Insulin regulation of insulin-like growth factor binding protein-1 in obese and nonobese humans.

Insulin is the principal regulator of hepatic insulin-like growth factor binding protein-1 (IGFBP-1) production, mediating the rapid decrease in plasma IGFBP-1 in response to nutritional intake. In this study, we defined IGFBP-1 regulation by insulin in upper and lower body obesity, conditions associated with insulin resistance and chronic hyperinsulinemia. Overnight postabsorptive IGFBP-1 levels in obese and nonobese women showed an inverse, nonlinear relationship with plasma insulin concentrations. Maximum suppression of IGFBP-1 was seen at 70-90 pmol/L plasma insulin. Both groups of obese women had mean fasting plasma insulin concentrations above this threshold level and, consequently, markedly suppressed IGFBP-1 levels. To assess the dynamics of insulin regulated IGFBP-1, 10 obese and 8 nonobese women were studied during sequential saline infusion (0-90 min), hyperinsulinemia (insulin infusion; 90-210 min) and hypoinsulinemia (somatostatin + GH infusion; 210-330 min). Insulin infusion rapidly decreased plasma IGFBP-1 levels in nonobese subjects (60% decrease in 2 h), but had little or no further suppressive effect in obese subjects. Complete insulin withdrawal resulted in a significant rise in plasma IGFBP-1 concentrations in all subjects, but the response was blunted in obese compared to nonobese groups. In contrast to plasma IGFBP-1, IGF-I concentrations did not vary during hyper- and hypoinsulinemic infusion periods and were not significantly different between groups. Basal GH levels were significantly higher in nonobese when compared to obese women, but did not change with infusions. In conclusion, low IGFBP-1 levels in obesity are related to elevated insulin levels which are, in turn, related to body fat distribution and insulin resistance. The chronically depressed levels of IGFBP-1 may promote IGF bioactivity as well as its feedback regulation of GH secretion, thus contributing to the metabolic and mitogenic consequences of obesity. In addition, our findings imply that hepatic insulin sensitivity in terms of IGFBP-1 production is preserved despite peripheral insulin resistance in obesity.     

The insulin-like growth factor binding protein-1 in low and high insulin responders before and during dexamethasone treatment.

To investigate the influence of normal insulin levels on levels of the insulin-like growth factor binding protein-1 (IGFBP-1) we measured this peptide postabsorptively and during hyperglycemic clamp in 17 healthy subjects, nine with low insulin response (LIR) and eight with high insulin response (HIR). The study was performed before and after 60 hours of treatment with dexamethasone 6 mg/d. The fasting levels of IGFBP-1 were significantly higher in LIR, 36 +/- 2.5 micrograms/L, than in HIR, 22 +/- 2.6 micrograms/L (P less than .01), while no differences in glucose, insulin, and C-peptide concentrations were found. Dexamethasone induced an increase in basal concentrations of insulin, while IGFBP-1 levels decreased to 18.8 +/- 2 micrograms/L in LIR (P less than .01) and to 14.0 +/- 0.9 micrograms/L in HIR (P less than .05). There was no correlation between the individual basal IGFBP-1 concentrations and basal insulin levels. In contrast, basal levels of IGFBP-1 were inversely correlated to the integrated insulin or C-peptide concentrations during the hyperglycemic clamp both before (r = -.67, P less than .01) and during dexamethasone (r = -.79, P less than .001). Dexamethasone, which increased the insulin resistance, did not change the relationship between basal IGFBP-1 and the glucose-induced insulin release. In conclusion, the morning levels of IGFBP-1 in healthy subjects reflect the acute beta-cell responsiveness to glucose, which may correspond to integrated diurnal insulin levels. The inhibitory effects of dexamethasone on the morning levels of IGFBP-1 can be explained by attendant hyperinsulinemia.     

Elevated circulating insulin-like growth factor binding protein-1 is sufficient to cause fetal growth restriction

IGF binding protein-1 (IGFBP-1) inhibits the mitogenic actions of the IGFs. Circulating IGFBP-1 is elevated in newborns and experimental animals with fetal growth restriction (FGR). To establish a causal relationship between high circulating IGFBP-1 and FGR, we have generated transgenic mice using the mouse alpha-fetoprotein gene promoter to target overexpression of human IGFBP-1 (hIGFBP-1) in the fetal liver. These transgenic mice (AFP-BP1) expressed hIGFBP-1 mainly in the fetal hepatocytes, starting at embryonic d 14.5 (E14.5), with lower levels in the gut. The expression peaked at 1 wk postnatally (plasma concentration, 474 +/- 34 ng/ml). At birth, AFP-BP1 pups were 18% smaller [weighed 1.34 +/- 0.02 g compared with 1.62 +/- 0.04 g for wild type (WT); P < 0.05], and they did not demonstrate any postnatal catch-up growth. The placentas of the AFP-BP1 mice were larger than WT from E16.5 onwards (150 +/- 12 for AFP-BP1 vs. 100 +/- 5 mg for WT at E16.5; P < 0.05). Thus, this model of FGR is associated with a larger placenta, but without postnatal catch-up growth. Overall, these data clearly demonstrate that high concentrations of circulating IGFBP-1 are sufficient to cause FGR.     

