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Biomedical subjects

E R Froesch

Publications and source records attributed to E R Froesch.

At least 55 records · Page 3Linked to original sources
PubMed1994

Metabolic and therapeutic effects of insulin-like growth factor I.

The administration of rhIGF-I in appropriate doses leads to a decrease of insulin and growth hormone secretion and to an increase of insulin sensitivity. In type 2 diabetic patients, IGF-I improves glycemic profiles. In normal subjects, IGF-I increases energy expenditure and lipid oxidation and has a protein-sparing effect. Total and VLDL-triglycerides as well as LDL-cholesterol are decreased by IGF-I administration. This metabolic profile of IGF-I allows speculation on its possible usefulness in conditions of relative insulin resistance often associated with increased cardiovascular morbidity and mortality.

Animals↗
PubMed1994

Comparison of the effects of growth hormone and insulin-like growth factor I on substrate oxidation and on insulin sensitivity in growth hormone-deficient humans.

Insulin-like growth factor-I (IGF-I) is considered to be the mediator of the growth-promoting effects of growth hormone (GH). The metabolic effects of these two hormones, however, are different. Whereas GH treatment leads to elevated insulin and glucose levels, reduced insulin sensitivity, and impaired glucose tolerance, IGF-I treatment leads to reduced insulin and GH levels and enhanced insulin sensitivity. IGF-I may, therefore, not only be the mediator of the growth-promoting effects of GH but also a modulator of the effects of GH on insulin action and glucose metabolism. To study the influence of GH and IGF-I on substrate metabolism and insulin sensitivity (assessed by euglycemic, hyperinsulinemic clamping combined with indirect calorimetry and glucose tracer infusion), we have treated eight GH-deficient adults with GH (2 IU/m2 daily subcutaneously [s.c.]), IGF-I (10 micrograms/kg.h s.c.), or both hormones together for 7 d, respectively, and compared the effects of these treatment regimens with a control phase. Our findings suggest that (a) both GH and IGF-I promote lipolysis and lipid oxidation, albeit by different mechanisms; (b) treatment with either hormone is followed by enhanced energy expenditure and reduced protein oxidation; and (c) IGF-I reverses the insulin resistance induced by GH.

Adult↗
PubMed1994

Expression and regulation of insulin-like growth factor-I (IGF-I) and IGF-binding protein messenger ribonucleic acid levels in tissues of hypophysectomized rats infused with IGF-I and growth hormone.

The expression and regulation of insulin-like growth factor-I (IGF-I) and IGF-binding protein-2 (IGFBP-2), -3, -4, and -5 messages were studied in liver, kidney, spleen, thymus, heart, brain, skeletal muscle, testes, and epididymal (white) adipose tissue (WAT) from hypophysectomized rats infused with saline, recombinant human (rh) IGF-I, or rhGH and compared with tissue messenger RNA (mRNA) levels in age-matched normal rats. The IGF-I message was present in all of these tissues. It was most abundant in liver and WAT, but was barely detectable in kidney, brain, and thymus. GH dependence was most pronounced in liver, skeletal muscle, and WAT and less so in heart, testes, kidney, spleen, and thymus. The IGF-I message in brain was not influenced by hypophysectomy. IGF-I infusion induced a small increase in its own mRNA in skeletal muscle and WAT, whereas it decreased its own message in liver. IGFBPs were expressed in a tissue-specific manner; IGFBP-2 mRNA was most abundant in testes and hypophysectomized liver, IGFBP-3 mRNA was most abundant in spleen, kidney, WAT, and liver, IGFBP-4 mRNA was most abundant in liver, and IGFBP-5 mRNA was most abundant in kidney, WAT, and skeletal muscle. After hypophysectomy, significant decreases in IGFBP expression were observed in liver (except IGFBP-2), skeletal muscle, brain, WAT (except IGFBP-4), and testes (except IGFBP-2), in contrast to heart, kidney, spleen, and thymus. GH infusion did not affect IGFBP-2 mRNA levels in liver (in contrast to IGF-I infusion) or brain. Like GH, IGF-I normalized IGFBP-3 mRNA levels in liver, but, in contrast to GH, had no effect on IGFBP-5 mRNA in WAT. It was considerably less effective than GH in raising IGFBP-5 mRNA levels in skeletal muscle. Thus, GH infusion can exert different effects on IGF-I and IGFBP expression than infused rhIGF-I. Differences may be due to direct actions of GH at the tissue level, including auto/paracrine effects of locally produced IGF-I.

Animals↗
PubMed1994

Interactions of insulin-like growth factor I with dexamethasone on trabecular bone density and mineral metabolism in rats.

