Olchovsky D, Bruno J F, Wood T L, Gelato M C, Leidy J W, Gilbert J M, Berelowitz M
Department of Medicine, State University of New York, Stony Brook 11794.
Endocrinology. 1990 Jan;126(1):53-61. doi: 10.1210/endo-126-1-53.
Diabetes mellitus in the rat is associated with loss of pulsatile GH secretion. An interplay between hypothalamic GH-releasing factor (GRF) and inhibitory factor [somatostatin (SRIF)] secretion is thought to account for episodic pituitary GH release. An increase in SRIF tone/action or a decrease in GRF release/response in diabetic rats could account for the suppressed GH levels. Pituitaries from streptozotocin-diabetic rats contained less GH than controls (15.9 +/- 2.5 vs. 29.5 +/- 4.6 micrograms/mg; P less than 0.05) despite normal somatotrope representation, as demonstrated using immunofluorescence studies. Basal GH secretion from monolayer culture of dispersed anterior pituitary (AP) cells from diabetic rats was proportionately decreased (150 +/- 10 vs. 103 +/- 10 ng/10(5) cells; P less than 0.005). GRF (10(-11)-10(-8) M)-induced release of GH from AP cells was decreased in diabetic rats (maximum response to 10(-8) M GRF, 401 +/- 60 vs. 618 +/- 41 ng/10(5) cells; P less than 0.01); however, sensitivity to GRF was unchanged (EC50, 79 +/- 41 vs. 128 +/- 67 pM). By contrast, SRIF (10(-7)-10(-10)-induced inhibition of GRF (10(-8) M)-mediated GH release was impaired in AP cells of diabetic rats compared to that in controls (IC50, 112 +/- 33 vs. 55 +/- 31 pM; P less than 0.05) associated with a decrease in AP plasma membrane SRIF receptor concentration (63.4 +/- 15.6 vs. 160.3 +/- 13.7 fmol/mg protein; P less than 0.05), with no change in affinity. These findings are consistent with chronic exposure to increased hypothalamic SRIF influence. GH synthesis has been shown to be independent of SRIF regulation; however, insulin-like growth factor-I and GRF inhibit and stimulate GH synthesis, respectively. In diabetic rats insulin-like growth factor-I levels were decreased, appropriate to low GH status, in serum (290 +/- 66 vs. 1662 +/- 92 ng/ml; P less than 0.001) and hypothalamus (6.8 +/- 1.0 vs. 13.0 +/- 0.4 pg/mg wet wt; P less than 0.001) and, thus, did not seem to account for the low AP GH content. Hypothalamic GRF content in diabetic rats (1.11 +/- 0.10 ng/hypothalamus) did not differ from that in controls (1.16 +/- 0.17 ng/hypothalamus). GRF mRNA levels, however, were reduced by 80% in diabetic rats compared to controls. Taken together these data support a combined role for decreased hypothalamic GRF and increased SRIF in mediating alterations of GH synthesis and secretion in streptozotocin-induced diabetes.
大鼠糖尿病与脉冲式生长激素（GH）分泌丧失有关。下丘脑生长激素释放因子（GRF）与抑制因子[生长抑素（SRIF）]分泌之间的相互作用被认为是垂体GH间歇性释放的原因。糖尿病大鼠中SRIF张力/作用增加或GRF释放/反应减少可能是GH水平受抑制的原因。尽管使用免疫荧光研究表明生长激素细胞数量正常，但链脲佐菌素诱导的糖尿病大鼠的垂体中GH含量低于对照组（15.9±2.5对29.5±4.6微克/毫克；P<0.05）。糖尿病大鼠分散的垂体前叶（AP）细胞单层培养的基础GH分泌成比例降低（150±10对103±10纳克/10⁵细胞；P<0.005）。糖尿病大鼠中GRF（10⁻¹¹ - 10⁻⁸M）诱导的AP细胞GH释放减少（对10⁻⁸M GRF的最大反应，401±60对618±41纳克/10⁵细胞；P<0.01）；然而，对GRF的敏感性未改变（半数有效浓度，79±41对128±67皮摩尔）。相比之下，与对照组相比，糖尿病大鼠AP细胞中SRIF（10⁻⁷ - 10⁻¹⁰）诱导的对GRF（10⁻⁸M）介导的GH释放的抑制作用受损（半数抑制浓度，112±33对55±31皮摩尔；P<0.05），这与AP质膜SRIF受体浓度降低有关（63.4±15.6对160.3±13.7飞摩尔/毫克蛋白质；P<0.05），亲和力无变化。这些发现与长期暴露于下丘脑SRIF增加的影响一致。已表明GH合成独立于SRIF调节；然而，胰岛素样生长因子-I和GRF分别抑制和刺激GH合成。糖尿病大鼠血清（290±66对1662±92纳克/毫升；P<0.001）和下丘脑（6.8±1.0对13.0±0.4皮克/毫克湿重；P<0.001）中胰岛素样生长因子-I水平降低，与低GH状态相符，因此似乎不能解释AP中低GH含量的原因。糖尿病大鼠下丘脑GRF含量（1.11±0.10纳克/下丘脑）与对照组（1.16±0.17纳克/下丘脑）无差异。然而，与对照组相比，糖尿病大鼠GRF mRNA水平降低了80%。综上所述，这些数据支持下丘脑GRF减少和SRIF增加在介导链脲佐菌素诱导的糖尿病中GH合成和分泌改变方面的联合作用。
