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Biomedical subjects

Allan Flyvbjerg

Publications and source records attributed to Allan Flyvbjerg.

At least 91 records · Page 5Linked to original sources
PubMed2003

Normalization of growth in hypophysectomized mice using hydrodynamic transfer of the human growth hormone gene.

Nonviral gene transfer was investigated as a potential treatment of growth hormone deficiency (GHD) using hypophysectomized mice as a model. After a single hydrodynamic administration of naked plasmid DNA containing the human growth hormone (hGH) gene controlled by an ubiquitin promoter, sustained elevation of circulating hGH was observed the entire observation period (68 days), with a concomitant normalization of circulating insulin-like growth factor I (IGF-I) and IGF-binding protein-3. Furthermore, longitudinal growth was corrected in terms of normalization of tibia length, tail length, and body weight gain. Liver, spleen, and lung weights were normalized, whereas heart weight was normalized partly. hGH mRNA was expressed exclusively in liver tissue. In conclusion, we showed that nonviral hGH gene transfer normalizes longitudinal growth in hypophysectomized mice, indicating that this method potentially could be relevant as a new therapeutic tool in the clinical handling of GHD.

Animals↗
PubMed2003

The effect of growth hormone on the development of diabetic kidney disease in rats.

BACKGROUND: Nephropathy is the most severe complication of diabetes mellitus. We investigated the effect of exogenous growth hormone (GH) administration on renal function and matrix deposition in the streptozotocin (STZ) model of type I-diabetic rat. METHODS: Adult female STZ-diabetic rats (D), non-diabetic control rats injected with saline (C) and control and diabetic rats injected with bovine GH for 3 months (CGH and DGH, respectively) were used. RESULTS: The usual renal hypertrophy seen in D animals was more pronounced in the DGH group. Creatinine clearance increased only in the D rats, but not in the other groups, including DGH. Albuminuria was observed in the D animals but was significantly elevated in the DGH group. Glomeruli from DGH animals showed more extensive matrix accumulation (manifested as an increase in mesangial/glomerular area ratio). Renal extractable insulin-like growth factor (IGF-I) mRNA was decreased in the D and DGH groups, but renal IGF-I protein was not significantly increased. Renal IGF binding protein-1 was increased in the D groups and further increased in the DGH group, at both the mRNA and protein levels. CONCLUSIONS: GH-treated diabetic rats had less hyperfiltration and more albuminuria, concomitant with more glomerular matrix deposition, when compared with regular diabetic animals. This was associated with a significant increase in renal IGFBP-1, and dissociated from IGF-I changes. Thus, in this model, GH exacerbates the course of diabetic kidney disease.

Albuminuria↗
PubMed2003

Role of insulin and the IGF system in renal hypertrophy in diabetic Psammomys obesus (sand rat).

BACKGROUND: Diabetic nephropathy is caused by multiple factors related to the altered metabolic environment in diabetes mellitus (DM). Experimental diabetic kidney disease is characterized by renal hypertrophy associated with increased tissue concentrations of insulin-like growth factor I (IGF-I). To assess the specific roles of serum insulin and glucose in mediating the development of diabetic nephropathy, the effects of both hyperinsulinaemic and hypoinsulinaemic DM were studied in Psammomys obesus (sand rat), a model of type 2 DM. METHODS: The IGF-I system was studied in normal Psammomys obesus gerbils and at 5, 15 and 70 days after the induction of either hyper- or hypoinsulinaemic DM. To induce hyperinsulinaemic DM, Psammomys were raised on a high-energy diet. Hypoinsulinaemic DM was induced by either administration of streptozotocin or a specially designed diet. RESULTS: Hyperinsulinaemic hyperglycaemic Psammomys did not exhibit renal hypertrophy (unchanged kidney/body-weight ratio) and renal IGF-I levels were in the normal range on days 5, 15 and 70. In contrast, Psammomys with hypoinsulinaemic hyperglycaemia induced either by streptozotocin injection or by pancreas exhaustion brought on by a long-term caloric excess diet, had significant increases in kidney/body-weight ratio which were associated with elevated renal IGF-I and mRNA and protein levels of kidney IGF binding protein I. CONCLUSIONS: This study shows that serum insulin levels in the presence of hyperglycaemia have an important role in the development of experimental diabetic nephropathy in the Psammomys model. The implication of this finding is that the pathophysiological mechanisms for diabetic kidney disease in experimental models may be different for type 1 and type 2 DM.