Association of elevated insulin-like growth factor binding protein-1 with insulin resistance in hyperthyroidism

OBJECTIVE: Insulin-like growth factor binding-protein-1 (IGFBP-1) has a role in glucose homeostasis and is present at high concentrations in hyperthyroidism. We have investigated the relationship between IGFBP-1 concentration and glucose homeostasis in hyperthyroidism. DESIGN: Patients and controls had intravenous glucose tolerance tests (IVGTT) and/or oral glucose tolerance tests (OGTT). Patients were tested when hyperthyroid and when euthyroid whilst the controls were tested once. The IVGTT was used to assess insulin sensitivity and the OGTT to establish that the study group had abnormal glucose tolerance. The hyperthyroid patients were treated with methimazole to restore euthyroidism. PATIENTS: Ten patients (9 females) and 13 healthy controls (9 females) consented to the study. Ten patients and nine controls (7 females) had IVGTT. Six patients (5 females) and six controls (4 females) had OGTT. MEASUREMENTS: Glucose, insulin, glucagon, GH and IGFBP-1 were measured during GTT. IGF-I, free thyroid hormones, and TSH concentrations were measured basally. RESULTS: Hyperthyroid subjects were insulin resistant and 67% had impaired glucose tolerance. Fasting IGFBP-1 levels were doubled in hyperthyroid subjects compared to healthy controls and correlated positively with free T4 (r = 0.84, P < 0.0001), with peak glucose during the OGTT (r = 0.68, P < 0.005) with peak insulin during the IVGTT (r = 0.51, P < 0.005) and negatively with glucose disappearance constant (r = - 0.52, P < 0.005). IGFBP-1 was highly phosphorylated in hyperthyroid and control subjects. Fasting insulin and IGFBP-1 levels were unrelated but IGFBP-1 suppressed acutely during GTT in all groups. GH levels fell less in patients with hyperthyroidism than in normals during GTTs. CONCLUSIONS: We conclude that in hyperthyroidism thyroid hormones directly increase fasting IGFBP-1 concentration but acute regulation of IGFBP-1 by insulin is normal and that elevated fasting phosphorylated IGFBP-1 concentration is associated with insulin resistance.     

The regulation of insulin-like growth factor binding protein (IGFBP)-1 during prolonged fasting

OBJECTIVE Insulin-like growth factor binding protein (IGFBP)-1 levels increase overnight, being inversely related to changes in insulin. With prolonged fasting IGFBP-1 levels increase further. In animal studies high IGFBP-1 levels increase plasma glucose levels possibly by regulating the insulin-like actions of ‘bio-available’ plasma IGF. Following prolonged fasting, there is an increase in insulin requirement. A proportion of this reversible insulin resistance may be due to inhibitory effects of high IGFBP-1 levels on IGF action. This study examined the regulation of IGFBP-1 in the presence of reversible insulin resistance. SUBJECTS Nine normal adult volunteers, seven female and two male (mean age 27.6 ± SD 2.6 years, range 21.7–46.0 years) of normal body mass index were studied. METHODS Subjects fasted from 2200 h day 0 to 0900 h day 3 (59 hours), the fast being completed with a 75-g glucose meal. At least one week later, an 11-hour overnight fast was performed, followed by a repeat glucose meal. Blood samples were taken at regular intervals from 0900 h day 1 and for 5 hours during both glucose meal studies via an indwelling cannula. MEASUREMENTS Serum levels of IGFBP-1, insulin, GH, glucose, IGF-I and cortisol were measured at varying intervals during the fast and both glucose meal studies. RESULTS Following the initial 11-hour overnight fast IGFBP-1 levels rose from (mean ± SEM) 32 ± 5 μg/l to reach a maximum of 144 ± 24μg/l after 32 hours of fasting. IGFBP-1 levels then fluctuated, falling in the morning (93 ± 8μ/l) and then rising overnight (126 ± 9μ/l), but not regaining the initial peak levels. The increase of IGFBP-1 from overnight fasting levels was associated with a fall in plasma insulin from 5.7 ± 0.7 to 2.2 ± 0.2 mU/l. In comparison, 30 minutes after termination of the fast with the glucose meal, IGFBP-1 levels fell from 120 ± 11 to 24 ± 2 μg/l within 4 hours. After an overnight fast IGFBP-1 levels fell from 35 ± 5 to 13 ± 2 μg/l within 3 hours. There was glucose intolerance and increased insulin levels following the glucose meal preceded by the 59-hour fast when compared with the overnight fast. The fall of IGFBP-1 levels after the glucose meal was best expressed, taking into account subject variation, by the following regression equations: Glucose meal preceded by 11-hour fast: log [IGFBP-1] = 1 64–0 255 log [1 h previous insulin] (R² 0.51); Glucose meal preceded by 59-hour fast: log [IGFBP-1] 1.41–0.265 log [1 h previous insulin] ± 0.557 log [current glucose] (R² 0.82). CONCLUSION In man, insulin appears to regulate circulating IGFBP-1 levels in all circumstances, this regulation being unaffected by the resistance to insulin action induced by prolonged fasting. The high IGFBP-1 levels were statistically related to the higher glucose levels and may have directly contributed to the increased insulin requirement observed after prolonged fasting.     