Glucocorticoid treatment causes osteoporosis and growth retardation in humans. Insulin-like growth factor I (IGF-I) stimulates differentiation and replication of cultured osteoblast-like cells and induces longitudinal bone growth in IGF-I-deficient rats. We investigated the influence of subcutaneously infused IGF-I on bone and mineral metabolism of male rats treated with a high dose of dexamethasone. Dexamethasone was added to the drinking water in a concentration of 1 mg/l. After 30 days of dexamethasone treatment, recombinant human IGF-I (300 micrograms/day) or solvent was infused sc by osmotic minipumps for 21 days while dexamethasone was continued. Age-matched untreated male rats served as healthy controls. Dexamethasone-treated rats lost weight. Their IGF-I levels were decreased to 36% of healthy controls. Infusion of IGF-I resulted in an increase in IGF-I serum levels (582% compared to healthy controls) and allowed some weight gain. Osteocalcin and calcitriol levels were markedly decreased in dexamethasone-treated rats and were not influenced significantly by IGF-I infusion. In contrast, IGF-I treatment restored the free calcitriol concentration (molar ratio of calcitriol to vitamin D-binding protein) towards normal. Furthermore, infusion of IGF-I partially corrected the dexamethasone-induced hyperinsulinemia. Histomorphometric analysis revealed no difference in vertebral trabecular bone density (i.e. growth-independent bone remodeling) between the three groups. In contrast, mean trabecular bone density in tibial metaphyses was increased markedly by dexamethasone, presumably due to osteoclast inhibition. Insulin-like growth factor I infusion did not significantly influence these structural metaphyseal bone parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1994

Beneficial metabolic effects of insulin-like growth factor I in patients with severe insulin-resistant diabetes type A.

Severe insulin resistance type A is due to mutations in the insulin receptor gene and is characterized by glucose intolerance or diabetes mellitus, despite extreme hyperinsulinemia, virilization and acanthosis nigricans. At present, there is no therapy for this condition. Recently, we showed that glucose levels in three such patients are promptly lowered by an i.v. bolus of recombinant human insulin-like growth factor I (rhIGF-I). In the present study, we investigated two of these rare patients again and determined fasting and postprandial glucose, insulin, C-peptide, proinsulin and lipid levels during five control, five treatment and three wash-out days while on a constant diet. Treatment consisted of 2 x 150 micrograms rhIGF-I/kg sc per day, which elevated total IGF-I levels 4.5-fold above the control. Fasting glucose levels (days 1-5) in the two patients were 9.6 +/- 1.3 and 9.2 +/- 1.2 mmol/l, respectively, and fell to 4.4 +/- 0.4 and 5.1 +/- 0.5 mmol/l on treatment days 8-10. Fasting insulin (2950 +/- 450 and 690 +/- 125 pmol/l), C-peptide (2217 +/- 183 and 1317 +/- 235 pmol/l) and proinsulin control levels (125 +/- 35 and 66 +/- 0 pmol/l) also decreased by approximately 65% during rhIGH-I treatment, as did the respective postprandial levels. Lipid levels hardly changed at all. In conclusion, IGF-I appears to correct partially some metabolic sequelae of severe insulin resistance and may, hence, be used as a new therapeutic agent.

Adolescent↗
PubMed1993

Growth hormone, but not insulin-like growth factor I, induces a serum protease activity for insulin-like growth factor binding protein-3 in hypophysectomized rats in vivo.

Insulin-like growth factor binding proteins (IGFBPs) modulate IGF action. Proteolytic cleavage of IGFBPs yields lower molecular forms with reduced ability to bind IGFs, thereby increasing IGF bioavailability. In serum from normal adult rats, we found a proteolytic activity for IGFBP-3, presumably a cation-dependent serine protease. It is lacking in serum from hypophysectomized rats and restored by infusion of growth hormone (GH), but not IGF I. Thus, IGF I does not appear to mediate the GH effect on IGFBP-3 proteolysis. Rather, GH seems to modulate IGF action indirectly via alteration of IGFBP-3 structure.

Animals↗
PubMed1993

Insulin-like growth factors (IGF) I and II and IGF binding proteins (IGFBPs) in human colostrum/transitory milk during the first week postpartum: comparison with neonatal and maternal serum.

