Biomedical subjects

A Flyvbjerg

Publications and source records attributed to A Flyvbjerg.

At least 127 records · Page 7Linked to original sources

PubMed1998

Octreotide prevents the early increase in renal insulin-like growth factor binding protein 1 in streptozotocin diabetic rats.

The early renal growth in streptozotocin (STZ)-induced diabetic rats is preceded by a transient rise in renal tissue insulin-like growth factor (IGF)-I concentration. Administration of the long-acting somatostatin analog octreotide to STZ diabetic rats inhibits the early increase in kidney IGF-I and the increase in kidney size without affecting metabolic control. We studied the effects of octreotide treatment on the intrarenal IGF axis at 2 and at 7 days after the induction of STZ diabetes. Two days after induction of diabetes, kidney IGF-I was increased from 850 +/- 43 ng/g tissue in controls to 1,648 +/- 165 ng/g tissue (P < 0.001) in diabetic animals. The diabetes-associated increase in renal IGF-I 48 h after STZ injection was totally prevented by octreotide (IGF = 780 +/- 57 ng/g tissue). However, 7 days after the induction of diabetes, kidney IGF-I was similar to that of control and was not affected by octreotide. No difference in serum IGF-I was observed between controls and diabetic rats after 2 days of diabetes; however, octreotide treatment resulted in a significant decrease of serum IGF-I after 2 days when compared with control rats (P < 0.05). Renal IGF-I mRNA was significantly decreased to the same extent in both diabetic groups 2 and 7 days after the induction of diabetes, while renal IGF-I receptor (IGF-IR) mRNA was unchanged in rats from either group. Two days after induction of diabetes, renal insulin-like growth factor binding protein (IGFBP)-1 mRNA and 30-kDa IGFBPs (containing IGFBP-1) increased by 186 and 192%, respectively, in untreated diabetic animals compared with controls. Octreotide treatment prevented the diabetes-associated rise in renal IGFBP-1 mRNA and protein. However, 7 days after the induction of diabetes, renal IGFBP-1 mRNA and protein were similarly increased in both octreotide-treated or untreated diabetic rats. Renal IGFBP-3 gene expression and protein and IGFPB-5 mRNA remained unchanged after 2 and 7 days of diabetes when treated or untreated with octreotide. We conclude that the well-known inhibitory effect of octreotide on the early increase in renal IGF-I concentration and renal size in diabetes may be mediated through a direct effect on renal IGFBP-1 levels.

Animals↗

PubMed1997

Effect of graded renal ablation on kidney and serum insulin-like growth factor-I (IGF-I) and IGF binding proteins in rats: relation to compensatory renal growth.

Kidney insulin-like growth factor-I (IGF-I) increases transiently following unilateral nephrectomy, thus preceding the compensatory renal growth. The aim of the present study was to investigate the effect of different degrees (1/7 to 2/3) of renal ablation on kidney and serum IGF-I and IGF binding proteins (IGFBPs) during a 7-day study period. All nephrectomized rats exhibited an increase in the weight of the remaining renal tissue. Kidney IGF-I measured in kidney pieces close to and away from the resected area increased transiently and more significantly away from the resected area, with significant correlation to the amount of tissue resected (day 1, r = .73, P < .0001; day 2, r = .49, P < .05; and day 7, r = .48, P < .05). No changes in kidney IGFBPs or serum IGF-I were observed. Serum IGFBP-4 correlated to the degree of renal resection, as did changes in serum urea and creatinine. In conclusion, significant correlations were observed between local changes in kidney IGF-I and serum IGFBP-4 levels and the degree of renal ablation, suggesting a role for IGF-I as a renotropic factor and, further, that IGFBP-4 is removed to a major extent through the kidney.

Animals↗

PubMed1997

The pharmacokinetics of octreotide in cirrhosis and in healthy man.

