Growth hormone and growth in diabetic rats: effects of insulin and insulin-like growth factor-I infusions

The effects of streptozotocin-induced diabetes on weight gain, bone growth and GH secretion have been studied in conscious chronically cannulated male rats. In addition to the classic diabetic symptoms (hyperphagia, polydipsia, polyuria, glycosuria and hyperglycaemia), the slow body weight gain (0.95 +/- 0.5 compared with 2.63 +/- 0.5 g/day in non-diabetic controls) was associated with a reduction in bone growth (from 162 +/- 9 to 48 +/- 4 microns/day) and a reduced pituitary GH content (from 1.5 +/- 0.2 to 0.6 +/- 0.06 mg/gland). Serial blood sampling during the day or overnight showed that the normal male episodic GH secretory pattern was obliterated in the diabetic animals. The constant osmotic stimulation of hyperglycaemia and high fluid turnover was reflected in a significant reduction in pituitary oxytocin and arginine vasopressin (AVP) stores. Intravenous insulin infusions (67-1340 pmol/h for 4 or 7 days) caused a large initial weight gain (greater than 20 g in 2 days) followed by a slower increase, and stimulated tibial bone growth (to 100 +/- 16 and 126 +/- 8 microns/day after 4 or 7 days respectively). Insulin infusion for 7 days also increased pituitary GH content (to 1 +/- 0.15 mg/gland), and the normal episodic GH secretory pattern returned. Intravenous infusions of insulin which reduced, but did not completely normalize, blood glucose levels, allowed the resumption of growth and pulsatile GH secretion. Continuous infusion of recombinant human insulin-like growth factor-I (hIGF-I) at 1110 pmol/h for 54 h also caused a large initial rise in body weight in diabetic rats (17.1 +/- 1.6 compared with 7.5 +/- 2.8 g in saline-infused controls) due primarily to increased fluid retention. This effect of hIGF-I occurred without any significant changes in pituitary GH, AVP, oxytocin, blood glucose or bone growth over this short-term infusion, nor was there any obvious effect on spontaneous GH secretion, monitored over the entire infusion period. We conclude that the diabetic rat is not a good model to study growth stimulation by short-term insulin or IGF-I treatments because the insulin-like effects of these peptides obscure their specific growth-promoting activities in this model.     

Insulin-like growth factor-I in diabetes mellitus: its physiology, metabolic effects, and potential clinical utility

Type 1 diabetes mellitus (DM) is a disease of insulin deficiency, resulting from the autoimmune-mediated destruction of pancreatic beta cells. However, as a likely consequence of intraportal insulin deficiency, patients with type 1 DM also exhibit abnormalities of the growth hormone (GH)/IGF/IGF-binding protein (IGFBP) axis, including GH hypersecretion, reduced circulating levels of insulin-like growth factor-I (IGF-I) and IGFBP-3, and elevated levels of IGFBP-1. These abnormalities not only exacerbate hyperglycemia in patients with type 1 DM, but may contribute to the pathogenesis of diabetes-specific complications, including diabetic neuropathy, nephropathy, and retinopathy. Therefore, therapeutic modalities aimed at restoring the GH-IGF-IGFBP axis are being considered. Herein, we review the efficacy of one such therapy, specifically IGF-I replacement therapy. To date, short-term beneficial metabolic effects of recombinant human IGF (rhIGF)-I therapy have been demonstrated in numerous diabetic conditions, including type 1 DM, type 2 DM, and type A insulin resistance. However, the long- term safety and metabolic efficacy of rhIGF-I therapy remains to be established. Moreover, the potential impact of rhIGF-I on the natural history of diabetic complications has yet to be explored.     

Diurnal pattern of plasma metformin concentrations and its relation to metabolic effects in type 2 (non-insulin-dependent) diabetic patients

