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.

The pharmacokinetics of free insulin-like growth factor-I in healthy subjects.

In a randomized cross-over study in five healthy males we compared 75-min constant i.v. infusion of saline, low-dose recombinant human (rh) insulin-like growth factor-I (rhIGF-I; 1.5 microg/kg/h) and high-dose rhIGF-I (9.0 microg/kg/h). Serum samples were analysed for ultrafiltered free IGF-I (fIGF-I), total IGF-I (tIGF-I), tIGF-II and IGF-binding protein-1 (IGFBP-1) and -3. Free and total IGF-I were unchanged during saline infusion. Low-dose rhIGF-I caused a small increment in fIGF-I [+41%, from 0.64 +/- 0.19 (mean +/- SEM) to 0.90 +/- 0.25 microg/l;P< 0.05] and tIGF-I (+9%, from 220 +/- 31 to 239 +/- 33 microg/l;P< 0.05). High-dose rhIGF-I increased tIGF-I by 40% (from 227 +/- 36 to 329 +/- 31 microg/l;P< 0.05), and fIGF-I by 11.5 times (from 0.56 +/- 0.20 to 6.46 +/- 1.39 microg/l;P< 0.05). The pharmacokinetic profile of fIGF-I was calculated after high-dose IGF-I only. The disappearance of fIGF-I followed first order kinetics with an apparent half-life of 14.4 +/- 1.0 [11.2-17.1 (range)] min. The clearance was estimated to 52 +/- 20 (16-128) ml/min/kg and the volume of distribution to 1102 +/- 464 (388-2899) ml/kg. In the three experiments, there were no differences in IGFBP-1, and tIGF-II and IGFBP-3 remained unchanged. In conclusion, fIGF-I remained within the physiological range after low-dose rhIGF-I, whereas high-dose rhIGF-I resulted in supraphysiological concentrations. Since the half-life estimates for each subject were remarkably similar, this parameter most likely does not explain the observed variation in clearance and volume of distribution of fIGF-I. Instead, differences in the circulating and cellular IGF-I binding capacity may be of importance.

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.

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.

Effects of short-term insulin-like growth factor-I (IGF-I) or growth hormone (GH) treatment on bone metabolism and on production of 1,25-dihydroxycholecalciferol in GH-deficient adults.

UNLABELLED: Administration of insulin-like growth factor-I (IGF-I) or growth hormone (GH) is known to stimulate bone turnover and kidney function. To investigate the effects of IGF-I and GH on markers of bone turnover, eight adult GH-deficient patients (48 +/- 14 yr of age) were treated with IGF-I (5 micrograms/kg/h in a continuous s.c. infusion) and GH (0.03 IU/kg/daily s.c. injection at 2000 h) in a randomized cross-over study. We monitored baseline values for three consecutive days before initiating the five-day treatment period, as well as the wash-out period of ten weeks. Serum osteocalcin, carboxyterminal and aminoterminal propeptide of type I procollagen (PICP and PINP, respectively) increased significantly within 2-3 days of both treatments (P < 0.02) and returned to baseline levels within one week after the treatment end. The changes in resorption markers were less marked as compared with formation markers. Total 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) rose significantly, whereas PTH and calcium levels remained unchanged during either treatment. CONCLUSIONS: Because the rapid increase in markers of bone formation was not preceded by an increase in resorption markers, IGF-I is likely to stimulate bone formation by a direct effect on osteoblasts. Moreover, because PTH, calcium, and phosphate remained unchanged, IGF-I appears to stimulate renal 1 alpha-hydroxylase activity in vivo.

Insulin-like growth factor-I stimulates myofibrillar genes and modulates atrial natriuretic factor mRNA in rat heart.

