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Hypoglycaemia causes degeneration of large myelinated nerve fibres in the vagus nerve of insulin-treated diabetic BB/Wor rats

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Abstract

The aim of this study was to find out whether dysglycaemia causes neuropathy in the vagus nerve of insulin-treated diabetic BB/Wor rats. Specimens were collected from the left vagus nerve proximal and distal to the level of recurrent laryngeal branch and from the recurrent branch itself in control rats and diabetic BB/Wor rats subjected to hyper- or hypoglycaemia. Myelinated and unmyelinated axons were counted and myelinated axon diameters were measured by electron microscopy. In controls, the vagus nerve proximal to the recurrent branch exhibited three regions in terms of fibre composition: part A was mainly composed of large myelinated axons, part B contained small myelinated and unmyelinated axons, and part C contained mainly unmyelinated axons. The distal level resembled part C at the proximal level and the recurrent branch resembled parts A and B. In hyperglycaemic rats, a normal picture was found at the proximal and distal levels of the vagus nerve and in the recurrent branch. In hypoglycaemic rats, signs of past and ongoing degeneration and regeneration of large myelinated axons were found at the proximal and distal levels and in the recurrent branch. We conclude that hypoglycaemia elicits degenerative alterations in large myelinated axons in the vagus and recurrent laryngeal nerves in diabetic BB/Wor rats. The absence of signs of neuropathy in unmyelinated and small myelinated axons suggests that the sensory and autonomic components of the nerve are less affected. In contrast, the hyperglycaemic rats examined here did not show obvious degenerative alterations.

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References

  1. Altschuler SM, Bao XM, Bieger D, Hopkins DA, Miselis RR (1989) Viscerotopic representation of the upper alimentary tract in the rat: sensory ganglia and nuclei of the solitary and spinal trigeminal tracts. J Comp Neurol 283:248–268

    CAS  PubMed  Google Scholar 

  2. Bolinder J, Sjöberg S, Persson A, Ahrén B, Sundkvist G (2002) Autonomic neuropathy is associated with impaired pancreatic polypeptide and neuropeptide Y responses to insulin-induced hypoglycaemia in Type 1 diabetic patients. Diabetologia 45:1043–1044

    CAS  PubMed  Google Scholar 

  3. Bott S, Bott U, Berger M, Mühlhauser I (1997) Intensified insulin therapy and the risk of severe hypoglycaemia. Diabetologia 40:926–932

    Article  CAS  PubMed  Google Scholar 

  4. Bottini P, Boschetti E, Pampanelli S, Ciofetta M, Del Sindaco P, Scionti L, Brunetti P, Bolli GB (1997) Contribution of autonomic neuropathy to reduced plasma adrenaline responses to hyperglycaemia in IDDM. Diabetes 46:814–823

    CAS  PubMed  Google Scholar 

  5. Chiarelli F, Verrotti A, Catino M, Sabatino G, Pinelli L (1999) Hypoglycaemia in children with type 1 diabetes mellitus. Acta Paediatr 427:31–34

    Google Scholar 

  6. Cryer PE (1999) Symptoms of hypoglycaemia, thresholds for their occurrence, and hypoglycaemia unawareness. Endocrinol Metab Clin North Am 28:495–500

    CAS  PubMed  Google Scholar 

  7. Dahlqvist Å, Carlsöö B, Hellström S (1982) Fibre components of the recurrent laryngeal nerve of the rat: a study by light and electron microscopy. Anat Rec 204:365–370

    CAS  PubMed  Google Scholar 

  8. Dahlqvist Å, Carlsöö B, Hellström S, Domeij S, Kourtopoulos H (1986) Fibre composition of the recurrent laryngeal nerve after experimental vagotomy and sympathectomy. A qualitative study by light and electron microscopy. Acta Anat 125:114–120

    CAS  PubMed  Google Scholar 

  9. Dahlqvist Å, Hellström S, Carlsöö B, Perquignot JM (1987) Paraganglia of the rat recurrent laryngeal nerve after long-term hypoxia: a morphometric and biochemical study. J Neurocytol 16:289–297

    CAS  PubMed  Google Scholar 

  10. Dahlqvist Å, Pequignot JM, Hellström S (1991) Laryngeal nerve paraganglia of the rat are morphologically and biochemically unchanged by long-term hypercapnia. Neurosci Lett 134:25–28

