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D W Miller, D Blache, and G B Martin

Abstract

The effect of nutrition on gonadotrophin secretion may be exerted through a central metabolic signal that reflects nutritional status. We have previously found that glucose and insulin concentrations are elevated in the cerebrospinal fluid (CSF) of rams in which the secretion of gonadotrophins has been stimulated by a nutritional supplement of lupin grain (Lupinus angustifolius). In the present study, we tested the hypothesis that insulin and/or glucose is a metabolic modulator of GnRH secretion and mediates the effects of nutrition on gonadotrophin secretion. Six mature rams were fed a diet that maintained live weight and then given a series of infusions, each for 12 h/day for 4 days, in a cross-over design. The treatments were: artificial CSF (aCSF), glucose (50 μmol/h) in aCSF, insulin (0·6 ng/h) in aCSF, and glucose (50 μmol/h) plus insulin (0·6 ng/h) in aCSF; all infused at a rate of 5 μl/min. At the same time as the infusion treatments, two other groups of four rams without cerebral cannulae were fed either the maintenance diet or the same diet supplemented with 750 g lupin grain per head per day for 4 days, again in a cross-over design. Rams fed the lupin supplement showed an increase in both LH pulse frequency and mean FSH on day 4 (P<0·05). Infusion of aCSF or glucose did not affect gonadotrophin secretion. Rams infused with insulin or insulin plus glucose showed an increase (P<0·05) in LH pulse frequency but no increase in FSH concentrations on day 4 of infusion. The magnitude of the LH response to insulin was similar to the nutritional response of feeding lupin supplements. There was no effect of any of the infusion treatments on plasma prolactin or insulin secretion. These data show that changes in insulin concentrations in the CSF lead to changes in LH secretion and support the hypothesis that insulin is a metabolic modulator of GnRH secretion and mediates the effects of nutrition on gonadotrophin secretion.

Journal of Endocrinology (1995) 147, 321–329

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S C Blair, I D Caterson, and G J Cooney

Abstract

The effect of adrenalectomy (ADX) on glucose tolerance and insulin secretion was examined in conscious mice made obese by a single injection of gold thioglucose (GTG). To facilitate such a study a chronic jugular catheter was implanted into the mice at the time of performing the ADX or sham-ADX. One week after ADX, the body weight (GTG-obese+sham-ADX, 35·6 ± 0·6 g; GTG-obese+ADX, 33·1 ± 0·6 g; P<0·05) and glycogen content of the liver (GTG-obese+sham-ADX, 2·4 ± 0·2 μmol/liver; GTG-obese+ADX, 1·6 ± 0·1 μmol/liver; P<0·05) of GTG-injected mice were reduced. Plasma glucose concentrations, in both the overnight fasted state and in response to an intravenous glucose load were also reduced following ADX of GTG-obese mice, but not to the level of the sham-ADX control mice. However, ADX completely normalized plasma insulin concentrations in both the basal state and also in response to a glucose load, as indicated by the finding that the integrated insulin secretory response of the ADX GTG-obese mice was not different from that of sham-ADX control mice (control+sham-ADX, 192 ± 5 min.μU/ml; GTG-obese+ADX, 196 ± 10 min.μU/ml). The effects of ADX on carbohydrate metabolism were not restricted to GTG-injected mice, as ADX of control mice decreased fasting plasma glucose levels and reduced liver glycogen and plasma insulin concentrations. The normalization of insulin release in ADX GTG-obese mice occurred while these mice were still obese and glucose intolerant. This suggests that the decreased insulin release was not due solely to an ADX-induced improvement in insulin sensitivity and/or weight loss. Removal of central glucocorticoid effects on the parasympathetic stimulation of insulin release may play a role in the reduced insulin release observed after ADX of obese and control mice, although peripheral effects of glucocorticoid deficiency on glycogen synthesis in the liver may also influence whole animal glucose homeostasis.

Journal of Endocrinology (1996) 148, 391–398

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J. Sieradzki, H. Fleck, A. K. Chatterjee, and H. Schatz

ABSTRACT

The influence of insulin-like growth factor-I (IGF-I) on both the growth and function of isolated pancreatic rat islets was studied. As a measure of islet cell replication, [3H]thymidine incorporation and DNA content was estimated at the same time as parameters for (pro)insulin biosynthesis and secretion as a measure of the functional capacity of B cells. Incorporation of [3H]thymidine was measured after tissue solubilization; DNA was determinated fluorometrically. (Pro-)insulin biosynthesis was determinated by incorporation of [3H]leucine after immunoprecipitation and binding to protein A–Sepharose. There was a significant increase in both [3H]thymidine incorporation and DNA content after the culture of islets with IGF-I. IGF-I resulted also in an increase in insulin biosynthesis and secretion from isolated pancreatic islets. These results demonstrate a role of IGF-I in regulating the growth and function of pancreatic islets.