Growth hormone and insulin-like growth factor binding protein-1 responses to oral glucose in patients with primary hyperparathyroidism

BACKGROUND: GH and IGFBP-1 both play a role in glucose homeostasis. OBJECTIVE: To assess the GH and IGFBP-1 responses to an oral glucose load and their relationship with glucose homeostasis in patients with primary hyperparathyroidism. DESIGN: A cross-sectional study with a control group followed by a longitudinal study after parathyroidectomy. PATIENTS AND METHODS: We studied 15 patients with primary hyperparathyroidism (eight women, aged 59.6 +/- 2.2 years) and nine healthy normocalcaemic controls. All subjects were ambulatory and were studied as outpatients. Glucose, insulin, GH and IGFBP-1 were measured during an oral glucose (75 g) tolerance test (OGTT). RESULTS: Patients with hyperparathyroidism showed similar glucose responses to OGTT to those found in controls. Insulin responses were higher in patients (peak insulin 96.33 +/- 9.71 mU/l) in relation to values found in controls (58.11 +/- 9.03 mU/l; P < 0.01). Suppression of GH levels after OGTT was more marked in patients [nadir 0.03 (0.02-0.05) microg/l] than in normocalcaemic subjects [nadir GH 0.12 (0.08-0.42) microg/l; P = 0.002]. However, baseline IGFBP-1 concentration and its decrease after glucose load were similar in patients and controls. Normalization of calcium levels after parathyroidectomy was not followed by any significant changes in glucose, insulin and GH responses to OGTT. The minimum concentration of IGFBP-1 and the area under the curve (AUC) of IGFBP-1 after OGTT were higher after parathyroidectomy (3.34 +/- 0.69 microg/l and 8.94 +/- 1.72 microg x h/l, respectively) than at diagnosis (2.19 +/- 0.42 microg/l and 6.74 +/- 1.28 microg x h/l, respectively; P < 0.05). No correlation was found between PTH, calcium and phosphorus concentrations and GH and IGFBP-1 values in patients before or after normalization of calcium metabolism. CONCLUSION: GH and IGFBP-1 do not seem to be directly involved in the hyperparathyroidism-associated changes in carbohydrate metabolism. The postoperative changes in the depression of IGFBP-1 after OGTT remain to be elucidated.     

Direct thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 production

CONTEXT AND OBJECTIVE: Hyperinsulinemia contributes to the pathogenesis of ovarian dysfunction in insulin-resistant states, including polycystic ovary syndrome (PCOS). Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists [thiazolidinediones (TZDs)] ameliorate hyperandrogenism in polycystic ovary syndrome presumably because they reduce systemic hyperinsulinemia. Direct effects of TZDs in the ovary, however, cannot be excluded. We explored direct effects of TZDs in cultured human ovarian cells. METHODS: Human ovarian cells, obtained from oophorectomy specimens, were cultured in the presence or absence of rosiglitazone or pioglitazone, insulin, and gonadotropins. Steroid hormone and IGF-binding protein-1 (IGFBP-1) concentrations were measured in conditioned tissue culture medium. RESULTS: Rosiglitazone or pioglitazone stimulated progesterone production up to 156% (P < 0.001) and 131% (P < 0.001) of baseline, respectively. Pioglitazone but not rosiglitazone, inhibited baseline and FSH-stimulated estradiol production by 20% (P < 0.001) and 50% (P < 0.001), respectively. Both rosiglitazone and pioglitazone abolished insulin-dependent stimulation of estradiol production in the presence of FSH. Rosiglitazone and pioglitazone inhibited testosterone production by 10% (P < 0.012) and 15% (P < 0.023), respectively, and abolished insulin-induced stimulation of testosterone production. In the absence of insulin, pioglitazone or rosiglitazone stimulated IGFBP-1 production up to 160% (P < 0.001) and 125% (P < 0.036) of baseline, respectively. Pioglitazone and rosiglitazone enhanced insulin-induced inhibition of IGFBP-1 production by 13% and 20%, respectively (P < 0.001). CONCLUSIONS: PPAR-gamma agonists directly stimulate progesterone and IGFBP-1 production, inhibit estradiol and testosterone production, abolish insulin-induced stimulation of testosterone production and insulin-dependent stimulation of estradiol production in the presence of FSH, and enhance insulin-induced inhibition of IGFBP-1 production in human ovarian cells. PPAR-gamma represents a novel system of ovarian regulation.     

