Biomedical subjects

Allan Flyvbjerg

Publications and source records attributed to Allan Flyvbjerg.

105 records · Page 6Linked to original sources

PubMed2002

Compensatory glomerular growth after unilateral nephrectomy is VEGF dependent.

Various growth factors and cytokines have been implicated in different forms of kidney enlargement. Vascular endothelial growth factor (VEGF) is essential for normal renal development and plays a role in diabetic glomerular enlargement. To explore a possible role for VEGF in compensatory renal changes after uninephrectomy, we examined the effect of a neutralizing VEGF-antibody (VEGF-Ab) on glomerular volume and kidney weight in mice treated for 7 days. Serum and kidney insulin-like growth factor I (IGF-I) levels were measured, since IGF-I has been implicated in the pathogenesis of compensatory renal growth, and VEGF has been suggested to be a downstream mediator of IGF-I. Placebo-treated uninephrectomized mice displayed an early transient increase in kidney IGF-I concentration and an increase in glomerular volume and kidney weight. In VEGF-Ab-treated uninephrectomized animals, increased glomerular volume was abolished, whereas renal hypertrophy was partially blocked. Furthermore, the renal effects of VEGF-Ab administration were seen without affecting the renal IGF-I levels. In conclusion, these results demonstrate that compensatory glomerular growth after uninephrectomy is VEGF dependent.

Adaptation, Physiological↗

PubMed2002

Physical capacity influences the response of insulin-like growth factor and its binding proteins to training.

The influence of initial training status on the response of circulating insulin-like growth factor (IGF) and its binding proteins (IGFBP) to prolonged physical training was studied in young men. It was hypothesized that highly standardized training would result in more extensive changes in the circulating IGF system in untrained subjects because of lower fitness level. Seven untrained (UT) and 12 well-trained (WT) individuals performed 11 wk of intense physical training (2-4 h daily). Fasting serum samples were analyzed for total and free IGF-I and -II, for IGFBP-1 to -4, as well as for IGFBP-3 proteolysis. Eleven weeks of physical training resulted in decreased levels of total IGF-I, free IGF-I, and IGFBP-4 in both the UT and WT groups. In the UT group, IGFBP-2 increased, IGFBP-3 decreased [from 4,255 +/- 410 (baseline) to 3,896 +/- 465 (SD) microg/l (week 4); P < 0.05], and IGFBP-3 proteolysis increased [from 28 +/- 8% (baseline) to 37 +/- 7% (week 4) and 39 +/- 12% (week 11); P < 0.05], whereas no significant changes were found in the WT group. In conclusion, intense physical training results in a marked influence on the IGF system and its binding proteins with generally more extensive changes seen in the untrained individuals. Also, prolonged physical training resulted in increased IGFBP-3 proteolysis in previously untrained individuals only, indicating that intense physical training affects trained and untrained individuals differently.

Adult↗

PubMed2002

Acute growth hormone administration causes exaggerated increases in plasma lactate and glycerol during moderate to high intensity bicycling in trained young men.

We studied the acute effects of a single, sc GH dose on exercise performance and metabolism during bicycling. Seven highly trained men [age, 26 +/- 1 yr (mean +/- SEM); weight, 77 +/- 3 kg; maximal oxygen uptake, 65 +/- 1 ml O(2).min(-1).kg(-1)] performed 90 min of bicycling 4 h after receiving 7.5 IU (2.5 mg) GH or placebo in a randomized, double-blinded, cross-over design trial. A standardized pre-exercise meal was given 2 h before exercise. Blood was sampled at rest and during exercise and analyzed for GH, IGF-I, glucose, lactate, insulin, glycerol, and nonesterified fatty acids (NEFA). In the placebo trial, all subjects completed the exercise protocol without any difficulties. In contrast, two subjects were not able to complete the exercise protocol in the GH trial, and one subject barely managed to complete the protocol. In addition, GH administration resulted in exaggerated increases in plasma lactate concentrations during exercise (P < 0.0001). The combined lipolytic effect of GH and exercise, evidenced by increased plasma glycerol and serum NEFA concentrations, was 3-fold greater than the effect of exercise alone (P < 0.0001), but this increased substrate availability did not result in increased whole body fat oxidation (indirect calorimetry). Plasma glucose was, on average, 9% higher during exercise after GH administration compared with placebo (P < 0.0001). We conclude that a single, relevant GH dose causes exaggerated increases in plasma lactate and glycerol as well as serum NEFA during 90 min of subsequent bicycling at moderate to high intensity. The exaggerated increase in plasma lactate may be associated with substantially decreased exercise performance.