    CAS  PubMed  Google Scholar 

  11. Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986

    Article  PubMed  Google Scholar 

  12. Diani AR, Grogan DM, Yates ME, Risinger DL, Gerritsen GC (1979) Radiologic changes and autonomic neuropathology in the digestive tract of the ketonuric diabetic Chinese hamster. Diabetologia 17:33–40

    CAS  PubMed  Google Scholar 

  13. Dovas A, Lucchi ML, Bortolami R, Grandis A, Palladino AR, Banelli E, Caretta M, Magni F, Paolocci N (1998) Collaterals of recurrent laryngeal nerve fibres innervate the thymus: a fluorescent tracer and HRP investigation of efferent vagal neurons in the rat brainstem. Brain Res 809:141–148

    Article  CAS  PubMed  Google Scholar 

  14. Duchen LW, Anjorin A, Watkins PJ, Mackay JD (1980) Pathology of autonomic neuropathy in diabetes mellitus. Ann Intern Med 92:301–303

    CAS  PubMed  Google Scholar 

  15. Evans DHL, Murray JG (1954) Histological and functional studies on the fibre composition of the vagus nerve of the rabbit. J Anat 88:320–337

    Google Scholar 

  16. Fox EA, Powley TL (1985) Longitudinal columnar organization within the dorsal motor nucleus represents separate branches of the abdominal vagus. Brain Res 341:269–282

    Article  CAS  PubMed  Google Scholar 

  17. Gabella G, Pease HL (1973) Number of axons in the abdominal vagus of the rat. Brain Res 58:465–469

    Article  CAS  PubMed  Google Scholar 

  18. Gaster B, Hirsch IB (1998) The effects of improved glycaemic control on complications in type 2 diabetes. Arch Intern Med 158:134–140

    Article  CAS  PubMed  Google Scholar 

  19. Gerich JE, Mokan M, Veneman T, Korytkowski M, Mitrakou A (1991) Hypoglycaemia unawareness. Endocr Rev 12:356–371.

    CAS  PubMed  Google Scholar 

  20. Greene EC (1963) Anatomy of the rat. Hafner, New York

  21. Guy RJC, Dawson JL, Garrett JR, Laws JW, Thomas PK, Sharma AK, Watkins PJ (1984) Diabetic gastroparesis from autonomic neuropathy: surgical considerations and changes in vagus nerve morphology. J Neurol Neurosurg Psychiatry 47:686–691

    CAS  PubMed  Google Scholar 

  22. Haak T (1999) New developments in the treatment of type 1 diabetes mellitus. Exp Clin Endocrinol Diabetes 107 Suppl 3:S108–113

    Google Scholar 

  23. Hinrichsen CFL, Ryan AT (1981) Localization of laryngeal motoneurons in the rat: morphologic evidence for dual innervation? Exp Neurol 74:341–355

    Article  CAS  PubMed  Google Scholar 

  24. Hisa Y, Lyon MJ, Malmgren LT (1985) Central projection of the sensory component of the rat recurrent laryngeal nerve. Neurosci Lett 55:185–190

    Article  CAS  PubMed  Google Scholar 

  25. Hoeldtke RD, Boden G (1994) Epinephrine secretion, hypoglycaemia unawareness and diabetic autonomic neuropathy. Ann Intern Med 120:512-517

    CAS  PubMed  Google Scholar 

  26. Jacob HJ, Pettersson A, Wilson D, Mao Y, Lernmark A, Lander ES (1992) Genetic dissection of autoimmune type I diabetes in the BB rat. Nat Genet 2:56–60

    Article  CAS  PubMed  Google Scholar 

  27. Jamali R, Ludvigsson J, Mohseni S (2002) Continuous monitoring of the subcutaneous glucose level in freely moving normal and diabetic rats and in humans with type 1 diabetes. Diabetes Technol Ther 4:305–312

    Article  CAS  PubMed  Google Scholar 

  28. Kalia M, Mesulam M-M (1980) Brain stem projections of sensory and motor components of the vagus complex in the cat. I. The cervical vagus and nodose ganglia. J Comp Neurol 193:435–465