The authors describe the diurnal profile of plasma metformin concentrations in a group of 6 Type 2 (noninsulin-dependent) diabetic patients studied at two different daily metformin doses (500 mg and 850 mg b.d.) and report data on the relationships between plasma metformin and metabolic effects over a 14 h period. In addition, the effect of circulating metformin on insulin binding to isolated monocytes has been evaluated. At the two different daily doses fasting plasma metformin concentrations were similar (3.23 +/- 0.35 mumol/l and 3.86 +/- 0.72 mumol/l, mean values +/- SEM, at low and high dose respectively). Drug peak values and averaged concentrations (4.66 +/- 0.39 mumol/l vs 6.35 +/- 0.69 mumol/l) were significantly higher when more drug was administered. Mean plasma glucose was lower when 1,700 mg/day instead of 1,000 mg/day of metformin was given (7.3 +/- 0.4 mmol/l vs 9.1 +/- 0.9 mmol/l, p less than 0.05). After dosing, at higher plasma metformin concentrations corresponded lower plasma glucose values. The averaged blood lactate levels resulted 1.46 +/- 0.4 mmol/l (p less than 0.05 vs matched diet treated diabetic patients) at the higher drug dose. A significant positive correlation emerged between mean plasma metformin concentrations and mean blood lactate levels (r: 0.76, p less than 0.02). Alanine, glycerol and B-OH-butyrate levels were similar at the two metformin daily doses, and were not correlated to plasma metformin. The binding of insulin to isolated human monocytes was similar in metformin-treated diabetic patients (4.48 +/- 0.45) as in healthy volunteers (4.62 +/- 0.34); insulin binding was correlated (p less than 0.05) with plasma metformin levels.     

Insulin-like growth factor-I in type 2 (non-insulin-dependent) diabetics with myocardial infarction and without macroangiopathy

In order to evaluate whether insulin-like growth factor-I (IGF-I) is associated with the development of diabetic macroangiopathy, we measured its plasma concentration in type 2 diabetics with definite myocardial infarction (MI), in type 2 diabetics without macroangiopathy (MA), and in non-diabetic healthy controls. We also compared plasma IGF-I concentration in non-diabetics with definite MI to that in non-diabetics without MA. There was a large interindividual variation in plasma IGF-I concentration in all groups of subjects studied. The median values were as follows: 0.60 IU/ml in diabetics with MI, 0.59 IU/ml in diabetics without MA, 0.48 IU/ml in non-diabetics with MI and 0.76 IU/ml in non-diabetic healthy controls. The only statistically significant difference between the groups was that between non-diabetics with MI and non-diabetics without MA. In diabetics, irrespective of MA, no significant correlation existed between plasma IGF-I level and the degree of glycemic control, renal function or various risk factors for atherosclerosis. The results of this study suggest that the high prevalence of macroangiopathy in type 2 diabetics cannot be imputed to IGF-I.     

Differential effects of growth hormone versus insulin-like growth factor-I on the mouse plasma proteome

The GH/IGF-I axis has both pre- and postpubertal metabolic effects. However, the differential effects of GH and/or IGF-I on animal physiology or the plasma proteome are still being unraveled. In this report, we analyzed several physiological effects along with the plasma proteome after treatment of mice with recombinant bovine GH or recombinant human IGF-I. GH and IGF-I showed similar effects in increasing body length, body weight, lean and fluid masses, and organ weights including muscle, kidney, and spleen. However, GH significantly increased serum total cholesterol, whereas IGF-I had no effect on it. Both acute and longer-term effects on the plasma proteome were determined. Proteins found to be significantly changed by recombinant bovine GH and/or recombinant human IGF-I injections were identified by mass spectrometry (MS) and MS/MS. The identities of these proteins were further confirmed by Western blotting analysis. Isoforms of apolipoprotein A4, apolipoprotein E, serum amyloid protein A-1, clusterin, transthyretin, and several albumin fragments were found to be differentially regulated by GH vs. IGF-I in mouse plasma. Thus, we have identified several plasma protein biomarkers that respond specifically and differentially to GH or IGF-I and may represent new physiological targets of these hormones. These findings may lead to better understanding of the independent biological effects of GH vs. IGF-I. In addition, these novel biomarkers may be useful for the development of tests to detect illicit use of GH or IGF-I.     