Adult↗

PubMed2002

Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody.

Diabetic nephropathy in type 2 diabetic patients is a frequent complication associated with increased morbidity and mortality. Various growth factors and cytokines have been implicated in the pathogenesis of diabetic kidney disease, including vascular endothelial growth factor (VEGF). To explore a role for VEGF in renal changes in type 2 diabetes, we examined the renal effects of a neutralizing murine VEGF antibody in the diabetic db/db mouse, a model of obese type 2 diabetes. One group of db/db mice was treated for 2 months with a VEGF antibody, while another db/db group was treated for the same period with an isotype-matched irrelevant IgG. A third group consisting of nondiabetic db/+ mice was treated with the same isotype-matched IgG for 2 months. Placebo-treated db/db mice showed a pronounced increase in kidney weight, glomerular volume, basement membrane thickness (BMT), total mesangial volume, urinary albumin excretion (UAE), and creatinine clearance (CrCl) when compared with nondiabetic controls. In VEGF antibody-treated db/db mice, increases in kidney weight, glomerular volume, BMT, and UAE were attenuated, whereas the increase in CrCl was abolished. VEGF antibody administration tended to reduce expansion in total mesangial volume. These effects in diabetic animals were seen without impact on body weight, blood glucose, insulin levels, or food consumption. In conclusion, chronic inhibition of VEGF in db/db mice ameliorates the diabetic renal changes seen in type 2 diabetes.

Albuminuria↗

PubMed2002

Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome.

The insulin resistance syndrome is characterized by several risk factors for cardiovascular disease. Chronic chemical activation of AMP-activated protein kinase by the adenosine analog 5-aminoimidazole-4-carboxamide-1-beta -D-ribofuranoside (AICAR) has been shown to augment insulin action, upregulate mitochondrial enzymes in skeletal muscles, and decrease the content of intra-abdominal fat. Furthermore, acute AICAR exposure has been found to reduce sterol and fatty acid synthesis in rat hepatocytes incubated in vitro as well as suppress endogenous glucose production in rats under euglycemic clamp conditions. To investigate whether chronic AICAR administration, in addition to the beneficial effects on insulin sensitivity, is capable of improving other phenotypes associated with the insulin resistance syndrome, obese Zucker (fa/fa) rats (n = 6) exhibiting insulin resistance, hyperlipidemia, and hypertension were subcutaneously injected with AICAR (0.5 mg/g body wt) daily for 7 weeks. Obese control rats were either pair-fed (PF) (n = 6) or ad libitum-fed (AL) (n = 6). Lean Zucker rats (fa/-) (n = 8) served as a reference group. AICAR administration significantly reduced plasma triglyceride levels (P < 0.01 for AICAR vs. AL, and P = 0.05 for AICAR vs. PF) and free fatty acids (P < 0.01 for AICAR vs. AL, and P < 0.05 for AICAR vs. PF) and increased HDL cholesterol levels (P < 0.01 for AICAR vs. AL and PF). AICAR treatment also lowered systolic blood pressure by 14.6 +/- 4.3 mmHg (P < 0.05), and AICAR-treated animals exhibited a tendency toward decreased intra-abdominal fat content. Furthermore, AICAR administration normalized the oral glucose tolerance test and decreased fasting concentrations of glucose and insulin close to the level of the lean animals. Finally, in line with previous findings, AICAR treatment was also found to enhance GLUT4 protein expression and to increase maximally insulin-stimulated glucose transport in primarily white fast-twitch muscles. Our data provide strong evidence that long-term administration of AICAR improves glucose tolerance, improves the lipid profile, and reduces systolic blood pressure in an insulin-resistant animal model. The present study gives additional support to the hypothesis that AMPK activation might be a potential future pharmacological strategy for treating the insulin resistance syndrome.