J. Endocr. (1988) 117, 59–62

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J. C. Escolar, R. Hoo-Paris, Ch. Castex, and B. Ch. J. Sutter

ABSTRACT

The direct effect of hypothermia on the inhibition of insulin secretion may result from inhibition of the availability of energetic substrates and/or the lack of metabolic signals. In order to verify this hypothesis, the insulin secretion and the main metabolic glucose pathways were measured during the incubation of rat islets. In the presence of 16·7 mmol glucose/l and at 37 °C, insulin secretion was 925 ± 119 μU/2 h per ten islets. With the same experimental conditions, glucose utilization, determined as the formation of 3H2O from [5-3H]glucose was 2225 ±184 pmol/2 h per ten islets, glucose oxidation measured as the formation of 14CO2 from [U-14C]glucose was 673 ± 51 pmol/2 h per ten islets, pentose cycle determined as the formation of 14CO2 from either [1-14C]glucose or [6-14C]glucose was 37 ± 5 pmol/2 h per ten islets; glucose oxidation by the tricarboxilic acid cycle, calculated to be the difference between glucose oxidation and pentose cycle values, was 636 pmol/2 h per ten islets.

Hypothermia highly inhibited glucose-induced insulin secretion and glucose utilization. Inhibition of insulin secretion was partial at 27 °C since it was 2·5 times lower than that at 37 °C, and it was complete at 17 °C. Glucose oxidation in the tricarboxilic acid cycle was markedly inhibited by hypothermia since the inhibition coefficient (Q10) between 37 and 27 °C was 5. In contrast, glucose oxidation in the pentose phosphate shunt was enhanced at 27 °C, reaching 92 ± 17 pmol/2 h per ten islets, and it was inhibited relatively little at 17 °C.

These results suggest that hypothermia markedly inhibits glucose metabolism with the exception of the pentose pathway which could play an important role by inducing the insulin secretion at 27 °C.

Journal of Endocrinology (1990) 125, 45–51

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R. D. G. MILNER

SUMMARY

Pieces of pancreas from 24-day and 30-day rabbit foetuses, 1-day-old rabbits and rabbits aged approximately 8 weeks were incubated in vitro and insulin secretion into the incubation medium was measured in response to a variety of stimuli. Glucagon, leucine, ouabain and potassium were effective stimuli at all ages studied. By the criteria of response chosen for these experiments, glucose did not stimulate insulin secretion from 24-day foetal pancreas but did so when pancreas from older animals was studied. It was concluded that the foetal β cell of the rabbit on the 24th day of gestation, although morphologically immature, shows evidence of functional competence.

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M. DE GASPARO, G. R. MILNER, P. D. NORRIS, and R. D. G. MILNER

SUMMARY

Foetal rat pancreatic rudiments explanted on day 14 of gestation were grown for 6 days in organ culture in medium containing glucose (5·5 or 16·5 mmol/l) and amino acids at the 'physiological' or seven times the 'physiological' concentration. At the end of the period of culture, the rudiments were compared with normal 20-day foetal pancreas for DNA content, insulin concentration and quantitative morphology. The secretion of insulin from the explants was tested during 2 h incubations in medium containing glucose (5·5 or 16·5 mmol/l).

Amino acid, but not glucose enrichment of the culture medium stimulated cellular growth of the rudiment which remained, nevertheless, smaller than that occurring in vivo. All culture conditions produced a smaller proportion of exocrine cells and a greater proportion of β and duct cells than were found in normal 20-day foetal pancreas. Enrichment with amino acids favoured the development of exocrine cells at the expense of duct cells. Glucose had no effect on the development of any type of cell. Enrichment with amino acids resulted in a higher concentration of insulin per β cell but the highest value observed in vitro was only one sixth of that occurring in vivo. The absolute number of β cells cultured in amino-acid-enriched medium was twice that occurring in vivo. Culture in a glucose-enriched medium had no effect on the ability of the explant to respond to an acute glucose challenge during a short incubation, but the basal and glucose-stimulated release of insulin from cultures grown in amino-acid-enriched medium were significantly greater.