    CAS  PubMed  Google Scholar 

  29. Kalia M, Mesulam M-M (1980) Brain stem projections of sensory and motor components of the vagus complex in the cat. II. Laryngeal, tracheobronchial, cardiac and gastrointestinal bronchus. J Comp Neurol 193:467–508

    CAS  PubMed  Google Scholar 

  30. Karnes J, Robb R, O’Brien PC, Lambert EH, Dyck PJ (1977) Computerized image recognition for morphometry of nerve attribute of shape of sampled transverse sections of myelinated fibres which best estimates their average diameter. J Neurol Sci 34:43–51

    Article  CAS  PubMed  Google Scholar 

  31. Kohno T, Mori S, Mito M (1987) Cells of origin innervating the liver and their axonal projections with synaptic terminals into the liver parenchyma in rats. Hokkaido Igaku Zasshi 62:933–946

    CAS  PubMed  Google Scholar 

  32. Kristensson K, Nordborg C, Olsson Y, Sourander P (1971) Changes in the vagus nerve in diabetes mellitus. Acta Pathol Microbiol Scand 79:684–685

    CAS  Google Scholar 

  33. Lu K-S, Chien C-L, Chau Y-P (1992) Effects of 5-hydroxydopamine and 6-hydroxydopamine on the ultrastructure of type I cells in paraganglia of the rat recurrent nerve. Arch Histol Cytol 55:57–65

    CAS  Google Scholar 

  34. Malik T, Trence DL (2003) Treating diabetes using oral agents. Prim Care 30:527–541

    PubMed  Google Scholar 

  35. Mandelbaum JA, Felten DL, Westfall SG, Newlin GE, Peterson RG (1983) Neuropathic changes associated with insulin treatment of diabetic rats: electron microscopic and morphometric analysis. Brain Res Bull 10:377–384

    CAS  PubMed  Google Scholar 

  36. Marca MC, Loste A, Unzueta A, Perez M (2000) Blood glycated hemoglobin evaluation in sick dogs. Can J Vet Res 64:141–144

    CAS  PubMed  Google Scholar 

  37. Mohseni S (2000) Hypoglycaemic neuropathy in diabetic BB/Wor rats treated with insulin implants affects ventral root axons but not dorsal root axons. Acta Neuropathol 100:415–420

    Article  CAS  PubMed  Google Scholar 

  38. Mohseni S (2001) Hypoglycaemic neuropathy. Acta Neuropathol 102:413–421

    CAS  PubMed  Google Scholar 

  39. Mohseni S, Hildebrand C (1998) Neuropathy in diabetic BB/Wor rats treated with insulin implants. Acta Neuropathol 96:144–150

    Article  CAS  PubMed  Google Scholar 

  40. Mohseni S, Hildebrand C (1998) Hypoglycaemic neuropathy in BB/Wor rats treated with insulin implants: electron microscopic observations. Acta Neuropathol 96:151–156

    Article  CAS  PubMed  Google Scholar 

  41. Mohseni S, Lillesaar C, Theodorsson E, Hildebrand C (2000) Hypoglycaemic neuropathy: occurrence of axon terminals in plantar skin and plantar muscle of diabetic BB/Wor rats treated with insulin implants. Acta Neuropathol 99:257–262

    CAS  PubMed  Google Scholar 

  42. Nordfeldt S, Ludvigsson J (1999) Adverse events in intensively treated children and adolescents with type I diabetes. Acta Paediatr 88:1184–1193

    CAS  PubMed  Google Scholar 

  43. Norgren R, Smith GP (1988) Central distribution of subdiaphragmatic vagal branches in the rat. J Comp Neurol 273:207–223

    CAS  PubMed  Google Scholar 

  44. Patrickson JW, Smith TE, Zhou S-S (1991) Motor neurons of the laryngeal nerves. Anat Rec 230:551–556

    CAS  PubMed  Google Scholar 

  45. Patrickson JW, Smith TE, Zhou S-S (1991) Afferent projections of the superior and recurrent laryngeal nerves. Brain Res 539:169–174

    Article  CAS  PubMed  Google Scholar 

  46. Perkins BA, Bril V (2003) Diabetic neuropathy: a review emphasizing diagnostic methods. Clin Neurophysiol 114:1167–1175