Animals↗
PubMed2003

Decreases in renal functional reserve and proximal tubular fluid output in conscious oophorectomized rats: normalization with sex hormone substitution.

Age-dependent glomerulosclerosis with reduced GFR develops earlier among men than among women. Therefore, whether female sex hormones could prevent the age-dependent decrease in GFR was investigated. The kidney function in oophorectomized rats treated with placebo (OOX group), estrogen (OOX+E(2) group), or estrogen plus progesterone (OOX+E(2)+P group) for 5 mo and in sham-operated rats (sham group) was examined. The rats were 13 mo of age at the time of the investigation. They were conscious and chronically instrumented. The results demonstrated that estrogen, alone or in combination with progesterone, was without effect on the baseline GFR and effective renal plasma flow but prevented severe decreases in the renal functional reserve and fractional proximal tubular fluid output (lithium clearance technique, fractional lithium excretion), which were observed in the OOX group. The renal functional reserve (estimated by stimulation with glycine) was -223 +/- 151, 483 +/- 129, 675 +/- 76, and 208 +/- 140 micro l/min in the OOX, OOX+E(2), OOX+E(2)+P, and sham groups, respectively. Fractional lithium excretion was 12.4 +/- 3.1, 26.8 +/- 2.0, 31.8 +/- 2.5, and 23.6 +/- 3.3% in the OOX, OOX+E(2), OOX+E(2)+P, and sham groups, respectively. In conclusion, oophorectomy at the age of 8 mo did not produce a decrease in baseline GFR in female rats within a period of 5 mo. However, oophorectomy led to severe decreases in the renal functional reserve and fractional proximal tubular fluid output. Both effects were prevented with administration of estrogen. Sham-operated rats demonstrated values for renal functional reserve and fractional lithium excretion that were between those observed for the OOX group and the groups treated with sex hormones.

Animals↗
PubMed2003

Low levels of the 150-kD insulin-like growth factor binding protein 3 ternary complex in patients with anorexia nervosa: effect of partial weight recovery.

BACKGROUND/AIM: In healthy adults, serum insulin-like growth factor I (IGF), IGF-binding protein 3 (IGFBP-3), and acid-labile subunit (ALS) form a 150-kD ternary complex under the control of growth hormone (GH). Circulating IGF-I half-life, bioavailability, and endocrine actions depend on the ternary complex formation. Despite GH hypersecretion, serum IGF-I, IGFBP-3, and ALS levels have all been reported to be low in patients with anorexia nervosa (AN), while the degree of ternary complex formation in AN is unknown. METHODS: Serum ALS and 150-kD ternary complex formation were measured in 6 women with AN at the time of diagnosis and after partial weight recovery and in 6 healthy age-matched women serving as controls. RESULTS: Patients with AN had low levels of ALS and IGFBP-3 contained in the 150-kD ternary complex and in the non-150-kD fraction. Following partial weight recovery, the 150-kD IGFBP-3 ternary complex was fully normalized, despite only partial normalization of serum GH and IGF-I levels. Patients with AN did not present with IGFBP-3 proteolysis different from controls. CONCLUSION: The present data indicate a pivotal role of the nutritional status in the regulation of each of the three components of the 150-kDa ternary IGFBP-3 complex and in the formation of the complex itself.

Adult↗
PubMed2003

Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span.

