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

Abstract

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.

3-D imaging and illustration of the perfusive mouse islet sympathetic innervation and its remodelling in injury

“…The maintenance of islet sympathetic nerve density in early insulitis is also consistent with the functional data reported in the study by Taborsky et al of NOD mice [36]. In the tyramine stimulation of the sympathetic nerves, the non-diabetic group (age 18 weeks) maintained an active islet response to increase glucagon secretion (260±32 ng/l increase in plasma concentration); the level was comparable to that of stimulated non-obese diabetes-resistant control mice (170±24 ng/l; age 13 weeks) and significantly higher than that of diabetic mice (145±23 ng/l; age 21 weeks).…”

“…In NOD mice, we have demonstrated remodelling of peri-islet sympathetic innervation in early insulitis, which is prior to the substantial loss of islet sympathetic nerves under diabetic conditions in the same animals reported by Taborsky et al [36]. Morphologically, our image data reveal heterogeneity of the islet microenvironment in early insulitis, which consists of a transition area with prominent sympathetic nerves at the interface between the inflammatory area and the normal islet domain.…”

Early sympathetic islet neuropathy in autoimmune diabetes: lessons learned and opportunities for investigation

“…The two models of spontaneous autoimmune diabetes, the biobreeder (BB) rat [19] and the NOD mouse [20], are characterised by a 70–90% loss of their islet sympathetic nerves. Similar results are observed in the rat insulin promoter–glycoprotein (RIP-GP) transgenic mouse in which immune-mediated diabetes can be induced by two different methods.…”

“…The best example of this phenomenon comes from experiments using beta cell toxins, either alloxan (ALX) or streptozotocin (STZ), which destroy beta cells by a mechanism that does not involve lymphocytic infiltration and therefore does not result in the loss of islet sympathetic nerves [19, 20]. High doses of either toxin produce a marked (75%) and rapid (less than 1 week) decrease in islet area [19, 20].…”

“…High doses of either toxin produce a marked (75%) and rapid (less than 1 week) decrease in islet area [19, 20]. If nerve density had been used to quantify islet sympathetic nerves one would have concluded that the sympathetic innervation of the islet had increased threefold.…”