Loss of islet sympathetic nerves and impairment of glucagon secretion in the NOD mouse: relationship to invasive insulitis

Diabetologia. 2009 Dec;52(12):2602-11. doi: 10.1007/s00125-009-1494-5. Epub 2009 Oct 2.


Aims/hypothesis: We hypothesised that non-obese diabetic mice (NOD) mice have an autoimmune-mediated loss of islet sympathetic nerves and an impairment of sympathetically mediated glucagon responses. We aimed: (1) to determine whether diabetic NOD mice have an early impairment of the glucagon response to insulin-induced hypoglycaemia (IIH) and a coincident loss of islet sympathetic nerves; (2) to determine whether invasive insulitis is required for this nerve loss; and (3) to determine whether sympathetically mediated glucagon responses are also impaired.

Methods: We measured glucagon responses to both IIH and tyramine in anaesthetised mice. We used immunohistochemistry to quantify islet sympathetic nerves and invasive insulitis.

Results: The glucagon response to IIH was markedly impaired in NOD mice after only 3 weeks of diabetes (change, -70%). Sympathetic nerve area within the islet was also markedly reduced at this time (change, -66%). This islet nerve loss was proportional to the degree of invasive insulitis. More importantly, blocking the infiltration prevented the nerve loss. Mice with autoimmune diabetes had an impaired glucagon response to sympathetic nerve activation, whereas those with non-autoimmune diabetes did not.

Conclusions/interpretation: The invasive insulitis seen in diabetic NOD mice causes early sympathetic islet neuropathy. Further studies are needed to confirm that early sympathetic islet neuropathy is responsible for the impaired glucagon response to tyramine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects
  • Diabetes Mellitus, Type 1 / chemically induced
  • Diabetes Mellitus, Type 1 / immunology
  • Female
  • Glucagon / metabolism*
  • Hyperinsulinism / chemically induced
  • Hyperinsulinism / etiology*
  • Hyperinsulinism / immunology
  • Islets of Langerhans / innervation*
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Oxidopamine / pharmacology
  • Sympathetic Nervous System / metabolism*
  • Sympathetic Nervous System / pathology
  • Tyramine / pharmacology
  • Tyramine / physiology


  • Oxidopamine
  • Cyclophosphamide
  • Glucagon
  • Tyramine