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Biomedical subjects

A Flyvbjerg

Publications and source records attributed to A Flyvbjerg.

At least 163 records · Page 9Linked to original sources
PubMed1995

Effects of diabetes, insulin treatment, and osmolality on contractility of isolated rat resistance arteries.

The effects of osmolality, diabetes, and insulin-treatment on microvascular contractility were examined in mesenteric resistance arteries (internal diameter approximately 250 microns) isolated from streptozotocin-induced diabetic rats, streptozotocin-induced diabetic rats treated with 1-3 U insulin/day during the week before being killed, and age- and sex-matched control rats. Vessels were mounted in a microvascular myograph for isometric tension recording and responses were generated in physiological salt solutions with varying amounts of glucose or mannitol added. The passive response (expressed as the diameter the vessels would maintain if relaxed and exposed to a transmural pressure of 100 mmHg), the maximal response to noradrenaline, and the response produced by partial depolarization with 50 mmol/l potassium were not dependent on glucose or mannitol concentrations of the bathing medium; also, these responses were not dissimilar in vessels from the three groups of rats tested. The sensitivity to noradrenaline, however, was inversely related to the concentration of glucose (P < 0.01) and mannitol (P < 0.01) of the bathing medium without significant differences in slopes of regression lines between rat groups. Moreover, vessels from streptozotocin-induced diabetic rats were less sensitive to noradrenaline than were vessels from control rats; vessels from insulin-treated streptozotocin-induced diabetic animals had the lowest sensitivity to noradrenaline. These data suggest that osmolality, diabetes, and insulin-treatment independently affect microvascular sensitivity to the endogenous neurotransmitter, noradrenaline.

Aging↗
PubMed1995

Effect of hyperthyroidism on circulating levels of free and total IGF-I and IGFBPs in rats.

Thyroid hormones are suggested to have a permissive role in growth hormone (GH) and insulin-like growth factor I (IGF-I) action and a specific effect on plasma levels of some of the GH-independent IGF binding proteins (IGFBPs). We have investigated the effect of thyroxine (T4) administration on circulating levels of free and total (extractable) IGF-I and IGFBPs in 8-wk-old rats treated with 0, 200, 400, and 600 micrograms/kg T4, respectively. Serum free IGF-I was determined by an ultrafiltration method, serum total IGF-I after acid-ethanol extraction, and serum IGFBPs using Western ligand blotting, which yielded four distinct molecular bands: two single bands at 24 and 30 kDa and a double band at 38 and 42 kDa (38-42 kDa). After 13 days of hyperthyroidism, serum total IGF-I and the high-molecular 38-42 kDa IGFBP were unchanged, whereas the 24-kDa IGFBP and 30-kDa IGFBP increased significantly (P < 0.05). Serum free IGF-I was significantly (P < 0.05) decreased in animals treated with 400 and 600 micrograms/kg T4. In addition, free IGF-I correlated inversely (P < 0.005) with the 24-kDa IGFBP, 30-kDa IGFBP, and serum total triiodothyronine. We conclude that hyperthyroidism in rats increases the circulating low-molecular IGFBPs and induces a reduction in free IGF-I. This may provide an important regulation of IGF bioactivity by thyroid hormones.

Animals↗
PubMed1995

Expression of insulin-like growth factor binding proteins in the rat kidney: effects of long-term diabetes.