Glucose metabolism, insulin-like growth factor-I, and insulin-like growth factor-binding protein-1 after alcohol withdrawal

Alcohol abusers often present with deteriorated glucose metabolism and insulin resistance. Changes in other glucoregulators, such as insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) may also be related to alcohol abuse. We studied the effects of alcohol withdrawal on blood glucose, serum insulin and C-peptide, and plasma IGF-I and IGFBP-1 levels in 27 noncirrhotic male alcoholics aged 43 +/- 9.0 (mean +/- SD) years on four consecutive days immediately after withdrawal. A 4-day monitoring period was conducted in four healthy nonalcoholic control men. The groups were similar in age and body mass index. Glucose, insulin, IGF-I, and IGFBP-1 did not differ significantly between the groups at the baseline, but C-peptide was higher in alcoholics (p < 0.01). After alcohol withdrawal, serum insulin and C-peptide levels increased in close correlation with each other (r = 0.82, p < 0.001). During the 4-day observation period in alcoholics, IGFBP-1 levels declined by 59%, whereas IGF-I increased by 41% (p < 0.001 for both comparisons). The change in insulin correlated inversely with the change in IGFBP-1 levels (r = -0.39, p < 0.05). In the control group, glucose, insulin, IGF-I, and IGFBP-1 remained unchanged during the 4-day monitoring period, whereas some reduction was observed in C-peptide. In conclusion, alcohol withdrawal enhances insulin production, as seen in increased C-peptide levels. An inverse correlation between the changes in insulin and that in IGFBP-1 might suggest that inhibition of IGFBP-1 by insulin remains largely unchanged during the acute phase of alcohol withdrawal.     

Octreotide stimulates insulin-like growth factor binding protein-1 (IGFBP-1) levels in acromegaly.

Insulin-like growth factors (IGFs) circulate in a complexed state with several binding proteins (BPs). Of these, IGFBP-1 is regulated by hormonal and nutritional factors. The somatostatin analogue, octreotide, has been used to effectively control hypersomaototropism in acromegaly. IGFBP-1 levels were measured by RIA in 17 acromegalic patients receiving octreotide. Serum hormone sampling was conducted hourly for 8 hr periods. Among 13 octreotide responders, mean pre-treatment basal GH, IGF-1, and IGFBP-1 levels were 19 +/- 5 micrograms/L, 1021 +/- 168 micrograms/L, and 36 +/- 8 micrograms/L respectively. One month following octreotide treatment, an acute subcutaneous injection (100 micrograms) maximally attenuated GH to 3 +/- 0.6 microgram/L (18% of control, P less than 0.03) and IGF-1 to 467 +/- 75 micrograms/L (46% of control, P less than 0.008) after 4 hrs. IGFBP-1 levels, however, were stimulated to 95 +/- 16 micrograms/L (297% of control, P less than 0.003) during the same time period. A significant increase in IGFBP-1 levels occurred within 2 hrs (158% of baseline, P less than 0.03), and was sustained until the 7th hr following injection. Insulin, a known suppressor of IGFBP-1, did not change during this time. Among the 4 octreotide non-responders, mean basal IGFBP-1 levels were 42 +/- 4 micrograms/L, and 4 hrs following octreotide administration IGFBP-1 was 40 +/- 7 micrograms/L. Octreotide induced a dynamic inverse relationship between circulating GH and IGFBP-1 levels (r = -0.73, P less than 0.001). The absence of IGFBP-1 changes in octreotide non-responders and the non-suppression of insulin in octreotide responsive patients, suggest a direct GH-mediated mechanism of IGFBP-1 regulation in octreotide treated patients with acromegaly. IGFBP-1 may be another useful marker in evaluating the response of acromegaly to octreotide treatment in patients who experience clinical benefit but equivocal GH and IGF-1 attenuation.     

Effects of a high-fat diet on postabsorptive and postprandial testosterone responses to a fat-rich meal.

Postprandial testosterone concentrations have been shown to significantly decrease after a fat-rich meal, which may be due to inhibition of testosterone production by chylomicrons. We examined the effects of a high-fat diet known to reduce postprandial chylomicrons on the testosterone response to a fat-rich meal. Total testosterone (TT), free testosterone (FT), cortisol, and insulin responses to a high-fat test meal containing 5.44 MJ (1,300 kcal, 11% carbohydrate, 3% protein, 86% fat) were determined before (week 0) and after (week 8) an 8-week high-fat diet (64% fat) in 11 healthy men. The high-fat diet resulted in significant reductions in postabsorptive and postprandial serum triacylglycerols (55% and 50%, respectively). There were no significant changes in postabsorptive serum TT, FT, and cortisol, but insulin concentrations were significantly (P < or = .05) lower at week 8 (-28%). There was a significant reduction 1 hour after the fat-rich meal for TT (-22%) and FT (-23%), which remained significantly below baseline for 8 hours. Postprandial TT and FT responses were not significantly different after the 8-week high-fat diet. Postprandial serum cortisol concentrations were significantly reduced 1 hour after the meal. There were no significant differences before and after the high-fat diet. Insulin was significantly increased at the 0-, 1-, and 2-hour postprandial time points before and after the high-fat diet. Compared with week 0, insulin concentrations were significantly lower prior to and immediately after the fat-rich meal at week 8. These data indicate a fat-rich meal results in a prolonged reduction in TT and FT concentrations that is not altered by lowering postprandial chylomicrons. Alternative mechanisms (eg, higher uptake at the receptor level of cells) other than chylomicron-induced or insulin-induced inhibition of steroidogenesis are likely responsible for the reduction in TT and FT after a fat-rich meal.     

Insulin-dependent regulation of insulin-like growth factor-binding protein-1.

