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Biomedical subjects

A R Hoffman

Publications and source records attributed to A R Hoffman.

At least 73 records · Page 4Linked to original sources
PubMed1994

Promoter-specific imprinting of the human insulin-like growth factor-II gene.

Genomic imprinting is a mechanism whereby only one of the two parental alleles is expressed. Loss or relaxation of genomic imprinting has been proposed as an epigenetic mechanism for oncogenesis in a variety of human tumours. Although the mechanism of imprinting is unknown, differential CpG methylation of the parental alleles has been implicated. The human insulin-like growth factor-II (IGF2) gene, which is transcribed from four promoters, P1-P4 (ref. 13), is imprinted in fetal liver but biallelic expression occurs in adult liver. Like most tissues, fetal liver uses primarily promoters P3 and P4 (ref. 17). Adult liver, however, transcribes IGF2 from promoter P1, and it has been suggested that the recruitment of P1 may be responsible for the absence of imprinting in human liver, and in choroid plexus and leptomeninges. We report here that in liver and chondrocytes, IGF2 transcripts from promoter P1 are always derived from both parental alleles, whereas transcripts from promoters P2, P3 and P4 are always from one parental allele. These findings demonstrate that imprinting and a lack of imprinting can both occur within a single gene in a single tissue, suggesting that regional imprinting factors may be important.

Adult↗
PubMed1994

Interactions of growth hormone and parathyroid hormone in renal phosphate, calcium, and calcitriol metabolism and bone remodeling in postmenopausal women.

The mechanisms underlying the effects of recombinant human growth hormone (rhGH) on vitamin D, mineral, and bone metabolism are not known. We examined whether these effects are mediated by parathyroid hormone (PTH) by measuring renal phosphorus (P) and calcium (Ca) handling, serum calcitriol, and markers of bone turnover for 24 h before and 72 h after an infusion of hPTH(1-34) in eight healthy postmenopausal women at baseline and following short-term (1 week) and sustained (5 weeks) rhGH treatment. On short-term rhGH, serum phosphorus and basal TmP/GFR were unaffected, but the fall in TmP/GFR after hPTH infusion was exaggerated (integrated response: -99.2 +/- 22.3 versus -144.1 +/- 15.0 minute-mg/dl, P = 0.0021). Basal calcitriol levels rose from 115 +/- 17 to 163 +/- 16 pM (P = 0.0002), but the increase in calcitriol following hPTH infusion was unaffected by short-term rhGH. The basal Ca excretion index (CEI) rose from 0.054 +/- 0.005 to 0.073 +/- 0.007 mM (P = 0.0095), but markers of bone turnover were unaffected. With sustained rhGH treatment, serum P (1.47 +/- 0.05 mM), basal TmP/GFR (4.29 +/- 0.24 mg/dl), and basal CEI (0.067 +/- 0.005 mM) were elevated compared with control values, and the PTH-induced lowering of TmP/GFR was again enhanced (-158.7 +/- 22.8 minute-mg/dl, P = 0.0021). Basal calcitriol concentrations returned to control levels (108 +/- 10 pM), but the calcitriol response to hPTH remained unchanged. Markers of bone remodeling were elevated with sustained rhGH treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1994

The insulin-like growth factor I generation test: resistance to growth hormone with aging and estrogen replacement therapy.

Circulating IGF-I is primarily regulated by growth hormone, but other factors such as nutritional status may also influence IGF-I secretion. The effects of age, gender, and estrogen replacement on responsiveness of serum IGF-I to GH administration have not been directly studied. The high-affinity circulating GH-binding protein (GHBP) has the same structure as the extracellular domain of the GH receptor and may reflect the sensitivity to GH in humans. To examine these issues, we employed an IGF-I generation test in which a single dose of GH (0.1 mg/kg SQ) was administered to 31 healthy adults comprising five groups: young (20-29 years) males (YM), young females in the follicular phase of the menstrual cycle (YF), older (60-69 years) males (OM), older females not on estrogen replacement (OFN), and older females on oral estrogen replacement (OFE). Blood was sampled for IGF-I and GHBP over 72 hours following GH administration. OM had lower peak IGF-I levels (323 +/- 38 vs. 497 +/- 85 micrograms/l, p = 0.0015) and a lower IGF-I response to GH (delta IGF-I: 187 +/- 33 vs. 293 +/- 57 micrograms/l, p = 0.0085) than YM. OFE had lower basal IGF-I (63 +/- 11 vs. 133 +/- 19 micrograms/l, p = 0.0046), peak IGF-I (174 +/- 28 vs. 400 +/- 40 micrograms/l, p = 0.0015), and delta IGF-I (111 +/- 21 vs. 268 +/- 27 micrograms/l, p = 0.0085) than OFN. IGFBP-3 levels were unchanged 24 hours after GH administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Anabolic effects of recombinant insulin-like growth factor-I in cachectic patients with the acquired immunodeficiency syndrome.

