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R G Clark

Publications and source records attributed to R G Clark.

At least 55 records · Page 3Linked to original sources
PubMed1997

Insulin-like growth factor binding protein-1 induces insulin release in the rat.

Injections of human insulin-like growth factor binding protein (hIGFBP-1) are reported to induce hyperglycemia in the rat, suggesting that IGFBP-1 acutely regulates glucose homeostasis. We now report the effects on glucose and insulin levels of administering recombinant (r) hIGFBP-1. In a series of studies, normal and streptozotocin (STZ) diabetic male Wistar rats (180-210 g), fasted for 6 or 16 h, were injected with rhIGFBP-1 (i.v., 80-500 microg/rat). rhIGFBP-1 did not affect blood glucose acutely but did stimulate insulin release in normal rats (5 min post injection; PBS, 103.5 +/- 8.5; rhIGFBP-1 (500 microg), 166.8 +/- 15.7; rhIGFBP-1 (100 microg); 151.4 +/- 14.1% initial). rhIGFBP-1 pretreatment, in normal and diabetic rats, reduced the hypoglycemic response to rhIGF-I (diabetic rats after 20 min: PBS, 103.4 +/- 11.4; BP-1 (500 microg) +/- rhIGF-I (50 microg), 97.6 +/- 3.6; rhIGF-I, 48.2 +/- 4.3% initial) but did not affect the hypoglycemic response to des(1-3)IGF-I or insulin (0.5 U/kg). These studies show that rhIGFBP-1 causes insulin release, has a minimal effect on blood glucose, and inhibits the hypoglycemic effect of rhIGF-I. These data suggest that endogenous IGF-I tonically suppresses insulin secretion and imply that aberrant IGFBP levels or reduced IGF-I bioactivity may lead to chronic hyperinsulinemia.

Animals↗
PubMed1996

Cardiovascular effects of insulin-like growth factor-1 and growth hormone in chronic left ventricular failure in the rat.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) appears to have favorable cardiac effects associated with left ventricular remodeling early after myocardial infarction in the rat. The present study was designed to determine whether IGF-1 combined with growth hormone would be beneficial later as well, when infarct healing and cardiac remodeling have occurred. METHODS AND RESULTS: Four weeks after coronary occlusion, 36 rats were randomized to IGF-1 (3 mg.kg-1.d-1) plus growth hormone (0.1 mg BID) or to placebo for 4 weeks. Treated rats had significant increases in body weight (22%), while the ratio of heart weight to body weight was unchanged. Under anesthesia, cardiac output (fluorescent microspheres) increased 46%, and systemic vascular resistance decreased by 21% (P < .001) in the treated group; a significant (22%) increase of the cardiac index was limited to treated rats with large myocardial infarctions. Small increases in the reduced left ventricular ejection fractions and left ventricular dP/dt(max) values with treatment were not significant. Treated rats showed a borderline (16%) increase in left ventricular end-diastolic volume (angiography), whereas the ratio of left ventricular end-diastolic volume to body weight was reduced in the treated group. CONCLUSIONS: IGF-1 plus growth hormone administered to rats with left ventricular failure starting 1 month after MI was associated with substantial body growth, decreased systemic vascular resistance, and increased cardiac output. The failing heart also underwent treatment-induced increases in left and right ventricular weights in proportion to body growth, but left ventricular remodeling was minor, and a decrease in the ratio of left ventricular end-diastolic volume to body weight reflected relatively less chamber dilation compared with controls. A significant interaction between size of the myocardial infarction and treatment was observed for several variables, and IGF-1 and growth hormone increased the cardia index (P < .035) in rats with a large myocardial infarction.

Animals↗
PubMed1996

Up and down the growth hormone cascade.

In this review we present a personal overview of current research at different levels of the control cascade that regulates growth hormone and insulin-like growth factors, the primary endocrine regulators of post-natal growth and metabolism. Given the broad scope of this topic we have focused on only a few key areas of current interest.

Animals↗
PubMed1996

Recombinant human growth hormone (GH)-binding protein enhances the growth-promoting activity of human GH in the rat.