BACKGROUND/AIM: The aim of the study was to evaluate the pharmacokinetics of octreotide in patients with cirrhosis compared to healthy volunteers. METHODS: Seventeen patients with cirrhosis and nine normals received an intravenous bolus of octreotide (0.75 microgram/kg), followed by a continuous infusion of 0.75 microgram.kg-1.h-1 for 12 h. Eight patients were decompensated with ascites, while nine were without signs of decompensation. Serum octreotide levels were followed by blood sampling during the infusion period and for 24 h afterwards. RESULTS: The average clearance (+/-SEM) was 151 +/- 15 ml/min in normals compared to 102 +/- 9 (p < 0.05) and 105 +/- 9 (p < 0.05) in patients with compensated and decompensated cirrhosis, respectively. The average area under the serum octreotide curve was significantly increased by 53% (p < 0.05) in decompensated and 46% (p < 0.05) in compensated cirrhosis compared to healthy volunteers, while no difference was observed between the groups with cirrhosis. This difference was also reflected by an increased maximum serum concentration during the infusion period of 9797 +/- 580 ng/l in the patients with cirrhosis compared to 7081 +/- 547 ng/l (p = 0.006) in normals. The serum half-life for the beta-phase (T1/2 beta) was 165 +/- 26 min in normals, 200 +/- 21 min in the compensated and 216 +/- 26 min in the decompensated group (NS). The volume of distribution (Vd beta) showed no difference between the three groups. Because of the slow equilibration between plasma and ascitic fluid in decompensated cirrhosis, the calculated clearance may have been overestimated and T1/2 beta and Vd beta underestimated in these patients. CONCLUSIONS: The present study demonstrates that the pharmacokinetics of octreotide in cirrhosis is substantially different from that found in normals.

Adult↗

PubMed1997

Measurement of renal vein blood flow in rats by high-field magnetic resonance.

The aim of the present study was to examine whether magnetic resonance imaging (MRI) based method for non-invasive in vivo measurement of vein blood flow in rats could be used to estimate renal blood flow (RBF). Measurements were performed using a high-field (7 Tesla) MRI scanner with a short echo time phase contrast velocity measurement pulse sequence. The method was evaluated in vitro by flow measurements in an acrylic pipe and in vivo by recording left renal vein blood flow in normal and unilaterally nephrectomized rats. In a subset of animals RBF was measured by a direct method using 14C-tetraethylammoniumbromide. In vitro a high accuracy was found between applied and MRI measured flow rates in the range from 0.5 to 33 ml/min (r = 0.997; P < 0.001). In vivo the MRI measured left renal vein blood flow was 70% higher in unilaterally nephrectomized animals compared to control animals (3.4 +/- 0.4 ml/min/ 100 g body wt vs. 2.0 +/- 0.1 ml/min/100 g body wt, P < 0.001). Direct measurements of RBF revealed comparable values (3.4 +/- 0.3 ml/min/100 g body wt vs. 2.3 +/- 0.4 ml/min/100 g body wt, P = 0.05). In addition, the left kidney volume was recorded by MRI with an increase amounting to 40% (1.18 +/- 0.05 ml vs. 0.84 +/- 0.02 ml; P < 0.001) in the nephrectomized group compared to controls. Finally, a positive correlation was seen between left renal vein blood flow and MRI measured renal volume (r = 0.91; P < 0.001). In summary, MRI is a non-invasive tool by which measurement of renal vein blood flow can be performed, and it is concluded that MRI-based renal vein flow measurements can be used to estimate RBF in small rodents.

Animals↗

PubMed1997

Relationship between MRI and morphometric kidney measurements in diabetic and non-diabetic rats.