The loss of lean body mass accompanying acquired immunodeficiency syndrome (AIDS)-associated cachexia is refractory to current modes of therapy. GH and insulin-like growth factor-I (IGF-I) stimulate protein accretion, but resistance to GH action has been reported in malnutrition and infection. We hypothesized that GH resistance occurs in AIDS-associated cachexia, but that treatment with IGF-I would be anabolic. A single injection of GH produced a smaller increase in circulating IGF-I in 21 patients with AIDS compared to that in 23 age-matched controls (141 +/- 15 vs. 194 +/- 15 micrograms/L; P < 0.02), indicating partial GH resistance. Ten subjects received either low or high dose iv recombinant IGF-I 12 h daily for 10 days. Cumulative nitrogen retention was positive for both dosage groups (low dose, 15.42 +/- 6.37 g; high dose, 3.62 +/- 4.15 g), but a significant increase in daily nitrogen retention occurred only in the low dose group on days 2, 4, 5, 6, and 7. Nitrogen balance and protein turnover (estimated by [13C]leucine and [15N] glycine kinetics) during the final 3 days of treatment were unchanged compared to baseline values, confirming the transient nature of the anabolic response. Repeated administration of IGF-I decreased IGF-binding protein-3 levels, producing lower intrainfusion levels of IGF-I and limiting its therapeutic efficacy. The basal metabolic rate increased with high dose IGF-I and may have contributed to the lack of anabolic effect. We conclude that partial GH resistance occurs in AIDS-associated cachexia. Treatment with low dose recombinant IGF-I produces significant, but transient, nitrogen retention. Alternate routes of IGF-I administration or coadministration with GH may prevent attenuation of IGF-I action.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men.

Normal aging is characterized by detrimental changes in body composition, muscle strength, and somatotropic function. Reduction in muscle strength contributes to frailty and risk for fracture in the elderly. Although older adults increase muscle strength as a result of resistance exercise training, the strength gains quickly level off, with only modest increases thereafter despite continued training. To investigate whether age-related deficits in the somatotropic axis limit the degree to which muscle strength can improve with resistance training in older individuals, we conducted a double blind, placebo-controlled exercise trial. Eighteen healthy elderly men (65-82 yr) initially underwent progressive weight training for 14 weeks to invoke a trained state. Subjects were then randomized to receive either 0.02 mg/kg BW.day recombinant human GH (rhGH) or placebo, given sc, while undertaking a further 10 weeks of strength training. Sequential measurements were made of muscle strength (one repetition maximum), body composition (dual energy x-ray absorptiometry), and circulating levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3. For each exercise, strength increased for both groups (P = 0.0001) through 14 weeks of training, with little improvement thereafter. Increases in muscle strength ranged from 24-62% depending on the muscle group. Baseline plasma IGF-I concentrations were similar in both groups (mean +/- SEM, 106 +/- 9 micrograms/L), approximately half that observed in healthy young adults. In the rhGH group, IGF-I levels increased to 255 +/- 32 micrograms/L at week 15 and 218 +/- 21 micrograms/L at week 24 (P < 0.001). In the placebo group, IGF-I increased slightly to 119 +/- 6 micrograms/L at 24 weeks. IGF-binding protein-3 also increased in the rhGH group (P < 0.05). rhGH had no effect on muscle strength at any time, and no systematic difference in muscle strength was observed between groups throughout the study. Body weight did not change in either group, but lean body mass increased, and fat mass decreased (P < 0.05) in the rhGH group. Supplementation with rhGH does not augment the response to strength training in elderly men. These results suggest that deficits in GH secretion do not underlie the time-dependent leveling off of muscle strength seen with training in the elderly and provide no support for the popular view of GH as an ergogenic aid.

