Insulin Secretion in Rats with Elevated Levels of Circulating Growth Hormone Due to MtT-W15 Tumor

Martin, Joseph V.; Åkerblom, Hans K.; Garay, Gabriel L.

doi:10.2337/diab.17.11.661

Cited by 40 publications

(14 citation statements)

References 12 publications

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“…Rats exposed to excess GH weigh more, whether fed ad libitum [28,29] or pair fed with control animals [30]. Increased hepatocyte size in our rats is consistent with the increase in liver weight [28,29].…”

Section: Discussionsupporting

confidence: 71%

“…This increase in organ weight is not accounted for by an increased water content [28]. Furthermore, in rats carrying GH-secreting tumours, lower glucose concentrations, especially after a glucose challenge [30,31], are associated with high circulating insulin levels [28,30,31], increased pancreatic islet mass [30,31], increased pancreatic insulin content [28,30] and increased insulin secretion by pancreatic slices and isolated islets [30]. Thus, although excess GH causes insulin antagonism in the intact rat, the ability of the pancreas to secrete additional insulin prevents the development of hyperglycaemia.…”

Section: Discussionmentioning

confidence: 99%

“…Since GH itself does not directly affect insulin binding [38,41,42] and hyperinsulinaemia characterizes states of GH excess, e.g. in acromegaly [1,38], GH-injected dogs [41 and humans [6, 81 and GHproducing tumours in rats [28,30,31], the diminished insulin binding in these cells probably reflects down regulation of the insulin receptor [43]. This suggestion is supported by the significant inverse correlation between insulin concentrations and the capacity of the high affinity, low capacity receptor in these 16 rats.…”

Section: Discussionmentioning

confidence: 99%

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Hepatocyte insulin binding and action in rats with sommatomammotrophic tumours

Davidson

Melmed

1983

Diabetologia

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Summary. The effects of chronic elevations of growth hormone levels on hepatic insulin binding and action were studied in rats with subcutaneously implanted growth hormoneproducing tumours. These animals were significantly heavier (p < 0.001 ; 388 _+ 29 versus 239_+ 4 g), had elevated insulin levels, (6.8 _ 0.6 versus 3.3 _ 0.5 ng/ml), lower glucose concentrations (6.0_+ 0.4 versus 9.3 _ 0.5 mmol/1) and larger hepatocyte diameters (28.7_ 0.6 versus 24.0_+ 0.4 p~m) and surface areas (2661 + 119 versus 1835 + 65 am 2) than control rats. Insulin binding and action [net (C~4)-glucose incorporation into glycogen] were compared in hepatocytes isolated from these two groups. Because of the difference in hepatocyte size, insulin binding was normalized for cell surface area. Binding of the tracer alone (0.9 _+ 0.05 versus 1.3 _+ 0.12%/cm:) and capacity of the high affinity, low capacity receptor (30.9_+ 5.9 versus 65.2 _+ 5.9 sites/Ixm 2) were significantly decreased (p < 0.02) in tumour-bearing rats. Dose-response curves of insulin action in hepatocytes chronically exposed to excess growth hormone were shifted to the fight. The maximal response was also significantly decreased. However, the relation between the amount of insulin bound and the proportion of the maximum insulin effect obtained were similar in cells from the two groups. Thus, in rat hepatocytes chronically exposed to excess growth hormone, both a receptor and a post-receptor defect occur while the insulin receptor itself functions normally. Material and MethodsGH3 cells were supplied by the American Type Culture Collection (Bethesda, Maryland). These cells are an established clonal strain of rat pituitary tumour cells secreting both GH and prolactin [12]. Cells were maintained in monolayer culture in a humidified atmosphere of 95% air -5% CO2 using Dulbecco's modified Eagle's medium (DMEM) supplemented with horse serum (15%), fetal calf serum (2.5%), penicillin (50 U/ml), streptomycin (50 p~g/ml) and glutamine (5 mmol/1) (Irvine Scientific, Santa Ana, California). For tumour generation, approximately 5-7 • 106 cells derived from the same parent culture were harvested by trypsinization, washed and resuspended in DMEM containing penicillin (50 U/ml) and streptomycin (50 p~g/ml). An aliquot of the cell suspension was counted in an automatic cell counter (Coulter Electronics, Hialeah, Florida), and the suspension was diluted to -106 cells/ml. One ml was injected SC into female Wistar-Furth rats as described previously [11]. Tumours were palpable by the end of 4 weeks. Control rats were treated similarly except that they received the media alone. Tumour-bearing and control rats were sacrificed alternately 6-8 weeks after inoculation.Rats were anaesthetized with sodium pentobarbital (60 mg/kg). A cannula was placed in the portal vein to prepare isolated hepatocytes (see below) but before the perfusion was started, blood was sampled from the inferior vena cava via a small needle attached to a syringe. Glucose concentrations were measured by a glucose oxidase met...

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hepatocyte insulin binding and action in rats with sommatomammotrophic tumours

Davidson

Melmed

1983

Diabetologia

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“…growth hormone could have a direct effect on pancreatic islets, the diabetogenic action of growth hormone (15,16), which includes insulin resistance, may be responsible for the changes noted in this study. It has been demonstrated (24-30) that glucose is a potent regulator of insulin biosynthesis in the rat.…”

Section: Discussionmentioning

confidence: 73%

Biosynthesis of rat insulins I and II: evidence for differential expression of the two genes.

Kakita¹,

Giddings²,

Permutt³

1982

Proc. Natl. Acad. Sci. U.S.A.