We have investigated the effect of a 6-day infusion of recombinant human (rh) IGF-I (0.3-1.0 mg/day) or rhGH (200 mU/day) into normal and hypophysectomized rats on the ventricular expression of myofibrillar genes (alpha- and beta-myosin heavy chain (MHC), skeletal and cardiac alpha-actin) and of atrial natriuretic factor (ANF). In normal rats, beta-MHC was not detectable either before or after IGF-I or GH, but alpha-MHC mRNA increased significantly (twofold) with GH (not statistically significant for IGF-I). In contrast to normal rats, hypophysectomized rats did not express alpha-MHC either before or after IGF-I or GH, but beta-MHC was strongly expressed and significantly stimulated (1.8-fold) by IGF-I (not statistically significantly with GH). Skeletal alpha-actin expression remained unchanged during IGF-I or GH treatment of normal rats, but was enhanced by both IGF-I and GH (2.5- and 2.8-fold respectively) in hypophysectomized rats. Expression of cardiac alpha-actin in normal and hypophysectomized rats was not altered by either treatment. IGF-I and GH decreased ventricular expression of ANF in normal rats by 63% and 45% respectively, but did not influence ANF expression in hypophysectomized rats. Our results show that IGF-I and GH (possibly via IGF-I) stimulate expression of myofibrillar genes and modulate ANF mRNA concentrations in rat heart ventricles in vivo, depending on the hormonal status of the animals. However, neither IGF-I nor GH caused a shift from the beta- to the alpha-MHC isoform in hypophysectomized rats.

Serum free IGF-I during a hyperinsulinemic clamp following 3 days of administration of IGF-I vs. saline.

In a randomized crossover study in eight healthy subjects, we compared the effect of 3 days of continuous subcutaneous administration of insulin-like growth factor I (IGF-I; 10 micrograms.kg-1.h-1) and saline on fasting serum levels of free IGF-I, total (extractable) IGF-I, and IGF-binding protein (IGFBP)-1 and -3. On the 3rd day a hyperinsulinemic (euglycemic and hypoglycemic) clamp was performed. When preclamp (baseline) levels were compared after 3 days, IGF-I administration had increased total IGF-I from 225 +/- 21 (means +/- SE) to 1,003 +/- 46 micrograms/l (P < 0.0001), free IGF-I from 0.5 +/- 0.2 to 10.4 +/- 1.7 micrograms/l (P < 0.001), IGFBP-3 from 2,908 +/- 148 to 3,591 +/- 179 micrograms/l (P < 0.01), and IGFBP-1 from 7.6 +/- 3.8 to 19.6 +/- 2.5 micrograms/l (P < 0.01). During the clamp, levels of free IGF-I increased gradually from baseline to 1.0 +/- 0.3 micrograms/l (saline; P < 0.01) and to 19.6 +/- 4.7 micrograms/l (IGF-I; P < 0.005). Concomitantly, levels of IGFBP-1 decreased gradually from baseline to 4.1 +/- 2.3 micrograms/l (saline; P < 0.0005) and to 4.6 +/- 1.8 micrograms/l (IGF-I; P < 0.0001). Total IGF-I exhibited minor changes only during the clamp (P < 0.05), and IGFBP-3 was unchanged. In conclusion, administration of IGF-I increased total IGF-I about fourfold, whereas free IGF-I increased 20-fold. Noteworthily, in both situations a further twofold increase in free IGF-I was observed during the hyperinsulinemic clamp, concomitant with a decrease in IGFBP-1. This supports the hypothesis that IGFBP-1 is important in the short-term regulation of free IGF-I in vivo.

IGF-I inhibits burst mass of pulsatile insulin secretion at supraphysiological and low IGF-I infusion rates.