Recent studies have shown that the renal synthesis of insulin-like growth factor binding proteins (IGFBPs) is altered in insulin-deficient diabetes mellitus, suggesting that these changes may be implicated in the alterations in renal function and morphology that accompany diabetes. To investigate the time course and the precise cellular distribution of changes in IGFBP expression, we used quantitative in situ hybridization to analyze renal IGF-I and IGFBP-1 to -5 messenger RNA (mRNA) localization and levels from 2 days to 6 months after the onset of streptozotocin-induced diabetes. There was an immediate sharp decline in IGF-I mRNA levels in the outer medulla that persisted for up to 3 months and a much smaller reduction in IGF-I mRNA levels in the medullary thick ascending limbs (MTALs). In nondiabetic animals, IGFBP-1 mRNA is most abundant in the MTALs. Immediately after the induction of diabetes, however, there was a greater than 2-fold increase in cortical IGFBP-1 mRNA and a 75% decrease in IGFBP-1 mRNA in MTALs. These changes persisted for up to 6 months in the diabetic animals. In contrast, IGFBP-5 mRNA levels were increased in the outer medulla and decreased in the cortex of diabetic kidneys. No significant changes in renal IG-FBP-2 mRNA levels or distribution were noted, and changes in IG-FBP-3 and -4 mRNA levels were subtle. In summary, streptozotocin-induced diabetes is associated with very prominent and complex alterations in renal IGF system gene expression, including robust increases in cortical IGFBP-1 and profound decreases in cortical IG-FBP-5 mRNA and medullary IGF-I mRNA levels. The divergent changes in IGFBP-1 and -5 mRNA levels in cortex vs. outer medulla indicate that regulation of IGFBP mRNA levels is quite complex.

Albuminuria↗
PubMed1995

Hormonal regulation of circulating insulin-like growth factor-binding protein-1 phosphorylation status.

Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) normally circulates as a single, highly phosphorylated species. However, IGFBP-1 phosphorylation status can be altered, such as in pregnancy where non- and lesser phosphorylated isoforms are also present. We have examined how hormonal regulators of circulating IGFBP-1 influence its phosphorylation status and, hence, its ability to modulate IGF activity. In response to insulin-induced hypoglycemia (0.2 U/kg, iv), an increase in the highly phosphorylated isoform was observed after 5 h [16 (range, 11.5-35.5) to 77 (range, 63-250) microgram/L; 4.8-fold increase; P = 0.009], but no non- or lesser phosphorylated variants could be detected. Glucagon (1 mg, sc), increased IGFBP-1 from 27 (range, 13-36.5) to 112 (range, 100.5-129) micrograms/L (4.1-fold increase; P = 0.009) after 90 min despite preceding insulin concentrations of more than 500 pmol/L, but again the IGFBP-1 remained in the highly phosphorylated form. Regulation of IGFBP-1 phosphorylation by sex steroids was studied by comparing women receiving a combined oral contraceptive with women on no medication. Although plasma IGFBP-1 levels were significantly elevated in the treatment group [120 (range, 97.5-237.5) vs. 52 (range, 38-70) micrograms/L; P < 0.004], there was no difference in the form of IGFBP-1 present. The acute effect of somatostatin (500 micrograms/h) on IGFBP-1 phosphorylation status was also studied. Somatostatin only increased the phosphoform characteristic of normal subjects; the appearance of non- or lesser phosphorylated variants was not induced. The effect of rhIGF-I (80 or 120 micrograms, sc) on plasma IGFBP-1 was studied in three subjects with Laron's syndrome. A transient increase in the highly phosphorylated isoform of IGFBP-1 was noted; there was no rise in the non- and lesser phosphorylated isoforms also found in the plasma of Laron's syndrome subjects. These data suggest that only the highly phosphorylated species of IGFBP-1 is under hormonal control; regulation of the non- and lesser phosphorylated variants remains to be determined.

Adult↗
PubMed1995

Concentrations, release, and disposal of insulin-like growth factor (IGF)-binding proteins (IGFBP), IGF-I, and growth hormone in different vascular beds in patients with cirrhosis.