To address the role of the GH-binding protein (GHBP) in GH physiology, two forms of recombinant human GHBP (rhGHBP) were given alone or in combination with rhGH to hypophysectomized rats or GH-deficient dwarf rats. Hypophysectomized rats were given daily sc injections of excipient, hGH, rhGHBP, or rhGH plus rhGHBP (produced in Escherichia coli) for 7 days. Injections of rhGH induced dose-related body weight gain and bone growth that were increased by the coadministration of rhGHBP with rhGH; rhGHBP alone had no effect. Serum insulin-like growth factor increased 24 h later when rhGH was given together with rhGHBP (P < 0.01), but not when rhGH was given alone. E. coli-derived rhGHBP also enhanced the bioactivity of coadministered rhGH in the GH-deficient dwarf rat. In contrast, the glycosylated rhGHBP, made in human A293 cells, inhibited the growth-promoting activity of coadministered rhGH. The opposite effects of these two forms of rhGHBP could be explained by clearance studies that showed radiolabeled rhGH bound to A293 cell-derived rhGHBP to be cleared more rapidly from the blood than free rhGH. Natural rabbit GHBP and E. coli-derived rhGHBP both prolonged the presence of rhGH in blood. It is proposed that by slowing the clearance of GH, GHBP increased the bioactivity of GH. In summary, codelivery of rhGHBP and rhGH caused a dose-dependent enhancement of the activity of rhGH in two rat models of GH deficiency. This suggests that endogenous circulating GHBP may increase the activity of blood-borne GH in a similar manner.

Animals↗
PubMed1996

The human growth hormone (hGH) antagonist G120RhGH does not antagonize GH in the rat, but has paradoxical agonist activity, probably via the prolactin receptor.

Human GH (hGH) acts by dimerizing two hGH receptors that bind to different sites in hGH. G120RhGH, an analog mutated in the second binding site to prevent receptor dimerization, acts as an antagonist in vitro. We have now tested the activity of this analog in vivo in rats with low or absent endogenous GH secretion. Surprisingly, treatment with G120RhGH failed to antagonize the effects of infusions or injections of hGH in hypophysectomized (Hx) rats and had little effect on hepatic GH-sensitive CYP2C transcripts in GH-deficient dwarf (dw) rats. Paradoxically, G120RhGH stimulated skeletal growth when infused into Hx rats; a pulsatile iv infusion was more effective than a continuous pattern. Coinfusion of G120RhGH with hGH produced an additive effect on growth. In addition, continuous, but not pulsatile, G120RhGH infusion elevated hepatic 2C12 messenger RNA (mRNA) expression and reduced 2C11 mRNA expression in Hx rats. The direct effects of G120RhGH on hepatic CYP2C transcripts were confirmed in cultured hepatocytes in vitro, which also revealed a significant action of PRL in elevating 2C12 mRNA expression. Binding studies revealed that G120RhGH bound preferentially to hepatic PRL receptors, as [125I]G120hGH was completely displaced by ovine PRL but was unaffected by bGH, a specific GH receptor ligand. The weak growth-promoting effects of G120RhGH were similar to those induced by recombinant hPRL in Hx rats. Our results show that G120RhGH is a poor in vivo GH antagonist in the rat, but shows a paradoxical agonist effect, probably mediated by PRL receptors in this species.

Animals↗
PubMed1996

The obese growth hormone (GH)-deficient dwarf rat: body fat responses to patterned delivery of GH and insulin-like growth factor-I.

We describe a new animal model of obesity and GH deficiency and report the effects on body fat of administering (GH) and insulin-like growth factor (IGF-I) in the model. Female GH-deficient dwarf rats fed a high-fat diet became obese and insulin-resistant compared with chow-fed controls. They were treated with recombinant human GH (rhGH 100-500 micrograms/day, s.c. for 14 days) by daily injection or minipump infusion with or without rhIGF-I (200 micrograms/day, sc infusion). Injections of rhGH increased body weight; infusions of rhGH caused weight loss. RhIGF-I by itself, or rhIGF-I plus GH injections had little effect, whereas rhGH infusions plus rhIGF-I caused a weight loss equivalent to the weight gained during the high-fat feeding and a decrease in fat pad weight. For some responses (serum IGF-1 and GHBP), the obese rats were GH resistant. Fat was lost from the internal fat pads when obese rats were returned to a chow diet, and injections of rhGH surprisingly attenuated this loss of fat. In obese dwarf rats, the lipolytic effects of rhGH are dose-regime dependent. By itself IGF-I is not insulin-like, but in the presence of GH it has antiinsulin actions causing a powerful net lipolysis. If GH plus IGF-I have similar effects in humans they may be useful for reducing body fat.