In previous studies it has been determined that food ingestion or glucose infusion suppresses serum insulin-like growth factor-binding protein-1 (IGFBP-1) concentrations in normal subjects. It has not been determined, however, whether glucose-dependent suppression is due to enhancement of insulin-stimulated glucose transport, to some other insulin-mediated effect, or to a direct effect of glucose. These studies were undertaken to determine if infusion of other nutrients or energy sources that activate glycolysis, but not insulin secretion, could lead to suppression of the plasma concentrations of this protein. After infusion of 50 g glucose over 4 h, the mean plasma IGFBP-1 concentration fell from 44.3 +/- 13.8 to 17.4 +/- 8.1 micrograms/L (P less than 0.001). In contrast, when 50 g fructose were infused over 4 h, IGFBP-1 decreased from 44.6 +/- 7.4 to only 32.7 +/- 6.7 micrograms/L (P less than 0.01). Comparison of these changes showed that the mean decrease after glucose infusion was significantly greater than that after fructose (P less than 0.01). In contrast to these decreases, infusion of an isocaloric amount of triglycerides resulted in no significant change in IGFBP-1 concentrations (from 49.8 +/- 14.1 to 40.2 + 10.4 micrograms/L; P = NS). Concomitant measurements of immunoreactive C-peptide during the glucose and fructose infusions showed that plasma C-peptide levels rose from 1.6 +/- 0.2 to 3.9 +/- 0.7 nM (P less than 0.001) during the glucose infusion, whereas the maximum increase was from 1.7 +/- 0.4 to only 2.3 +/- 0.4 nM (P less than 0.05) during the fructose infusion. The difference between these mean changes was also significant. The change in C-peptide correlated inversely with the changes in IGFBP-1 during the glucose infusion (r = -0.68); P less than 0.001), but not during fructose infusion (r = -0.31). The results of this study suggest that insulin stimulation of cellular metabolic pathways is an important variable regulating the suppression of plasma IGFBP-1 concentrations. Activation of noninsulin-dependent glycolytic pathways appears to result in an equivalent degree of suppression, whereas provision of other energy substrates has no effect. We conclude that both insulin and glucose are important regulators of plasma concentrations of IGFBP-1 in vivo, and in this way they may significantly influence IGF action.     

Increased 24h mean insulin-like growth factor binding protein-3 proteolytic activity in pubertal type 1 diabetic boys

Hyperglycaemia and increased variability of blood glucose in pubertal children with type 1 diabetes may be related to increased growth hormone (GH) secretion and insulin resistance. The role of changes in insulin-like growth factor-I (IGF-I) bioavailability for the glycaemic control in these patients has not been completely elucidated. In particular, the possible role of increased IGF binding protein-3 (IGFBP-3) proteolysis reported in other insulin resistant states awaits further characterization. The aims of this study were to assess if hyperglycaemia in children with type 1 diabetes was associated with changes in free dissociable IGF-I (fdIGF-I) and IGF binding protein-3 protease activity (IGFBP-3-PA) and if increased insulin resistance during puberty was associated with changes in IGFBP-3-PA in healthy and diabetic children. In diabetic boys in the period of maximal linear growth (Tanner stage 3, n = 5), the mean level and the variability of IGFBP-3-PA, determined every second hour throughout 24 h, were significantly higher both compared to postpubertal diabetic boys (n = 6; P = 0.003 and P = 0.001, respectively), and to age matched healthy boys (n = 4; P = 0.006 and P < 0.001 respectively). This activation of IGFBP-3-PA was most prominent during the day time.The mean 24 h blood glucose level (determined hourly) was the only parameter studied that significantly predicted the changes in mean 24 h IGFBP-3-PA in the diabetes group. The mean 24 h concentrations of fdIGF-I were decreased in the diabetic boys compared to the healthy controls but statistical significance was only achieved in Tanner Stage 5 (p = 0.03). We speculate that the elevated levels of IGFBP-3-PA in Tanner 3 diabetic boys are related to deteriorated glucose homeostasis and that it may be a compensatory mechanism to attenuate the decrease in fdIGF-I in order to partly restore insulin sensitivity and glycemic control.     

Insulin-like growth factors, insulin-like growth factor-binding proteins, insulin-like growth factor-binding protein-3 protease, and growth hormone-binding protein in lipodystrophic human immunodeficiency virus-infected patients

Human immunodeficiency virus (HIV)-lipodystrophy is associated with impaired growth hormone (GH) secretion. It remains to be elucidated whether insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), IGFBP-3 protease, and GH-binding protein (GHBP) are abnormal in HIV-lipodystrophy. These parameters were measured in overnight fasting serum samples from 16 Caucasian males with HIV-lipodystrophy (LIPO) and 15 Caucasian HIV-infected males without lipodystrophy (NONLIPO) matched for age, weight, duration of HIV infection, and antiretroviral therapy. In LIPO, abdominal fat mass and insulin concentration were increased (>90%, P < .01) and insulin sensitivity (Log10ISI(composite)) was decreased (-50%, P < .001). Total and free IGF-I, IGF-II, IGFBP-3, and IGFBP-3 protease were similar between groups (all P > .5), whereas, in LIPO, IGFBP-1 and IGFBP-2 were reduced (-36%, P < .05 and -50%, P < .01). In pooled groups, total IGF-I, free IGF-I, total IGF-II, and IGFBP-3, respectively, correlated inversely with age (all P < .01). In pooled groups, IGFBP-1 and IGFBP-2 correlated positively with insulin sensitivity (age-adjusted all P < .05). IGFBP-3 protease correlated with free IGF-I in pooled groups (r(p) = 0.47, P < .02), and in LIPO (r(p) = 0.71, P < .007) controlling for age, total IGF-I, and IGFBP-3. GHBP was increased, whereas GH was decreased in LIPO (all P < .05). GH correlated inversely with GHBP in pooled groups (P < .05). Taken together the similar IGFs and IGFBP-3 concentrations between study groups, including suppressed GH, and increased GHBP in LIPO, argue against GH resistance of GH-sensitive tissues in LIPO compared with NONLIPO; however, this notion awaits examination in dose-response studies. Furthermore, our data suggest that IGFBP-3 protease is a significant regulator of bioactive IGF-I in HIV-lipodystrophy.     