The aim of the present study was to determine the applicability of magnetic resonance imaging (MRI) as a non-invasive measure of kidney volume in vivo in diabetic and non-diabetic rats. Magnetic resonance, T1 weighted Spin Echo, images were obtained after injection of contrast in anesthetized control (N = 14) and hyperglycemic streptozotocin (STZ)-diabetic rats (N = 14). On MRI imaging the total kidney, cortex, medullary and pelvic volumes were calculated. Immediately after MRI measurements the left kidneys were removed before weighing either as a clamped kidney weight (that is, the kidney containing blood and urine) or as a wet kidney weight (the kidney drained of blood and urine), while the right kidneys were perfusion-fixed for morphometric measurements. On thin kidney slices obtained from perfusion-fixed kidneys the cortex, medullary and pelvic fractions were measured and subsequently the cortex, medulla and pelvic volumes were calculated. The cortical volume was measured according to three different approaches. The corticomedullary boundary was defined either to the arcuate arteries, to a curved line following the glomeruli, or to a line at the top of the medullary rays. Both in control and diabetic rats, MRI measured kidney volumes were similar to the volume of perfusion-fixed kidneys, while the clamped kidney weight, and in particular the wet kidney weights, were smaller than the MRI obtained volumes. Good agreement was found between the MRI measured cortex and medulla volumes when the cortex was defined to the top of the medullary rays in the morphometric analysis. In conclusion, the present study demonstrates that MRI allows a reliable non-invasive estimate of renal morphology at a macroscopic level in both diabetic and non-diabetic rats.

Animals↗

PubMed1997

Moderate hyperthyroidism reduces liver amino nitrogen conversion, muscle nitrogen contents and overall nitrogen balance in rats.

There are conflicting data on the effect of thyroid hormones on nitrogen metabolism. We determined the basal blood amino nitrogen (amino-N) concentrations, the urea nitrogen (urea-N) synthesis rate and the maximum hepatic capacity of urea nitrogen synthesis during saturating infusion of alanine, in moderately acutely (24 h) and chronically (7 days) hyperthyroid rats and compared this with changes in organ nitrogen contents in muscles and kidney, nitrogen excretion and nitrogen balance. Forty-three rats were made acutely hyperthyroid through administration of 5 microg 100 g(-1) triiodothyronine twice daily (T3: 2.2 +/- 0.7 vs. 0.87 +/- 0.04 nmol L(-1), P < 0.01). Fifty-one rats were made chronically hyperthyroid through administration of 12.5 microg 100 g(-1) thyroxine twice daily (T3: 2.63 +/- 0.18 vs. 0.87 +/- 0.04 nmol L(-1), P < 0.01). Weight gain was halved in this group. Both acute and chronic hyperthyroidism increased basal blood amino-N concentration in both groups by 16% (4.5 +/- 0.15 vs. 3.9 +/- 0.13 mmol L(-1) and 4.7 +/- 0.12 vs. 3.9 +/- 0.13 mmol L(-1), respectively, P < 0.01), and decreased basal urea-N synthesis rate in both groups by 30% [2.7 +/- 0.3 vs. 4.1 +/- 0.3 micromol (min x 100 g)(-1) and 3.1 +/- 0.3 vs. 4.1 +/- 0.3 micromol (min x 100g)(-1), respectively, P < 0.01]. The capacity of urea-N synthesis during saturation fell in both groups by 35% compared with controls [6.5 +/- 0.4 vs. 9.3 +/- 0.5 micromol (min x 100 g)(-1) and 5.7 +/- 0.5 vs. 9.3 +/- 0.6 micromol (min x 100g)(-1), respectively, P < 0.01]. Nitrogen contents in the muscles, soleus and extensor digitorum longus, of chronically hyperthyroid rats decreased by 22% and 11%, respectively, whereas kidney N-content increased by 12% (P < 0.05). N-balance and urinary urea-N excretion fell by 30%, whereas faeces-N excretion increased by 80% in hyperthyroid rats. Overall liver function assessed by galactose elimination capacity did not differ among groups. Both acute and chronic moderate hyperthyroidism increase blood amino-N and decrease basal and maximum rate of urea formation. Furthermore, chronic hyperthyroidism reduces N-contents of muscles, urinary urea-N excretion and N-balance. Thyroid hormones thus mobilize muscle-N, whereas amino-N in the liver is spared from irretrievable conversion into urea.