Insulin-like growth factor I (IGF-I) shares structural and functional features with insulin, affects carbohydrate metabolism, and inhibits insulin secretion. Insulin secretion is pulsatile, and it is regulated by changing frequency and/or mass of secretory bursts. To examine the mechanism of IGF-I's inhibition of insulin secretion, eight healthy volunteers were studied three times. During glucose infusion (2.5 mg x kg(-1) x min(-1)) blood was sampled minutely at time 75-200 min for triplicate insulin concentration measurements by enzyme-linked immunosorbent assay (ELISA; coefficient of variation 2.1%). Time 125 min infusion of saline, low-dose IGF-I (0.025 microg x kg(-1) x min(-1)) or high-dose IGF-I (0.15 microg x kg(-1) x min(-1)) was commenced and continued until 200 min. Data were compared before (75-125 min) vs. during infusion (150-200 min). Insulin concentration time series were deconvolved, using validated pulse-detection criteria, to assess insulin secretory burst mass and frequency. During saline infusion no time effect occurred. After IGF-I infusion, serum C-peptide decreased (582 +/- 85 vs. 481 +/- 82 pM, low-dose IGF-I, P < 0.05; 539 +/- 84 vs. 427 +/- 69 pM, high-dose IGF-I, P < 0.01). Total insulin secretion rates decreased by 17 and 21%, respectively, via specific inhibition of the insulin secretory burst mass (31 +/- 8 vs. 20 +/- 4 pmol/ml, low-dose IGF-I, P = 0.06; 22 +/- 4 vs. 17 +/- 3 pmol/ml, high-dose IGF-I, P < 0.05), whereas the frequency was not affected (10.5 +/- 1.3 vs. 10.7 +/- 1.3 pulses/h, low-dose IGF-I, P = 0.85; 8.7 +/- 1.0 vs. 11.1 +/- 1.2 min/pulse, high-dose IGF-I, P = 0.15). We conclude that IGF-I inhibits pulsatile insulin secretion by specific inhibition of mass but not frequency of secretory bursts.

Effects of short-term insulin-like growth factor-I or growth hormone treatment on bone turnover, renal phosphate reabsorption and 1,25 dihydroxyvitamin D3 production in healthy man.

OBJECTIVES: To find out whether insulin-like growth factor-I (IGF-I) mimics the stimulatory effects of growth hormone (GH) on bone turnover and renal tubular phosphate reabsorption. DESIGN: Randomized, crossover study. SETTING: University Hospital, Zürich, Switzerland. SUBJECTS: Seven young healthy male subjects. INTERVENTIONS: Each subject was studied three times at 2-week intervals, treated with saline 0.9% (S), IGF-I [8 micrograms kg-1 h-1] by a continuous subcutaneous infusion and finally with GH (6 U. twice daily s.c.) for 5 days. MAIN OUTCOME MEASURES: 36 h after the start of treatment, IGF-I, biochemical markers of bone turnover, calcium, calcium regulating hormones, kidney function and phosphate reabsorption were measured in serum and in 2 h urine in fasting state. RESULTS: Serum levels of IGF-I were 26.8 +/- 7.3 (S), 119.4 +/- 11.4 (IGF-I) (P < 0.02) and 58.4 +/- 12.9 nmol L-1 (GH) (P < 0.02), respectively. Serum osteocalcin and carboxyterminal propeptide of type I collagen (PICP) as well as the urinary deoxypyridinoline/creatinine and the calcium/ creatinine ratios were all significantly higher after IGF-I (P < 0.02) or GH (P < 0.02) than after saline treatment. PTH levels did not change in response to treatment. Total albumin-corrected calcium increased only after GH treatment (P < 0.05). The free calcitriol index rose from 2.2 +/- 0.5 x 10(-5) (S) to 2.81 +/- 0.25 x 10(-5) (IGF-I) (P < 0.03) and 2.45 +/- 0.25 x 10(-5) (GH), respectively. Serum phosphate and maximal tubular reabsorption divided by glomerular filtration rate (TmP/GFR) were significantly raised by GH (P < 0.03) but not by IGF-I as compared to saline 0.9%. CONCLUSIONS: (i) Similar to GH, IGF-I rapidly activates bone turnover. (ii) IGF-I does not mimic the effect of GH on renal phosphate reabsorption in spite of comparable effects on renal blood flow and glomerular filtration rate. (iii) IGF-I increases free calcitriol index in face of unchanged serum levels of calcium, phosphate and PTH, consistent with a direct stimulatory effect on 25-OHD-1a-hydroxylase.

Effects and fate of human IGF-binding protein-5 in rat osteoblast cultures.