3-O-Methylglucose↗

PubMed2000

Renal enlargement precedes renal hyperfiltration in early experimental diabetes in rats.

The order of appearance between renal hypertrophy and hyperfunction in early experimental diabetes is still disputed. The reason for previous discrepant results is believed to be methodologic problems, as most previous studies of renal function have been performed in anesthetized animals. In the present study in nondiabetic and streptozotocin-diabetic animals, renal volume was measured by a noninvasive magnetic resonance imaging technique, while renal function parameters were measured in conscious, chronically catheterized animals. To avoid artifacts caused by the procedures associated with induction of streptozotocin-diabetes (fasting, brief anesthesia, and transient hypoglycemia) on renal growth and function, diabetic animals were injected with insulin to obtain euglycemia for 4 d before study start. At day 0, insulin administration was withdrawn and all animals developed hyperglycemia within 12 h. Renal volume and kidney function were measured on days 0, 1, 2, 3, 5, and 7. Renal enlargement was detectable at day 1 (20%) and reached an increase of 40% at day 7. No changes were seen in effective renal plasma flow or effective renal vascular resistance within the first 7 d after development of hyperglycemia. GFR tended to rise on day 5 and was increased by 16% at day 7. The absolute proximal reabsorption showed a pronounced rise (30%) at day 7, whereas no change was seen in the proximal tubular fluid output. It is concluded that renal enlargement precedes renal hyperfunction in the early phase after onset of experimental diabetes.

Absorption↗

PubMedDate not supplied

Decreased serum testosterone levels in rats exposed intraperitoneally to bismuth subnitrate.

The consumption of bismuth is increasing and knowledge of the potential teratogenic and reproductive damage of bismuth exposure is fragmentary. In the present study we used autometallography (AMG)--the histochemical silver amplification technique--to trace bismuth in the testis and pituitary glands of Wistar rats injected intraperitoneally with bismuth subnitrate. Large amounts of bismuth AMG grains were concentrated in the lysosomes of Leydig cells, and serum testosterone levels were reduced when compared with controls. No histochemical traces of bismuth were found in the anterior lobe of the pituitary gland. Compared with their corresponding controls, neither follicle-stimulating hormone nor luteinizing hormone were affected. The selective uptake of bismuth in Leydig cells, followed by decreased testosterone levels, emphasizes a potential hazard of bismuth-provoked male reproductive impairment.

Animals↗

PubMedDate not supplied

Effects of glycine on glomerular filtration rate and segmental tubular handling of sodium in conscious rats.

1. Infusion of the amino acid glycine leads to an increase in effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) by a mechanism that possibly involves stimulation of nitric oxide (NO). Because NO also increases proximal tubular fluid output (Vprox) by inhibition of proximal tubular Na+ reabsorption and modulation of the tubuloglomerular feedback system, we hypothesized that glycine would increase Vprox as measured by lithium clearance (CLi). 2. In the first series of experiments, the effect of glycine infusion (4 mg/min) was examined in conscious, unstressed, chronically catheterized rats. In an additional series of experiments, the effect of glycine was examined under similar conditions in rats pretreated with a NO synthase (NOS) inhibitor (NG-nitro-L-arginine methyl ester (L-NAME), 2.5 microg/min). 3. Glycine significantly increased ERPF (from 3268 to 4018 microL/min per 100 g bodyweight (BW)), GFR (from 874 to 1009 microL/min per 100 g BW), CLi (from 275 to 461 microL/min per 100 g BW) and Na+ clearance (CNa; from 2.9 to 14.0 microL/min per 100 g BW). Fractional excretion of lithium (FELi; from 32 to 46%) and CNa/CLi (from 0.99 to 2.99%) also rose, indicating inhibition of proximal and distal nephron Na+ reabsorption, respectively. In the rats pretreated with L-NAME, similar haemodynamic and tubular responses to glycine infusion were seen, suggesting that the effects were not mediated by NO. 4. We conclude, that glycine increases ERPF and GFR and it also inhibits proximal and distal nephron Na+ reabsorption leading to an increase in CLi and CNa. There was no indication that any of these effects were mediated by NO.