Amino Acids↗

PubMed1997

Systemic administration of insulin-like growth factor I (IGF-I) causes growth of the rat prostate.

PURPOSE: To investigate the effects of insulin-like growth factor I (IGF-I) and epidermal growth factor (EGF) on the rat prostate. In addition, we investigated the effect of ornithine decarboxylase (ODC) inhibition with alpha-diflouromethylornitine (DFMO) on the expected growth of the prostate. MATERIALS AND METHODS: Eight week old Wistar rats were allocated into groups of eight, receiving systemic treatment for 3 and 7 days with either IGF-I (400 micrograms/rat/day) or EGF (30 micrograms/rat/day) alone or in combination with DFMO. RESULTS: Systemic treatment with IGF-I for 7 days resulted in a 29% (p < 0.01) increase in the mean wet weight of the ventral prostate. The mean weight of the dorsolateral lobe of the prostate increased by 39% (p < 0.05), and the seminal vesicle and coagulating gland increased 69% (p < 0.05) compared to controls. The ODC-activity in the prostate was significantly increased by IGF-I after 3 days of treatment, and administration of IGF-I concomitantly with DFMO significantly inhibited ODC activity and the weight increase of the prostate. Stereological examination of the prostate in the IGF-I-treated animals showed growth of the epithelial component of the gland. Systemic treatment with EGF did not affect the mean weight of the prostate or the seminal vesicle compared to controls. CONCLUSION: The results demonstrate that treatment with IGF-I but not EGF for 7 days induces profound growth of the rat prostate and the seminal vesicle, and that the growth is dependent on an intact ODC-activity.

Animals↗

PubMed1997

Effect of GH/IGF-I deficiency on long-term renal changes and urinary albumin excretion in diabetic dwarf rats.

Growth hormone (GH) and insulin-like growth factor I (IGF-I) may play a role in early diabetic renal and glomerular growth and in the later development of experimental diabetic kidney disease. Rats from a genetic GH/IGF-I-deficient dwarf rat strain were made streptozotocin diabetic and were compared with nondiabetic dwarf rats. GH/IGF-I-intact rats with and without diabetes served as controls. After 6 mo of diabetes, kidney weight and total glomerular volume increased significantly in GH/IGF-I-intact diabetic rats compared with the nondiabetic GH/IGF-I-intact rats (P < 0.05), whereas the diabetic dwarf rats had insignificant changes compared with dwarf control rats. By the end of the study, urinary albumin excretion (UAE) increased from similar base levels of approximately 15-20 micrograms/24 h to 473 +/- 52 (SE) micrograms/24 h in GH/IGF-I-intact diabetic rats compared with 151 +/- 32 micrograms/24 h in diabetic dwarf rats (P < 0.01). In conclusion, isolated GH/IGF-I deficiency reduces the degree of renal and glomerular hypertrophy and the increase in UAE after 6 mo of experimental diabetes in GH/IGF-I-deficient rats.

Albuminuria↗

PubMed1997

Changes in facilitative glucose transporter messenger ribonucleic acid levels in the diabetic rat kidney.