Modulation of somatostatin binding to rat pituitary membranes by exogenously administered growth hormone

The effect of exogenously administered GH on somatostatin (SRIF) receptor regulation was studied in rat anterior pituitary membranes. A single class, high affinity specific receptor for SRIF was identified by binding studies with [125I-Tyr11]SRIF [binding capacity (mean +/- SD), 129.4 +/- 23.3 fmol/mg protein; binding affinity, 2.8 +/- 0.6 X 10(10) M-1]. A single injection of rat GH (150 micrograms) caused a significant reduction in capacity, but not in affinity, of SRIF receptors 2 and 6 h after injection (mean decrease, 23% and 24%, respectively) from that in controls. In contrast, mean SRIF binding capacity 24 h after a single injection of rat GH was increased 48% above control values, but affinity was unaffected. Measurement of membrane SRIF content indicated that these changes could not be explained by alterations in receptor occupancy. When rat GH was injected repeatedly for 3 days (150 micrograms/rat X day), the mean binding capacity, though not the affinity, of SRIF receptors was decreased 23% from that in controls 24 h after the last injection. The results can be explained by stimulation of SRIF release from the hypothalamus by GH and somatomedins, with subsequent internalization of the pituitary plasma membrane SRIF receptor. They suggest yet another level of neuroendocrine regulation of GH secretion.     

Insulin-like growth factor-I response to a single bolus of growth hormone is increased in obesity

Reduced GH levels are found in obesity; despite which IGF-I levels are reported as low normal or normal. Previously peripheral responsiveness to GH has been investigated and reported to be increased in obese men and premenopausal women; however, the use of weight-based GH doses in these studies made data interpretation difficult. GH binding protein (GHBP) measurement constitutes an indirect estimate of GH receptor number. GHBP has been reported to be elevated in obesity; however, results from a recent study implied that this was only in men and premenopausal but not postmenopausal women. Therefore, we pursued this question further by challenging a cohort of healthy normal-weight and obese subjects with a non-weight-based dose of GH and examined the relationship of GHBP with the IGF-I response in the context of their body composition. Ninety-eight (40 male) healthy subjects with a wide range of ages and body mass index (BMI) were studied. Ninety-one (34 male) of these subjects were divided into groups of similar age: men and women with a BMI less than 30 [normal-weight men (NM), BMI 26 (22-29) kg/m(2) (n = 19) and women (NW), BMI 24 (19-29) kg/m(2) (n = 23) and with a BMI > 30 (obese men (OM), 41 (30-72) kg/m(2) (n = 15) and women (OW), 43 (30-68) kg/m(2) (n = 34)]. Fat mass and percentage fat were measured by a bioelectrical impedance analyzer. An IGF-I generation test, which involved a sc injection of 21 IU (7 mg) GH, was performed. At baseline serum samples were assayed for GHBP; serum IGF-I and IGFBP3 levels were measured both at baseline and 24 h after GH administration. There was a higher increment IGF-I in obese men and women, compared with the equivalent normal-weight subjects [NM vs. OM: 245 (33-342) vs. 291 (192-427) ng/ml (P < 0.05); NW vs. OW: 220 (103-435) vs. 315 (144-450) ng/ml (P < 0.0005)]. Increment IGF-I was negatively correlated with baseline IGF-I (F = 12.1) and positively correlated with GHBP (F = 18.2) (R(2) = 0.29). GHBP levels were significantly higher in OM and OW (pre- and postmenopausal) than in the equivalent normal-weight groups [NM vs. OM: 2175 (995-4190) vs. 3030 (1540-5470) pmol/liter (P < 0.05); NW vs. OW: 2131 (1010-5040) vs. 3585 (1540-5740) pmol/liter (P < 0.0005)]. GHBP levels correlated highly with BMI, percentage fat, and fat mass (R > 0.6, P < 0.0001). Baseline IGF-I was not affected by body composition. In conclusion, in obese compared with normal-weight healthy subjects, there is a larger increment IGF-I to a single bolus of GH in men, and irrespective of menopausal status, women. Increment IGF-I is associated positively with GHBP level, which in turn is associated with markers of increasing obesity in men and women. GH responsiveness is increased in obesity.     

Insulin-like growth factor-I restores the reduced somatostatinergic tone controlling growth hormone secretion in cirrhotic rats