Aged↗
PubMed1993

mRNA structure, in situ, as assessed by microscopic techniques.

The secondary and tertiary structure of RNA, in situ, is thought to be involved in distinct functions such as directing association of the RNA with the cytoskeleton, enzymatic activity of some RNAs, and the control of translation. In situ transcription (IST), a procedure by which cDNA is synthesized in situ, has been used to assess mRNA structure in situ using fixed cells or tissues. Distinct banding patterns were noted for mouse and rat POMC. Unique IST banding patterns were observed when an oligonucleotide complementary to a putative POMC stem-loop structure was used to prime IST. Indeed local changes in banding patterns could be elicited by pharmacological agents which modulate POMC translation. Inhibition of POMC synthesis with NaF or dexamethasone decreased the number of POMC mRNAs in the polysome fractions and increased the intensity of high molecular weight IST-derived bands. Forskolin, a stimulator of POMC synthesis, had the opposite effect. One mechanism by which translational control is thought to occur is by regulation of ribosome movement down the mRNA by specific binding of cytosolic proteins to RNA structure. Cytosolic protein fractions from AtT20 pituitary cells have been shown to specifically bind to the IST-predicted RNA structure. These findings suggest that 1) mRNA structure can be assessed in situ, 2) translation may be altered by the secondary and tertiary structure of mRNAs, and 3) a predicted stem-loop structure exists in situ in the 5'-end of POMC mRNA.

Animals↗
PubMed1993

Regulation of neutrophil interleukin 8 gene expression and protein secretion by LPS, TNF-alpha, and IL-1 beta.

Neutrophils are possibly involved in the pathogenesis of various lung diseases through the release of numerous mediators. In the present study, we studied the regulation of IL-8 gene induction and protein secretion in human blood neutrophils. Northern blot analysis revealed that LPS increased IL-8 mRNA levels in neutrophils, with a maximal fivefold increase by 2 h. IL-8 mRNa levels returned to baseline values within 12 h. In contrast, LPS-stimulated monocytes demonstrated a sustained increase of IL-8 mRNA levels for more than 24 h. TNF-alpha, IL-1 beta, and phorbol myristate acetate also increased IL-8 mRNA levels in neutrophils. Immunohistochemical analysis confirmed that IL-8 was localized within stimulated neutrophils. IL-8 secretion by neutrophils and monocytes was quantified using a specific ELISA for IL-8. Resting neutrophils secreted minimal IL-8 activity. However when cells were stimulated with LPS, TNF-alpha, or IL-1B, neutrophils secreted IL-8. IL-8 secretion was most marked during the first 2 h after stimulation and decreased thereafter. In contrast, monocytes maintained a high rate of IL-8 secretion over 12 h. Although a single monocyte secreted 70-fold more IL-8 than did a single neutrophil after 4 h of incubation, the high abundance of neutrophils in peripheral blood made the neutrophil-secreted IL-8 more significant. During the first 2 h, neutrophils secreted approximately 40% of the IL-8 released by monocytes in the same volume of blood. This ratio decreased to 9% after 12 h. Neutrophil-secreted IL-8 may play an autocrine or paracrine role during the initial stage of inflammation.

Cells, Cultured↗
PubMed1993

Insulin-like growth factor (IGF), IGF binding protein (IGFBP), and IGF receptor gene expression and IGFBP synthesis in human uterine leiomyomata.

