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Biomedical subjects

J Zapf

Publications and source records attributed to J Zapf.

At least 37 records · Page 2Linked to original sources
PubMed1999

Hepatic and pulmonary metastases from a meningeal hemangiopericytoma and severe hypoglycemia due to abnormal secretion of insulin-like growth factor: a case report.

A 42-year-old woman was hospitalized for severe hypoglycemic coma. She had a voluminous hepatic metastasis and multiple small lung metastases from a meningeal hemangiopericytoma initially operated on 11 years earlier. High blood levels of an abnormal form of insulin-like growth factor type 2 (IGF II) associated with low blood levels of insulin, growth hormone, IGF I, and IGF BP3 were observed. After surgical resection of the liver and pulmonary metastases, serum glucose levels and hormonal abnormalities returned to normal.

Adult↗
PubMed1999

Leptin is suppressed during infusion of recombinant human insulin-like growth factor I (rhIGF I) in normal rats.

To examine whether insulin-like growth factor I (IGF I) or growth hormone (GH) influences leptin in vivo we measured leptin mRNA in epididymal fat pads and serum leptin of normal rats infused subcutaneously for 6 days with recombinant human (rh)IGF I (1 mg/day), rhGH (200 mU/day), or vehicle. In addition, we determined fat pad weight and food consumption as well as IGF I, insulin, glucose, non-esterified fatty acid (NEFA), glycerol, beta-hydroxybutyrate and triglyceride (TG) serum concentrations. Food intake was identical during all three treatments. RhIGF I but not rhGH raised IGF I serum concentrations, reduced fat pad weight (60.3 +/- 7.4% of control rats, p = 0.019), and suppressed leptin mRNA (38.8 +/- 11.9% of control rats, p = 0.002), serum leptin (51.6 +/- 10.5% of control rats, p = 0.0028) and serum triglycerides (39.3 +/- 8.0% of control rats, p = 2.6 x 10(-6)). Both rhIGF I and rhGH reduced non-esterified fatty acids (NEFA) (p = 0.00001 and 0.0007, respectively), whereas serum glycerol, beta-OH butyrate and glucose concentrations remained unchanged. Serum insulin concentrations during rhIGF I were lower than during rhGH infusion and correlated with leptin mRNA (r = 0.589, p = 0.016) and fat pad weight (r = 0.643, p = 0.007). Reduction of adipose tissue mass and suppression of leptin by IGF I appear to be due to reduced circulating insulin leading to enhanced fat mobilization and NEFA oxidation as well as to increased gluconeogenesis from glycerol. In contrast, decreased NEFA concentrations during rhGH in the presence of unchanged fat pad weight, serum glycerol and triglycerides might result from more efficient re-esterification of released fatty acids within the triglyceride-fatty acid cycle. The results also show that exogenously infused IGF I and GH act on lipid metabolism by different mechanisms and suggest an IGF-independent, probably direct, metabolic effect of GH. Finally, in agreement with previous studies in GH-infused hypophysectomized rats, it appears unlikely that GH regulates leptin in the rat.

3-Hydroxybutyric Acid↗
PubMed1999

Insulin-like growth factor-I lowers fasting and postprandial triglyceride levels without affecting chylomicron clearance in healthy men.

OBJECTIVES: To study whether IGF-I treatment alters the postprandial lipid and lipoprotein metabolism. DESIGN: Randomized, crossover study. SETTING: University Hospital, Zürich, Switzerland. SUBJECTS: Seven young healthy male subjects (aged 27+/-4 years, body mass index (BMI) 21.8+/-1.7 kg m(-2)). INTERVENTIONS: Each subject was studied two times at 2-week intervals, treated with saline 0.9% (S) and IGF-I (8 microg kg(-1) h(-1)) by a continuous subcutaneous infusion. 60 h after the start of treatment a vitamin A loading test was performed after an overnight 12-h fast. MAIN OUTCOME MEASURES: Glucose, insulin, total and free IGF-I, FFA, triglycerides and retinyl palmitate, total cholesterol, HDL and LDL cholesterol, lipoprotein (a) and apolipoprotein B were measured in serum before and after the fatty meal. RESULTS: Total IGF-I levels rose from 29.0+/-3.3 nmol L(-1) to 113.3+/-9.0 nmol L(-1) (P<0.02) and free IGF-I from 0.24+/-0.05 to 1.08+/-0.28 nmol L(-1) (P<0.02) during IGF-I treatment. IGF-I administration reduced insulin concentrations by 50% (P<0.02), as assessed by the area under the curve. Serum triglyceride levels were significantly lower at baseline and after the fat load during IGF-I treatment (P<0.02), whereas the retinyl palmitate concentrations in chylomicron and nonchylomicron lipoprotein fractions were similar during both treatment periods. CONCLUSIONS: IGF-I treatment reduces the triglyceride levels most probably by decreasing insulin secretion and the production of VLDL particles, and possibly by increasing their turnover. IGF-I treatment has no significant effect on the metabolism of intestine-derived triglyceride-rich lipoproteins after a high fat meal in healthy young men.

