To discover whether islet sympathetic nerves are damaged during the autoimmune destruction of islet B-cells, we immunostained sections of pancreas from BioBreeder (BB) diabetic rats, using antibodies against vesicular monoamine transporter 2 (VMAT2), a marker of sympathetic nerve terminals. We found a marked decrease in the VMAT2-positive fiber area in the islets of BB rats that had been diabetic for only 1-2 weeks compared with their nondiabetic controls. In contrast, there was no significant decrease in the VMAT2-positive fiber area in the exocrine pancreas in these early diabetic BB rats. Furthermore, streptozotocin-diabetic rats showed no decrease in VMAT2-positive fiber area in their islets compared with controls. The classical diabetic autonomic neuropathy (DAN) that eventually occurs in the heart was not present in BB diabetic rats at this early stage as evidenced by normal cardiac VMAT2 immunostaining and normal cardiac norepinephrine content. Also, in contrast to DAN, this islet neuropathy did not worsen with duration of diabetes. These data provide evidence of a heretofore unrecognized early sympathetic islet neuropathy (eSIN). Because eSIN occurs selectively in the islet, is rapid in onset, and is associated with autoimmune but not chemically induced diabetes, it is distinct from DAN in location, time course, and mechanism. Diabetes 51:2997-3002, 2002 T he sympathetic nerves of the pancreas can inhibit insulin release from the islet B-cells (1,2) and stimulate glucagon release from the islet A-cells (1,2). For example, activation of these nerves is sufficient to mediate the glucagon response to insulin-induced hypoglycemia (3). It is interesting that this specific glucagon response is lost in type 1 diabetes (4).Type 1 diabetes in humans is associated with an autoimmune attack on islet B-cells involving a variety of cytokines, including interleukin 1 and tumor necrosis factor-␣ (5). These two cytokines are also neurotoxic (6) and therefore could injure islet nerves during the autoimmune attack on islet B-cells. Injured adult sympathetic nerves, in turn, are known to increase their dependence on nerve growth factor (NGF) for function and survival (7). Islet B-cells seem to be the source of the growth factors that influence both the sympathetic and sensory innervation of the islet (8), a specificity ascribed to NGF itself. Indeed, at least in vitro, islet B-cells seem to make NGF mRNA as demonstrated by RT-PCR and NGF protein as demonstrated by immunohistochemistry (9). In addition, they secrete NGF as demonstrated by bioassay and enzyme-linked immunosorbent assay (9). These observations suggest the possibility that the autoimmune attack on the B-cells during the development of type 1 diabetes will lead to a loss of the islet sympathetic nerves, first by injuring these nerves and then by depriving them of now critical neurotrophic support.To determine whether the hypothesized loss of islet sympathetic nerves actually occurs, we first needed a marker of the sympathetic innervation of the pancreatic islet...

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We investigated the direct pancreatic effects of noradrenaline in vivo on the secretion of insulin, glucagon, and somatostatin from the in situ pancreas in halothane-anaesthetized dogs. Noradrenaline was infused into the superior pancreatic artery at 12 ng min-1, a rate that did not alter systemic glucose or noradrenaline levels nor heart rate or blood pressure. This pancreatic infusion of noradrenaline did not affect the basal pancreatic output of insulin, yet did markedly inhibit arginine-stimulated insulin secretion. The acute insulin response (AIR) to an intravenous injection of arginine (2.5 g), which was 4293 +/- 1260 microM min-1 under control conditions, was reduced to 1054 +/- 396 microU min-1 by noradrenaline (P less than 0.01). Noradrenaline increased basal pancreatic glucagon output from 321 +/- 130 pg min-1 to 876 +/- 309 pg min-1 after 20 min of infusion (P less than 0.05) and the acute glucagon response (AGR) to arginine, being 1033 +/- 203 pg min-1 under control conditions and 1746 +/- 249 pg min-1 during noradrenaline infusion (P less than 0.05). The basal output of somatostatin did not change during noradrenaline infusion, but arginine-stimulated somatostatin secretion was impaired. The acute somatostatin response (ASLIR) to arginine was 473 +/- 124 fmol min-1 under control conditions and was decreased to 140 +/- 80 fmol min-1 by noradrenaline (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)