Facilitative glucose transporter (GLUTs 1, 2, 4, and 5) messenger RNAs (mRNAs) are differentially distributed in the rat nephron: GLUT1 is widely expressed, GLUT4 is selectively concentrated in thick ascending limbs, and GLUT2 and 5 are exclusively localized in proximal tubules, consistent with differential roles for these transporters in renal glucose handling. In the present study, quantitative in situ hybridization was used to evaluate changes in these mRNA levels during acute (2 and 7 days) and chronic (30, 90, and 180 days) streptozotocin-induced diabetes mellitus (STZ-DM). Medullary GLUT1 and GLUT4 mRNA levels were significantly increased during the acute phase but returned to normal after 1 week. Cortical GLUT1 mRNA levels, however, were decreased significantly from 7 days through 6 months of STZ-DM. Cortical GLUT2 mRNA was slightly increased acutely and increased 5-fold in chronic STZ-DM, with the largest increase focally concentrated in the convoluted portion of the proximal tubule. Proximal tubule GLUT5 mRNA levels also were increased significantly during chronic STZ-DM. In summary, medullary GLUT1 and GLUT4 mRNA levels are acutely increased in STZ-DM, paralleling the increased renal epithelial metabolic activity accompanying early diabetes. Proximal tubular GLUT2 and 5 mRNA levels were increased in chronic STZ-DM, possibly adapting to the increased need for glucose transport out of these epithelial cells, whereas the concomitant decrease in cortical GLUT1 expression may reflect the decreased requirement for basolateral import of glucose into these same cells. Thus, renal GLUTs demonstrate complex, nephron segment-specific and duration-dependent responses to the effects of STZ-DM.

Acute Disease↗

PubMed1997

Increased levels of serum fibroblast growth factor-2 in diabetic pregnant women with retinopathy.

Fibroblast growth factor-2 (FGF-2) is a potent mitogen and angiogenic factor normally absent from the adult circulation. We have previously shown that it appears in normal maternal serum and that circulating FGF-2 levels are elevated in pregnancies complicated by diabetes. This study was performed to determine whether serum FGF-2 is more abundant in pregnant diabetic women with retinopathy than in those without. Serum was collected monthly between 14-30 weeks gestation and every 2 weeks from then until delivery (35-38 weeks) from 36 women with type 1 diabetes. FGF-2 was extracted by heparin-Sepharose affinity chromatography and quantified by specific RIA. Patients were divided according to the White classification of diabetes. In 17 women without retinopathy (White groups B, C, and D0), immunoreactive FGF-2 was detectable at 14 weeks (mean +/- SEM, 154 +/- 39 pmol/L), was maximal after 26 weeks (306 +/- 38 pmol/L), after which values steadily declined to term (212 +/- 48 pmol/L). In 19 women with simplex or proliferative retinopathy (White groups D+ and R), circulating levels of FGF-2 were significantly greater between 22-32 weeks gestation (22 weeks, 480 +/- 102 vs. 239 +/- 38 pmol/L; P < 0.05). Serum FGF-2 was significantly correlated with hemoglobin A1c levels at 22, 30, and 34 weeks gestation. The mean birth weight of the infants did not significantly differ between groups. Macroalbuminuria was absent in all patients, and creatinine clearance and blood pressure did not significantly differ between the two groups. The results suggest that serum FGF-2 is substantially elevated in pregnant diabetic women with retinopathy in second and early third trimesters. It is unlikely that in these patients this was primarily due to altered FGF-2 clearance, but may relate to excessive production by the utero-placental compartment. The high circulating levels of FGF-2 may be causally related to the development of diabetic retinopathy.

Adult↗

PubMed1997

Elevated serum insulin-like growth factor-binding protein 2 (IGFBP-2) and decreased IGFBP-3 in epithelial ovarian cancer: correlation with cancer antigen 125 and tumor-associated trypsin inhibitor.

