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M. J. Parkes and J. M. Bassett


Insulin, glucose, lactate and alpha-amino acid nitrogen concentrations were measured in the plasma of ewes and their hypophysectomized fetal lambs during intravenous infusions of GH, prolactin or saline into the fetus in utero. Prolactin and saline had no effect on mother or fetus. Infusion of GH at 1·2 mg/kg per day for 2 days or at 0·4 mg/kg per day for 4 days caused a sustained twofold increase in the level of insulin and a smaller, but sustained, increase in the level of glucose in fetal plasma. We suggest that GH antagonizes the action of insulin in the fetus. Glucose supplies to the fetal brain and placenta may be protected by such antagonism of insulin use during glucose shortage.

J. Endocr. (1985) 105, 379–382

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M Bendayan and I-S Park


The existence of extrapancreatic islets in the duodenal mucosa of the adult rat has been established by morphological studies and the development of these islets has been followed from the early embryonic stage to neonatal and adult life. Like the pancreatic islets, glucagon cells were the first to appear at day 12 of gestation. However, in contrast to the pancreatic islets, insulin was not detected in the extrapancreatic islets until birth. At this stage, the different endocrine cells assume their classical topography, insulin cells being surrounded by non-insulin endocrine cells. In addition, the behaviour of these extrapancreatic islets in diabetic conditions was evaluated on streptozotocin-induced diabetic rats as well as on spontaneous BB Wistar diabetic rats. In both conditions, the extrapancreatic islets were found in the duodenal mucosa but were mainly composed of glucagon cells, the insulin cells having disappeared. These results demonstrate that the extrapancreatic islets are a common normal feature of the rat duodenal mucosa. They appear during fetal development, are present in different strains of rats and behave similarly to the pancreatic islets under spontaneous or chemically induced diabetic conditions. Although their exact role remains to be established, they probably react to local hyperglycaemic environment due to intestinal absorption.

Journal of Endocrinology (1997) 153, 73–80

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M. J. Parkes and D. J. Hill


Fetal lambs were hypophysectomized and, after 8 days of recovery, given infusions of GH, prolactin, thyroxine and insulin with glucose. Hypophysectomy caused no consistent reduction in fetal plasma somatomedin-like activity. Fetal infusions of GH or prolactin caused no consistent change in plasma somatomedin-like activity. It was concluded that fetal somatomedin-like activity is not GH dependent. After hypophysectomy fetal lambs showed no reduction in body weight or length at term.

J. Endocr. (1985) 104, 193–199

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Gross deformities appeared in Xenopus laevis maintained for about 2 yr. under laboratory conditions on a diet containing no live food. Radiographs of the affected animals revealed defective calcification of the skeleton. All animals bred in the colony were defective, and only the original adults taken from the wild had normal bones. A description of the different types of skeleton found, and later produced experimentally, is given. An analysis of the conditions under which the defects became manifest showed X. laevis to be very susceptible to lack of vitamin D. Calcification in this species is greatly affected by the nature of the basal food. Normal bones are formed when the toads are fed on a diet of rabbit liver (or ox liver) supplemented with cod-liver oil and calcium. Horse liver is toxic, causing a depression of growth and a failure of calcification even with the supplements. With guinea-pig muscle a far larger supplement of vitamin D is required to prevent the development of general calcium deficiency and to permit normal bone formation. The failure of calcification is identified as rickets with osteoporosis and its relation to these diseases in other species is discussed.

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IS Park, YZ Che, M Bendayan, SW Kang, and BH Min

Clusterin is a heterodimeric glycoprotein which has been shown to play important roles in programmed cell death and/or in tissue reorganization not only during embryonic development but also in damaged tissues. Recently, we reported the transient induction of clusterin in pancreatic endocrine cells during early developmental stages of islet formation. In the present study, we have investigated the expression of clusterin in pancreatic tissue of streptozotocin-treated rats which were undergoing extensive islet tissue reorganization due to degeneration of insulin beta cells. Clusterin was found in endocrine cells identified as glucagon-secreting alpha cells at the periphery of the islet. Using immunoelectron microscopy, clusterin-positive cells showed the typical ultrastructural features of pancreatic alpha cells. In addition, colocalization of clusterin and glucagon in the same secretory granules was shown by double immunogold labeling. These results imply that clusterin is a secretory molecule having endocrine and/or paracrine actions in parallel with glucagon. Further, we noted that clusterin expression was increased in pancreatic alpha cells during the process of beta cell death upon streptozotocin injection. The increase was significant as early as 1-3 h after streptozotocin treatment prior to any morphological alteration of islet beta cell and any manifestation of hyperglycemia. The expression of clusterin was steady-stately up-regulated during the process of islet reorganization caused by streptozotocin-induced cytotoxic injury. Therefore, we suggest that clusterin might be considered as a molecule induced by both embryonic development and drug-induced reorganization of the endocrine pancreas. Since clusterin expression is up-regulated in alpha cells, but not in beta cells undergoing degeneration, it may play a protective role against the cytotoxic insult.

