Antibodies against gonadotropin-releasing hormone (GnRH) in patients with diabetes mellitus is associated with lower body weight and autonomic neuropathy

BMC Research Notes

Bodil Ohlsson³  Klas Sjöberg²  Gunilla Nordin Fredrikson⁵  Ragnar Alm¹  Anders Frid⁴  Kerstin Berntorp⁴ 

[1] Department of Clinical Sciences, Experimental Cardiovascular Research Unit, Skåne University Hospital, Malmö, Lund University, Lund, Sweden;Department of Clinical Sciences, Division of Gastroenterology, Skåne University Hospital, Malmö, Lund University, Lund, Sweden;Department of Clinical Sciences, Division of Internal Medicine, Skåne University Hospital, Malmö, Lund University, Lund, Sweden;Department of Clinical Sciences, Division of Endocrinology, Skåne University Hospital, Malmö, Lund University, Lund, Sweden;Faculty of Health and Society, Malmö University, Malmö, Sweden

关键词: Secondary complications;    Gonadotropin-releasing hormone (GnRH);    Gastroparesis;    Esophageal dysmotility;    Diabetes mellitus;    Autoantibodies;   

Others  :  1141852
DOI  :  10.1186/1756-0500-6-329

 received in 2012-12-13, accepted in 2013-08-16,  发布年份 2013

【 摘 要 】

Background

Esophageal dysmotility and gastroparesis are common secondary complications in patients with diabetes mellitus. Patients with dysmotility express antibodies against gonadotropin-releasing hormone (GnRH) in serum. The aim of the present study was to scrutinize patients with diabetes mellitus with regard to the presence of GnRH antibodies, and to examine associations between antibodies and clinical findings.

Results

Thirty-nine consecutive patients with diabetes mellitus were included in the study after clinical examination and examination by esophageal manometry and gastric emptying scintigraphy. Serum was analyzed for the presence of antibodies against GnRH using an ELISA, and values are expressed as relative units (RU). Two age- and gender-matched healthy subjects per each patient served as controls. The prevalence of IgM GnRH antibodies in patients was 33% compared to 14% in controls (p = 0.027), with a higher antibody titer; 1.2 (0.6-5.0) and 0.2 (0.1-0.3) RU, respectively (p = 0.000). The expression of IgG antibodies was 15% in patients and none in controls (p = 0.000). Lower body mass index was associated with the presence of IgM antibodies (OR = 0.835, 95% CI = 0.699–0.998), and autonomic neuropathy with the presence IgG antibodies (OR = 9.000, 95% CI = 1.327–61.025). Esophageal dysmotility (69%) or gastroparesis (18%) were not associated with the presence of IgM antibodies (OR = 0.589, 95% CI = 0.143–2.424 and OR = 3.407, 95% CI = 0.633–18.350, respectively). Neither was esophageal dysmotility associated with IgG antibodies (OR = 2.500, 95% CI = 0.259–24.096).

Conclusions

Antibodies against GnRH are more common in patients with diabetes mellitus compared with healthy controls. IgM antibodies are associated with lower body mass index and IgG antibodies are associated with autonomic neuropathy.