Animals↗

PubMedDate not supplied

Effect of mild hypoinsulinemia on renal hypertrophy: growth hormone/insulin-like growth factor I system in mild streptozotocin diabetes.

The metabolic aberrations associated with diabetes mellitus profoundly alter the growth hormone/insulin-like growth factor I (GH/IGF-I) system. In severe experimental diabetes, serum IGF-I level is reduced, reflecting altered hepatic expression. On the other hand, increased levels of kidney IGF-I have been implicated in the development of diabetic kidney disease. This study aimed to examine the effect of mild experimental diabetes with hypoinsulinemia on both the systemic and renal GH/IGF-I systems in a low-dose streptozotocin (STZ)-induced diabetic rat. Diabetic animals with mild hypoinsulinemia developed renal hyperfiltration within 3 days of diabetes, whereas the renal size increased significantly only between 30 and 48 days of diabetes. Plasma GH levels were unchanged during the entire course of the study, but a decrease in serum IGF-I, IGF-binding protein 3 (IGFBP-3), and IGF-binding protein 4 (IGFBP-4) occurred after 10, 30, and 48 days. Kidney IGF-I and IGF-binding protein 1 (IGFBP-1) mRNA expression increased after 10 and 30 days of diabetes. A significant increase in kidney IGFBP-1/2, IGFBP-3, and IGFBP-4 proteins was seen after 48 days of diabetes. A positive correlations was found between renal growth and insulin/glucose ratio (r=.57), kidney IGF-I (r=.57), IGFBP-1 mRNA (r=.43), IGFBP-1/2 (r=.41), and IGFBP-4 levels (r=.40). These results demonstrate hyperfiltration within 3 days of diabetes and a similar response in the IGF-I system in mildly and severely hypoinsulinemic rats; however, renomegaly develops slower in mildly diabetic rats at least partly due to delayed changes in the renal IGF and IGF BPs.

Animals↗

PubMedDate not supplied

Glomerular structural changes in pregnant, diabetic, and pregnant-diabetic rats.

Kidneys enlarge both during pregnancy and in diabetes. The enlargement and morphology of glomeruli was studied during pregnancy and in diabetes in order to examine possible similarities, differences, and interactions in the growth in these conditions. Morphometric investigations were performed on glomeruli in pregnant rats, in rats with 2 weeks' diabetes, and in pregnant-diabetic rats. Kidneys were enlarged 22% in the midterm pregnant rats compared with controls, 74% in diabetic rats, and a further 21% in pregnant-diabetic rats. Glomerular volume was enlarged by 26% during midterm pregnancy in normal animals. Diabetes induced an enlargement in glomerular volume of 58% and a further 18% in midterm diabetic animals due to pregnancy. Within the glomerulus, pregnancy in normal animals induced minor non-significant changes. Diabetes induced significant increase in several parameters: mesangial volume and cell volume, capillary and glomerular basement membrane volume, capillary wall surface area, foot process width, filtration slit length, and nuclear number. Pregnancy in diabetic animals induced no significant additional changes. In conclusion, kidney enlargement in pregnancy shows very few glomerular changes in either normal or diabetic animals. Enlargement of glomeruli in diabetes involves hypertrophy and hyperplasia concurrent with several morphological changes within the glomerulus.

