Regulation of pulsatile luteinizing hormone secretion by insulin in the diabetic male lamb

This study tested the hypothesis that LH secretion is modulated by insulin and that the responsiveness to hypoinsulinemia is enhanced by sex steroids. The model was the developing male lamb (12-26 wk of age) rendered diabetic by chemically induced necrosis of insulin-secreting tissue (streptozotocin ). Our approach was to monitor LH secretion under diabetic conditions, with or without insulin supplementation, either in the presence or in the absen ce of gonadal steroids. The first experiment determined if chronic insulin supplementation could sustain LH secretion in diabetic lambs. After documen tation of the induced diabetic condition, twice-daily treatment with a long -acting insulin preparation (Lente) minimized diabetes-induced hyperglycemi a, sustained growth, and maintained LH pulse frequency at levels comparable to pre-diabetic conditions. A second experiment evaluated the acute regula tion of LH secretion by insulin. Twenty-four hours of insulin withdrawal de creased LH pulse frequency, increased circulating glucose levels, increased the concentration of plasma non-esterified fatty acids (NEFAs), and increa sed urinary output of ketones. LH pulse frequency continued to decline afte r 96 h of insulin withdrawal. By contrast, 24 h of insulin re-supplementati on increased LH pulse frequency, reduced circulating glucose and NEFA conce ntrations, decreased plasma cortisol, and reduced urinary output of ketones . After 96 h of insulin re-supplementation, LH pulse frequency increased fu rther, to levels comparable with those before insulin withdrawal. A third e xperiment determined if the effects of insulin withdrawal on LH secretion a re influenced by the presence of gonadal steroids. The same individuals wer e treated with a physiologic dose of estradiol (Silastic capsule, s.c.) and subsequently monitored for changes in LH secretion in the presence and in the absence of exogenous insulin. Prior to insulin withdrawal, estradiol de creased both LH pulse frequency and pulse amplitude. Moreover, after 96 h o f insulin withdrawal, estradiol potentiated the decline in LH pulse frequen cy (47% reduction in LH pulse frequency in the presence of estradiol versus 26% reduction in LH pulse frequency in the absence of estradiol). These fi ndings support the contention that insulin and/or insulin-dependent changes in glucose availability modulate LH(GnRH) pulse frequency, and that such e ffects are potentiated by, but not dependent upon, gonadal steroids.