【 授权许可】

   
2013 Berntorp et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Parkman HP, Camilleri M, Farrugia G, McCallum RW, Bharucha AE, Mayer EA, Tack JF, Spiller R, Horowitz M, Vinik AI, Galligan JJ, Pasricha PJ, Kuo B, Szarka LA, Marciani L, Jones K, Parrish CR, Sandroni P, Abell T, Ordog T, Hasler W, Koch KL, Sanders K, Norton NJ, Hamilton F: Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil 2010, 22:113-133.
• [2]Ohlsson B, Melander O, Thorson O, Olsson R, Ekberg O, Sundkvist G: Oesophageal dysmotility, delayed gastric emptying and autonomic neuropathy correlate to disturbed glucose homeostasis. Diabetologia 2006, 49:2010-2014.
• [3]Faraj J, Melander O, Sundkvist G, Olsson R, Thorsson O, Ekberg O, Ohlsson B: Oesophageal dysmotility, delayed gastric emptying and gastrointestinal symptoms in patients with diabetes mellitus. Diabet Med 2007, 24:1235-1239.
• [4]Gustafsson RJ, Littorin B, Berntorp K, Frid A, Thorsson O, Olsson R, Ekberg O, Ohlsson B: Oesophageal dysmotility is more common than gastroparesis in diabetes mellitus. Rev Diabet Stud 2011, 8:258-265.
• [5]Borg J, Melander O, Johansson L, Uvnas-Moberg K, Rehfeld JF, Ohlsson B: Gastroparesis is associated with oxytocin deficiency, oesophageal dysmotility with hyperCCKemia, and autonomic neuropathy with hypergastrinemia. BMC Gastroenterol 2009, 9:17. BioMed Central Full Text
• [6]Maeda K, Ohkura S, Uenoyama Y, Wakabayashi Y, Oka Y, Tsukamura H, Okamura H: Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res 2010, 1364:103-115.
• [7]Hazum E, Conn PM: Molecular mechanism of gonadotropin releasing hormone (GnRH) action, I. The GnRH receptor. Endocr Rev 1988, 9:379-386.
• [8]Ohlsson B, Veress B, Ekblad E, Montgomery A, Janciauskiene S: Antibodies against gonadotropin-releasing hormone (GnRH) and destruction of enteric neurons in 3 patients suffering from gastrointestinal dysfunction. BMC Gastroenterol 2010, 10:48. BioMed Central Full Text
• [9]Soldani G, Del Tacca MM, Bambini G, Polloni A, Bernardini C, Martinotti E, Martino E: Effects of gonadotropin-releasing hormone (GnRH) on gastric secretion and gastrin release in the dog. J Endocrinol Invest 1982, 5:393-396.
• [10]Khanna R, Browne RM, Heiner AD, Clench MH, Mathias JR: Leuprolide acetate affects intestinal motility in female rats before and after ovariectomy. Am J Physiol 1992, 262:G185-G190.
• [11]Mathias JR, Baskin GS, Reeves-Darby VG, Clench MH, Smith LL, Calhoon JH: Chronic intestinal pseudoobstruction in a patient with heart-lung transplant. Therapeutic effect of leuprolide acetate. Dig Dis Sci 1992, 37:1761-1768.
• [12]Gama P, Alvares EP: LHRH and somatostatin effects on the cell proliferation of the gastric epithelium of suckling and weaning rats. Regul Pept 1996, 63:73-78.
• [13]Chen L, He HX, Sun XD, Zhao J, Liu LH, Huang WQ, Zhang R-Q: Expression of gonadotropin-releasing hormone receptor and effect of gonadotropin-releasing hormone analogue on proliferation of cultured gastric smooth muscle cells of rats. World J Gastroenterol 2004, 10:1780-1784.
• [14]Hammar O, Ohlsson B, Veress B, Alm R, Fredrikson GN, Montgomery A: Depletion of enteric gonadotropin-releasing hormone is found in a few patients suffering from severe gastrointestinal dysmotility. Scand J Gastroenterol 2012, 47:1165-1173.
• [15]Sand E, Voss U, Hammar O, Alm R, Nordin Fredrikson G, Ohlsson B, Ekblad E: Gonadotropin-releasing hormone analog buserelin causes neuronal loss in rat gastrointestinal tract. Cell Tissue Res 2013, 351:521-534.
• [16]Ohlsson B, Scheja A, Janciauskiene S, Mandl T: Functional bowel symptoms and GnRH antibodies: common findings in patients with primary Sjögren’s syndrome but not in systemic sclerosis. Scand J Rheumatol 2009, 23:1-2.