Adipose Tissue↗
PubMed1996

Differential long-term effects of insulin-like growth factor-I (IGF-I) growth hormone (GH), and IGF-I plus GH on body growth and IGF binding proteins in hypophysectomized rats.

The long-term effects of recombinant human insulin-like growth factor-I (rhIGF-I) and GH (rhGH) on body growth and the IGF-I/IGF binding protein (IGFBP)/acid-labile subunit (ALS) axis were investigated in hypophysectomized (hypox) rats given excipient, rhIGF-I (2 mg/kg.day s.c., minipumps), rhGH (2 mg/kg.day, s.c., daily injections), or rhIGF-I plus rhGH for 28 days. The relative growth-promoting activity of the treatments was rhGH plus rhIGF-I more than rhGH more than rhIGF-I. Weight gain induced by rhIGF-I progressively declined after 4 days, compared with a more maintained effect of rhGH. At day 28, growth responses did not correlate with serum IGF-I levels [rhGH plus rhIGF-I (492 +/- 140) > rhIGF-I (322 +/- 75) > rhGH (85 +/- 26) > control (39 +/- 7 ng/ml)]. Serum ALS concentrations in hypox rats were remarkably low (0.42 +/- 0.04 micrograms/ml) but were restored toward normal by rhGH (12.55 +/- 4.78) or rhGH plus rhIGF-I (12.85 +/- 6.64) but not by rhIGF-I alone (0.85 +/- 0.25). Antibodies against rhGH were present at day 28, with titer being negatively related to weight gain, IGF-I, and ALS levels. All treatments increased serum IGFBP-3. The molecular size distribution of IGFBP-3 in rhGH-treated rats was similar to that of normal rats (IGFBP-3 in the 150K mol wt range), due to rhGH increasing serum ALS, but was altered by rhIGF-I (IGFBP-3 in the 200-300K and 44K mol wt range). In a GH-deficient animal, restoring the IGF/IGFBP-3/ALS axis towards normal is associated with greater growth promotion.

Animals↗
PubMed1996

Effects of 14-day infusions of growth hormone and/or insulin-like growth factor I on the obesity of growing Zucker rats.

The response of fat tissue to GH or insulin-like growth factor I (IGF-I) differs between humans with hypopituitarism and those with exogenous obesity; the effects of combined GH and IGF-I administration have not been compared in these two situations. In GH-deficient dwarf rats (who have a primary GH deficiency), the excessive fat deposition induced by a high fat diet is completely reversed by combined infusion of GH and IGF-I. Whether the same phenomenon would be observed in genetically obese Zucker rats (in whom, as in obese humans, the decrease in GH secretion is secondary to the obese state) remained to be determined. Growing (6-week-old) female obese Zucker rats received a continuous sc infusion of vehicle, recombinant human GH, recombinant human IGF-I, or GH plus IGF-I for 14 days (3 mg/kg x day for both GH and IGF-I). Combined GH and IGF-I stimulated body weight gain and in naso-anal length to the same extent as IGF-I alone, whereas GH alone was less potent. Because all treatments stimulated weight linear growth proportionately, the progression of obesity was similar in treated and control animals. However, GH plus IGF-I (but not either agent alone) induced a 25% decrease in the relative weight of inguinal fat. GH and IGF-I exerted distinct effects on the relative weights of liver, kidney, and spleen and on the circulating levels of IGF-I and IGF-binding protein-3. Circulating glucose and insulin levels did not change in any group. In summary, GH plus IGF-I infusions decrease the relative weight of inguinal fat in Zucker rats as in obese GH-deficient dwarf rats; however, this effect is of more modest magnitude despite the use of a 2- to 3-fold higher dose and is limited to the inguinal site. Thus, GH plus IGF-I infusions did not influence the obesity index in Zucker rats. Inasmuch as Zucker rats are a better model of childhood-onset obesity than dwarf rats fed a high fat diet, the present results do not appear promising for extrapolation to clinical studies in children. The mechanisms by which the primary vs. secondary nature of the decreased GH secretion influences the effect of GH plus IGF-I on obesity remain to be determined.

