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a Laboratory of Veterinary Reproduction, Tokyo University of Agriculture and Technology, Tokyo, Japan
b Reproductive Sciences Program, University of Michigan, Ann Arbor, Michigan 48109-0404
c Primate Research Institute, Kyoto University, Inuyama, Japan
d Laboratory of Animal Reproduction, Nagoya University, Nagoya, Japan
e Departments of Physiology,
f Obstetrics & Gynecology,
g and Biology, University of Michigan, Ann Arbor, Michigan 48109-0404
This study tested the hypothesis that central mechanisms regulating luteinizing hormone (LH) secretion are responsive to insulin. Our approach was to infuse insulin into the lateral ventricle of six streptozotocin-induced diabetic sheep in an amount that is normally present in the CSF when LH secretion is maintained by peripheral insulin administration. In the first experiment, we monitored cerebrospinal fluid (CSF) insulin concentrations every 3–5 h in four diabetic sheep given insulin by peripheral injection (30 IU). The insulin concentration in the CSF was increased after insulin injection, and there was a positive relationship between CSF and plasma concentrations of insulin (r = 0.80, P < 0.01). In the second experiment, peripheral insulin administration was discontinued, and the sheep received either an intracerebroventricular (i.c.v.) infusion of insulin (12 mU/day in 2.4 ml saline) or saline (2.4 ml/day) for 5 days (n = 6) in a crossover design. The dose of insulin (i.c.v.) was calculated to approximate the increase in CSF insulin concentration found after peripheral insulin treatment. To monitor LH secretory patterns, blood samples were collected by jugular venipuncture at 10-min intervals for 4 h on the day before and 5 days after the start of i.c.v. insulin infusion. To monitor the increase in CSF insulin concentrations, a single CSF sample was collected one and four days after the start of the central infusion. The i.c.v. insulin infusion increased CSF insulin concentrations above those in saline-treated animals (P < 0.05) and maintained them at or above the peak levels achieved after peripheral insulin treatment. Central insulin infusion did not affect peripheral (plasma) insulin or glucose concentrations. LH pulse frequency in insulin-treated animals was greater than that in saline-treated animals (3.5 ± 0.2 vs. 2.3 ± 0.3 pulses/4 h, P < 0.01), but it was less than that during peripheral insulin treatment (4.8 ± 0.2 pulses/4 h, P < 0.01). Our findings suggest that physiologic levels of central insulin supplementation are able to increase pulsatile LH secretion in diabetic sheep with low peripheral insulin. These results are consistent with the notion that central insulin plays a role in regulating pulsatile GnRH secretion.
1 This study was supported by travel grants from the Japanese Ministry of Education, Science, Culture and Sports (9-Y-40); by JSPS-NSF Cooperative Science Program (NSF INT-9603310); and research grants from NIH (HD-18394 and HD-18258). A preliminary report of this work was presented at the 28th Annual Meeting of the Society for Neuroscience, Los Angeles, CA, November, 1998 (Abstract #110.2).
2 Correspondence: Douglas L. Foster, Room 1138, 300 North Ingalls Building, University of Michigan, Ann Arbor, MI 48109-0404. FAX: 734 936 8620; dlfoster{at}umich.edu
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