Adult↗
PubMed1999

Insulin-like growth factor binding protein-4 proteolytic degradation in ovine preovulatory follicles: studies of underlying mechanisms.

The regulation of insulin-like growth factor binding protein (IGFBP)-4 proteolytic degradation by insulin-like growth factors (IGFs) has been largely studied in vitro, but not in vivo. The aim of this study was to investigate the involvement of IGFs, IGFBP-2, IGFBP-3, and IGFBP-3 proteolytic fragments in the regulation of IGFBP-4 proteolytic activity in ovine ovarian follicles. Follicular fluid from preovulatory follicles contains proteolytic activity degrading exogenous IGFBP-4. The addition of an excess of IGF-I enhanced IGFBP-4 proteolytic degradation, whereas addition of IGFBP-2 or -3 or monoclonal antibodies against IGF-I and -II dose dependently inhibited IGFBP-4 proteolytic degradation. IGF-I and IGF-II, but not LongR3-IGF-I, reversed this inhibition in a dose-dependent manner. C-terminal, but not N-terminal, proteolytic fragments derived from IGFBP-3 (aa 161-264), as well as heparin-binding domain-containing peptides derived from the C-terminal domain of IGFBP-3 and -5 also induced the inhibition of IGFBP-4 proteolytic degradation. Other heparin-binding domain-containing peptides derived from the connective tissue growth factor (CTGF) and from proteins not related to IGFBP, heparan/heparin interacting protein (HIP) and vitronectin, but not from p36 subunit of annexin II tetramer, inhibited IGFBP-4 degradation. Furthermore, IGFBP-3, mutated on its heparin-binding domain, was not able to inhibit IGFBP-4 proteolytic degradation. So, in ovine preovulatory follicles, IGFBP-4 proteolytic degradation both 1) depends on IGFs, and 2) is inhibited by IGFBP-3 via its C-terminal heparin-binding domain as well as by heparin-binding domain containing peptides. These data suggest that in early atretic follicles, the increase in IGFBP-2 participates in the decrease in IGFBP-4 degradation. In late atretic follicles, the increase in the levels of C-terminal IGFBP-3 proteolytic fragments, generated by IGFBP-3 degradation, as well as the increase in IGFBP-5 expression would strengthen the inhibition of IGFBP-4 degradation. This inhibition might be partly mediated by direct interaction of IGFBP-4 proteinase(s) and heparin-binding domain within the C-terminal region from IGFBP-3 and -5.

Animals↗
PubMed1999

Insulin-like growth factor I: an attractive option for chronic heart failure?

Chronic congestive heart failure is a syndrome with a poor prognosis. Currently, the only therapy providing the possibility of long term survival is heart transplantation. Therefore, new therapeutic strategies continue to be investigated. One such new approach may be the application of recombinant human insulin-like growth factor (IGF)-1. IGF-1 has both acute and long term cardiovascular effects. Acute administration of IGF-1 resulted in a reduction in afterload and positive inotropic effects in patients with heart failure. In vitro and animal studies have demonstrated that IGF-1 can stimulate myofibril formation. In addition, IGF-1 administration has beneficial metabolic effects. The benefits of prolonged IGF-1 therapy have yet to be investigated.

Animals↗
PubMed1999

Insulin-like growth factor 1 and 2 serum concentrations in dialysis patients with secondary hyperparathyroidism and adynamic bone disease.