Oestradiol is important in the growth of uterine leiomyomata and may act primarily or secondarily through mediators such as growth factors, including the insulin-like growth factors (IGF-I and IGF-II), mitogenic peptides. IGF binding proteins (IGFBPs) modulate IGF actions at their target cells. The objective of this study was to examine the possible steroid dependence of IGF, IGFBP and IGF receptor gene expression and IGFBP synthesis in uterine leiomyomata, using tissues from women cycling normally and made hypo-oestrogenic by a gonadtrophin-releasing hormone agonist (GnRHa). Using a solution hybridization ribonuclease protection assay, anti-sense RNA probes for IGF-I, IGF-II and beta-actin (control) were hybridized with total RNA isolated from leiomyomata exposed in vivo to a range of serum oestradiol (< 40-240 pg/ml) and progesterone (0-10 ng/ml) concentrations. IGF-I gene expression was most abundant in leiomyomata obtained during the late proliferative phase of the cycle and was undetectable in leiomyomata from hypo-oestrogenic patients. IGF-II gene expression was not dependent on endogenous steroid concentrations or cycle stage. IGFBP gene expression was investigated by Northern blotting. The order of relative abundance of IGFBP mRNAs was IGFBP-4 >>> IGFBP-3 >> IGFBP-5 > IGFBP-2 and was not dependent on the in-vivo oestrogen status. Type I and type II IGF receptor gene expression was investigated by polymerase chain reaction using gene-specific primers. Type I and type II IGF receptor mRNAs were detected in leiomyomata and were not dependent on cycle stage or in-vivo oestrogen status. Explant cultures of leiomyomata and myometrium synthesized IGFBP-3 (mol. wt = 38-43 kDa), IGFBP-4, and binding proteins of mol. wt = 34 and 31 kDa. Identification of IGFBP-2 was inconclusive, and IGFBP-1 was not detected. These data support the hypothesis that IGF-I, but not IGF-II, may be a mediator of oestradiol action in the growth of uterine leiomyomata, and that IGFBPs may further modulate, by an autocrine or paracrine mechanism, IGF-I action in this tissue.

Base Sequence↗
PubMed1993

Mechanisms of thyroid hormone action on the insulin-like growth factor system: all thyroid hormone effects are not growth hormone mediated.

Normal somatic growth requires that both the thyroid hormone axis and GH axis be intact. Thyroid hormone stimulates GH secretion, and many thyroid hormone actions on the insulin-like growth factor (IGF) system can be explained by this mechanism. We have previously described distinct changes in IGF binding protein (IGFBP) expression in experimental hypothyroidism in the rat; these changes could be completely corrected by thyroid hormone replacement. To see if the effects of thyroid hormone on IGFBP expression are, in fact, indirect GH effects, we rendered both newborn and adult rats hypothyroid with methimazole treatment, and investigated whether we could correct the resulting IGF and IGFBP changes with GH replacement. The prolonged high expression of serum IGFBP-2 and liver IGFBP-2 messenger RNA (mRNA) during the perinatal period in hypothyroid rat pups could not be normalized by GH therapy, although serum IGF-I values (reduced to 54% of control levels in the hypothyroid animals) were brought up to control level. In adult hypothyroid rats, serum IGF-I concentrations (51% of control levels), were increased up to 79% of control levels, but not totally corrected, by GH therapy. Reduced IGFBP-3 expression (80% of control serum and 50% of control liver mRNA levels) in adult hypothyroid animals was normalized by GH, but there was no correction of the reduced IGFBP-4 serum levels (50% of control levels). Hepatic mRNA levels for the type 1 and 2 IGF receptors were not altered by hypothyroidism, or by thyroid or GH replacement. Somatic growth in hypothyroid pups and adults was only partially corrected by GH therapy. We conclude that GH treatment of hypothyroid animals normalized serum IGF-I levels in the hypothyroid rat pup, but did not correct their prolonged IGFBP-2 expression. In the mature animal, serum IGF-I levels were partially corrected and IGFBP-3 levels were normalized by GH, but no change could be induced in the reduced serum IGFBP-4 levels. All the above changes were normalized by thyroid hormone replacement. Thus, the effects of thyroid hormone on serum IGF levels and IGFBP-3 expression seem to be mediated indirectly via GH. The effects on IGFBP-2 ontogeny, and IGFBP-4 expression in the mature animal, however, are either direct thyroid hormone effects, or mediated by some other route, independent of GH, IGFs, or IGF receptors.

Aging↗
PubMed1993

Differential expression of messenger ribonucleic acids encoding insulin-like growth factors and their receptors in human uterine endometrium and decidua.

