR (1993) Persisting antibodies to glutamic acid decarboxy-lase in type 1 (insulin-dependent) diabetes mellitus are not associated with neuropathy. Diabetologia 36: 685 (Letter)
Pirart J (1978) Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973. Diabetes Care 1: 168–188
Masaoka S, Lev-Ran A, Hill LR, Vakil G, Hon EHG (1985) Heart rate variability in diabetes: relationship to age and duration of the disease. Diabetes Care 8: 64–68
Bergström B, Lilja B, Österlin S, Sundkvist G (1987) Autonomic neuropathy in type 1 diabetes: influence of duration and other diabetic complications. Acta Med Scand 222: 147–154
Björk E, Kämpe O, Karlsson FA et al. (1992) Glucose regulation of the autoantigen GAD 65 in human pancreatic islets. J Clin Endocrinol Metab 75: 1574–1576
Erlander M, Tillakaratne N, Feldblum S, Patel N, Tobin AJ (1991) Two genes encode distinct glutamate decarboxylases. Neuron 7: 91–100
Atkinson MA, Maclaren NK, Scharp DW, Lacy PE, Riley WJ (1990) 64000 Mr autoantibodies as predictors of insulin-dependent diabetes. Lancet 335: 1357–1360
Bärmeier H, McCulloch DK, Neifing JL et al. (1991) Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64 K antibodies. Diabetologia 34: 727–733
Christie M, Landin-Olsson M, Sundkvist G, Dahlquist G, Lernmark Å, Bækkeskov S (1988) Antibodies to a Mr-64000 islet cell protein in Swedish children with newly diagnosed type 1 (insulin-dependent) diabetes. Diabetologia 31: 597–602
Hagopian WA, Karlsen AE, Gottsäter A et al. (1993) Quantative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64 K autoantibody positivity at onset predicts diabetes type. J Clin Invest 91: 368–374
Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR (1993) Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42: 359–362
Zanone MM, Peakman M, Purewal T, Watkins PJ, Vergani D (1993) Autoantibodies to nervous tissue structures are associated with autonomic neuropathy in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 36: 564–569
Bergström B, Manhem P, Bramnert M, Lilja B, Sundkvist G (1989) Impaired responses of plasma catecholamines to exercise in diabetic patients with abnormal heart rate reactions to tilt. Clin Phys 9: 259–267
Brown MF, Smith AM, Longway S, Rabinowe SL (1990) Adrenal medullitis in type I diabetes. J Clin Endocrinol Metab 71: 1491–1495
Brown FM, Zuckerman M, Longway S, Rabinowe SL (1989) Adrenal medullary fibrosis in IDDM of long duration. Diabetes Care 12: 494–497
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sundkvist, G., Velloso, L.A., Kämpe, O. et al. Glutamic acid decarboxylase antibodies, autonomic nerve antibodies and autonomic neuropathy in diabetic patients. Diabetologia 37, 293–299 (1994). https://doi.org/10.1007/BF00398057
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00398057