    PubMed  Google Scholar 

  47. Powley TL, Fox EA, Berthoud HR (1987) Retrograde tracer technique for assessment of selective and total subdiaphragmatic vagotomies. Am J Physiol 253:361–370

    Google Scholar 

  48. Prechtl JC, Powley TL (1987) A light and electron microscopic examination of the vagal hepatic branch of the rat. Anat Embryol 176:115–126

    CAS  PubMed  Google Scholar 

  49. Prechtl JC, Powley TL (1990) The fibre composition of the abdominal vagus of the rat. Anat Embryol 181:101–115

    Article  CAS  PubMed  Google Scholar 

  50. Qi BQ, Merei J, Farmer P, Hasthorpe S, Myers NA, Beasley SW, Hutson JM (1997) The vagus and recurrent laryngeal nerves in the rodent experimental model of esophageal atresia. J Pediat Surg 32:1580–1586

    Article  CAS  PubMed  Google Scholar 

  51. Robertson DM, Sima AAF (1980) Diabetic neuropathy in the mutant mouse [C57BL/ks(db/db)]: a morphometric study. Diabetes 29:60–67

    CAS  PubMed  Google Scholar 

  52. Romeo HE, Diaz MC, Ceppi J, Zaninovich AA, Cardinali DP (1988) Effect of inferior laryngeal nerve section on thyroid function in rats. Endocrinology 122:2527–2532

    CAS  PubMed  Google Scholar 

  53. Scheen AJ (2003) Treatment of type 2 diabetes. Acta Clin Belg 58:318–324

    PubMed  Google Scholar 

  54. Schmidt RE, Plurad SB, Modert CW (1983) Experimental autonomic neuropathy. Characterization in streptozotocin-diabetic Sprague-Dawley rats. Lab Invest 49:538–552

    CAS  PubMed  Google Scholar 

  55. Sharma AK, Thomas PK (1974) Peripheral nerve structure and function in experimental diabetes. J Neurol Sci 23:1–15

    Article  CAS  PubMed  Google Scholar 

  56. Sharma AK, Duguid IGM, Blanchard DS, Thomas PK (1985) The effect of insulin treatment on myelinated nerve fibre maturation and integrity and on body growth in streptozotocin-diabetic rats. J Neurol Sci 67:285–297

    Article  CAS  PubMed  Google Scholar 

  57. Smith D, Amiel SA (2002) Hypoglycaemia unawareness and the brain. Diabetologia 45:949–958

    Article  CAS  PubMed  Google Scholar 

  58. Stathakis P, Fernando DA, Lord RSA (1994) The course of the right recurrent laryngeal nerve within the vagus nerve of the rat. Acta Anat 149:70–73

    CAS  PubMed  Google Scholar 

  59. Tay SS, Wong WC (1994) Short- and long-term effects of streptozotocin-induced diabetes on the dorsal motor nucleus of the vagus nerve in the rat. Acta Anat (Basel) 150:274-281

    Google Scholar 

  60. Westfall SG, Felten DL, Mandelbaum JA, Moore SA, Peterson RG (1983) Degenerative neuropathy in insulin-treated diabetic rats. J Neurol Sci 61:93–107

    Article  CAS  PubMed  Google Scholar 

  61. Yagihashi S, Sima AAF (1986) Diabetic autonomic neuropathy in BB rat. Ultrastructural and morphometric changes in parasympathetic nerves. Diabetes 35:733–743

    CAS  PubMed  Google Scholar 

  62. Zhang W-X, Chakrabarti S, Greene DA, Sima AF (1990) Diabetic autonomic neuropathy in BB rats and effect of ARI treatment on heart-rate variability and vagus nerve structure. Diabetes 39:613–618

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by grants from the Swedish Science Council (Proj. No. 3761), the County Council of Östergötland, and by the Faculty of Health Sciences, Linköping University. Comments on the manuscript by Prof. Claes Hildebrand are gratefully acknowledged.

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Correspondence to Simin Mohseni.

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Jamali, R., Mohseni, S. Hypoglycaemia causes degeneration of large myelinated nerve fibres in the vagus nerve of insulin-treated diabetic BB/Wor rats. Acta Neuropathol 109, 198–206 (2005). https://doi.org/10.1007/s00401-004-0932-1

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