During the menstrual cycle, the endometrium undergoes characteristic changes in response to circulating sex steroids. Intense mitotic activity of glands and stroma occurs in the proliferative (estradiol-dominant) phase, and glandular secretion and stromal differentiation in the secretory (progesterone-dominant) phase. The insulin-like growth factors (IGF-I and IGF-II) promote cellular growth and differentiation and have been proposed to participate in these cyclic endometrial events, acting as mediators of steroid hormones. The objective of this study was to determine whether the messenger RNAs (mRNAs) encoding the IGF peptides and the type I and type II IGF receptors are differentially expressed in human endometrium during the menstrual cycle and in early pregnancy. A solution hybridization ribonuclease protection assay, using 32P-labeled riboprobes for IGF-I, IGF-II, and beta-actin (control), revealed IGF-I gene expression primarily in proliferative and early secretory endometrium and abundant IGF-II gene expression in mid-late secretory endometrium and early pregnancy decidua. Northern analysis, using IGF-I and IGF-II complementary DNA probes, revealed multiple IGF-I mRNAs [2-7.6 kilobase (kb)], expressed primarily in proliferative and early secretory endometrium, and IGF-II mRNAs (1.4-6.0 kb), expressed primarily in secretory endometrium and in early pregnancy decidua. The 7.6-kb IGF-I mRNA and the 6.0-kb IGF-II mRNA were most abundantly expressed. IGF-IEa and IGF-IEb mRNA splicing variants were present in a ratio of about 9:1, respectively. Type I and type II IGF receptor gene expression in endometrium was investigated using specific riboprobes and the ribonuclease protection assay. Messenger RNAs encoding both receptors were more abundantly expressed in the secretory phase and during early pregnancy, compared to the proliferative phase. These results show that mRNAs encoding the IGF peptides and their receptors are differentially expressed in human endometrium, depending on the steroid hormone milieu. The preferential expression of IGF-I mRNA in the proliferative phase supports the hypothesis that IGF-I is an estromedin in human endometrium. The expression of endometrial IGF-II mRNA in the mid to late secretory phase and in early pregnancy supports a role for IGF-II in differentiative functions of the endometrium, perhaps including endometrial tissue shedding in the menstrual cycle or remodeling during early pregnancy.

Base Sequence↗
PubMed1993

The renin-angiotensin system in streptozotocin-induced diabetes mellitus in the rat.

It has been hypothesized that the renin-angiotensin system plays a pathophysiologic role in the renal hemodynamic abnormalities that occur in diabetes mellitus and thereby contributes to the development of diabetic nephropathy. In this study, the tissue-specific regulation of renin and angiotensinogen mRNA levels and the abundance of glomerular angiotensin II receptors were examined in male Sprague-Dawley rats (160 to 240 g) made diabetic with streptozotocin. One subgroup of diabetic rats remained untreated, whereas a second diabetic subgroup received twice-daily doses of insulin to ameliorate hyperglycemia. Animals were euthanized 2 wk after the induction of diabetes. Mean plasma glucose levels at the time of euthanasia were significantly elevated in the untreated diabetic animals when compared with controls or insulin-treated diabetic rats. Weight gain was similar in control and insulin-treated diabetic rats, whereas the untreated diabetic rats gained significantly less. Plasma renin concentration did not differ between control, diabetic, and insulin-treated diabetic groups. In the kidney, no significant differences were found in either angiotensinogen or renin mRNA levels in diabetic animals, whereas glomerular angiotensin II receptors were significantly less abundant in untreated rats as compared with control or insulin-treated diabetic subgroups. Angiotensinogen mRNA levels were significantly lower in the livers and adrenals of diabetic rats in comparison to those in controls and insulin-treated diabetic rats, whereas angiotensinogen mRNA levels in the brain remained unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensinogen↗
PubMed1992

Growth hormone therapy in the elderly: implications for the aging brain.

Growth hormone (GH) secretion declines during normal aging, resulting in lower serum insulin-like growth factor (IGF)-I levels. It has been proposed that many of the catabolic changes seen in normal aging, including osteoporosis and muscle atrophy, are in part caused by the decreased action of the GH-IGF-I axis. In addition, patients with GH deficiency have increased overall cardiovascular mortality. Several investigators have initiated GH treatment for elderly patients with relative hyposomatotropinemia. Initial reports suggest that GH can increase muscle mass, improve exercise tolerance, increase REM sleep and cause an enhanced sense of well-being. The basis for neuropsychiatric changes during GH therapy may be due to a direct CNS action of GH itself, to the increased IGF-I secretion which GH elicits, or to enhanced functioning of peripheral organ systems. Long-term studies will determine whether GH or IGF-I can exert a neurotrophic action in the aging brain.