BACKGROUND: Insulin-like growth factor-1 and -2 exert well characterized effects on bone metabolism via paracrine and endocrine pathways. However, the role of circulating levels of IGFs and their binding proteins (IGFBP) in renal bone disease is still controversial. PATIENTS AND METHODS: To investigate whether circulating IGFs play a role in the pathogenesis of different forms of renal bone disease, we performed a cross sectional study in 38 stable dialysis patients (32 hemodialysis, 6 peritoneal dialysis). Patients were selected for the type of bone disease according to biochemical bone markers and bone histology. 25 Patients had adynamic bone disease (ABD; defined by plasma iPTH < 1,5 fold the upper limit of normal). Thirteen patients had secondary hyperparathyroidism (sHPT; defined by plasma iPTH > 10 fold the upper limit of normal). Serological diagnosis was confirmed in a subgroup of patients by bone histology (12 patients with type IIa according to Delling, ABD; 9 patients with type IIIb according to Delling, sHPT). Patients with signs or symptoms of aluminum toxicity were excluded from the study. RESULTS: Serum IGF-1 and -2 concentrations were comparable in both groups and were within the reported normal range for an age matched healthy control population. They did not correlate with biochemical markers (iPTH, bAP, osteocalcin) or histological manifestations of renal bone disease. Furthermore, semiquantitative analysis of IGFBP-2 and -3 carried out in patients with bone biopsies did not correlate with biochemical markers or histological indices of renal bone disease. CONCLUSION: In conclusion, in contrast to previous reports, the present data do not confirm a correlation between serological or histological markers of renal osteodystrophy and circulating IGF-1 or -2 or IGFBP-2 and -3. This does not exclude that potential alterations of the local IGF system may play a role in the pathogenesis of uremic bone disease.

Chronic Kidney Disease-Mineral and Bone Disorder↗
PubMed1998

Insulin-like growth factor-binding protein 5 complexes with the acid-labile subunit. Role of the carboxyl-terminal domain.

We have recently shown that insulin-like growth factor (IGF)-binding protein 5 forms ternary complexes with IGF-I or IGF-II and the acid-labile subunit (ALS) (Twigg, S. M., and Baxter, R. C. (1998) J. Biol. Chem. 273, 6074-6079). Because IGF-binding protein 3 (IGFBP-3) binds to ALS through its basic carboxyl-terminal domain, we tested whether a homologous region present in IGFBP-5 is involved in IGFBP-5 binding to ALS. Chimeric peptides were generated by carboxyl-terminal domain interchange between recombinant human IGF-BP-5 and IGFBP-6, producing two IGFBP peptides designated 5-5-6 and 6-6-5. Determined by immunoprecipitation and by Superose chromatography, 6-6-5 formed ternary complexes, albeit less potently than IGF-BP-5. In contrast, 5-5-6, like IGFBP-6, did not form ternary complexes by these methods. Whereas 6-6-5, like IGFBP-6, had a marked preference for binary complex formation with IGF-II rather than IGF-I, it formed ternary complexes more efficiently with IGF-I, like IGF-BP-5. The glycosaminoglycans heparin and heparan sulfate bind to IGFBP-5 through its basic carboxyl-terminal domain. At high concentrations, these glycosaminoglycans inhibited ALS binding to binary complexed IGF-BP-5. In addition, in the absence of IGFs, IGFBP-5, a synthetic peptide representing the basic carboxyl-terminal sequence IGFBP-5(201-218), and the corresponding IGFBP-3 basic sequence IGFBP-3(215-232), competed weakly for ALS binding to covalent IGF-IGFBP-5 complex, as did a random-sequence synthetic peptide with the same composition as IGFBP-5(201-218). These findings are consistent with the basic carboxyl-terminal domain on IGFBP-5 being the principal site in IGFBP-5 that binds to ALS.

Amino Acid Sequence↗
PubMed1998

Mechanisms of insulin-like growth factor regulation of programmed cell death of developing avian motoneurons.