Osteoblasts prepared from calvaria of newborn rats produce insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP), IGFBP-5 was discovered in bone extracts. However, we could not detect IGFBP-5 in the medium of newborn rat osteoblasts, although we found mRNA expression. To find an explanation for this discrepancy and to learn more about the physiological role of IGFBP-5 in these cells, we studied the biological activity and the fate of recombinant human (rh) IGFBP-5 in comparison to rhIGFBP-3. IGFBP-5 but not IGFBP-3 stimulated thymidine incorporation into DNA both in the absence and presence of IGF-I. However, IGFBP-5 did not enhance uridine incorporation into RNA and glucose incorporation into glycogen. 125I-rhIGFBP-5 but not 125I-rhIGFBP-3 rapidly disappeared from the culture medium consistent with the observation that endogenous (rat) IGFBP-3 but not IGFBP-5 accumulated in the medium. However, intact 125I-labeled or unlabeled rhIGFBP-5 was associated with the cell-layer matrix, whereas IGFBP-5 fragments appeared in the medium. Trapping of IGFBP-5 in the cell layer matrix may enhance local availability of IGF.

Cardiovascular and metabolic effects of insulin-like growth factor I at rest and during exercise in humans.

To determine whether insulin-like growth factor I (IGF-I) has systemic cardiovascular effects in humans, 60 micrograms/kg IGF-I or saline were injected sc in a cross-over, randomized, double blind fashion into eight healthy male volunteers. Cardiac function and performance were evaluated by echocardiography and exercise test. In parallel, the metabolic effects of IGF-I during exercise were investigated. IGF-I improved cardiac performance with a significant increase in stroke volume and cardiac output by 14% and 18% (P < 0.03 and P < 0.04), respectively. Ejection fraction increased by 9% after IGF-I treatment (P < 0.05). Heart rate was not significantly increased at rest or during exercise. Systolic blood pressure was slightly increased by IGF-I, whereas diastolic blood pressure was slightly decreased, resulting in a continuous increase in the blood pressure amplitude at rest and during exercise, but without reaching statistical significance. Maximal exercise duration and peak oxygen consumption were not changed. Exercise was uneventful, without pathological changes on electrocardiogram records. Glucose levels were unchanged, whereas insulin and C peptide levels were decreased by IGF-I at rest. During exercise, insulin levels were further decreased, and the insulin-sparing effect of exercise resulted in a further enhancement of tissue sensitivity to insulin. GH levels were suppressed by IGF-I treatment at rest, but were still stimulated by exercise. In conclusion, IGF-I has positive inotropic effects in man. Further investigation of the potential role of IGF-I in cardiac conditions such as heart failure appears to be warranted.

In-frame exon 2 deletion in insulin receptor RNA in a family with extreme insulin resistance in association with defective insulin binding: a case report.

The phenotype and allelic expression of the insulin receptor gene is presented in a family with a patient with type A insulin resistance. Compared to controls, insulin receptor binding in transformed lymphocytes was 100%. 33% and 13% in the father, mother and proband, respectively. Reduced insulin receptor binding co-segregated with altered insulin receptor mRNA expression; the mother and daughter expressed eight insulin receptor mRNA species, including a set of four normal sized and a set of four shorter mRNA transcripts. In the proband the levels of the normal sized mRNA transcripts were suppressed relative to the shorter transcripts. Reverse polymerase chain reaction (PCR) revealed that the shorter transcripts contained an in-frame deletion of exon 2. Sequencing of the entire insulin receptor coding region revealed a paternally inherited A to T substitution in nucleotide 3205, converting isoleucine 996 to phenylalanine, which does not co-segregate with reduced binding. Therefore, we hypothesize that two findings are necessary for the presentation of type A insulin resistance in this patient: an in-frame deletion of the insulin receptor exon 2 that codes for amino acids crucial for insulin binding: and an inhibition of expression of the paternal insulin receptor allele.

Reduced ob mRNA in hypophysectomised rats is not restored by growth hormone (GH), but further suppressed by exogenously administered insulin-like growth factor (IGF) I.

To examine whether GH and IGF-I participate in the regulation of obese (ob) mRNA expression we determined ob mRNA levels in epididydimal fat pads of hypophysectomised (hypox) rats, hypox rats treated with recombinant human (rh) GH or rhIGF-I and normal, weight-matched controls. We found that 1. ob mRNA was markedly suppressed after hypophysectomy (37 +/- 25% of controls), 2. GH infusion had no effect on ob mRNA, but stimulated IGF-I mRNA in fat pads, 3. IGF-I treatment further suppressed ob mRNA (3.5% +/- 0.6% of controls) and 4. serum insulin levels were decreased in all hypox groups (11.2 to 15.9% of controls). In conclusion, exogenous and GH-induced IGF-I differ in their effects on ob mRNA expression and GH is unable to restore ob mRNA towards normal at low insulin levels.

