Both Human Pituitary Growth Hormone and Recombinant DNA-Derived Human Growth Hormone Cause Insulin Resistance at a Postreceptor Site*

Rosenfeld, Ron G.; Wilson, Darrell M.; Dollar, Laura A.; Bennett, A. E.; Hintz, Raymond L.

doi:10.1210/jcem-54-5-1033

Cited by 159 publications

(63 citation statements)

References 24 publications

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“…The effect of GHT on glucose metabolism is predominantly insulin antagonistic. A marked hyperinsulinemia and a resistance to the action of insulin, as demonstrated by euglycemic clamp studies in healthy subjects, have been demonstrated [7,32]. We already demonstrated an increase in HOMA-IR, related to the increased insulin levels and without any untoward effect on glucose metabolism, in a small group of GHD children after GHT [33].…”

Section: Discussionsupporting

confidence: 55%

Utility of C-peptide for a reliable estimate of insulin secretion in children with growth hormone deficiency

Ciresi

Cicciò

Radellini

2016

Growth Hormone & IGF Research

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Objective: GH treatment (GHT) can lead to glucose metabolism impairment through decreased insulin sensitivity and impaired pancreatic β-cell function, which are the two key components of the pathogenesis of diabetes. Therefore, in addition to insulin sensitivity, during GHT it is very important to perform a reliable evaluation of insulin secretion. However, conflicting data exist regarding the insulin secretion in children during GHT. C-peptide provides a more reliable estimate of β-cell function than insulin, but few studies evaluated it during GHT. Our aim was to assess the usefulness of C-peptide in the evaluation of insulin secretion in GH deficiency (GHD) children. Design: In 48 GHD children, at baseline and after 12 and 24 months of GHT, and in 56 healthy subjects we evaluated fasting and glucagon-stimulated (AUC Cpep ) C-peptide levels in addition to other commonly used secretion indexes, such as fasting and oral glucose tolerance test-stimulated insulin levels (AUC INS ), Homa-β, and insulinogenic index. The main outcomes were the change in C-peptide during GHT and its correlation with the auxological and hormonal parameters. Conclusions: C-peptide, rather than the insulin-derived indexes, has proved to be the most useful marker of insulin secretion correlated to IGF-I levels in GHD children. Therefore, we suggest the use of glucagon test both as diagnostic test for the GH assessment and as a useful tool for the evaluation of insulin secretion during GHT in children.

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Section: Discussionsupporting

confidence: 55%

Utility of C-peptide for a reliable estimate of insulin secretion in children with growth hormone deficiency

Ciresi

Cicciò

Radellini

2016

Growth Hormone & IGF Research

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“…Indeed, the individual response to rhGH remains highly variable, and some effects of replacement therapy, for example, on glucose metabolism, are still a matter of debate. In fact, while it is well known that GH influences glucose homeostasis through increased lipolysis and insulin antagonism (16), low GH and IGF1 levels are associated with impaired glucose tolerance (IGT) in adults (17). Several reports have evaluated the effects of rhGH replacement on glucose metabolism in GHD adults, mostly documenting a short-term and transient deterioration of insulin sensitivity with a successive long-term stabilization, probably due to the persistent reduction in BF%, as also confirmed by a study performed by our group (18).…”

Section: Introductionmentioning

confidence: 99%

Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy

Giavoli

Ferrante

Profka

et al. 2010

European Journal of Endocrinology

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Objective: A common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked with increased response to recombinant human GH (rhGH) in some patients with or without GH deficiency (GHD). The aim of the study was to investigate the impact of the GHR genotype on the phenotype of GHD adults and on the metabolic effect of rhGH therapy. Design: Prospective study of GHD patients evaluated before and during short-(1 year, nZ100) and long-term (5 years, nZ50) rhGH therapy. Methods: Effects of rhGH on IGF1 levels, body composition (body fat percentage, BF%), body mass index, lipid profile, and glucose homeostasis (fasting insulin and glucose, insulin sensitivity indexes) were evaluated according to the presence or the absence of the d3GHR variant. Results: The different genotype did not influence basal phenotype of GHD. Short-term rhGH determined normalization of IGF1 levels, decrease in BF%, and worsening of insulin sensitivity, independently from the presence of the d3GHR allele. A significant increase in high-density lipoprotein cholesterol occurred in the d3GHR group. Normalization of IGF1 levels and decrease in BF% were maintained after 5 years. Insulin sensitivity restored to basal values, though in d3GHR patients fasting glucose remained significantly higher than at baseline. After both 1 and 5 years, percentage of subjects with impaired glucose tolerance, similar in the two groups at baseline, decreased in fl/fl while doubled in d3GHR patients. In this last group, a long-term significant reduction in total and low-density lipoprotein cholesterol was also observed. Conclusion: The functional difference of d3GHR may influence some metabolic effects of rhGH on GHD adults.

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“…In studies utilizing liver membranes prepared from normal or hypophysectomized rats injected with GH [37] or monocytes isolated from acromegalic patients [38], a decreased binding capacity was offset by an increased binding affinity so that little change in total insulin binding was noted. In other studies in which GH was administered to children with hypopituitarism [39] or to normal subjects [8,40], no changes in insulin-binding capacities or affinities were observed.…”

Section: Discussionmentioning

confidence: 80%

“…Therefore, both a receptor and post-receptor defect occur. However, since subjects exposed to excess GH for short, intermittent periods of time demonstrate insulin antagonism in the face of normal insulin binding [8,39,40], we suggest that the post-receptor defect causing decreased tissue responsiveness occurs earlier and is more important in altering carbohydrate metabolism than the receptor defect causing impaired tissue sensitivity.…”

Section: Discussionmentioning

confidence: 81%

“…Growth hormone (GH) is a potent insulin antagonist; this has been demonstrated by its effects on carbohydrate metabolism when secreted in excess by pituitary tumours in acromegaly [1], when injected into normal cats [2], dogs [3,4] or man [5][6][7][8] and when secreted physiologically 3-5 h post-prandially [9] or shortly after falling asleep [10]. Although the liver plays a central role in carbohydrate homeostasis, little data are available concerning the interaction between GH and insulin on hepatic carbohydrate metabolism.…”

mentioning

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...

show abstract

Both Human Pituitary Growth Hormone and Recombinant DNA-Derived Human Growth Hormone Cause Insulin Resistance at a Postreceptor Site*

Cited by 159 publications

References 24 publications

Utility of C-peptide for a reliable estimate of insulin secretion in children with growth hormone deficiency

Utility of C-peptide for a reliable estimate of insulin secretion in children with growth hormone deficiency

Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy

Hepatocyte insulin binding and action in rats with sommatomammotrophic tumours

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