GH participates in growth, metabolism, and cellular differentiation. To study these roles, we previously generated two different dwarf mouse lines, one expressing a GH antagonist (GHA) and the other having a disrupted GH receptor and binding protein gene (GHR -/-). In this study we compared the two dwarf lines in the same genetic background (C57BL/6J). One of the most striking differences between the mouse lines was their weight gain profile after weaning. The weights of the GHA dwarfs gradually approached controls over time, but the weights of the GHR -/- dwarfs remained low throughout the analysis period. Additionally, fasting insulin and glucose levels were reduced in the GHR -/- mice but normal in the GHA mice. IGF-I and IGF binding protein 3 (IGFBP-3) levels were significantly reduced, but by different degrees, in both mouse lines, but IGFBP-1 and -4 levels were reduced and IGFBP-2 levels increased in GHR -/- mice but unaltered in GHA mice. Finally, life span was significantly extended for the GHR -/- mice but remained unchanged for GHA dwarfs. These results suggest that the degree of blockade of GH signaling can lead to dramatically different phenotypes.

Animals↗
PubMed2003

Age-related changes in cortical bone content of insulin-like growth factor binding protein (IGFBP)-3, IGFBP-5, osteoprotegerin, and calcium in postmenopausal osteoporosis: a cross-sectional study.

Serum GH and IGF-I levels decline with increasing age, whereas osteoprotegerin (OPG) increases. IGFs as well as OPG are present in bone matrix and mediate the effects of many upstream hormones (e.g. estrogen). To evaluate whether changes in these proteins may to some extent explain the decrease in bone mass in postmenopausal or senile osteoporosis, we measured bone contents of IGF-I, IGF-II, IGF binding protein (IGFBP)-3, IGFBP-5, and OPG in combined extracts obtained after EDTA and guanidine hydrochloride extraction in 60 postmenopausal women aged 47-74 (mean, 63) yr with a previous distal forearm fracture and a hip or spine Z-score less than 0. We found age-related increases in IGFBP-3 (r = 0.35; P < 0.01), IGFBP-5 (r = 0.59; P < 0.001), and OPG (r = 0.36; P < 0.01) in cortical bone, significantly inversely correlated with femoral neck and lumbar spine BMD. A correlation between age and OPG was also detected in trabecular bone (r = 0.27; P < 0.05). A pronounced age-related decrease in cortical calcium contents (r = -0.60; P < 0.001), positively correlated with femoral neck and lumbar spine BMD, was also found. No age-related changes were detected for IGF-I or IGF-II. The present study demonstrates age-related changes in cortical bone contents of IGFBPs, calcium, and OPG, possibly related to the pathophysiology of postmenopausal osteoporosis. As for OPG, our findings probably represent compensatory responses to increased osteoclastic resorption.

Age Factors↗
PubMed2003

The effect of growth hormone on the insulin-like growth factor system during fasting.

The present study investigates the possible stimulatory effect of endogenous GH on IGF and IGF-binding protein (IGFBP) levels during fasting. Eight normal subjects were examined on four occasions: 1) in the basal postabsorptive state; 2) after 40 h of fasting; 3) after 40 h of fasting with somatostatin suppression of GH; and 4) after 40 h of fasting with suppression of GH and exogenous GH replacement. The two somatostatin experiments were identical in terms of hormone replacement (except for GH). Short-term fasting led to a 50% reduction in free IGF-I. The reduction in free IGF-I was paralleled by an increase in IGFBP-1, an increase in the complex formation of IGFBP-1 and IGF-I, and a modest reduction in IGFBP-3 proteolysis. GH deprivation during fasting led to a 35% reduction in total IGF-I and a 70% reduction in free IGF-I. GH replacement increased free and total IGF-I to levels similar to those observed during plain fasting and decreased IGFBP-1, however, without affecting IGFBP-1-bound IGF-I. Finally, IGFBP-3 proteolysis was slightly increased by GH replacement. In conclusion, the major new finding of the present study is that the GH hypersecretion seen during short-term fasting is not merely secondary to a reduction in IGF bioactivity.

Adult↗
PubMed2003

Inhibition of the interaction of AGE-RAGE prevents hyperglycemia-induced fibrosis of the peritoneal membrane.