Insulin-like growth factor binding protein-1 in NIDDM: relationship with the insulin resistance syndrome

OBJECTIVE: In order to examine the role of insulin-like growth factors in the pathogenesis of accelerated macrovascular disease in noninsulin-dependent diabetes mellitus (NIDDM), we investigated the relationship between the insulin resistance syndrome and the IGF axis. DESIGN: Cross-sectional analysis of the relationship between insulin resistance syndrome variables and concentrations of IGF-1, IGF-2, IGFBP-1 and IGFBP-3 in 80 subjects with NIDDM. RESULTS: After correcting for age, sex and body mass index, concentrations of IGFBP-1, correlated with those of HDL-cholesterol (r = 0.40; P < 0.001), triglycerides (r = -0.24; P = 0.04), insulin (r = -0.39; P < 0.001), intact proinsulin (r = -0.32; P = 0.006), des 31,32 proinsulin (r = -0.40; P = 0.001), and with insulin sensitivity (r = 0.38; P = 0.001) and PAI-1 activity (r = -0.24; P = 0.05); IGF-1 levels only correlated with those of HDL-cholesterol (r = -0.33; P = 0.005), and this was not explained by IGFBP-1 or insulin sensitivity. With additional correction for insulin, concentrations of IGFBP-1 still correlated with HDL-cholesterol (r = 0.40; P < 0.001), but not those of triglycerides or PAI-1 activity. There were no significant relationships between levels of IGF-2 and any of the variables investigated, and IGFBP-3 levels only correlated with those of total cholesterol (r = 0.24, P = 0.04). CONCLUSIONS: In NIDDM, concentrations of IGFBP-1 are related to those of insulin, insulin sensitivity, serum lipoproteins and PAI-1 activity. The relationship between concentrations of IGFBP-1 and HDL-cholesterol is not explained by insulin. Concentrations of IGF-1 are linked to HDL-cholesterol, and this is not explained by levels of IGFBP-1. IGFBP-1 concentrations were related to PAI-1 activity, and this may be explained by insulin, which regulates the production of IGFBP-1 and PAI-1.     

Regulation of insulin-like growth factor binding protein-1 (IGFBP-1) in insulin-dependent diabetes mellitus

The aim of the present study was to characterize the effect of 44 h of hyperglycaemia on diurnal levels of insulin-like growth factor binding protein-1 (IGFBP-1), insulin-like growth factor-1 (IGF-1), growth hormone (GH) and glucagon in 7 well-controlled subjects with insulin-dependent diabetes mellitus (IDDM). Hyperglycaemia (15 mmol/l) was induced by a glucose infusion, while the degree of insulinisation was similar to that of a corresponding period with near normoglycaemia (6.9 mmol/l). Hyperglycaemia for 44 h did not alter the normal diurnal IGFBP-1 levels when the degree of insulinisation was unchanged. The diurnal secretion pattern of IGFBP-1 was preserved in both genders and without any difference between the control and hyperglycaemic periods. However, the IGFBP-1 levels were increased in these IDDM subjects despite a peripheral hyperinsulinemia. An inverse correlation was found between IGFBP-1 and peripheral insulin levels both during periods of rapid changes in IGFBP-1 and insulin concentrations (i.e. morning hours) as well as during the total 24-h sampling period. Total IGF-1 levels were low, but no further decrease was seen after 24 h of hyperglycaemia in the presence of unchanged insulin levels. In conclusion, the present study clearly shows that the increased IGFBP-1 level seen during poor metabolic control in IDDM is not caused by hyperglycaemia. Glucose levels per se do not influence either total IGF-1 or IGFBP-1 concentrations in well-insulinised diabetic patients.     

