Early, Selective, and Marked Loss of Sympathetic Nerves From the Islets of BioBreeder Diabetic Rats

Early, Selective, and Marked Loss of Sympathetic Nerves From the Islets of BioBreeder Diabetic Rats Qi Mei , Thomas O. Mundinger , Ake Lernmark and Gerald J. Taborsky, Jr From the Division of Endocrinology and Metabolism, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, Washington; and the University of Washington, Seattle, Washington Abstract 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. Footnotes Address correspondence and reprint requests to Qi Mei, Division of Endocrinology and Metabolism (151), Veterans Affairs Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108. E-mail: qmei{at}u.washington.edu . Received for publication 15 November 2001 and accepted in revised form 24 May 2002. 6-OHDA, 6-hydroxydopamine; DAN, diabetic autonomic neuropathy; eSIN, early sympathetic islet neuropathy; NE, norepinephrine; NGF, nerve growth factor; STZ, streptozotocin; VMAT2, vesicular monoamine transporter 2. DIABETES