BACKGROUND/AIMS: An altered growth hormone/insulin-like growth factor-I (GH/IGF-I) axis occurs in advanced liver cirrhosis, characterised by diminished serum levels of IGF-I and increased concentrations of GH. Under normal conditions, GH release is mediated by somatostatin (SS) inhibition. However, the influence of SS on GH release in cirrhosis is not well known. IGF-I supplementation has beneficial effects in experimental cirrhosis, and - under physiological conditions - IGF-I increases SS, inhibiting GH. The aims of this work were to study SS tone in cirrhotic animals and to evaluate whether IGF-I treatment influences SS tone, controlling GH secretion in cirrhosis. METHODS: We studied the influence of SS on GH secretion by assessing GH response to pyridostigmine (PD) in cirrhotic rats treated and untreated with IGF-I. Liver cirrhosis was induced with CCl4-inhalation for 11 weeks in male Wistar rats. The animals were randomly divided into two groups: CI+IGF (n=12), which received IGF-I treatment for 12 days (2 microg/100 g body wt-1 x d-1) and CI (n=12), which received saline. Healthy controls (CO, n=12) were studied at the same time. On day 13, animals from each group were subdivided into two groups (n=6) in order to explore the effect of a PD intrajugular bolus (10 microg x 100 gbw-1) on serum GH levels (at 0,10,20,30 and 60 min), which were assessed by RIA. RESULTS: PD bolus did not exert any effect on GH serum levels in the CI group, suggesting a low SS tone in cirrhotic rats. However, PD induced an increase in GH levels into CO and CI+IGF groups. In conclusion, as occurs under normal conditions, the cholinergic system is a significant modulator of GH secretion in experimental liver cirrhosis. CONCLUSION: Cirrhotic rats have a reduced somatostatinergic tone which can be restored by IGF-I supplementation, suggesting that somatostatin is the main factor involved in the feed-back regulation between GH and IGF-I in cirrhosis.     

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

Summary 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 g · 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 IGFI, 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 mol/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 mol/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^–1after 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.Abbreviations AUC Area under the curve - C-peptide connecting peptide - EE energy expenditure - FFM fat-free mass - GH growth hormone - IGF-I insulin-like growth factor-I - NEFA non-esterified fatty acid - Ra rate of glucose appearance - Rd rate of glucose disposal - FGU forearm glucose uptake - CV coefficient of variation     

Insulin-like growth factor-I at physiological concentrations is a potent inhibitor of insulin secretion

Insulin-like growth factors I and II (IGF-I and IGF-II) are thought to primarily regulate the growth and development of a number of tissues. However, it has recently been observed that when IGF-I is infused into man and animals, plasma insulin levels fall, raising the possibility that IGF-I may also be an inhibitor of insulin secretion. This study used the in vitro perfused rat pancreas and recombinant human IGF-I and IGF-II to determine if either of these peptides affected insulin and/or glucagon secretion from normal rats. IGF-I given with 7.8 mM glucose suppressed insulin secretion by as much as 65%, with the half-maximal effect occurring at less than 10 ng/ml. Glucose-induced insulin secretion (7.8 mM glucose) and arginine-induced insulin secretion (10 mM arginine plus 7.8 mM glucose) were inhibited equally (40%) by 2 ng/ml IGF-I. Insulin secretion returned to normal within minutes of stopping IGF-I. IGF-II (200 ng/ml) also suppressed insulin release, but the effect was less pronounced than for IGF-I and was present at 16.7 mM glucose, but not at 7.8 mM glucose. In contrast to the effects on insulin release, neither peptide altered glucagon secretion. We conclude from these results that 1) IGF-I at physiological concentrations is a potent inhibitor of both glucose- and arginine-induced insulin secretion; 2) the magnitude of the inhibition depends on the background glucose concentration; and 3) the inhibition fully reverses when IGF-I is stopped. These results support an in vivo effect of IGF-I to modulate insulin output.     

胰岛素样生长因子-Ⅰ与老年男性的癌症死亡率

在美国,癌症已成为越来越严重的公共健康问题,估计2007年有144万新病例发生,并有56万人死于癌症.预计癌症不久将取代心脏病成为头号死因.考虑到癌症与年龄有关以及人口的老龄化,未来数十年中这一问题的严重性将大大增加.在搜寻癌症发生的危险因素时,人们的注意力日益集中于胰岛素样牛长因子(IGFs,包括IGF-I)的作用.IGFs是与胰岛素结构相似、能刺激生长的多肽,对各种组织的生长和发育均有影响.     

Cafeteria diet-induced obesity is associated with a low spontaneous growth hormone secretion and normal plasma insulin-like growth factor-I concentrations.