Adult↗
PubMed1992

Developmental regulation of lipoprotein lipase in rats.

To evaluate changes in lipoprotein lipase (LPL) expression during development, levels of LPL mRNA, protein, and enzyme activity were measured in heart, epididymal fat, kidney, and brain of rats, from late gestation through 24 mo. LPL mRNA, protein, and enzyme activity were low in fetal and neonatal hearts. LPL mRNA increased 11-fold by 60 days and remained at this level thereafter; LPL protein and enzyme activity increased 10-fold by weaning, before declining to low values by 3 mo. LPL mRNA levels, protein, and enzyme activity did not change in epididymal fat from 3 wk to 21 mo. In the kidney, LPL mRNA levels were high at the end of gestation but fluctuated during the first month. LPL protein and activity were low at day 1 and rose eightfold to peak values by day 7 before decreasing to low levels by weaning. LPL mRNA levels were relatively high in fetal brains and then fell 60% during the neonatal period. LPL protein peaked at day 7 before falling 95% by weaning. Thus LPL is under complex tissue-specific regulation involving transcriptional and posttranscriptional mechanisms.

Adipose Tissue↗
PubMed1992

Regulation of lipoprotein lipase in the diabetic rat.

Diabetes mellitus is associated with a reduction of lipoprotein lipase (LPL) activity and development of hypertriglyceridemia. In the current experiments the mechanisms involved in the regulation of LPL have been examined in control rats, streptozocin-induced diabetic rats, and diabetic rats treated chronically or with a single injection of insulin. Diabetes decreased adipose tissue LPL activity partially by decreasing immunoreactive LPL protein and the steady-state levels of LPL mRNA, but primarily by reducing the catalytic activity of LPL. Both chronic and acute insulin increased adipose tissue LPL activity by correcting the defect in the catalytic activity of LPL and increasing immunoreactive LPL protein; however, only chronic insulin restored LPL mRNA levels to normal. In the heart, LPL activity tended to be elevated with diabetes in parallel to an increase in immunoreactive LPL protein even though levels of LPL mRNA declined. Both chronic and acute insulin normalized LPL activity and immunoreactive LPL protein, while only chronic insulin corrected the levels of LPL mRNA. No changes in the catalytic activity of LPL in heart were detected among the groups. Thus, diabetes and insulin treatment regulate LPL expression pretranslationally, translationally, and post-translationally, with tissue-specific differences apparent in the mechanisms involved.

Adipose Tissue↗
PubMed1992

Regulation of insulin-like growth factor-binding protein expression by thyroid hormone in rat GH3 pituitary tumor cells.

Rat pituitary GH3 tumor cells express GH and insulin-like growth factor-I (IGF-I) mRNAs and possess specific IGF-I and IGF-II receptors which mediate the inhibitory effect of IGF on GH secretion. T3 increases the rate of cell replication and GH gene transcription, and causes an increase in IGF-I binding to cell membranes. Since the IGFs circulate in association with specific binding proteins (IGFBPs) that appear to modulate the access of IGFs to their receptors, we have investigated the effect of T3 treatment on the expression of IGFBPs in GH3 cells. Cells were grown in serum-free defined medium, and IGFBP secretion was determined by Western ligand blotting of conditioned medium after the addition of T3 and/or various peptides for 48-72 h. The conditioned medium of GH3 cells revealed a complex of bands migrating at 40-45 Mr, a pattern typical of rat (r) IGFBP-3. T3 treatment resulted in an increase in rIGFBP-3. IGF-I, IGF-II, and insulin did not alter rIGFBP-3 levels. After concentrating (10-fold) conditioned medium samples, two additional bands at 24K and 28K mol wt were also seen. These bands corresponded in size to rIGFBP-4 (24K) and its glycosylated form (28K). The mRNAs for both rIGFBP-3 and rIGFBP-4 were present in GH3 cells; T3 treatment increased steady state levels of rIGFBP-3 mRNA, but did not affect BP-4 mRNA levels. To learn whether the increased expression of IGFBPs could be responsible for the increased IGF-I binding seen after T3 treatment, [125I]IGF-I was cross-linked to GH3 membranes, and the proteins were separated on a 5-15% gradient sodium dodecyl sulfate-polyacrylamide gel under reducing conditions. T3 treatment induced a large increase in the intensity of bands migrating at 135K and 280K, representing the alpha-subunit of the IGF-I receptor and an incompletely reduced alpha-alpha-dimer, respectively. No membrane-associated IGFBPs were detected. In conclusion, GH3 cells express two IGFBPs, rIGFBP-3 and rIGFBP-4, which are differentially regulated by T3. The increased binding of IGF-I to GH3 cell membranes after T3 treatment indicates that thyroid hormone induces an up-regulation of IGF-I receptors and that the increased IGF-I binding to GH3 membranes is not due to increased expression of membrane-associated IGFBPs.