Diurnal variation of sex hormone binding globulin and insulin-like growth factor binding protein-1 in women with polycystic ovary syndrome

OBJECTIVES The aim of this study was to examine (1) the diurnal variation In SHBG and (2) the Inter-relatlonshlps of Insulin, IGF-I, SHBG and IGFBP-1 over 24 hours In 10 women with anovulatory PCOS and compare them with weight-matched ovulatory controls. PATIENTS AND METHODS The two groups comprised 10 anovulatory women with PCOS (as defined by clinical, ultrasound and biochemical criteria) and 10 weight matched controls. Serum samples were taken at two-hourly Intervals for 24 hours and stored for measurement of SHBG, IGFBP-1, insulin and IGF-I. Differences between the groups were compared using the Wllcoxon ranked paired tests of the Individual peak and trough concentrations in each group. The variation In Insulin, IGFBP-1 and SHBG concentrations over 24 hours was tested using two-way analysis of variance with the factors time and subject. Spearman's correlation coefficient was calculated from the subjects’median value over 24 hours. RESULTS The median (interquartile range) body mass Index (BMI) was 25-2 (22-2-29-3) in the PCOS group and 24-3 (23-2-25-7) kg/m2 In the control group. Serum testosterone (T) and LH levels were significantly raised in the PCOS group compared to the control group; T 3-8 (2-9-5-6) vs 1-9 (1-9-2-5) nmol/l (P < 0-007) and LH 12 (10-15) vs 4-1 (3-6-4-5) IU/I (P< 0-005) respectively. There was no diurnal variation In SHBG. The median (interquartile ranges) of the peak SHBG concentrations was lower In the PCOS group: 29-4 (14-9-39-4) vs 52-1 (39-4-61) nmol/l In the control group (P < 0-01). The fasting levels of Insulin at 0600 h (median (Interquartile ranges)) were not significantly different between the groups; 6-6 (5-4-9-8) and 6-2 (1-9-7-6) mU/l, respectively, although the peak median concentrations were significantly different; PCOS 66-1 (50-9-129-2) vs 40 (36-1-74-2) mU/l (P<005). Two-way analysis of variance showed a diurnal variation In Insulin concentrations In the control group (P=0-001) but not in the PCOS group (P=0-1). The diurnal variation In IGFBP-1 was similar in the two groups but the peak median levels were lower In the women with PCOS 54-9 (22-3-79-2) vs 71-5 (60-5-99-3) μg/I (P<003). The decline In IGFBP-1 concentrations correlated with the increase In insulin concentrations. The IGF-I concentrations were similar In the two groups. There was a significant negative correlation between SHBG and insulin (P<0-05) and between Insulin and IGFBP-1 (P<001). CONCLUSION This study demonstrates that there Is no diurnal variation In SHBG concentrations and confirms the finding of a marked diurnal variation in the concentration of IGFBP-1. Women with PCOS who are anovulatory have an abnormal pattern of Insulin secretion with an absence of diurnal variation compared to weight matched controls. This provides further evidence of the relative Insulin resistance which is independent of weight found In women with anovulatory PCOS. The inverse correlations of insulin concentrations with SHBG and IGFBP-1 support the role of Insulin as a possible regulator of the circulating levels of these binding proteins although the difference in the time course of their response makes It unlikely that they are co-regulated.     

Serum insulin-like growth factor type 1, insulin-like growth factor-binding protein-1, and insulin-like growth factor-binding protein-3 concentrations in patients with thyroid dysfunction.

Thyroid hormones play a role in the regulation of insulin-like growth factor type 1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) expression, and both IGF-1 and IGFBPs have been shown to be related to the function and growth of the thyroid. Our aim was to evaluate serum concentrations of IGF-1, IGFBP-1, and IGFBP-3 in patients with thyroid dysfunction before and after normalization of thyroid function. The study was performed in 86 patients with thyroid dysfunction (43 hyperthyroid and 43 hypothyroid patients) and 17 euthyroid subjects. Serum growth hormone (GH), insulin, IGF-1, IGFBP-1, and IGFBP-3 were measured in all patients before and after normalizing serum thyroid hormone concentrations. Hyperthyroid patients showed IGF-1 (198.8 +/- 17.0 microg/L) and IGFBP-3 levels (4.2 +/- 0.2 mg/L) similar to those found in the control group (217.9 +/- 20.3 microg/L and 4.2 +/- 0.3 mg/L, respectively). After therapy these levels significantly decreased to 156.6 + 11.1 microg/L (p < 0.01) and 3.3 +/- 0.1 mg/L (p < 0.001), respectively. IGFBP-1 concentrations were clearly higher than those found in controls (22.7+/- 2.6 vs. 5.7 +/- 1.5 microg/L, p < 0.001) and exhibited a significant reduction after therapy for thyroid hyperfunction (11.0 +/- 1.7 microg/L, p < 0.001). Patients with hypothyroidism showed serum concentrations of IGF-1 (161.5 +/- 13.1 microg/L, p < 0.05) and IGFBP-3 (3.2 +/- 0.3 microg/L, p < 0.05) significantly lower than those found in healthy volunteers. However, replacement therapy with levothyroxine did not induce any significant modification of these concentrations (152.6 +/- 10.6 microg/L and 3.2 +/- 0.2 mg/L, respectively). Similarly, patients with thyroid hypofunction exhibited raised levels of IGFBP-1 (15.5 +/- 0.9 microg/L, p < 0.05 vs. control group) that were significantly decreased after therapy (8.8 +/- 1.4 microg/L, p < 0.01). The results of the present study show that thyroid status affects GH/IGF axis. Hypothyroidism is associated with significant reductions of IGF-1 and IGFBP-3, and IGFBP-1 is elevated in both hypothyroidism and hyperthyroidism.     