Animals↗

PubMedDate not supplied

Effect of combination therapy with a calcium channel blocker and an angiotensin-converting enzyme inhibitor on renal hypertrophy and urinary albumin excretion in diabetic rats.

The objective of this study was to compare the effect of an angiotensin-converting enzyme (ACE) inhibitor and a calcium channel blocker on the development of renal changes in diabetic rats. Diabetes was induced by an intravenous injection of streptozotocin in normotensive Wistar rats. Treatment was commenced immediately in 1 set of rats with 4 treatment arms: nitrendipine (250 mg/kg fodder), enalapril (35 mg/L drinking water), both treatments in combination, or placebo. Treatment was continued for 9 weeks. Another set of rats was left with untreated diabetes for 3 months followed by 7 weeks treatment as above. When starting treatment right after induction of diabetes, nitrendipine significantly reduced urinary albumin excretion (UAE) to the nondiabetic level (P < .05) without reducing blood pressure (BP), whereas enalapril failed to significantly reduce UAE despite a reduction in BP. Combining the two treatments showed no further reduction in UAE compared to monotherapy with nitrendipine, despite a lower BP. When leaving diabetic rats untreated for 3 months, only the coadministration of nitrendipine and enalapril showed a significant reduction in UAE compared to monotherapy and placebo treatment, but showed no significant effect on BP.

Albuminuria↗

PubMedDate not supplied

Growth hormone (GH) hypersecretion and GH receptor resistance in streptozotocin diabetic mice in response to a GH secretagogue.

The growth hormone (GH) and insulin-like growth factor I (IGF-I) axis were studied in streptozotocin (STZ) diabetic and nondiabetic female mice following intravenous (IV) injection of the GH secretagogue (GHS) ipamorelin or saline. On day 14, blood samples were obtained before and 10 minutes after the injection. Livers were removed and frozen for determination of the mRNA expressions of the GH receptor, GH-binding protein, and IGF-I, and hepatic IGF-I peptide. Serum samples were analyzed for GH and IGF-I. Following ipamorelin injection, the GH levels were found to be 150 +/- 35 microg/L and 62 +/- 11 microg/L in the diabetic compared to the nondiabetic mice (P <.05). Serum IGF-I levels were lower in diabetic than in nondiabetic animals, and rose after stimulation only in the nondiabetic animals. Furthermore, hepatic GH resistance and IGF-I mRNA levels and IGF-I peptide were increased in nondiabetic animals in response to GH stimulation, whereas the low levels per se of all these parameters in diabetic mice were unaffected. The study shows that STZ diabetic mice demonstrate a substantial part of the clinical features of type 1 diabetes in humans, including GH hypersecretion and GH resistance. Accordingly, it is proposed that STZ diabetic mice may be a better model of the perturbations of the GH/IGF-I axis in diabetes than STZ diabetic rats.

Animals↗

PubMedDate not supplied

The effect of long-term somatostatin analogue treatment on free and total insulin-like growth factor (IGF) -I, -II and IGF binding protein -1, -2 and -3 serum levels in euthyroid patients with active thyroid eye disease.