Analysis of Variance↗
PubMed1995

Growth hormone secretagogues: characterization, efficacy, and minimal bioactive conformation.

Another class of growth hormone (GH) secretagogues has been discovered by altering the backbone structure of a flexible linear GH-releasing peptide (GHRP). In vitro and in vivo characterization confirms these GH secretagogues as the most potent and smallest (M(r) < 500) reported. Anabolic efficacy is demonstrated in rodents with intermittent delivery. A convergent model of the bioactive conformation of GHRPs is developed and is supported by the NMR structure of a highly potent cyclic analog of GHRP-2. The model and functional data provide a logical framework for the further design of low-molecular weight secretagogues and illustrate the utility of an interdisciplinary approach to elucidating potential bound-state conformations of flexible peptide ligands.

Amino Acid Sequence↗
PubMed1995

Affinity purification and microcharacterization of recombinant DNA-derived human growth hormone isolated from an in vivo model.

A procedure has been developed for the isolation and purification of trace amounts of unlabeled proteins from biological solutions. Using a combination of affinity chromatography and reversed-phase HPLC, microgram amounts of recombinant DNA-derived human growth hormone (rhGH) were purified from an in vivo rat model. Microcharacterization techniques were developed, and picomole amounts of the recovered protein were digested with trypsin and characterized using capillary HPLC peptide mapping. The described procedures were used to study the chemical changes that occur in rhGH following intravenous administration. The study demonstrated that both deamidation and oxidation can occur in vivo, although the former would occur to a significant extent only in proteins with an extended half-life.

Animals↗
PubMed1995

Effects of growth hormone in rats with postinfarction left ventricular dysfunction.

Growth hormone may affect cardiac function. In rats, chronic hypersecretion of growth hormone leads to increased maximum isometric contractile force of the left ventricular papillary muscle in vitro. In humans, administration of growth hormone can increase myocardial contractility. However, cardiac effects of growth hormone in heart failure or cardiac dysfunction have not been studied to date. The current study was to evaluate the cardiac effects of growth hormone in conscious rats with postinfarction left ventricular dysfunction and sham controls. Ligation of the left coronary artery or sham operation was performed, then 4 weeks after surgery, recombinant human growth hormone (2 mg/kg/day, SC) or vehicle was administered for 15 days. Catheters were implanted 13 days after treatment with growth hormone or vehicle. Hemodynamic parameters were measured in conscious rats 2 days after catheterization. In vehicle-treated rats, left ventricular systolic pressure, maximum dP/dt, and arterial pressure were significantly decreased and left ventricular end-diastolic pressure was significantly increased in the ligation group compared with sham controls. Growth hormone treatment increased left ventricular systolic pressure (p < 0.05) and dP/dt (p < 0.05) and reduced left ventricular end-diastolic pressure (p < 0.05), significantly in the ligated rats. In sham rats, growth hormone tended to decrease arterial pressure but did not alter ventricular contractility. Neither ligation nor growth hormone significantly altered heart rate and right atrial pressure. These results suggest that growth hormone treatment may improve cardiac function by increasing myocardial contractility in cardiac dysfunction or heart failure.

Analysis of Variance↗
PubMed1995

A study of high lamb liver copper concentrations on some farms in Otago and Southland.

Lamb copper status is commonly assessed by measuring copper concentrations in four liver samples collected from lines of lambs sent to meat slaughtering premises. High liver copper concentrations were found in lambs examined in April and May. Five farms with two or more lamb liver copper concentrations greater than 3000 micromol/kg on a wet matter basis and two farms with adequate copper concentrations but less than 3000 micromol/kg in the autumn of 1992 were selected for a more detailed investigation into the factors affecting their lamb copper status in 1993. High liver copper status was associated with low pasture molybdenum, grazing paddocks recently topdressed with copper sulphate, supplementing with mineralised drenches and copperised salt licks, and the high copper content in chicory. Lamb liver copper concentrations were significantly (p<0.05) higher in the autumn than in the summer on two of three farms.