The peritoneal membrane of long-term peritoneal dialysis patients is characterized by a loss of ultrafiltration capacity, associated morphologically with submesothelial fibrosis and neoangiogenesis. Exposure to high glucose concentrations in peritoneal dialysate and the resultant advanced glycation end-products (AGE) accumulation have been implicated in the development of these changes, but their exact pathophysiological role is unknown. We examined the effect of the interaction of AGE with one of their receptors (i.e., RAGE) on the function and structure of the peritoneum exposed to high ambient glucose concentrations. Streptozotocin-induced diabetic rats and control rats were treated during 6 wk with either neutralizing monoclonal anti-RAGE antibodies or control antibodies. The expression of RAGE was strongly enhanced in the peritoneal membrane of the diabetic animals. The diabetic peritonea were characterized by an elevated transport of small solutes, lower ultrafiltration rates, a higher vascular density, and an upregulation of endothelial nitric oxide synthase expression. These parameters were unaffected by treatment with anti-RAGE antibodies. In contrast, anti-RAGE but not control antibodies prevented upregulation of TGF-beta, development of submesothelial fibrosis, and fibronectin accumulation in the peritoneum of diabetic animals. In conclusion, binding of AGE to RAGE increases the expression of TGF-beta and contributes to the development of submesothelial fibrosis. Neoangiogenesis and the resultant loss of ultrafiltration capacity are mediated by different pathogenetic pathways.

Albumins↗
PubMed2003

Increased serum IGF-I during pregnancy is associated with progression of diabetic retinopathy.

The IGF system has been associated with development and progression of diabetic retinopathy. We examined whether a simple measurement of the IGF system (serum total IGF-I) correlated with progression of diabetic retinopathy in pregnancy in type 1 diabetes. A prospective observational study was performed in 103 pregnant women with type 1 diabetes. Serum IGF-I was measured in maternal serum from week 14, every fourth week until week 30, and every second week until delivery. Twenty-four-hour blood pressure was measured with a portable oscillometry monitor. The women had visual acuity testing and fundus photography before pregnancy, once in each trimester, and 4 months after birth. Each eye was assigned an overall retinopathy grade on a scale from 1 to 6 independently by two experienced graders. During pregnancy, serum IGF-I increased with increasing gestational age until a plateau was reached in week 32. Progression of retinopathy was significantly associated with a higher level of IGF-I (P < 0.01). Serum IGF-I increased with increasing progression of retinopathy. Change of retinopathy was significantly associated with level of IGF-I (P < 0.01). During pregnancy, serum IGF-I increased with increasing birth weight until a plateau was reached in week 32. Birth weight was significantly associated with a higher level of serum IGF-I (P < 0.01).

Adult↗
PubMed2003

Human placental growth hormone, insulin-like growth factor I and -II, and insulin requirements during pregnancy in type 1 diabetes.

Human placental GH (hPGH) replaces pituitary GH during pregnancy. hPGH is correlated to serum IGF-I in normal pregnancies and in pregnancies complicated by fetoplacental disorders. In gestational diabetes and type 2 diabetes no correlation between hPGH and IGF-I has been found. The relationship between hPGH and IGF-I in type 1 diabetes mellitus has not been investigated thoroughly. Furthermore, hPGH may be involved in the development of insulin resistance during pregnancy. In this prospective, longitudinal study, 51 type 1 diabetic subjects were followed with repeated blood sampling during pregnancy (median, 14 blood samples/subject; range, 8-26). Maternal concentrations of serum hPGH, IGF-I, and IGF-II were measured and compared with insulin requirements and birth characteristics. hPGH was detected from as early as 6 wk gestation. In all subjects, a rise in serum hPGH was observed during pregnancy, and the rise between wk 16 and 25 was correlated to the rise between wk 26 and 35 (P < 0.001). From wk 26 onward, the increase in hPGH values was significantly correlated to the birth weight, expressed as a z-score (r(s) = 0.54; P < 0.001), as were the absolute hPGH values. Also, a positive influence of hPGH on placental weight was found. Serum IGF-I values decreased significantly from the first to the second trimester (P < or = 0.021). Serum hPGH correlated to serum IGF-I from wk 24- 35, and changes in IGF-I followed the increase in hPGH between wk 26-35 (r(s) = 0.53; P < 0.001), as did IGF-II (r(s) = 0.37; P = 0.008). Changes in IGF-I and IGF-II between wk 26-35 also correlated to the birth weight z-score (P < or = 0.020), but only hPGH remained significant in multiple regression analysis. Similar results were found in the subgroup delivering at term. Interestingly, the increase in hPGH was not correlated to the increase in insulin requirements, nor was any consistent relationship revealed during each gestational period. In conclusion, our study suggests a role for hPGH in the regulation of both IGFs and fetal growth in type 1 diabetes. In contrast, the increase in insulin requirements during pregnancy in type 1 diabetic subjects could not be related to hPGH levels.