Day 1 human colostrum contains 5 times more IGF I than IGF II. By day 3 postpartum, IGF I drops by 80% to constant levels whereas IGF II increases 3-fold up to day 7. Colostrum contains mainly IGFBP-2, little IGFBP-3 and no detectable IGFBP-1 or IGFBP-4. IGFBP-2 rises 20-fold up to day 6 of lactation. The major IGFBPs of newborn serum are IGFBP-2, -3 and -4. Early maternal serum contains only small amounts of IGFBP-2 and -3 and no detectable IGFBP-4. The pronounced differences between the IGFBP patterns of colostrum and early maternal serum suggest that IGFBP-2 does not pass from maternal blood into colostrum but is produced and secreted by mammary tissue itself. On the other hand, most of the IGF I, but not IGF II, in day 1 colostrum appears to stem from the maternal circulation.

Breast Feeding↗
PubMed1993

Improvement of lipid profile in type 2 (non-insulin-dependent) diabetes mellitus by insulin-like growth factor I.

Type 2 (non-insulin-dependent) diabetes mellitus is associated with increased glucose, insulin, total and VLDL-triglyceride, and often total and LDL-cholesterol levels which promote vascular disease. Recombinant human insulin-like growth factor-I which mimics many effects of insulin, decreased insulin, total and VLDL-triglyceride, and total and LDL-cholesterol levels in healthy man as well as glucose and insulin levels in Type 2 diabetic patients. We, therefore, investigated total and fractionated triglyceride and cholesterol levels, lipoprotein(a), non-esterified fatty acid, and apolipoprotein levels in eight Type 2 diabetic patients during five control, five treatment, and three wash-out days. They received a constant diet throughout and daily 2 x 120 micrograms insulin-like growth factor-I/kg s.c. during the treatment period. Fasting total and VLDL-triglyceride, total and LDL-cholesterol control levels were (mean +/- SD) 3.1 +/- 2.6, 1.3 +/- 1.0, 6.3 +/- 1.3, and 4.5 +/- 1.1 mmol/l and decreased to 1.6 +/- 0.8, 0.6 +/- 0.4, 5.0 +/- 1.0, and 3.5 +/- 1.1 mmol/l, respectively, on the last treatment day (p < 0.01). During therapy, fasting lipoprotein(a) levels and the postprandial area under the triglyceride curve decreased by 48 +/- 22 and 32 +/- 18% of control (p < 0.01), respectively. In conclusion, insulin-like growth factor-I lowered lipid levels in Type 2 diabetic patients directly or indirectly or both because of decreased glucose and insulin levels. Long-term trials would be of interest with respect to the cardiovascular risk in Type 2 diabetes and patients with hyperlipidaemia.

Adult↗
PubMed1993

Insulin-like growth factor I stimulates lipid oxidation, reduces protein oxidation, and enhances insulin sensitivity in humans.

To elucidate the effects of insulin-like growth factor I (IGF-I) on fuel oxidation and insulin sensitivity, eight healthy subjects were treated with saline and recombinant human (IGF-I (10 micrograms/kg.h) during 5 d in a crossover, randomized fashion, while receiving an isocaloric diet (30 kcal/kg.d) throughout the study period. On the third and fourth treatment days, respectively, an L-arginine stimulation test and an intravenous glucose tolerance test were performed. A euglycemic, hyperinsulinemic clamp combined with indirect calorimetry and a glucose tracer infusion were performed on the fifth treatment day. IGF-I treatment led to reduced fasting and stimulated (glucose and/or L-arginine) insulin and growth hormone secretion. Basal and stimulated glucagon secretion remained unchanged. Intravenous glucose tolerance was unaltered despite reduced insulin secretion. Resting energy expenditure and lipid oxidation were both elevated, while protein oxidation was reduced, and glucose turnover rates were unaltered on the fifth treatment day with IGF-I as compared to the control period. Enhanced lipolysis was reflected by elevated circulating free fatty acids. Moreover, insulin-stimulated oxidative and nonoxidative glucose disposal (i.e., insulin sensitivity) were enhanced during IGF-I treatment. Thus, IGF-I treatment leads to marked changes in lipid and protein oxidation, whereas, at the dose used, carbohydrate metabolism remains unaltered in the face of reduced insulin levels and enhanced insulin sensitivity.

Adult↗
PubMed1993

Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by growth hormone in rat white adipose tissue.