During development of the avian neuromuscular system, lumbar spinal motoneurons (MNs) innervate their muscle targets in the hindlimb coincident with the onset and progression of MN programmed cell death (PCD). Paralysis (activity blockade) of embryos during this period rescues large numbers of MNs from PCD. Because activity blockade also results in enhanced axonal branching and increased numbers of neuromuscular synapses, it has been postulated that following activity blockade, increased numbers of MNs can gain access to muscle-derived trophic agents that prevent PCD. An assumption of the access hypothesis of MN PCD is the presence of an activity-dependent, muscle-derived sprouting or branching agent. Several previous studies of sprouting in the rodent neuromuscular system indicate that insulin-like growth factors (IGFs) are candidates for such a sprouting factor. Accordingly, in the present study we have begun to test whether the IGFs may play a similar role in the developing avian neuromuscular system. Evidence in support of this idea includes the following: (a) IGFs promote MN survival in vivo but not in vitro; (b) neutralizing antibodies against IGFs reduce MN survival in vivo; (c) both in vitro and in vivo, IGFs increase neurite growth, branching, and synapse formation; (d) activity blockade increases the expression of IGF-1 and IGF-2 mRNA in skeletal muscles in vivo; (e) in vivo treatment of paralyzed embryos with IGF binding proteins (IGF-BPs) that interfere with the actions of endogenous IGFs reduce MN survival, axon branching, and synapse formation; (f) treatment of control embryos in vivo with IGF-BPs also reduces synapse formation; and (g) treatment with IGF-1 prior to the major period of cell death (i.e., on embryonic day 6) increases subsequent synapse formation and MN survival and potentiates the survival-promoting actions of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) administered during the subsequent 4- to 5-day period of PCD. Collectively, these data provide new evidence consistent with the role of the IGFs as activity-dependent, muscle-derived agents that play a role in regulating MN survival in the avian embryo.

Animals↗
PubMed1998

A source of response regulator autophosphatase activity: the critical role of a residue adjacent to the Spo0F autophosphorylation active site.

Two-component signaling systems are used by bacteria, plants, and lower eukaryotes to adapt to environmental changes. The first component, a protein kinase, responds to a signal by phosphorylating the second component; a response regulator protein that often acts by inducing the expression of specific genes. Response regulators also have an autophosphatase activity that ensures that the proteins are not permanently activated by phosphorylation. The magnitude of this activity varies by at least 1000-fold between various response regulators, and the molecular features responsible for this varied autophosphatase activity have not been clearly defined. Using wild-type and mutant derivatives of the sporulation response regulator Spo0F, it has been demonstrated that a key residue in determining the magnitude of this activity is that at position 56 of Spo0F approximately P; this residue is adjacent to the site of phosphorylation, Asp 54. For example, Spo0F approximately P K56N has a 23-fold greater autophosphatase activity (t1/2 = 8 min) than wild-type Spo0F approximately P (t1/2 = 180 min). It is suggested that, by analogy to the GTPase activity of p21(ras) and by examining the crystallographic structure of Spo0F, that the carboxyamide of the mutant Asn 56 may favorably position a catalytic water near the protein acyl phosphate to promote Spo0F approximately P K56N hydrolysis. It is also deduced that Lys 56 in the wild-type protein is critical for the efficient interaction and phosphoryl transfer between Spo0F and it's cognate protein kinase, KinA. Comparison of the known response regulators shows that inefficient autophosphatases (t1/2 on the order of hours) typically contain an amino acid residue with a long side chain at the position equivalent to 56 in Spo0F, whereas efficient autophosphatases (t1/2 on the order of minutes) frequently contain a residue with a carboxyamide or carboxylate side chain at this position. It appears that, by altering residues adjacent to the active site, the autophosphatase activity of response regulator proteins has been attenuated to match the diverse biological roles played by these proteins.

Adenosine Triphosphate↗
PubMed1998

Growth promotion by insulin-like growth factor I in hypophysectomized and diabetic rats.