1 alpha,25-dihydroxyvitamin D3 increases IGF binding protein-5 expression in cultured osteoblasts.

Rat osteoblasts produce insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs). Expression of IGFBP-5, an IGFBP which stimulates DNA synthesis of osteoblasts, was studied in vitro under the influence of 1 alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) and parathyroid hormone (PTH). These two calcium-regulating hormones stimulated the expression of IGFBP-5 mRNA in cultured rat osteoblasts at low concentrations (10 pM) and in a dose- and time-dependent manner. Intact IGFBP-5 was not detected in the culture medium, but was found attached to the cell layer. IGFBP-5 may thus direct IGFs to the sites of bone remodeling.

Insulin-like growth factor-I in man enhances lipid mobilization and oxidation induced by a growth hormone pulse.

Growth hormone (GH) secretion is suppressed during insulin-like growth factor-I (IGF-I) administration. The aim of the study was to examine whether IGF-I alters the metabolic response to a GH pulse. Seven healthy male subjects (age 27 +/- 4 years, BMI 21.8 +/- 1.7 kg/m2) were treated with NaCl 0.9% (saline) or IGF-I (8 micrograms.kg-1.h-1) for 5 days by continuous subcutaneous infusion in a randomized, crossover fashion while receiving an isocaloric diet (30 kcal.kg-1.day-1). On the third treatment day an intravenous bolus of 0.5 U GH was administered. Forearm muscle metabolism was examined by measuring arterialized and deep venous blood samples, forearm blood flow by occlusion plethysmography and substrate oxidation by indirect calorimetry. IGF-I treatment significantly reduced insulin concentrations by 80% (p < 0.02) and C-peptide levels by 78% (p < 0.02), as assessed by area under the curve. Non-esterified fatty acid (NEFA), glycerol and 3-OH-butyrate levels were elevated and alanine concentration decreased. Forearm blood flow rose from 2.10 +/- 0.43 (saline) to 2.79 +/- 0.37 ml.100ml-1. min-1 (IGF-I) (p < 0.02). GH-pulse: 10 h after i.v. GH injection serum GH peaked at 40.9 +/- 7.4 ng/ml. GH did not influence circulating levels of total IGF-I, C-peptide, insulin or glucose, but caused a further increase in NEFA, glycerol and 3-OH-butyrate levels, indicating enhanced lipolysis and ketogenesis. This effect of GH was much more pronounced during IGF-I: NEFA rose from 702 +/- 267 (saline) and 885 +/- 236 (IGF-I) to 963 +/- 215 (saline) (p < 0.05) and 1815 +/- 586 mumol/l (IGF-I) (p < 0.02), respectively; after 5 h, 3-OH-butyrate rose from 242 +/- 234 (saline) and 340 +/- 280 (IGF-I) to 678 +/- 638 (saline) (p < 0.02) and 1115 +/- 578 mumol/l (IGF-I) (p < 0.02) respectively. After injection of GH, forearm uptake of 3-OH-butyrate was markedly elevated only in the subjects treated with IGF-I: from 44 +/- 195 to 300 +/- 370 after 20 min (p < 0.03) and to 287 +/- 91 nmol.100 ml-1. min-1 after 120 min (p < 0.02). In conclusion, the lipolytic and ketogenic response to GH was grossly enhanced during IGF-I treatment, and utilization of ketone bodies by skeletal muscle was increased.

Insulin-like growth factor-I in the therapy of non-insulin-dependent diabetes mellitus and insulin resistance.

Recombinant DNA technology has made large amounts of insulin-like growth factor-I (IGF-I) available for studies in animal models and humans. It has been shown that treatment with IGF-I is associated with increased insulin sensitivity in normal subjects as well as in patients with growth hormone deficiency, Type 1 and Type 2 diabetes mellitus and type A insulin-resistance. The metabolic effects of IFG-I appear to be beneficial in these conditions. The reported side effects of IGF-I, which may be largely due to overdosage, have limited its use to small and mostly short-term clinical studies.