Animals↗
PubMed1992

Effects of recombinant human insulin-like growth factor-I (rhIGF-I) on total and free IGF-I concentrations, IGF-binding proteins, and glycemic response in humans.

To examine the effects of repeated administration of recombinant human insulin-like growth factor-I (rhIGF-I) on IGF-I levels, free IGF-I pharmacokinetics, glycemic response, and IGF-binding proteins (IGFBP), we administered rhIGF-I (0.03 mg/kg iv bolus) to 12 healthy males each morning for 5 consecutive days. Serum was collected over 24 h on days 1 and 5 for measurement of total and free IGF-I, glucose, insulin, and IGFBP. Total IGF-I was measured by RIA after acid/ethanol extraction. Free IGF-I was separated from binding protein-complexed IGF-I using size exclusion high performance liquid chromatography before measurement by RIA. IGFBP were quantitated by optical densitometry of Western ligand blots. Total IGF-I increased significantly from 0-24 h after administration on day 1 (mean +/- SD, micrograms/L: 120 +/- 44 to 166 +/- 51, P = 0.0002) but did not increase significantly from 24 h on day 1 to 0 h on day 5 (166 +/- 51 to 178 +/- 62) or from 0-24 h on day 5 (178 +/- 62 to 209 +/- 89). The area under the total IGF-I concentration curve was greater on day 5 than day 1 (311 +/- 99 min.g/L vs. 249 +/- 77, P = 0.0001). There were no significant differences in free IGF-I concentration or pharmacokinetic parameters or in the degree or timing of hypoglycemia between days 1 and 5. Plasma insulin levels decreased significantly following rhIGF-I administration (day 1 baseline: 53 +/- 11 pmol/L, nadir: 18 +/- 6 pmol/L at 30 min, P = 0.003); day 5 baseline: 47 +/- 15 pmol/L, nadir: 16 +/- 8 pmol/L at 30 min, P = 0.0003. Western ligand blotting revealed the transient appearance of a 30-kilodalton band which migrates in a manner similar to IGFBP-1. This band was undetectable at baseline, peaked between 150 and 210 min after rhIGF-I administration, and diminished by 480-600 min. The response was similar on days 1 and 5. There were no substantial changes in the serum levels of any other IGFBP. In summary, repeated iv bolus administration of rhIGF-I increased the level of total circulating IGF-I without changing free IGF-I disposition or glycemic response. A 30-kilodalton IGFBP band, most likely IGFBP-1, appeared transiently following rhIGF-I administration, probably as a result of suppression of insulin levels. IGFBP-2, -3, and -4 were unaffected.

Adult↗
PubMed1992

Rheumatologic and skeletal changes in acromegaly.

The anabolic functions of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in cartilage and bone metabolism are important in the normal physiology of these tissues. The effects of chronic elevation of GH and IGF-I levels on bony structures produce the typical physical changes associated with acromegaly, whereas the effects on cartilage result in arthropathy, which is usually degenerative. This article presents an overview of the physiologic roles of GH and IGF-I in cartilage and bone metabolism, the clinical features of the degenerative arthropathy and other rheumatologic syndromes associated with acromegaly, effects of acromegaly on bone and mineral metabolism, and an unusual bone disease that is occasionally associated with acromegaly, the McCune-Albright syndrome.

Acromegaly↗