Two animal models, the hypophysectomized (hypox) and the streptozotocin-diabetic rat, both of which are GH-deficient, were used to study the effects of infused IGF I and its molecular size distribution in serum, and to investigate whether GH and IGF I act identically on growth plate chondrocyte maturation. In hypox rats. IGF I (300 microg/rat per day) stimulated body weight gain, total growth plate height and longitudinal growth rate, although less than GH (200 mU/rat per day), and mimicked the effect of GH at all stages of chondrocyte differentiation. including stem cells. Infused IGF I was nearly exclusively found in a < 100 kDa IGF binding protein (IGFBP) complex, whereas free IGF I was barely detectable. These findings argue against the 'dual effector theory' in vivo which postulates priming of the stem cells by GH before IGF I stimulates proliferation. They also suggest that IGF I bound to the < 100 kDa IGFBP complex is bioavailable for growth. In diabetic rats infused with 2.5 mg/rat per day of IGF I, body weight, tibial epiphyseal width and accumulated bone growth increased dramatically despite persisting hyperglycemia. Insulin infusion (2.5 U/rat per day), which nearly normalized elevated blood sugar values, raised endogenous IGF I serum levels and stimulated growth parameters to a similar extent as IGF I, in line with a similar distribution of the infused exogenous and the insulin-induced endogenous IGF I between the free and the < 100 kDa-bound form. Since GH secretion is inhibited in diabetic rats and the animals are resistant to GH action, these results, like those in hypox rats, demonstrate that IGF I can act on growth independently of GH. Because insulin restores GH secretion and the responsiveness of the liver to GH in diabetic rats, one may conclude that insulin acts on growth of diabetic rats mainly via restoration of the GH/IGF I axis.

Animals↗
PubMed1998

Calcium and insulin-like growth factor I stimulation of sodium-dependent phosphate transport and proliferation of cultured rat osteoblasts.

Calcium (Ca) stimulates proliferation of osteoblasts in vitro, an effect proposed to be mediated by IGF I. Addition of 1 mM Ca or of 1 nM IGF I to the medium (0.3 mM Ca) of a rat bone-derived cell line, PyMS, stimulated not only DNA synthesis but also sodium-dependent (Nad) phosphate (Pi) uptake, the latter, within 2 h. These cells barely express and produce IGF I. IGF binding protein-3 which inhibits IGF action decreased neither basal nor Ca-stimulated but IGF I-stimulated NadPi transport and DNA synthesis, indicating that Ca stimulated NadPi transport and DNA synthesis independently of IGF I. The effects of Ca and IGF I on DNA synthesis were additive. 1 microM nifedipine blocked IGF I- and Ca-stimulated DNA synthesis but not NadPi transport, suggesting that Ca influx is not mediating the NadPi transport-enhancing IGF I signal but is required for IGF I-induced osteoblast proliferation.

Alanine↗
PubMed1998

Increased levels of circulating free insulin-like growth factors in patients with non-islet cell tumour hypoglycaemia.

Non-islet cell tumour hypoglycaemia (NICTH) is characterised by severe and recurrent fasting hypoglycaemia, and is usually caused by secretion of insulin-like growth factor-II (IGF-II) by the tumour. This induces secondary changes in the circulating levels of insulin, growth hormone (GH), and the IGF-binding proteins (IGFBPs), resulting in an increased insulin-like hypoglycaemic activity of IGF-II. A participating role of IGF-I is not established. We measured serum levels of free IGF-I and free IGF-II, total IGF-I, total IGF-II, big IGF-II and IGFBP-1, IGFBP-2 and IGFBP-3 in patients with NICTH before (n=14) and after surgical removal of the tumour (n=3). A control group (n=20) was included for comparison. In NICTH patients, free IGF-II was 20-fold increased (26.8+/-8.1 [mean+/-SEM] vs. 1.3+/-0.1 microg/l), and free IGF-I was four fold increased (2.8+/-0.4 vs. 0.7+/-0.1 microg/l), as compared to control subjects (p < 0.0001). In accordance with earlier observations levels of total IGF-I, total IGF-II, and IGFBP-3 were decreased, whereas IGFBP-1 and IGFBP-2 were increased in NICTH (all p-values < 0.05). The highly elevated levels of free IGF-I and free IGF-II most likely imply a considerable hypoglycaemic insulin-like activity, and may, by negative feedback explain the marked suppression of the GH/IGF-I axis observed in NICTH. Finally, free IGF-II seems to be a powerful biochemical marker in the diagnosis of NICTH.

Adenoma, Islet Cell↗
PubMed1998

Hepatoma with severe non-islet cell tumor hypoglycemia.

We report a 22-yr-old male patient with chronic hepatitis B and a large, well differentiated hepatoma who developed episodes of symptomatic fasting hypoglycemia, which were caused by paraneoplastic secretion of unprocessed "big" insulin-like growth factor-II. Initially, the patient presented with normal liver function, which deteriorated during the clinical course. Therapeutic attempts to reduce tumor mass failed and the patient subsequently died because of metastases of the hepatoma. The pathophysiology of non-islet cell tumor hypoglycemia, differential diagnosis, and therapeutic options are discussed.