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The purpose of these experiments was to determine the relative content and biosynthetic rate of insulins I and II under various experimental conditions. The two insulins were quantitated by polyacrylamide gel electrophoresis, electrotransfer to nitrocellulose paper, photoaffinity crosslinking, and immunodetection with anti-insulin antibody and '5I-labeled protein A. The ratio (mean ± SEM) of insulins, I/HI, was 1.2 ± 0.2 in Wistar-Furth rats fasted for 4 days, 1.6 ± 0.2 in normal rats, and 5.5 ± 0.8 in growth hormone-tumor-bearing hyperinsulinemic rats (P < 0.01). The increase in content of rat insulin I compared to II in the growth hormone-tumor-bearing animals was confirmed by radioimmunoassay ofgel slices. To determine whether the difference in contents of rat insulins Iand El in the hyperinsulinemic rats was due to increased biosynthesis or a different turnover rate, isolated rat islets were incubated in [3H]leucine for 4 hr with 5.5 mM or 16.0 mM glucose in the incubation medium. Glucose stimulated insulin biosynthesis >8-fold. The ratio of synthesis of rat insulin I relative to II was 0.9 ± 0.1 at 5.5 mM glucose and 9.8 ± 3.3 (P < 0.01) at 16.0 mM glucose. Therefore, under conditions that stimulate insulin biosynthesis, there was a marked preferential synthesis ofrat insulin I relative to H. These studies suggest that the two rat insulin genes are expressed independently and that, under stimulatory conditions, there is preferential expression of the rat insulin I gene.In rats (1, 2), mice (3, 4), and certain fish (5, 6), two different insulins have been found. The rat insulins have been shown to be encoded by two nonallelic genes separated by at least 9,000 base pairs of DNA (7,8). The mRNAs are quite similar, approximately 93% homologous in the coding regions with only 34 of 439 nucleotides different (9, 10). Preproinsulins I and II, the initial translation products, differ by three amino acids in the preregion (7-11), two in the B chain, and two in the C peptide (see Fig. 1).Although the structures of the two genes, RNAs, and preproinsulins have been completely determined, little is known about the regulation of expression of the individual genes. In insulin isolated from Sprague-Dawley rat pancreas by Clark and Steiner (2), analysis by polyacrylamide gel electrophoresis indicated 58% insulin I and 42% insulin II. Biosynthesis of rat insulins I and II has been shown to occur in a ratio of 60:40 in several studies (2,(12)(13)(14).The present experiments were initiated in the course of the development ofan immunoelectrophoretic method for studying pancreatic extracts of insulin. We noted, in a hyperinsulinemic rat, that the ratio of rat insulins, I/IL, appeared to be greater than 5:1, a value very different from that previously reported. We therefore decided to do a more complete analysis of the proportion of rat insulins I and II under various experimental conditions and to examine their relative rates of synthesis. Our analysis confirmed that both the steady-state content and synthesis ofrat ins...

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“…Nevertheless, the actual diabetogenicity of elevated PRL and GH levels had already been questioned by the classic studies of transplantation of pituitary tumors in rats that failed to show the induction of diabetes even in presence of extremely high hormone levels (38)(39)(40). Only in the presence of a severely reduced -cell mass (80% pancreatectomy), transplantation of GH-and PRL-releasing tumors was followed by overt diabetes (41).…”

Section: Fig 3 In Vivo Graft Vascularization Of a Representative Pumentioning

confidence: 96%

Pituitary cotransplantation significantly improves the performance, insulin content, and vascularization of renal subcapsular islet grafts.

et al. 1999

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Because the pituitary contains hormones with beta-cell trophic activity, we evaluated whether cotransplantation of pituitary tissue with pancreatic islets might be beneficial for islet graft function and survival. Streptozotocin diabetic nude mice were transplanted under the kidney capsule with 150 handpicked islets alone or mixed with two diced pituitaries and were then followed for 4 weeks. Mice transplanted with mixed islet/pituitary grafts had higher levels of circulating prolactin (PRL) than mice transplanted with islets only, while serum cortisol, growth hormone, and follicle-stimulating hormone were similar in the two groups. After transplantation, recipients of mixed islet/pituitary grafts showed a more pronounced decrease in glycemic levels and higher systemic insulin levels than mice transplanted only with islets. Mixed islet/pituitary grafts were macroscopically characterized by an excellent vascularization and were biochemically characterized by higher insulin and PRL content than pure islet grafts. Histologically, posttransplantation remodeling originated a hybrid organ in which healthy, well-vascularized islets were adjacent to pituitary cell clusters. Transplantations performed to address the specific effect of the anterior versus the intermediate pituitary lobes indicated the former as responsible for the improved function of cotransplanted islets. Mixed islet/pituitary grafts composed of anterior lobes were also the best vascularized and were histologically characterized by the presence of many folliculo-stellate cells. In conclusion, we obtained evidence that pituitary cotransplantation significantly improves the function, insulin content, and vascularization of suboptimal islet grafts. Evidence suggesting that ectopically produced PRL and/or locally released angiogenic peptides might play a causal role is provided.

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Insulin Secretion in Rats with Elevated Levels of Circulating Growth Hormone Due to MtT-W15 Tumor

Cited by 40 publications

References 12 publications

Hepatocyte insulin binding and action in rats with sommatomammotrophic tumours

Hepatocyte insulin binding and action in rats with sommatomammotrophic tumours

Biosynthesis of rat insulins I and II: evidence for differential expression of the two genes.

Pituitary cotransplantation significantly improves the performance, insulin content, and vascularization of renal subcapsular islet grafts.

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