Adult↗
PubMed2003

Human placental growth hormone, insulin-like growth factor I and -II, and insulin requirements during pregnancy in type 1 diabetes.

Human placental GH (hPGH) replaces pituitary GH during pregnancy. hPGH is correlated to serum IGF-I in normal pregnancies and in pregnancies complicated by fetoplacental disorders. In gestational diabetes and type 2 diabetes no correlation between hPGH and IGF-I has been found. The relationship between hPGH and IGF-I in type 1 diabetes mellitus has not been investigated thoroughly. Furthermore, hPGH may be involved in the development of insulin resistance during pregnancy. In this prospective, longitudinal study, 51 type 1 diabetic subjects were followed with repeated blood sampling during pregnancy (median, 14 blood samples/subject; range, 8-26). Maternal concentrations of serum hPGH, IGF-I, and IGF-II were measured and compared with insulin requirements and birth characteristics. hPGH was detected from as early as 6 wk gestation. In all subjects, a rise in serum hPGH was observed during pregnancy, and the rise between wk 16 and 25 was correlated to the rise between wk 26 and 35 (P < 0.001). From wk 26 onward, the increase in hPGH values was significantly correlated to the birth weight, expressed as a z-score (r(s) = 0.54; P < 0.001), as were the absolute hPGH values. Also, a positive influence of hPGH on placental weight was found. Serum IGF-I values decreased significantly from the first to the second trimester (P </= 0.021). Serum hPGH correlated to serum IGF-I from wk 24-35, and changes in IGF-I followed the increase in hPGH between wk 26 and 35 (r(s) = 0.53; P < 0.001), as did IGF-II (r(s) = 0.37; P = 0.008). Changes in IGF-I and IGF-II between wk 26 and 35 also correlated to the birth weight z-score (P </= 0.020), but only hPGH remained significant in multiple regression analysis. Similar results were found in the subgroup delivering at term. Interestingly, the increase in hPGH was not correlated to the increase in insulin requirements, nor was any consistent relationship revealed during each gestational period. In conclusion, our study suggests a role for hPGH in the regulation of both IGFs and fetal growth in type 1 diabetes. In contrast, the increase in insulin requirements during pregnancy in type 1 diabetic subjects could not be related to hPGH levels.

Adult↗
PubMed2002

Physiological effects of human growth hormone produced after hydrodynamic gene transfer of a plasmid vector containing the human ubiquitin promotor.

Human growth hormone (hGH) deficiency causes retarded growth and abnormalities in body fat distribution and abundance, muscle growth, and bone mineralization. While injection of recombinant hGH may reverse or ameliorate symptoms of deficiency, therapy aiming at in vivo synthesis of hGH is still of considerable clinical interest. Hydrodynamic injection of a simple plasmid vector containing a human ubiquitin promotor and the hGH gene were found to result in high and prolonged expression. Synthesis of hGH was achieved both in NOD/SCID mice and in three different inbred strains of immune competent mice. Although hGH antibodies were produced in immunocompetent mice, physiological effects of the protein were documented by increase in body weight, increased serum levels of insulin-like growth factor I and relative increased weight of the internal organs. Nonviral gene therapy may be regarded as a potential future way of reconstituting hGH expression in deficient individuals.

Animals↗
PubMed2002

Regulation of insulin-like growth factor binding protein secretion by human granulosa luteal cells in a polycystic ovary-like environment.