Adult↗
PubMed1998

Proteolysis of insulin-like growth factor binding proteins by a novel 50-kilodalton metalloproteinase in human pregnancy serum.

Insulin-like growth factor binding proteins (IGFBP) proteases have been proposed to be involved in changes of serum IGFBP pattern during pregnancy. IGFBP-4 and -5 are degraded specifically by proteases in pregnancy serum in vitro, whereas IGFBP-3 proteolytic activity was also detected in nonpregnancy serum. To identify and characterize IGFBP proteases, human pregnancy serum was fractionated by size exclusion chromatography revealing IGFBP-4 protease activities in fractions coeluting with proteins of approximately 600-kDa and 50- to 100-kDa molecular mass. In both fractions, a predominant 50-kDa gelatinase was found, suggesting that parts of the gelatinase activity might aggregate or are complexed with other proteins forming a higher molecular complex. Hydroxyapatite chromatography and chromatofocusing of the 50- to 100-kDa serum fraction showed that the IGFBP-4 protease and the 50-kDa gelatinase activity were copurified. When the 50-kDa gelatinase-containing band was excised from the polyacrylamide gel, it exhibited IGFBP-4 proteolytic activity, resulting in the formation of 17- and 10-kDa fragments. [125I] IGFBP substrate zymography combined with fragment blotting showed that the 1,10-phenanthroline-sensitive 50-kDa protease activity purified by chromatofocusing also cleaved IGFBP-3 and -5. Other proteases detected in pregnancy serum fractions with Mr estimates of 79-, 30-, and 22-kDa degraded IGFBP-3 and -5 but not IGFBP-4. [125I] IGFBP-5 substrate zymography revealed that the 30-kDa IGFBP protease was inhibited by serine protease inhibitors. Whereas 1,10-phenanthroline inhibited the IGFBP proteolytic activity in the solution assay, serine protease inhibitors failed to affect proteolysis, indicating the predominant contribution of the metalloproteinase to IGFBP proteolysis. Tissue inhibitors of matrix metalloproteinases-1 and -2 revealed weak or no inhibition of IGFBP-4 and -5 proteolytic activity, whereas a hydroxamic acid-based inhibitor, potentially inhibiting disintegrin metalloproteases, completely prevented the proteolysis of IGFBPs. Whereas no specific immunoreactivity of the 50-kDa protein with antimatrix metalloproteinase-1, -2, -3, -9, or -13 antibodies was observed, antidisintegrin domain-specific antibodies bound to the 50-kDa gelatinase. These studies provide the first direct biochemical evidence that human pregnancy serum contains a 50-kDa IGFBP protease with properties of a soluble disintegrin metalloproteinase that appears to be potentially involved in regulating IGF bioavailability for placental and fetal growth.

Chromatography, Gel↗
PubMed1998

Acute cardiovascular effects of insulin-like growth factor I in patients with chronic heart failure.

Insulin-like growth factor I (IGF-I) enhances myofibrillar development in cardiomyocytes of rats in culture and in vivo. In addition, IGF-I has vasodilatory effects and improves cardiac function in healthy volunteers. This study was conducted to evaluate the acute hemodynamic effects of IGF-I in patients with chronic heart failure Eight patients with chronic heart failure were randomized to receive recombinant human IGF-I (60 micrograms/kg) or placebo, i.v., over 4 h in a cross-over, double blind study on 2 consecutive days. Electrocardiogram as well as systemic hemodynamics were continuously monitored over 7 h by flow-guided thermodilution and radial artery catheters. IGF-I was well tolerated by all patients, and no pathological changes on electrocardiogram were recorded. Compared with placebo, IGF-I increased the cardiac index by 27 +/- 3.7% (+/- SE; P < 0.0005) and the stroke volume index by 21 +/- 5.6% (P < 0.05), and decreased systemic vascular resistance by 28 +/- 4.4% (P < 0.0002), right atrial pressure by 33 +/- 9.0% (P < 0.003), and pulmonary artery wedge pressure by 25 +/- 6.1% (P < 0.03). Mean systemic and pulmonary artery pressure as well as heart rate and pulmonary vascular resistance were not significantly influenced by IGF-I treatment. Insulin and C peptide levels were decreased by IGF-I, whereas glucose and electrolyte levels remained unchanged. Urinary levels of norepinephrine decreased significantly (P < 0.05) during IGF-I infusion. Thus, acute administration of IGF-I in patients with chronic heart failure is safe and improves cardiac performance by afterload reduction and possibly by positive inotropic effects. Further investigations to establish whether the observed acute effects of IGF-I are maintained during chronic therapy appear to be warranted.