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) recently have been shown to play a physiological role in the female genital system, including the ovarian follicular system. However, little is known about the role of the IGF system in malignant ovarian disease. To assess possible mutual correlations between alterations in circulating IGFBP profiles and tumuor markers in patients with epithelial ovarian cancer, we performed an RIA for IGFBP-2 and IGFBP-3 and a Western ligand blotting (WLB) in serum samples from 20 patients with epithelial ovarian cancer, 10 patients with benign ovarian tumors, and 8 healthy age-matched controls. The epithelial ovarian cancer group had a mean IGFBP-2 level that was 253% (RIA) and 105% (WLB) above that of controls. IGFBP-2 even correlated positively with the highly sensitive serum tumor marker, cancer antigen 125 (CA 125) (r = 0.71, P < 0.001) but not with the less sensitive tumor-associated trypsin inhibitor. In contrast, serum IGFBP-3 (by RIA and WLB) was decreased in patients with ovarian cancer, and IGFBP-3 proteolytic activity was detectable in some of the patients. Neither IGFBP-3 nor IGFBP-3 proteolytic activity correlated with CA 125; but the former correlated inversely, and the latter positively, with tumor-associated trypsin inhibitor. In conclusion, IGFBP-2 levels are high in serum of epithelial ovarian cancer patients, and the increment in serum IGFBP-2 correlates positively with CA 125. Alterations in serum IGFBP-2 levels may therefore, serve as a potential additional marker for ovarian cancer.

Aged↗

PubMed1997

IGF, type I IGF receptor and IGF-binding protein mRNA expression in kidney and liver of potassium-depleted and normal rats infused with IGF-I.

Dietary potassium (K) depletion is known to reduce body weight gain and organ growth, except for kidney which increases in weight. This renal hypertrophy is preceded by increased renal IGF-I levels. In the present study, we investigated IGF-I and -II, type I IGF receptor and IGF-binding protein (IGFBP) mRNA expression in liver and kidney of K-depleted and normal rats infused with vehicle or recombinant human IGF-I. Body weight gain was almost completely arrested in K-depleted rats without any stimulatory effect of IGF-I infusion. Both absolute and relative kidney weight (kidney weight/body weight) were significantly increased in K-depleted rats and this was further enhanced by IGF-I infusion. In contrast, relative liver weight was comparable in the different groups and unaffected by IGF-I infusion. IGF-I mRNA expression was significantly lower in kidney and liver of K-depleted animals whereas type I IGF receptor levels were unchanged. In contrast, in kidney, K depletion increased IGFBP-1 and -2 mRNA expression with no additional effect of IGF-I infusion. In liver of K-depleted animals, IGFBP-1 mRNA expression was increased whereas increased IGFBP-1 and -2 mRNA expression was observed when these animals were infused with IGF-I. These observations may point towards a differential mode of action of the IGFBPs. In kidney increased IGFBP-1 and -2 mRNA expression may enhance IGF-I bioavailability with subsequent kidney growth. In liver, with clearly detectable type I IGF receptor mRNA expression, increased IGFBP levels may protect from IGF-I-induced organ growth by decreasing IGF-I bioavailability.

Animals↗

PubMed1997

Magnetic resonance imaging as a monitor of kidney enlargement and regression in experimental diabetes in rats.

The aim of the present study was to use magnetic resonance imaging as a non-invasive measure of renal enlargement and regression in experimental diabetes in rats. Rats were randomized into three groups: (1) non-diabetic control animals, (2) diabetic animals, untreated for 30 days after streptozotocin treatment and (3) diabetic animals treated with insulin from day 21 to day 30 after streptozotocin administration. Magnetic resonance images were obtained from anaesthetized rats and kidney, cortex, medulla and pelvis volumes were calculated throughout the experiment until day 30. In untreated diabetic animals, a marked increase in kidney volume was seen 4 days after the induction of diabetes (P < 0.05) and after 30 days this increase amounted to 73%, with similar increases in the cortex (63%) and medulla (69%). No change was seen in the pelvis volume. Insulin administration on day 21 to untreated diabetic rats abruptly reduced kidney volume by 21%, cortex volume by 27% and medulla volume by 18%, and after 4 days all three parameters were similar to those seen in non-diabetic controls. In conclusion, the present study has demonstrated the applicability of magnetic resonance imaging as a non-invasive measure of renal enlargement and regression in experimental diabetes in rats. In untreated hyperglycaemic diabetic rats, with manifest diabetic renal enlargement, acute regression in renal volume was observed concomitant with insulin-induced normoglycaemia.