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S-K Park, D A Strouse, and M Selmanoff


Central catecholaminergic neurones projecting to specific hypothalamic structures are involved in stimulating and inhibiting the activity of the GnRH-containing neurosecretory neurones. Both testosterone and elevated circulating prolactin (PRL) levels inhibit postcastration LH release. Three groups of adult male rats were orchidectomized and adrenalectomized, received corticosterone replacement and were: (i) administered purified ovine PRL (oPRL; 2400 μg/s.c. injection) or (ii) its diluent, polyvinylpyrrolidone (PVP), every 12 h, or (iii) received physiological testosterone replacement for 2 days. At 0, 2 and 6 days postcastration, norepinephrine (NE), epinephrine (E) and dopamine (DA) turnover were estimated by the α-methyl-p-tyrosine method in three micro-dissected hypothalamic structures: the diagonal band of Broca at the level of the organum vasculosum of the lamina terminalis (DBB(ovlt)), the medial preoptic nucleus (MPN) and the median eminence (ME). In control (PVP-treated) rats, serum LH concentrations increased eightfold at 2 and 6 days postcastration and this rise was prevented by testosterone. oPRL treatment transiently suppressed LH secretion at 2 but not 6 days postcastration. Castration significantly decreased basal rat PRL (rPRL) levels at 2 and 6 days and testosterone administration partially prevented this effect.

NE turnover in the ME and E turnover in the MPN increased markedly at 2 and 6 days postcastration, and testosterone replacement for 2 days prevented these increases. Thus, noradrenergic neurones innervating the ME and adrenergic neurones innvervating the MPN may drive postcastration LH secretion by providing stimulatory afferent input to the GnRH neurones. It was striking to observe that oPRL blocked the increases in both ME NE and MPN E turnover at 2 but not 6 days postcastration. Hence, oPRL may transiently suppress LH release by an inhibitory action on these NE and E neurones.

DA turnover in the DBB(ovlt) was significantly decreased by 6 days postcastration. Testosterone-treated (2 days postcastration) and oPRL-treated (2 and 6 days postcastration) rats exhibited turnover values indistinguishable from day 0 controls. Hence, the A14 dopaminergic neurones, which synapse on GnRH neurones in the rostral preoptic area and may exert an inhibitory effect on them, are positively regulated by PRL and perhaps by testosterone as well.

Autoregulatory feedback suppression of endogenous rPRL secretion by oPRL was observed both 2 and 6 days postcastration. In contrast to the A14 dopaminergic neurones, turnover in the A12 tuberoinfundibular dopaminergic (TIDA) neurones innervating the ME increased significantly by 6 days postcastration in control rats while oPRL administration further increased ME DA turnover at both 2 and 6 days. Hence, autofeedback regulation of rPRL secretion persists through at least 6 days of oPRL exposure temporally associated with markedly increased turnover in the TIDA neurones. In summary, our results support the hypothesis that the inhibitory effect of PRL on postcastration LH release is mediated by suppression of the activity of NE neurones innervating the ME and E neurones terminating in the MPN which, with time, become refractory to continued PRL exposure.

Journal of Endocrinology (1996) 148, 291–301

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BH Min, SY Jeong, SW Kang, BG Crabo, DN Foster, BG Chun, M Bendayan, and IS Park

Clusterin has been known to play important roles not only in remodeling damaged tissues, but also in tissue reorganization during embryonic development. In the present study, we have investigated the expression of clusterin in the endocrine pancreas during embryonic development. Although a weak immunoreaction was detected in some pancreatic primordial cells at day 14 of gestation, distinct clusterin expression was identified by immunocytochemistry and Northern blot analysis at the 16th day of gestation. Clusterin-producing cells, which corresponded to insulin-containing cells, accounted for the major portion of the developing islet of Langerhans up to 18 days of gestation. Thereafter, clusterin-producing cells display similar distribution and morphological features to glucagon-producing cells. Clusterin expressed in the pancreas was shown by Western blot analysis to be a disulfide-linked heterodimer of 70 kDa with an alpha-subunit of 32 kDa. During early developmental stages, however, we found that proteolytic internal cleavage of the clusterin molecule occurred from the 18th day of gestation. Only one 70 kDa band on the 16th day and two bands (32 kDa and 70 kDa) on the 18th day of gestation were detected by Western blot analysis even in reducing conditions, while only a single 32 kDa band was detected on the second day after birth. The levels of clusterin mRNA in the pancreas transiently increased from the 16th day of gestation to the second day after birth, during the period when active cellular reorganization takes place to form the classic cellular features of the islet. Among various tissue (kidney, brain, liver, heart, lung and pancreas) the levels of clusterin mRNA were the highest in the pancreas from the 18th day of gestation to the second day after birth. In contrast, the lowest expression was observed in adult pancreatic tissue. The higher expression of clusterin in developing pancreas must indicate its involvement in tissue organization during development.