The aim of this study was to investigate the effect of long-term somatostatin analogue (SM-a) treatment on serum levels of free (F) and total (T) insulin-like growth factor (IGF)-I, -II and IGF binding protein (IGFBP) - 1, -2 and -3 in euthyroid patients with active thyroid ophthalmopathy. For this purpose, we measured the above-mentioned parameters in 21 patients (11M, 10F), aged 50.8+/-11.8 years (range 35-70) and 19 healthy individuals matched for age, gender and body mass index (BMI). A total of 4 SM-a (sandostatin LAR((R))-30) injections, each monthly, were administered in each patient and measurements were performed prior to treatment and 20-30 days after the last injection, while in control individuals the same determinations were performed only once. All patients had active thyroid eye disease (TED), with clinical activity scores (CAS) >/= 4 (5.3+/-1.1) and positive orbital octreoscan in both eyes. Serum F and T IGF-I and IGF-II were determined using non-competitive, time-resolved monoclonal immunofluorometric assays. IGFBP-1 and IGFBP-2 were determined by an in-house radioimmunoassay, while IGFBP-3 by commercially available IRMA. Our results showed that F and T IGF-I, -II and IGFBP-1, -2 and -3 levels in patients before and after administration of SM-a were comparable and the levels did not differ significantly from those of controls. Furthermore, no statistically significant differences emerged in the ratio between molar weights of TIGF-I/IGFBP-3 and TIGF-II/IGFBP-3, as well as in the ratio of F/TIGF-I and F/TIGF-II in patients before and after SM-a therapy. Fourteen patients (66%) experienced a decline in CAS of at least >1 point in each eye after SM-a administration, whereas in the remaining the CAS did not change. Finally, no relationship was found between the levels of the above-mentioned parameters (post therapy) and CAS, octreoscan scores and thyroid hormones levels. In conclusion, we showed that although SM-a administration in euthyroid patients with active TED had a beneficial effect in a significant percentage of patients, this effect was not associated with a decline in the circulating IGF-I, -II and IGFBP-1, -2 and -3 levels, at least under the conditions of the present study. It can be postulated that if the mechanism of action of SM-a is through reduction of IGF-I levels, this effect is possibly exerted in the retrobulbar tissues by local paracrine/autocrine action.

Journal Article↗

PubMedDate not supplied

Effects of tamoxifen on insulin-like growth factors, IGF binding proteins and IGFBP-3 proteolysis in breast cancer patients.

BACKGROUND: Recently an association between increased serum insulin-like growth factor I (IGF-I) levels and the development of breast cancer was demonstrated. Tamoxifen used in the postoperative treatment of breast cancer patients may exert significant effects on the IGF-I system. MATERIALS AND METHODS: To examine the effect of Tamoxifen treatment (20 mg/day) on changes in the IGF-I axis in 11 breast cancer patients before and after 4 months of Tamoxifen treatment and compared to 8 healthy subjects. IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 and IGFBP-6 were examined by specific assays. IGFBPs were examined by Western ligand blotting and IGFBP-3 proteolytic activity by specific protease assay. RESULTS: Serum IGF-I was decreased before (63%) and increased during Tamoxifen treatment (60%). Total IGFBP-3 levels measured by IRMA were unchanged, however, intact IGFBP-3 measured by WLB was decreased (58%) before and increased (67%) during Tamoxifen treatment. IGFBP-3 proteolysis was increased before and reduced during treatment. IGFBP-4 and IGFBP-6 were decreased before and increased during Tamoxifen treatment. CONCLUSION: Significant changes in the IGF system were demonstrated before and during Tamoxifen treatment and may in part be involved in the effects of Tamoxifen treatment in breast cancer patients.

Breast Neoplasms↗

PubMedDate not supplied

Insulin-like growth factor binding protein 1 (IGFBP-1) in vaginal fluid in pregnancy.

OBJECTIVE: To examine vaginal insulin-like growth factor binding protein 1 (IGFBP-1) as a marker of preterm delivery, amniotic fluid leakage or vaginal infection. MATERIALS AND METHODS: The material consisted of a nested case-control study (67 with idiopathic preterm delivery and 406 randomly selected women with term deliveries) from a prospective cohort of 2,846 women. RESULTS: Vaginal npIGFBP-1 was weakly associated with preterm delivery. Elevated npIGFBP-1 gave an increased risk of preterm delivery (OR 2.8 [1.4-6. 7]). Elevated IGFBP-1 provided a sensitivity of 13% at a false-positive rate of 4.4% in a low-risk population. When adjusting for other covariates associated with preterm delivery the association between npIGFBP-1 and preterm delivery disappeared; there was an interaction between alcohol consumption and npIGFBP-1. CONCLUSION: The current study found vaginal npIGFBP-1 to be weakly associated with gestational age at delivery. However, in this study the association may potentially be explained by alcohol consumption.

Amniotic Fluid↗