Animals↗

PubMed1997

Renal hypertrophy in hyperglycemic non-obese diabetic mice is associated with persistent renal accumulation of insulin-like growth factor I.

The non-obese diabetic mouse is a model of spontaneous insulin-dependent diabetes as a result of autoimmune destruction of pancreatic beta cells, similar to the disease seen in human Type I diabetes. This mouse strain develops glomerular lesions reminiscent of those seen in human disease. The study presented here investigated the changes in renal insulin-like growth factor (IGF) system in hyperglycemic non-obese diabetic mice. Female non-obese diabetic mice and their age- and sex-matched controls were euthanized 4 days, 2 wk, and 4 wk after the onset of glycosuria. Kidney weight increased in diabetic mice, beginning at 2 wk after the onset of glycosuria. This renal hypertrophy was associated with an increase in renal extractable IGF-I protein. However, a decrease in IGF-I mRNA was observed at the same time. Serum IGF-I levels remained stable after 2 wk of diabetes and decreased at 1 month. No change was detected in renal IGF-I receptor mRNA levels. Renal cortical IGF binding protein (IGFBP)-1 mRNA levels were increased. Ligand blot analysis revealed a significant increase in serum and renal 30-kd IGFBP and a decrease in serum and kidney IGFBP-3 and IGFBP-4 at 30 days of diabetes. Insulin therapy prevented the increases in kidney weight, renal IGF-I, and 30-kd IGFBP, but did not reverse the decreased serum IGF-I levels observed at 1 month of diabetes. In summary, renal hypertrophy in non-obese diabetic mice is associated with a persistent accumulation of renal IGF-I and, IGFBP-1. These changes were partially reversed with insulin therapy, which did not correct the hyperglycemia, suggesting an important role for insulin deficiency in mediating these changes in the IGF system. These findings suggest that the IGF system may play a potential role in the development of diabetic nephropathy.

Animals↗

PubMed1997

Role of growth hormone, insulin-like growth factors (IGFs) and IGF-binding proteins in the renal complications of diabetes.

This review has updated recent facets of evidence for the significance of the GH/IGF system in the development of diabetic kidney disease. It seems evident, however, that there is still an extensive number of questions that need to be answered before diabetic kidney disease is fully understood. The knowledge we have today indicates that GH/IGF axis, through a complex system comprising GHR, GHBP, IGFs, IGF receptors and IGFBPs may be responsible for both early and late renal changes in experimental diabetes (Fig. 3). In view of the complexity of the GH/IGF system, it will be a challenge to fully characterize the renal effects of GH/IGFs in diabetic kidney disease. There is no doubt that information on this topic will occur with increasing pace in the near future and that a understanding of the above-mentioned mechanisms will allow the further development of existing antagonists and design of new drugs, which may prove to be useful for therapeutic manipulation in the treatment of diabetic nephropathy. The development of long-acting somatostatin analogues and GH antagonists, both with a specific action on the GH/IGF axis, seems to be one important step ahead. The combined administration of one of these antagonists with other drugs with a well described renoprotective action (such as ACE inhibitors) opens an interesting new dimension.

Diabetic Nephropathies↗

PubMed1996

Renal enlargement and insulin-like growth factor-1 accumulation in the Wistar rat model of experimental diabetes is not prevented by angiotensin converting enzyme inhibition.