Pituitary growth hormone (GH) secretion has been shown to be blunted in human and animal obesity. With respect to human obesity, cafeteria diet-induced obesity might be an appropriate model to study spontaneous GH secretion. In 6 cafeteria diet-overfed obese male Wistar rats and 6 control rats with chronically implanted catheters, GH levels were measured every 15 min over 6 h by standard RIA. A significantly lower GH secretion, reflected by the integrated GH concentration, was found in the obese rats (median 16.46, [range 10.55-19.13] ng/ml x 6 h vs 35.63 [range 21.90-41.50] ng/ml x 6 h, P < 0.05). The GH secretion in the obese rats was significantly negatively correlated with the body fat percentage, assessed by dual X-ray absorptiometry (Rho = -0.95, P < 0.05). Median plasma insulin-like growth factor-I (IGF-I) concentration was comparable between the two groups, while the median insulin concentration was significantly higher in the obese group (1.95 [range 1.76-3.55] ng/ml vs 1.21 [range 0.86-2.13] ng/ml, P < 0.05). No significant correlation existed between GH secretion and the plasma insulin concentration. In conclusion, cafeteria diet-induced obesity is associated with a low spontaneous GH secretion and normal plasma IGF-I concentration. The hyperinsulinemia present in this model probably explains the normal IGF-I concentrations, but not the GH hyposecretion.     

Insulin treatment normalizes reduced free insulin-like growth factor-I concentrations in diabetic children

OBJECTIVE We have recently demonstrated multiple aberrations in the GH–IGF axis in the sera of children with untreated insulin-dependent diabetes mellitus (IDDM) which were restored after insulin replacement. However, the net result of these alterations in the IGF system on the concentrations of free/biologically available IGF-I in the serum have not been examined directly in diabetic children. In the present study, the effect of diabetes and subsequent insulin replacement on the circulating free IGF-I concentrations are assessed. DESIGN Fasting venous serum samples were obtained longitudinally, before and at various times after the initiation of insulin treatment in untreated diabetic subjects. SUBJECTS Ten prepubertal, aged (mean ± SEM) 6.3±1.0 years, and six adolescent, aged 12.7±1.1 years, subjects with newly diagnosed and untreated IDDM, and age and pubertal status-matched control children and adolescents were recruited. METHODS The serum samples were collected before initiating insulin treatment and 12–24h, 1 week, and 1 month thereafter in subjects with IDDM. Insulin doses ranged from 0.5 to 1.2 U/kg/day. MEASUREMENTS Free IGF-I concentration was assayed by a recently developed two-site immunoradiometric assay. Total IGF-I was measured by radioimmunoassay after acid–ethanol extraction of binding proteins. Differences in free and total IGF-I concentrations in IDDM subjects before and during insulin treatment were analysed by repeated measures analysis of variance followed by pairwise multiple comparisons test. In seven subjects with IDDM, where serum IGFBP-1 and IGFBP-3 concentrations, and IGFBP-3 protease activity had also been measured in a previous study, the relationship between these variables and circulating free IGF-I concentrations were examined by linear regression analysis. RESULTS Free IGF-I concentrations in prepubertal subjects with IDDM were 0.9±0.2, 1.5±0.3, 1.6±0.3 and 2.5±0.4μg/l before, 1 day, 1 week and 1 month after insulin treatment, respectively. Free IGF-I concentrations of control prepubertal children were 2.6±0.5μg/l. Pubertal subjects had higher free IGF-I concentrations than prepubertal subjects but demonstrated a similar type of pattern; before insulin 2.3±1.1, 1 day 3.8±1.3, 1 week 3.7±0.6, 1 month 6.5±1.5 vs pubertal controls 7.7±2.0μg/l. Total IGF-I concentrations were also reduced in untreated diabetic subjects and showed a slower pattern of normalization than free IGF-I concentrations. Free IGF-I concentrations correlated positively with total IGF-I and negatively with IGFBP-1 concentrations. There was no significant correlation between free IGF-I and either serum IGFBP-3 concentrations or IGFBP-3 protease activity. CONCLUSION Alterations in the IGF system during untreated IDDM lead to a reduction in circulating free IGF-I concentrations which is restored progressively during insulin treatment. An increase in free IGF-I precedes that of total IGF-I suggesting that the former is a more sensitive indicator of the metabolic status. An inverse correlation between free IGF-I and IGFBP-1 supports the hypothesis that IGFBP-1 plays an important role in the acute modulation of free IGF-I levels.     