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R. J. Frampton, H. A. Jonas, and R. G. Larkins

ABSTRACT

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) may be important factors in the control of neonatal growth. We have examined the production, in vitro, of IGFBPs and IGFs by hindlimb skeletal muscle from normal and small-for-gestational age (SGA) neonatal rats. Conditioned medium was collected from muscle strips after incubation at 37 °C for 2 h in Ham's F-12 medium. The conditioned medium was subjected to acid-gel permeation chromatography to separate IGFBPs from IGFs. The binding of 125I-labelled IGF-I to IGFBPs from both control and SGA muscle was displaced equipotently by IGF-I and IGF-II and not at all by insulin. IGFBPs from control and SGA muscles bound IGF-I with comparable affinities (K d = 0·071 and 0·069 nmol/l respectively). When IGF-II was used as tracer, neither IGF-I nor insulin competed for binding. Western ligand blots of IGFBPs in conditioned media from both control and SGA muscles showed three bands of radioactivity at molecular masses equivalent to 24, 30 and 40 kDa. When the release of IGFBPs by muscle tissue in vitro was quantified by measuring the number of IGF-I binding sites in acid-fractionated medium it was apparent that the muscles from SGA pups secreted significantly more IGFBPs (39·3±7·5 fmol/mg muscle protein per 2 h) than the muscles from control pups (17·8±2·7 fmol/mg protein per 2 h; P < 0·05). In contrast to the IGFBPs, more IGF activity was secreted by the muscles from the control pups (61·1±15·6 fmol/mg muscle protein per 2 h) than the muscles from the SGA pups (12·6±5·8 fmol/mg muscle protein per 2 h; P < 0·05). Analysis of the IGF activity with assays specific for IGF-I and IGF-II showed that both SGA and control muscles secreted predominantly IGF-II with approximately 10% of the total IGF activity measurable as IGF-I. This differential secretion of IGFBPs and IGFs may be associated with the reduced growth potential of the SGA neonate.

Journal of Endocrinology (1991) 130, 33–42

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J. M. BASSETT, G. D. THORBURN, and DIANNE H. NICOL

SUMMARY

Intravenous infusions of glucose into lambs in utero (130–150 days) and after birth, confirmed the marked post-natal increase in the magnitude of the response of plasma insulin to glucose. These studies also suggest that insulin secretion in foetal lambs is stimulated by glucose at lower plasma concentrations than in lambs after birth. The short-chain fatty acid, valeric acid, given as the sodium salt, caused a very rapid increase in the plasma insulin level of foetal lambs, when given either by intravenous injection or infusion. When birth was induced after only 135 days of gestation by i.v. infusion of a synthetic adrenocorticotrophin preparation (Synacthen) into foetal lambs there was also a prematurely induced maturation of the insulin secretory response to glucose. In these prematurely born lambs the insulin secretory response to i.v. glucose infusion was similar to that of normal lambs after birth and differed greatly from that of normal foetuses of similar age.

The results indicate that maturation of the insulin secretory mechanism in the lamb is associated with parturition and suggest that these changes may be consequences of the increasing corticosteroid secretion in the foetus during the last few days of gestation.

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A Martinez, R Pio, J Lopez, and F Cuttitta

Adrenomedullin (AM) is a ubiquitous peptide hormone which, among other functional roles, reduces insulin secretion in the pancreas. Recently we have described the interaction between AM and the complement regulator protein factor H, which results in mutual modulation of their respective functions. Here we identify the expression of factor H in the beta cells of the rat pancreatic islets by immunohistochemistry and multiple immunofluorescence followed by confocal microscopy. In addition, double immunogold staining under the electron microscope showed coexistence of insulin and factor H immunoreactivities within the same secretory granules; interestingly, factor H staining was found in the electron-lucent haloes whereas the insulin antibody labeled preferentially the dense cores. The existence of factor H mRNA in the pancreas was confirmed by RT-PCR and in situ hybridization. The function of factor H in the pancreas was investigated with an insulin secretion assay. Addition of factor H to freshly isolated islets in the presence of AM resulted in a further reduction in insulin secretion with a concomitant elevation of cAMP, suggesting that factor H increases AM function in glucose homeostasis. The expression of factor H in the pancreas may play other important roles such as protection against complement-mediated cell lysis.

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D. G. Lambert and T. W. Atkins

ABSTRACT

The effects of the islet cell hormones glucagon, somatostatin-28 and pancreatic polypeptide on insulin secretion from cultured cloned pancreatic B cells (HIT-T15 and RINm5F) have been investigated. Glucagon stimulates the secretion of insulin from HIT-T15 cells in the absence and presence of glucose and from RINm5F cells in the absence and presence of glyceraldehyde. HIT-T15 cells were more sensitive to the stimulatory effect of glucagon than RINm5F cells. Somatostatin-28 and pancreatic polypeptide, both alone and in combination, reduced glucose- and glucagon-stimulated insulin release from HIT-T15 cells and glyceraldehyde- and glucagon-stimulated insulin release from RINm5F cells. HIT-T15 cells were more sensitive to the inhibitory actions of somatostatin-28 and pancreatic polypeptide than RINm5F cells. This study supports the hypothesis that insulin release from normal B cells may be modified by the paracrine activity of islet hormones, glucagon, somatostatin and pancreatic polypeptide and probably occurs before any fine tuning imposed by subsequently released insulin.

Journal of Endocrinology (1989) 121, 479–485