Experimental diabetes is associated with renal enlargement and glomerular hyperfiltration. Possible mechanisms for these changes could be the direct effects of growth factors such as insulin-like growth factor-1 and angiotensin II. We investigated whether treatment with trandolapril, an angiotensin converting enzyme inhibitor, prevented renal enlargement in streptozotocin-diabetic rats. Seven groups of male Wistar rats were studied: C (control + placebo); CL (control + low-dose trandolapril, 0.01 mg.kg-1.day-1); CH (control + high-dose trandolapril, 0.5 mg.kg-1.day-1; DP (diabetic + placebo); DI (diabetic, insulin-treated); DL (diabetic + low-dose trandolapril); DH (diabetic + high-dose trandolapril) and DI (diabetic + insulin). From day 2 glucose concentrations and body weight were similar in the non-diabetic and diabetic animals treated with insulin. Diabetic animals treated with placebo and low-dose trandolapril weighed significantly less compared to the control group. The diabetic groups, not treated with insulin, showed marked hyperglycaemia throughout the study. Kidney weight was greater in the diabetic, non insulin-treated groups compared with the control and insulin-treated groups. After 24 h of diabetes, kidney insulin-like growth factor-1 content was significantly increased from baseline levels in groups DP, DL and DH but by 48 h these levels had returned to normal. Renal tissue angiotensin converting enzyme activity was similar in groups C and DI but significantly reduced in all trandolapril-treated animals. Despite inhibiting renal angiotensin converting enzyme activity renal enlargement with increased tissue insulin-like growth factor-1 still occurred. This suggests that neither angiotensin II nor glomerular hyperfiltration, with raised intraglomerular pressure, play a role in the initial renal enlargement seen in experimental diabetes. Renal accumulation of insulin-like growth factor-1 appears to be an important factor in early renal hypertrophy and its effects are not modulated by angiotensin converting enzyme or angiotensin II.

Analysis of Variance↗

PubMed1996

Effect of insulin-like growth factor I (IGF-I) administration on the healing of colonic anastomoses in rats.

BACKGROUND: The gastrointestinal tract is highly responsive to the tropic effect of growth hormone (GH). GH stimulates the healing of colonic anastomoses either directly or through insulin-like growth factor I (IGF-I) since specific GH receptor as well as IGF-I receptor have been demonstrated in colon. AIM: To determine whether exogenous treatment with IGF-I could stimulate the healing of left colonic anastomoses in rats. METHODS: After colonic anastomotic operations adult rats were randomised to treatment with either IGF-I (500 mu g per day) or vehicle (controls). Anastomotic breaking strength and collagen deposition were determined at day after surgery. RESULTS: IGF-I treatment increased the anastomotic collagen content by 23% compared with controls. This resulted in a lower extensibility of the anastomosis (P < 0.05), whereas the anastomotic breaking strength did not differ between groups. The treatment resulted in a 3 fold increase in serum IGF-I of IGF-I treated rats, compared to controls. The postoperative body weight increased by 5% in the IGF-I rats from day 0 to day 3, while the control group had a weight loss of 2% in the same period (P < 0.001). CONCLUSION: Treatment of colon-operated rats with IGF-I increased the postoperative body weight and stimulates the collagen deposition of left colonic anastomoses, whereas the anastomotic strength may be unaffected by IGF-I treatment.

Anastomosis, Surgical↗

PubMed1996

Redistribution of axoplasm in the motor root in experimental diabetes.

Early experimental diabetes is associated with a reduction in axonal caliber. To elucidate the changes of nerve caliber further, we investigated the proximal and distal regions of the anterior root of rats after 5 weeks of streptozocin-induced diabetes. After vascular perfusion fixation, the fifth lumbar motor root was excised and two 3-mm segments were isolated, one at the level of the spinal cord and one at the dorsal root ganglion. The areas of myelinated fibers and their axons were measured by point counting. Axons from diabetic mice were enlarged proximally as compared to the controls, and reduced distally. It has been hypothesized that the reduction in axonal caliber is caused by an impairment of axonal transport of structural proteins rather than by osmotic shrinkage. Our findings indicate a redistribution of axoplasm in the nerves of the diabetic mice and support the hypothesis that changes in the axonal transport of neurofilaments are responsible for the structural changes seen in early diabetes. Similar changes could also play a role in the development of neuropathy in man.

Animals↗