Adult↗
PubMed1998

Effects of IGF-I on cardiac growth and expression of mRNAs coding for cardiac proteins after induction of heart hypertrophy in the rat.

Adult rat cardiomyocytes in long-term culture reexpress several fetal cardiac proteins which also reappear during overload heart hypertrophy in vivo. IGF-I decreases reexpression of some of these proteins and stimulates myofibrillogenesis. IGF-I might therefore contribute to enhancing readaptation of the heart to overload. In order to test this hypothesis, hypertension was induced in male Wistar Kyoto rats by constriction of the left renal artery, and an infusion of 500 microg/day of recombinant human IGF-I (rhIGF-I) or vehicle was started after the operation via intraabdominally implanted osmotic minipumps. In the vehicle-treated hypertensive animals body weight gain was reduced after 3, 7 and 14 days, whereas rhIGF-I-treated hypertensive animals continued to gain weight like sham-operated animals. Left ventricular weight and the left, but not the right ventricle/body weight ratio increased more in rhIGF-I- than in vehicle-infused rats. Left ventricular IGF-I mRNA levels remained unchanged after renal clipping in both vehicle- and rhIGF-I-treated rats. However, beta-myosin heavy chain (MHC) mRNA in the left ventricle was 6- to 10-fold increased in clipped controls during the whole postoperative period, and rhIGF-I reduced this increase by more than 50% on days 7 and 14. On the first postoperative day, rhIGF-I prevented the decrease (50%) of alpha-MHC mRNA and the increase (2.5-fold of atrial natriuretic factor mRNA in the left ventricle. Renal clipping did not alter cardiac alpha-actin, but enhanced skeletal alpha-actin mRNA expression in the left ventricle up to 2.5-fold. However, both mRNAs were unaffected by rhIGF-I treatment. Restoration of body weight gain and stimulation of left ventricular cardiac weight by rhIGF-I as well as partial reversion of hypertension-induced changes in cardiac protein expression may reflect beneficial effects contributing to enhance readaptation of the heart to overload.

Actins↗
PubMed1997

Direct effects of leptin on brown and white adipose tissue.

Leptin is thought to exert its actions on energy homeostasis through the long form of the leptin receptor (OB-Rb), which is present in the hypothalamus and in certain peripheral organs, including adipose tissue. In this study, we examined whether leptin has direct effects on the function of brown and white adipose tissue (BAT and WAT, respectively) at the metabolic and molecular levels. The chronic peripheral intravenous administration of leptin in vivo for 4 d resulted in a 1.6-fold increase in the in vivo glucose utilization index of BAT, whereas no significant change was found after intracerebroventricular administration compared with pair-fed control rats, compatible with a direct effect of leptin on BAT. The effect of leptin on WAT fat pads from lean Zucker Fa/ fa rats was assessed ex vivo, where a 9- and 16-fold increase in the rate of lipolysis was observed after 2 h of exposure to 0.1 and 10 nM leptin, respectively. In contrast, no increase in lipolysis was observed in the fat pads from obese fa/fa rats, which harbor an inactivating mutation in the OB-Rb. At the level of gene expression, leptin treatment for 24 h increased malic enzyme and lipoprotein lipase RNA 1.8+/-0.17 and 1.9+/-0.14-fold, respectively, while aP2 mRNA levels were unaltered in primary cultures of brown adipocytes from lean Fa/fa rats. Importantly, however, no significant effect of leptin was observed on these genes in brown adipocytes from obese fa/fa animals. The presence of OB-Rb receptors in adipose tissue was substantiated by the detection of its transcripts by RT-PCR, and leptin treatment in vivo and in vitro activated the specific STATs implicated in the signaling pathway of the OB-Rb. Taken together, our data strongly suggest that leptin has direct effects on BAT and WAT, resulting in the activation of the Jak/STAT pathway and the increased expression of certain target genes, which may partially account for the observed increase in glucose utilization and lipolysis in leptin-treated adipose tissue.

Adipocytes↗