Journal Article↗
PubMed1995

Beneficial effects of growth hormone and insulin-like growth factor-1 in experimental heart failure in rats treated with chronic ACE inhibition.

The effects of growth hormone (GH) plus insulin-like growth factor-1 (IGF-1) were tested in an experimental model of cardiac failure treated with chronic angiotensin-converting enzyme (ACE) inhibition. Myocardial infarction was induced in rats by left coronary artery ligation. Two weeks after ligation, the animals received either captopril (2 g/L in drinking water) or water for 3 months. The rats were then given either GH (2 mg/kg/day) plus IGF-1 (2 mg/kg/day) or vehicle for 14 days. Captopril treatment decreased mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) (p < 0.05), and increased cardiac index (CI) and stroke volume index (SVI) (p < 0.05). GH/IGF-1 or captopril+GH/IGF-1 treatment decreased MAP, LVEDP, and SVR (p < 0.05), and increased left ventricular maximum dP/dt, CI, and SVI (p < 0.05). The increases in CI and SVI were significantly greater in the captopril+GH/IGF-1-treated animals than in those treated with captopril alone (p < 0.05). The beneficial effect of captopril in reducing cardiac hypertrophy was preserved in the captopril+GH/IGF-1 group. The results indicate that GH/IGF-1 and captopril can improve cardiac performance in congestive heart failure by independent and complementary mechanisms.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

A conjugative transfer system for the rumen bacterium, Butyrivibrio fibrisolvens, based on Tn916-mediated transfer of the Staphylococcus aureus plasmid pUB110.

A limitation of genetic studies of the rumen bacterium, Butyrivibrio fibrisolvens, has been the availability of suitable vectors and transfer systems. Using the conjugative tetracycline resistant transposon, Tn916, the Staphylococcus aureus plasmid, pUB110, and the pUB110-based shuttle vector, pUBLRS, a conjugative transfer system was developed for B. fibrisolvens. B fibrisolvens donor strains H17c2 and H17c12, containing Tn916 and pUB110 or pUBLRS, respectively, were used in mating experiments with selected B. fibrisolvens strains. Kanamycin resistant transconjugants, containing pUB110, of strains 193, 194, and 195 were detected at a combined average frequency of 7.78 x 10(-7) per donor and 1.11 x 10(-5) per recipient. Transconjugants of strains 193 and 194, containing pUBLRS, were detected at an average frequency of 1.22 x 10(-6) per donor and 4.70 x 10(-8) per recipient. Southern hybridization analysis confirmed the presence of pUB110 and pUBLRS in transconjugants. Results indicated that Tn916 was necessary for mobilization of pUB110 as transconjugants were not detected when the transposon was absent from the donor strains. The ability to mobilize pUB110 and pUBLRS between B. fibrisolvens strains provides a conjugative transfer system that circumvents problems encountered with electroporation.

Animals↗
PubMed1994

Enhanced body growth in uremic rats treated with IGF-I and growth hormone in combination.

The efficacy of seven days treatment with IGF-I (1.7 mg/kg/day), growth hormone (GH) (2 mg/kg/day), IGF-I+GH (1.7 mg/kg/day + 2 mg/kg/day) or vehicle, in promoting growth was investigated in female Sprague-Dawley rats with 5/6 nephrectomies (N = 8 per group). Treatment commenced after chronic renal failure had been present for seven weeks. Significant increases in body weight gain were found in all groups versus control, with IGF-I+GH causing the greatest response, and increased body weight gains correlating with increased nitrogen retention. GH treatment alone significantly stimulated food intake. IGF-I+GH resulted in close to additive increases in food conversion efficiency (18.8%, 21.5% and 39.6% increases with IGF-I, GH and IGF-I+GH, respectively, over control levels) and longitudinal bone growth (39%, 37% and 67% increases with IGF-I, GH and IGF-I+GH, respectively, vs. control). Serum insulin and cholesterol levels significantly decreased with IGF-I and IGF-I+GH treatment. Creatinine clearance did not change, suggesting there were no effects of treatment on kidney function. Although IGF-I at the doses used did not result in a greater anabolic response than GH, IGF-I+GH caused significantly enhanced growth while reducing serum insulin and cholesterol levels.

Animals↗