Ontogeny and secretory patterns of plasma insulin-like growth factor-I concentrations in meat-type chickens

The ontogeny and secretory pattern of plasma insulin-like growth factor-I (IGF-I) in relation to GH secretion were studied in meat-type (broiler) poultry during pre-pubertal and post-pubertal growth. Male and female broiler chickens of two commercial strains (strains A and B) were reared from 1 to 198 days of age. From 1 to 49 days of age birds were reared in raised-wire cages and thereafter in deep-litter pens, with food available ad libitum. Blood samples were taken at regular intervals during growth, and at 29 and 43 days of age representative birds were cannulated and serial blood samples taken at 10-min intervals for 5 to 7 h. Plasma concentrations of GH and IGF-I were measured by radioimmunoassay. Birds of strain A were heavier (P less than 0.05) than those of strain B from 12 to 35 days of age. In general, male birds were heavier (P less than 0.01) than females from 12 to 35 days of age. Plasma GH concentrations were significantly higher (P less than 0.05) from 12 to 35 days of age, while plasma IGF-I concentrations were lower (P less than 0.05) from 6 to 21 days of age in male compared with female birds. Plasma IGF-I concentration increased with age, reaching a plateau at 28 days of age, while plasma GH concentration declined over the same period. Plasma IGF-I concentrations declined in a linear manner from 49 to 198 days of age, and there was no evidence of a pubertal increase.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of systemic insulin, insulin-like growth factor-I and growth hormone on bone growth and turnover in spontaneously diabetic BB rats.

Spontaneously diabetic BB rats have a markedly depressed longitudinal bone growth and bone formation/turnover. In this study, male diabetic BB rats were infused intraperitoneally or subcutaneously for 2 weeks with hormones that are believed to stimulate skeletal growth and/or trabecular bone formation: insulin (3 or 4 U/day), human GH (hGH; 400 mU/day), recombinant human insulin-like growth factor-I (rhIGF-I; 300 or 600 micrograms/day) and testosterone (80 micrograms/100 g body weight per day). Saline-treated diabetic BB rats had decreased plasma concentrations of IGF-I and osteocalcin (OC) (OC, 3.7 +/- 0.3 vs 13.1 +/- 0.8 (S.E.M.) nmol/l in controls); bone histomorphometry showed decreased epiphyseal width, osteoblast surface (0.04 +/- 0.04 vs 1.5 +/- 0.3%) and osteoid surface, and mineral apposition rate (MAR) (1.8 +/- 0.5 vs 7.9 +/- 0.6 microns/day). Testosterone and hGH infusions had no effect on weight loss or on decreased skeletal growth and bone formation of diabetic rats, nor did they increase plasma IGF-I concentrations. Insulin infusions into diabetic rats resulted in hyperinsulinaemia and accelerated weight gain. The epiphyseal width, osteoblast/osteoid surfaces and OC levels of insulin-treated rats were normalized or stimulated well above control values (osteoblast surface, 4.3 +/- 0.8%; plasma OC, 16.1 +/- 1.4 nmol/l); the MAR (4.0 +/- 0.9 microns/day) was only partly corrected after the 2-week infusion. Infusions of rhIGF-I into diabetic rats doubled but did not restore plasma IGF-I levels to normal; weight gain, however, was similar to that in control rats. IGF-I treatment had no effect on epiphyseal width, osteoblast/osteoid surfaces and OC concentrations, but improved the decreased MAR (4.6 +/- 1.2 microns/day).(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin-like growth factor-I expression is not increased in the retina of diabetic BB/W-rats.

A combination of immunocytochemistry, in situ hybridization and ligand binding were used to investigate the localization of IGF-I and its receptor in the retina of diabetic and non-diabetic BB/W-rats. Immunocytochemical localization revealed the presence of IGF-I in retinal pigment epithelium, ganglion cells, Muller cell processes and in microvessels. In most sites immunoreactivity was increased in the diabetic retina compared to that of non-diabetic BB/W-rats. In microvessels, however, immunoreactivity was decreased in diabetes. In situ hybridization using an antisense IGF-I riboprobe provided evidence of IGF-I synthesis in all retinal layers with a similar grain density in diabetic and non-diabetic rats. Autoradiographic localization of IGF-I receptors, using [125I]-IGF-I binding, demonstrated a diffuse localization in all retinal layers, with an increase in diabetic animals. These findings suggest that IGF-I synthesis is not altered in the diabetic retina, and that the increased immunoreactivity of IGF-I detectable in the various layers of the retina from diabetic rats may be due to an increased uptake of blood-derived IGF-I suggested by increased receptor density in diabetic rats.