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A double antibody radioimmunoassay for canine luteinizing hormone (LH) was devised. The assay can measure immunoreactive LH in the peripheral plasma of the normal male and female dog. An increase in hormone concentration was found on the 2nd day of oestrus in the female. Ovariectomy raised plasma concentrations of the hormone to levels greater than those observed during oestrus. The administration of LH-releasing factor induced a rapid increase in the plasma concentrations of LH.

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For the study of their various physiological and chemical properties, protein hormones in urine have usually been purified by adsorption or precipitation (Heller & Chandler, 1942; Bradbury, Brown & Brown, 1949; Johnsen, 1955; Albert, 1955; Butt, 1958; Loraine & Brown, 1959). Methods using kaolin adsorption followed by acetone precipitation have been widely used for the extraction of urinary gonadotrophins (HPG). However, for the immunochemical and biological characterization of isolated gonadotrophins, the kaolin-acetone method presents some potential drawbacks. Adsorption of the active constituents may be incomplete, and elution at the required high pH (11·5) as well as treatment with acetone may cause denaturation. Hobson & Wide (1964) have reported a decrease in the ratio of immunological properties to biological activity during the kaolin-acetone concentration of human chorionic gonadotrophin (HCG). In an attempt to minimize these difficulties, we have used ultrafiltration for the isolation of HPG. The results have been compared with

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E Kim, S Sohn, M Lee, J Jung, R D Kineman, and S Park

The impact of streptozotocin (STZ)-induced, insulinopenic diabetes on the GH axis of rats and mice differs from study to study, where this variation may be related to the induction scheme, severity of the diabetes and/or the genetic background of the animal model used. In order to begin differentiate between these possibilities, we compared the effects of two different STZ induction schemes on the GH axis of male Sprague–Dawley rats: (1) a single high-dose injection of STZ (HI STZ, 80 mg/kg, i.p.), which results in rapid chemical destruction of the pancreatic β-cells, and (2) multiple low-dose injections of STZ (LO STZ, 20 mg/kg for 5 consecutive days, i.p.), which results in a gradual, autoimmune destruction of β-cells. STZ-treated animals were killed after 3 weeks of hyperglycemia (>400 mg/dl), and in both paradigms circulating insulin levels were reduced to <40% of vehicle-treated controls. HI STZ-treated rats lost weight, while body weights of LO STZ-treated animals gradually increased over time, similar to vehicle-treated controls. As previously reported, HI STZ resulted in a decrease in circulating GH and IGF-I levels which was associated with a rise in hypothalamic neuropeptide Y (NPY) mRNA (355% of vehicle-treated controls) and a fall in GH-releasing hormone (GHRH) mRNA (45% of vehicle-treated controls) levels. Changes in hypothalamic neuropeptide expression were reflected by an increase in immunoreactive NPY within the arcuate and paraventricular nuclei and a decrease in GHRH immunoreactivity in the arcuate nucleus, as assessed by immunohistochemistry. Consistent with the decline in circulating GH and hypothalamic GHRH, pituitary GH mRNA levels of HI STZ-treated rats were 58% of controls. However, pituitary receptor mRNA levels for GHRH and ghrelin increased and those for somatostatin (sst2, sst3 and sst5) decreased following HI STZ treatment. The impact of LO STZ treatment on the GH axis differed from that observed following HI STZ treatment, despite comparable changes in circulating glucose and insulin. Specifically, LO STZ treatment did suppress circulating IGF-I levels to the same extent as HI STZ treatment; however, the impact on hypothalamic NPY mRNA levels was less dramatic (158% of vehicle-treated controls) where NPY immunoreactivity was increased only within the paraventricular nucleus. Also, there were no changes in circulating GH, hypothalamic GHRH or pituitary receptor expression following LO STZ treatment, with the exception that pituitary sst3 mRNA levels were suppressed compared with vehicle-treated controls. Taken together these results clearly demonstrate that insulinopenia, hyperglycemia and reduced circulating IGF-I levels are not the primary mediators of hypothalamic and pituitary changes in the GH axis of rats following HI STZ treatment. Changes in the GH axis of HI STZ-treated rats were accompanied by weight loss, and these changes are strikingly similar to those observed in the fasted rat, which suggests that factors associated with the catabolic state are critical in modifying the GH axis following STZ-induced diabetes.