The liver is thought to be the major source of circulating insulin-like growth factor (IGF-I) and IGF-binding protein-1 (IGFBP-1), whereas the primary production site of circulating IGFBP-3 remains unknown. As other tissues may contribute to the circulating pool of IGF-I and IGFBP, the aim of the present study was to assess the hepatic and renal arterio-venous difference and production rates of IGF-I, IGFBP-1, IGFBP-3, and GH in cirrhotic patients (n = 22) and matched control subjects (n = 27). IGFBP-1 and -3, IGF-I, and GH levels were measured by RIA in hepatic, renal, and peripheral veins and in the femoral artery. Levels of IGFBP-1 to -4 were additionally determined by Western ligand blotting. Hepatic venous IGFBP-1 was significantly increased in the cirrhotic patients (mean +/- SEM, 33.6 +/- 9.1 vs. 10.4 +/- 1.9 micrograms/L; P < 0.001), and arterio-renal-venous extraction was significant in both patients (6 +/- 2%; P < 0.01) and controls (11 +/- 1%; P < 0.001). Conversely, IGFBP-3 was decreased in the cirrhotic patients (1265 +/- 149 vs. 2712 +/- 137 micrograms/L; P < 0.001). IGFBP-3 correlated significantly with the wedged hepatic venous pressure (r = -0.49; P < 0.05), serum aspartate aminotransferase (r = -0.66; P < 0.01), serum bilirubin (r = -0.65; P < 0.01), serum albumin (r = 0.64; P < 0.01), and the Child score (r = -0.57; P < 0.01). IGF-I was significantly lower in the cirrhotics (57 +/- 10 vs. 143 +/- 11 micrograms/L; P < 0.001). No significant IGFBP-3 proteolysis was demonstrated in cirrhotics or controls. No significant differences were found in the values obtained simultaneously from hepatic, renal, and brachial veins or femoral artery, which suggests that no major net production or release of IGFBP-3 or IGF-I occurs in these tissues. No differences in IGFBP-2 or IGFBP-4 determined by Western ligan blot were found between patients and controls. The IGF-I concentrations correlated significantly with parameters of biochemical liver function. Basal GH concentrations were significantly higher in the cirrhotics (1.19 +/- 0.13 vs. 0.58 +/- 0.08 micrograms/L; P < 0.001). A significant hepatic disposal of GH was found in the patients (P < 0.05) and controls (P < 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Effect of sodium selenite on growth, insulin-like growth factor-binding proteins and insulin-like growth factor-I in rats.

Selenium is an essential trace element although at higher doses it is also known to be a toxic agent causing a wide range of symptoms including growth retardation. In order to investigate the effect of sodium selenite on growth, insulin-like growth factor-binding proteins (IGFBPs) and insulin-like growth factor-I (IGF-I), 30 male Wistar rats were randomized into three groups. Group A was treated with sodium selenite in the drinking water (3.3 mg selenium/l). Group B was ad libitum fed with free access to standard fodder and tap water and group C was pair fed relative to the selenium-treated rats. Serum IGF-I and IGFBPs were determined on days 0, 14 and at the end of the study on day 35. Selenium-treated rats had significantly lower body weights compared with group B rats on day 9 and group C rats on day 14 (P < 0.05). Tibia length was measured at the end of the study and no difference was observed between groups B and C (3.77 +/- 0.04 cm vs 3.60 +/- 0.02 cm); however, selenium-treated rats had significantly shorter tibia lengths (3.46 +/- 0.03 cm) compared with rats in groups B (P < 0.001) and C (P < 0.05). Selenium treatment induced a significant reduction in circulating IGF-I by the end of the study compared with ad libitum and pair fed rats (P < 0.05). Serum subjected to Western ligand blots showed four distinct IGFBP bands with apparent relative molecular weights of 38-47 kDa (doublet) (IGFBP-3), 30 kDa (IGFBP-1 and/or IGFBP-2) and 24 kDa (IGFBP-4).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effect of octreotide on experimental diabetic renal and glomerular growth: importance of early intervention.

IGF-I acts as a renotropic factor in early streptozotocin-induced diabetes. Somatostatin analogue (octreotide) treatment initiated at the onset of diabetes prevents kidney IGF-I accumulation and renal growth. Seven days of octreotide treatment initiated after 3, 5, 7 or 9 days of untreated diabetes was investigated. Diabetic renal hypertrophy was followed by renal hyperplasia. Compared with placebo-treated diabetic rats, the earliest octreotide intervention was followed by a greater reduction in renal growth compared with intervention later on (days 3 to 10, 12%; days 5 to 12, 10%; days 7 to 14, 9%; days 9 to 16, 6%; P < 0.05). Octreotide treatment was unable to reduce protein accumulation and kidney DNA increase consistently. No difference in glomerular volume fraction or total glomerular volume was observed between placebo- and octreotide-treated diabetic rats. Octreotide treatment was followed by reduced kidney and serum IGF-I especially following early intervention, while no effect over that of diabetes was observed in the later intervention periods. The results confirm the notion that initial renal IGF-I accumulation is a prerequisite for early diabetic kidney hypertrophy in rats and show that delayed octreotide treatment cannot reverse renal and glomerular growth which is already manifest.