Alcohol-induced increases in insulin-like growth factor binding protein-1 are partially mediated by TNF

BACKGROUND: Alcohol (EtOH) alters the plasma and tissue content of insulin-like growth factor (IGF)-I, an important anabolic hormone. However, the bioavailability and bioactivity of IGF-I can also be modulated by changes in soluble proteins that bind IGF-I (IGFBPs). The purpose of the present study was to determine whether EtOH intoxication in rats alters the plasma concentration and tissue mRNA content of various IGFBPs. Based on initial results subsequent studies were performed to assess potential mechanisms by which EtOH increased IGFBP-1. METHODS: Rats were administered EtOH (75 mmol/kg) and blood and tissues collected at various times thereafter. Separate groups of rats were also pretreated with 4-methylpyrazole (4-MP; alcohol dehydrogenase inhibitor), cyanamide (inhibitor of acetaldehyde metabolism), RU486 (glucocorticoid receptor antagonist) or the tumor necrosis factor (TNF) antagonist (TNF(BP)) prior to EtOH administration. RESULTS: Acute EtOH intoxication did not alter the mRNA content of IGFBP-3, -4 or -5 in liver or kidney. However, EtOH increased IGFBP-1 in blood (5-fold), which was associated with an up-regulation of IGFBP-1 mRNA content in liver and kidney (2- to 3-fold). Likewise, the injection of the nonmetabolizable alcohol -butanol also increased IGFBP-1 in plasma, liver, and kidney. The increased IGFBP-1 in blood and tissues was not prevented by inhibiting alcohol metabolism with 4-MP. However, pretreatment with cyanamide markedly accentuated the EtOH-induced increase in IGFBP-1 in blood (20-fold), liver (3.5-fold), and kidney (12-fold), indicating that accumulation of acetaldehyde can enhance IGFBP-1 synthesis. A time course study indicated that EtOH increased plasma IGFBP-1 levels as early as 0.5-1 hr, and that this response was associated with elevated IGFBP-1 mRNA in liver but not kidney. Pretreatment with RU486 did not prevent or attenuate the EtOH-induced increase in IGFBP-1. However, the alcohol-induced increase in IGFBP-1 was attenuated by TNF(BP). CONCLUSIONS: These data suggest that the acute alcohol-induced increase in IGFBP-1 is mediated, at least in part, by TNF and is independent of EtOH metabolism and increases in endogenous glucocorticoids.     

Thyroxine treatment increases circulating levels of insulin-like growth factor binding protein-1: a placebo-controlled study

OBJECTIVE Thyroid hormones affect carbohydrate metabolism in the liver, and hepatic insulin-like growth factor binding protein-1 (IGFBP-1) participates in glucose counter-regulation, so we studied the effects of oral thyroxine on serum IGFBP-1. DESIGN The study was performed on a placebo-controlled cross-over basis covering 3 months’ thyroxine and 3 months’ placebo administration. PATIENTS Eight patients taking anticonvulsant medication and four patients with hypothalamic hypothyroidism were given thyroxine, 150–200 μg daily for 3 months, or placebo. MEASUREMENTS Serum IGFBP-1, sex hormone binding globulin, free T3 and free T4, TSH and IGF-I levels were measured after an overnight fast before treatment, and at the end of each 3-month period. RESULTS Anticonvulsant medication had no significant effect on serum IGFBP-1. After 3 months’ thyroxine treatment the serum IGFBP-1 levels (69; 58-167 μ g/l; median and interquartile range, respectively) were significantly higher than those after placebo treatment (44; 23-58 μ g/l; P= 0 002), or the pretreatment levels (54; 19-81 μ g/l, P= 0 005). The IGFBP-1 levels rose in all 12 patients after thyroxine treatment, the median rise being 2.1-fold compared to placebo levels. No change was found in serum IGF-I concentrations. CONCLUSIONS Oral thyroxine produces a rise in serum IGFBP-1 level without a change in serum IGF-I concentration.     

High-fat meal impairs vascular compliance in a subgroup of young healthy subjects

Postprandial hypertriglyceridemia impairs endothelial function and may possibly worsen vascular compliance by increasing oxidative stress. Large (C1) and small (C2) artery compliance, glucose, insulin, and triglycerides (TGs) were measured hourly for 6 hours in 18 young healthy volunteers after a low-fat meal and a high-fat meal, with and without antioxidant vitamins. C1 and C2 declined significantly for 6 hours after fat ingestion in 8 subjects ("fat reactors") and increased in 10 ("nonreactors"). Fat reactors had higher fasting and peak serum TGs after fat loading and increased baseline glucose and insulin levels and homeostasis model assessment of insulin resistance (HOMA(IR)). Fasting insulin correlated with C1 and C2 only in fat reactors. After fat intake, plasma nitric oxide metabolites decreased more in fat reactors than in nonreactors (17.0% +/- 5.1% vs 4.8% +/- 2.1%; P < .05). In fat reactors, pretreatment with antioxidant vitamins before the high-fat meal blunted the fall in C1 but not in C2. Compliance was unchanged after the low-fat meal. Normal weight young subjects with an insulin resistance phenotype show significantly decreased vascular compliance, increased postprandial TG peaks, and markedly reduced plasma nitric oxide metabolites after a high-fat meal.