OBJECTIVE: To determine the effect of androstenedione (A), insulin, and LH on secretion of insulin-like growth factor binding proteins (IGFBPs) from human granulosa luteal cells. DESIGN: Human granulosa cells were cultured for a total of 4 days in serum-free medium containing A (10(-6) mol/L), with or without insulin (100 microU/mL-800 microU/mL), LH (1 microU/mL-10 microg/L), and A (10(-5) mol/L). SETTING: Granulosa cells were obtained from IVF procedures. PATIENT(S): Women undergoing IVF for tubal disease. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Immunoassay and autoradiographs of Western ligand blotting detected IGFBP accumulations in the medium. RESULT(S): Cultured granulosa cells secreted IGFBP-1 through IGFBP-4. Insulin (100 microU/mL-800 microU/mL), LH (1 microg/L-10 microg/L), and A (10(-5) mol/L) caused a significant decrease in IGFBP-1 accumulation in the medium both alone and when added in combination. The release of IGFBP-2 and IGFBP-4 was significantly stimulated by insulin, whereas LH had no effect. Elevated levels of androgen (10(-5) mol/L) significantly stimulated the secretion of IGFBP-2, whereas the release of IGFBP-4 was reduced. CONCLUSION(S): These results demonstrate that androgen and insulin are important regulators of IGFBP release and that elevated levels of the two hormones may contribute to the altered IGFBP profile found in PCOS follicles, compared with the case of estrogen-dominant follicles.

Androstenedione↗
PubMed2002

High protein-induced glomerular hypertrophy is vascular endothelial growth factor-dependent.

BACKGROUND: Various growth factors and cytokines have been implicated in different forms of kidney enlargement such as renal growth following induction of diabetes, unilateral nephrectomy, and exposure to high protein diet. Vascular endothelial growth factor (VEGF) is essential for normal renal development and plays a role in diabetes-associated renal and glomerular enlargement. METHODS: To elucidate a possible role for VEGF in high protein-induced renal/glomerular enlargement, we examined the effect of a neutralizing VEGF-antibody (VEGF-ab) on kidney weight and glomerular volume in mice fed a high protein diet for up to seven days. RESULTS: At day 2 and day 7 of the experimental period, high protein diet induced a significant increase in the mean glomerular volume. This high protein-induced glomerular hypertrophy was completely prevented by treatment with VEGF-ab. Kidney weight was increased significantly only at day 7, and was not influenced by VEGF-ab treatment. High protein diet and/or VEGF-ab treatment had no effect on body weight, food intake, and liver or heart weight. CONCLUSIONS: The administration of a neutralizing VEGF-ab in mice fed a high protein diet for one week completely abolished the glomerular hypertrophy seen in placebo-treated animals on the same diet, without affecting kidney and body weight. These results demonstrate, to our knowledge for the first time, that high protein-induced glomerular hypertrophy is VEGF-dependent.

Animals↗
PubMed2002

High-protein induced renal enlargement is growth hormone independent.

BACKGROUND: Growth hormone (GH) and insulin-like growth factors (IGFs) have been postulated as pathogenic factors in several forms of renal growth, including that induced by high-protein (HP) diets. Compensatory renal growth (CRG) following renal uninephrectomy is strictly GH dependent, while the exact role of GH as a regulating factor in HP induced renal growth has not been fully clarified. METHODS: To elucidate a possible direct role for GH in HP-induced renal growth, we examined the effect of a newly developed specific GH-receptor (GHR) antagonist (B2036-PEG) on renal growth and renal GH/IGF-system expression in HP-fed mice. RESULTS: Mice fed a HP diet (45% protein) for one week demonstrated renal hypertrophy and increased renal IGF-I. GH receptor antagonist (GHRA) treatment neither modified renal IGF-I nor abolished the renal hypertrophy. In contrast, however, GHRA administration did modify renal mRNA expression of many members of the GH and IGF systems. CONCLUSIONS: The major new finding is that HP-induced renal growth in adult mice is GH independent.

Animals↗