Animals↗
PubMed1995

Growth hormone (GH) receptor and GH-binding protein deficiency in the growth failure of potassium-depleted rats.

Potassium (K+) deficiency is associated with growth retardation in both man and experimental animals. Growth hormone (GH) administration to such animals prevents, to some extent, weight loss and selective muscle atrophy, but does not affect tail and tibia length even with supraphysiological doses. The present study was undertaken to investigate the possible effect of K+ deficiency on the hepatic GH receptor and GH-binding protein (BP). Young female Wistar rats were maintained on K(+)-deficient fodder and distilled water, and compared with pair-fed and ad-libitum-fed control groups. After 15 days GH-BP and electrolytes were measured in sera, GH receptors were studied in liver membranes by 125I-labeled human GH binding and muscles were weighed and saved for electrolyte measurements. K(+)-deficient rats showed complete growth arrest compared with an intermediate weight gain of the pair-fed group. Serum K+ was very low, at 1.5 +/- 0.1 mmol/l, compared with the mean value of 5.3 mmol/l of control animals. Somatogenic and lactogenic receptors in liver membranes and serum GH-BP levels were significantly (P < 0.05) lower in K+ deficiency, as compared with their pair-fed controls. Liver GH receptors correlated significantly (P < 0.05) with serum GH-BP levels. The growth variables correlated positively with both hepatic somatogenic and lactogenic receptors and serum GH-BP levels, with correlation coefficients that were highest against serum GH-BP and lowest against liver lactogenic receptors. Serum and muscle K+ correlated significantly (P < 0.05) with both liver GH receptors and serum GH-BP, with correlation coefficients that were higher against serum GH-BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Stimulation of hepatic insulin-like growth factor-binding protein-1 and -3 gene expression by octreotide in rats.

It has recently been demonstrated in various clinical experiments that native somatostatin and its long-acting analogues increase circulating levels of insulin-like growth factor-binding protein-1 (IGFBP-1) within 1-2 h, independent of effects on circulating insulin or glucose levels. Using human hepatoma cells in vitro the somatostatin analogue, octreotide, has been shown to increase IGFBP-1 mRNA within 24 h indicative of a direct stimulatory effect of octreotide on IGFBP-1 synthesis. In order to ascertain whether octreotide acutely stimulates IGFBP-1 mRNA in vivo, placebo or two doses of octreotide were injected subcutaneously into three groups of rats. One hour after saline or octreotide administration, liver, kidney and serum were obtained for the measurement of IGFBPs-1 to -6 mRNA in tissue and IGFBPs and IGF-I in serum. Octreotide increased liver IGFBP-1 (562%) and IGFBP-3 (23%) mRNA expression with a concomitant rise in the circulating 30 kDa (106%) and 38-42 kDa (23%) IGFBPs. No detectable changes were seen in other liver IGFBP transcripts, other circulating IGFBPs or in any of the kidney IGFBP transcripts. Serum IGF-I increased by 37% in the animals receiving the high octreotide dose. No concomitant changes were observed in glucose or insulin levels. These data show that octreotide acutely stimulates hepatic IGFBP-1 and -3 mRNA in vivo in rats. The stimulating effect on IGFBP-3 presents a possible hitherto unknown form of regulation of IGFBP-3 whilst the effect on IGFBP-1 indicates that the stimulatory effect of octreotide on circulating IGFBP-1 described in clinical trials may be due to increased hepatic production. The present findings may be of importance in the clinical use of octreotide.

Animals↗
PubMed1994

Comparative effects of IGF-I and insulin on the glucose transporter system in rat muscle.