Insulin-like growth factor-I (IGF-I) mRNA levels in rat white adipose tissue (WAT) are in the same range as those in liver, the major source of serum IGF-I, and are far above the levels in other tissues. IGF-I mRNA and IGF-I peptide levels in WAT decrease drastically after hypophysectomy and are restored to near normal by GH treatment in vivo. IGF-I gene expression in WAT from hypophysectomized rats is also stimulated by GH in vitro; half-maximal stimulation of IGF-I mRNA occurs between 0.25-0.5 nM GH, and maximal stimulation (3.5- to 5.5-fold) at 15 nM after 2 h. However, maximally stimulated IGF-I mRNA levels in vitro lie far below those measured in vivo in normal or GH-treated hypophysectomized rats. T3 does not enhance the GH effect in vitro. Rat WAT expresses the messages for IGF-binding protein (IGFBP)-2, -3, -4, -5, and -6. IGFBP-2, -3, -5, and -6 mRNAs are all regulated by GH. IGF-I mRNA and IGFBP-5 mRNA are localized in both adipocytes and stromal-vascular cells, whereas IGFBP-2 and -3 expression is restricted to stromal-vascular tissue. As physiological concentrations of IGF-I are able to induce adipocyte differentiation in vitro, we suggest that locally produced IGF-I and IGFBPs play a crucial role in the in vivo differentiation of adipose cells from stromal-vascular cells.

Adipocytes↗
PubMed1992

Differential regulation of insulin-like growth factor binding protein (IGFBP)-2 mRNA in liver and bone cells by insulin and retinoic acid in vitro.

Isolated cells produce insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Two distinct cell types were studied with regard to IGFBP-2 expression: (i) rat hepatocytes, which produce IGF I at a high rate and thus regulate its plasma concentration; and (ii) rat osteoblasts, which are targets of IGF I action. IGFBP-2 expression is low in hepatocytes prepared from normal adult rats and high in calvaria cells from newborn rats. Retinoic acid stimulates IGFBP-2 production by liver cells. Insulin suppresses both basal and retinoic acid-induced IGFBP-2 mRNA expression in hepatocytes and has no such effect on osteoblasts. Retinoic acid and insulin regulate IGFBP-2 expression in a tissue-specific manner.

Animals↗
PubMed1992

Prostaglandin E2 stimulates synthesis of insulin-like growth factor binding protein-3 in rat bone cells in vitro.

Prostaglandin E2 is produced by bone cells and increases cyclic AMP in these cells. Like PTH and dibutyryl cyclic AMP, PGE2 is a potent stimulator of IGF-I synthesis in cultured rat osteoblasts and inhibits DNA synthesis and type I procollagen gene expression. In addition, PGE2 inhibits the response of the cells toward IGF-I after 1 day but not after 4 days of incubation. Rat calvaria osteoblasts constitutively release IGFBPs into the culture medium, in particular IGFBP-2 and IGFBP-3. Like growth hormone, PGE2 stimulates the accumulation of IGFBP-3. PGE2 rapidly increases IGF-I and IGFBP-3 mRNA expression in calvaria cells, with a time course clearly different from that observed in response to growth hormone. Thus, PGE2 modifies not only the synthesis of IGF-I but also that of IGFBP-3 in skeletal tissue.

Animals↗
PubMed1992

Insulin-like growth factors in lysosomal storage disease.

Recent data indicate that insulin-like growth factor II (IGF II) and lysosomal enzymes bind to a common receptor. We measured serum IGF I and II levels in 16 patients with various lysosomal storage disorders. The IGF serum concentrations were normal as long as no marked liver disease was present. Under these conditions no direct interconnection between the lysosomal system and the serum IGF levels was found.

Adolescent↗
PubMed1992

Effects of insulin-like growth factor-I on glucose tolerance, insulin levels, and insulin secretion.

Insulin-like growth factor-I (IGF-I) and insulin interact with related receptors to lower plasma glucose and to exert mitogenic effects. Recombinant human IGF-I (rhIGF-I) was recently shown to decrease serum levels of insulin and C-peptide in fasted normal subjects without affecting plasma glucose levels. In this study we have investigated in six healthy volunteers the responses of glucose, insulin, and C-peptide levels to intravenous rhIGF-I infusions (7 and 14 micrograms/kg.h) during standard oral glucose tolerance tests (oGTT) and meal tolerance tests (MTT), respectively. Glucose tolerance remained unchanged during the rhIGF-I infusions in the face of lowered insulin and C-peptide levels. The decreased insulin/glucose-ratio presumably is caused by an enhanced tissue sensitivity to insulin. The lowered area under the insulin curve during oGTT and MTT as a result of the administration of rhIGF-I were related to the fasting insulin levels during saline infusion (oGTT: r = 0.825, P less than 0.05; MTT: r = 0.895, P less than 0.02). RhIGF-I, however, did not alter the ratio between C-peptide and insulin, suggesting that the metabolic clearance of endogenous insulin remained unchanged. In conclusion, rhIGF-I increased glucose disposal and directly suppressed insulin secretion. RhIGF-I probably increased insulin sensitivity as a result of decreased insulin levels and suppressed growth hormone secretion. RhIGF-I, therefore, may be therapeutically useful in insulin resistance of type 2 diabetes, obesity, and hyperlipidemia.

Adult↗