• [17]Ohlsson B, Sjöberg K, Alm R, Nordin Fredrikson G: Patients with irritable bowel syndrome and dysmotility express antibodies against gonadotropin-releasing hormone in serum. Neurogastroenterol Motil 2011, 23:1000-1006.
• [18]Hoelzel W, Weykamp C, Jeppsson JO, Miedema K, Barr JR, Goodall I, Hoshino T, John WG, Kobold U, Little R, Mosca A, Mauri P, Paroni R, Susanto F, Takei I, Thienpont L, Umemoto M, Wiedmeyer HM, IFCC Working Group on HbA1c Standardization: IFCC reference system for measurement of hemoglobin A1c in human blood and the national standardization schemes in the united states, japan, and sweden: a method-comparison study. Clin Chem 2004, 50:166-174.
• [19]Spechler SJ, Castell DO: Classification of oesophageal motility abnormalities. Gut 2001, 49:145-151.
• [20]Castell JA, Dalton CB, Castell DO: Online computer analysis of human lower esophageal sphincter relaxation. Am J Physiol 1988, 255:G794-G799.
• [21]Hanson M, Lilja B: Gastric emptying in smokers. Scand J Gastroenterol 1987, 22:1102-1104.
• [22]Ho JS, Nagle GT, Mathias JR, Clench MH, Fan X, Kalmaz GD, Sallustio JE, Eaker EY: Presence of gonadotropin-releasing hormone (GnRH) receptor mRNA in rat myenteric plexus cells. Comp Biochem Physiol B Biochem Mol Biol 1996, 113:817-821.
• [23]Huang W, Yao B, Sun L, Pu R, Wang L, Zhang R: Immunohistochemical and in situ hybridization studies of gonadotropin releasing hormone (GnRH) and its receptor in rat digestive tract. Life Sci 2001, 68:1727-1734.
• [24]Darro F, Camby I, Kruczynski A, Pasteels JL, Martinez J, Kiss R: Characterisation of the influence of anti-gastrin, anti-epidermal growth factor, anti-oestradiol, and anti-luteinising hormone releasing hormone antibodies on the proliferation of 27 cell lines from the gastrointestinal tract. Gut 1995, 36:220-230.
• [25]Aguilar-Rojas A, Huerta-Reyes M: Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review). Oncol Rep 2009, 22:981-990.
• [26]Murdoch WJ: Immunolocalization of a gonadotropin-releasing hormone receptor site in murine endometrium that mediates apoptosis. Cell Tissue Res 1995, 282:527-529.
• [27]Wang L, Wu J, Cao H, Chen R, Zhang N, Fu J, Gao B, Zhang J, Hou R, Tang C, Ji Q: The correlation between intestinal gonadotropin-releasing hormone (GnRH) and proglucagon in hyperlipidemic rats and Goto-Kakizaki (GK) rats. Endocrin Pathol 2009, 20:227-234.
• [28]Krstevska-Konstantinova M, Jancevska A, Gucev Z: Autoimmune thyroiditis and diabetes mellitus type 1 after long-term gonadotropin-releasing hormone agonist treatment for central precocious puberty: evolution or coincidence? J Pediatr Endocrinol Metab 2010, 23:403-406.
• [29]Schloegl H, Percik R, Horstmann A, Villringer A, Stumvoll M: Peptide hormones regulating appetite–focus on neuroimaging studies in humans. Diabetes Metab Res Rev 2011, 27:104-112.
• [30]Small CJ, Stanley SA, Bloom SR: Appetite control and reproduction: leptin and beyond. Semin Reprod Med 2002, 20:389-398.
• [31]Fetissov SO, Sinno MH, Coquerel Q, Do Rego JC, Coëffier M, Gilbert D, Gilbert T, Déchelotte P: Emerging role of autoantibodies against appetite-regulating neuropeptides in eating disorders. Nutrition 2008, 24:854-859.
• [32]Ukkola O: Peripheral regulation of food intake: new insights. J Endocrinol Invest 2004, 27:96-98.
• [33]Mattsson T, Roos R, Sundkvist G, Valind S, Ohlsson B: Sympathetic nerve dysfunction is common in patients with chronic intestinal pseudo-obstruction. J Clin Gastroenterol 2008, 42:174-177.
• [34]Ejskjaer N, Arif S, Dodds W, Zanone MM, Vergani D, Watkins PJ, Peakman M: Prevalence of autoantibodies to autonomic nervous tissue structures in type 1 diabetes mellitus. Diabet Med 1999, 16:544-549.
• [35]Granberg V, Ejskjaer N, Peakman M, Sundkvist G: Autoantibodies to autonomic nerves associated with cardiac and peripheral autonomic neuropathy. Diabetes Care 2005, 28:1959-1964.