The acute effect of insulin-like growth factor I (IGF-I) and insulin on glucose uptake and the glucose transport system in in vitro incubated rat soleus muscles was examined using 3-O-methylglucose and the ATB-[3H]BMPA exofacial photolabeling technique. IGF-I and insulin both stimulated 3-O-methylglucose uptake and GLUT-4 translocation in a dose-dependent manner with a maximal effect six- to sevenfold above basal. No additive effects of IGF-I and insulin on maximal 3-O-methylglucose uptake were found. On a molar basis, IGF-I was 13 times less potent than insulin. Receptor binding experiments showed that IGF-I exhibited a much lower affinity for the insulin receptor [half-maximal effective dose (ED50) = 28.5 nM] than that of insulin (ED50 = 0.20 nM). In contrast, IGF-I bound to the partially purified IGF-I receptor with an apparent affinity (ED50 = 3.7 nM) that was similar to the concentrations of IGF-I which caused half-maximal activation of 3-O-methylglucose uptake (ED50 = 2.4 nM) and GLUT-4 translocation (ED50 = 2.5 nM). Our findings suggest that IGF-I exerts its insulin-like effects on glucose uptake primarily through its own specific receptor and that the molecular events underlying IGF-I and insulin actions on glucose uptake in skeletal muscle are similar, namely caused by a translocation of the GLUT-4 transporter from an intracellular pool to the cell surface.

3-O-Methylglucose↗
PubMed1994

Somatostatin-stimulated insulin-like growth factor binding protein-1 release is abolished by hyperinsulinemia.

It was demonstrated recently that administration of lanreotide and octreotide, two somatostatin octapeptide analogs, increased circulating insulin-like growth factor binding protein 1 (IGFBP-1) levels. The present study demonstrates that native somatostatin 14 shares this ability and that the increase in abolished by concomitant hyperinsulinemia within the physiological range. Five fasting healthy volunteers underwent a hyperinsulinemic as well as a normo-insulinemic (i.e. basal insulinemic) euglycemic clamp lasting 8 h (serum insulin levels remained constant, about 570 vs. 16 pmol/L). Immediately before the clamps, a somatostatin infusion (500 micrograms/h) was started and continued throughout. During normo-insulinemia, IGFBP-1 levels increased slowly from 6.3 +/- 6.2 to 36.1 +/- 14.8 micrograms/L (P < 0.05) reaching maximum after 7 h constant somatostatin infusion, whereas hyperinsulinemia induced a significant decrease from basal levels (from 4.7 +/- 5.4 to 1.1 +/- 1.5 micrograms/L) after 8 h (mean +/- SD, n = 5). These results may indicate hitherto unnoticed interactions of somatostatin and insulin on IGFBP-1 release with possible impact on IGF-I action at the cellular level.

Adult↗
PubMed1994

Dose-dependent stimulation of insulin-like growth factor-binding protein-1 by lanreotide, a somatostatin analog.

It was recently reported that octreotide, besides its many, almost obligatory, inhibitory actions, stimulates the release of insulin-like growth factor-binding protein-1. The present study sought to exclude the possibility that the inescapable preceding somatostatin analog-induced reduction in serum insulin participated in the observed effect. We, therefore, administered sc two clinically relevant doses (5 and 80 micrograms/kg) of lanreotide, another somatostatin octapeptide analog, which induced identical 60% initial suppressions of serum insulin. In spite of this, clear dose-dependent increases in insulin-like growth factor-binding protein-1 were observed, starting between 1-2 h after administration of lanreotide, and levels were still elevated several-fold 5 h after administration of 80 micrograms/kg lanreotide. In addition, we found that infusion of amino acids had no discernible effect on binding protein-1 release. The changes found in immunoreactive binding protein-1 were confirmed employing Western ligand blotting. The data indicate that the lanreotide-induced increase in binding protein-1 levels in serum is not due to the changes in circulating insulin. The magnitude and duration of the increase raise the possibility that the stimulation may have clinically relevant implications in somatostatin analog treatment.

Adult↗
PubMed1994

Lanreotide, a somatostatin analogue, reduces insulin-like growth factor I accumulation in proliferating aortic tissue in rabbits in vivo. A preliminary study.

