title: The search for the mechanism of early sympathetic islet neuropathy in autoimmune diabetes.
abstract: This review outlines our search for the mechanism causing the early loss of islet sympathetic nerves in autoimmune diabetes. Since our previous work has documented the importance of autonomic stimulation of glucagon secretion during hypoglycaemia, the loss of these nerves may contribute to the known impairment of this specific glucagon response early in human type 1 diabetes. We therefore briefly review the contribution that autonomic activation, and sympathetic neural activation in particular, makes to the subsequent glucagon response to hypoglycaemia. We also detail evidence that animal models of autoimmune diabetes mimic both the early loss of islet sympathetic nerves and the impaired glucagon response seen in human type 1 diabetes. Using data from these animal models, we examine mechanisms by which this loss of islet nerves could occur. We provide evidence that it is not due to diabetic hyperglycaemia, but is related to the lymphocytic infiltration of the islet. Ablating the p75 neurotrophin receptor, which is present on sympathetic axons, prevents early sympathetic islet neuropathy (eSIN), but, interestingly, not diabetes. Thus, we appear to have separated the immune-related loss of islet sympathetic nerves from the immune-mediated destruction of islet β-cells. Finally, we speculate on a way to restore the sympathetic innervation of the islet.
authors.affiliation: Division of Endocrinology/Metabolism, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA; Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Taborsky
authors.forename: Q
authors.initials: Q
authors.lastname: Mei
authors.forename: D J
authors.initials: DJ
authors.lastname: Hackney
authors.forename: T O
authors.initials: TO
authors.lastname: Mundinger
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003929:Diabetic Neuropathies / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology / Q000294:innervation* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D018345:Mice, Knockout; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009444:Neuritis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
chemical_list: D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse
keywords: P75 neurotrophin receptor; glucagon; hypoglycaemia; neuropathy; sympathetic; type 1 diabetes