Coronary artery restenosis following percutaneous transluminal angioplasty occurs with a very high incidence. Major efforts have been aimed at revealing the mechanisms and at developing therapies that might prevent or delay the myointimal proliferation. Most clinical trials have been unsuccessful. Endothelial denudation was induced in 30 rabbits using balloon catheterization of iliac arteries and aorta. Immunoreactive insulin-like growth factor I (IGF-I) was measured in arterial tissue samples obtained 1, 2 and 4 days postoperatively using a double extraction procedure to remove IGF-I binding proteins. Half of the animals were treated with subcutaneous injections of lanreotide, 10 micrograms/kg twice daily, and the other half served as controls. In the latter group, arterial IGF-I was unaltered from baseline at day 1 and increased by 300 and 400% at days 2 and 4. No increase was observed in the rabbits treated with lanreotide. The results indicate that initial local accumulation of IGF-I may be one of the mechanisms involved in myointimal proliferation after experimental arterial injury. The reduction of local IGF-I accumulation by lanreotide may be involved in the previously observed reduction in myointimal proliferation.

Animals↗
PubMed1994

Increased kidney and liver insulin-like growth factor II/mannose-6-phosphate receptor concentration in experimental diabetes in rats.

Diabetic renal hypertrophy is preceded by a transient increase in kidney insulin-like growth factor I and insulin-like growth factor binding protein concentration suggesting a renotropic function in diabetic kidney growth. In order to further examine the possible involvement of the insulin-like growth factor system in initial diabetic kidney growth, we have studied the expression of the kidney insulin-like growth factor II/mannose-6-phosphate receptor during the first 4 days after induction of diabetes in rats. Using a specific antiserum (#3637) raised against the insulin-like growth factor II/mannose-6-phosphate receptor of rat chondrosarcoma a specific band with an apparent molecular weight of 220 kDa was identified in Western blotting experiments with kidney and liver protein extracts. In untreated diabetic rats a transient increase of the kidney and liver insulin-like growth factor II/mannose-6-phosphate receptor concentration was measured 24-48 h after the induction of diabetes (mean increase in kidney 140% and liver 112%, n = 5). This increase was followed by a subsequent decrease in the insulin-like growth factor II/mannose-6-phosphate receptor protein concentration after 3-4 days of diabetes. Insulin treatment prevented the rise both in kidney and liver tissue. Kidney weight in untreated diabetic rats increased by 25% after 4 days. In conclusion, the present study shows a transient increase of insulin-like growth factor II/mannose-6-phosphate receptor concentration in hypertrophying diabetic kidneys and in diabetic livers, contemporarily with the previously described increase in kidney insulin-like growth factor I and insulin-like growth factor binding protein content.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The impact of renal growth, regression and regrowth in experimental diabetes mellitus on number and size of proximal and distal tubular cells in the rat kidney.

Diabetic renal growth, regression and regrowth was studied using stereological methods on perfusion-fixed rat kidneys. The study lasted 13 weeks and comprised one control group and three diabetic groups. The first diabetic group was hyperglycaemic for 13 weeks. The second group was hyperglycaemic for 10 weeks and then normoglycaemic for 3 weeks. The third group was similar to the second group except that during the last week the animals were again hyperglycaemic. Using an optical dissector on the plastic-embedded kidney slices, the number and size of proximal and distal tubular cells were estimated. The number of proximal and distal tubular cells increased by 37% and 36% during 13 weeks of experimental diabetes and the mean volume of the proximal tubular cells increased by 12% whereas the 16% increase in mean tubular cell volume was only borderline significant as compared to the control group. Normoglycaemia for 3 weeks normalized the mean volume of distal tubular cells but the proximal tubular cells tended to be 7% smaller than those in control rats. The number of proximal cells remained increased by 21% compared with the control rats and the number of distal tubular cells retained a 17% insignificant increase. After regrowth the volume of proximal tubular cells was 20% greater than in the second diabetic group and the other parameters were unchanged. In conclusion, 13 weeks of experimental diabetes induced formation of 36% more tubular cells that were enlarged only by about 14%. Normoglycaemia for 3 weeks failed to normalize the cell number. Repeated hyperglycaemia for 1 week after 2 weeks of normoglycaemia increased the size of the proximal tubular cells.

Animals↗