Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Streptozotocin-induced diabetes causes a decrease in growth hormone and prolactin receptors in the livers of female rats, and in the serum concentration of somatomedin-C/insulin-like growth factor-I, concomitantly with an increase in the serum testosterone levels. In this study, a possible role for adrenal androgens in the loss of receptors was examined. Rats were adrenalectomised bilaterally 3 days after the induction of diabetes with streptozotocin (100 mg/kg intravenously), and livers were removed 3 days later. Adrenalectomy had no effect on binding of ovine prolactin or bovine growth hormone to liver microsomal membranes from non-diabetic rats, but in diabetic rats it entirely abolished the 56% decrease in prolactin binding and significantly reversed the 66% decrease in growth hormone binding and the parallel fall in serum levels of somatomedin-C/insulin-like growth factor-I (p less than 0.05). Adrenalectomy also prevented the diabetes-induced rise in serum testosterone. Daily injection of testosterone to normal and diabetic rats for 12 days significantly reduced both prolactin and growth hormone binding (p less than 0.001), with the effect of diabetes being additive upon the testosterone effect. Implantation of testosterone-filled silastic capsules at the time of adrenalectomy (i.e. for 3 days) did not prevent the adrenalectomy-induced restoration of both growth hormone and prolactin receptors. The resulting high serum testosterone level did not reduce binding to growth hormone receptors in control rats over the 3 day period, and caused no further decrease in diabetic rats. However, binding to prolactin receptors was reduced by 47% in control animals with no further loss in diabetic animals (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Adrenal involvement in the diabetes-induced loss of growth hormone and prolactin receptors in the livers of female rats. 300 52

The insulin and growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis are two endocrine systems that are interlinked at many levels. GH is one of the glucose counter-regulatory hormones, rising in response to hypoglycaemia, it has both intrinsic hyperglycaemic actions and causes insulin resistance. Both IGF-I and its receptor have high structural and functional homology to insulin and its receptor. Insulin can regulate IGF-I production, acting on the GH receptor or at a post-receptor site. Conversely IGF-I is thought to have a permissive effect on the pancreatic insulin response to glucose. Growth is compromised in poorly controlled diabetic children; however, a causal link with altered GH/IGF-I levels has not been proven. Insulin-dependent diabetes clearly causes derangements in the GH/IGF-I axis. In poorly controlled diabetics GH levels are invariably raised whilst normal or low levels of IGF-I are found, indicating a dissociation between the two factors. Altered IGF-binding protein levels are also found, with high levels of small binding protein and low levels of large binding protein. These derangements are probably the result of interactions at many levels although the exact mechanisms are not fully understood. Raised GH levels could result from altered hypothalamic/pituitary control or reduced feedback inhibition. The latter could, in turn, result from low IGF-I levels, reduced availability of IGF-I to relevant receptors or increased levels of inhibitors (possibly the small binding protein). Low IGF-I levels could be directly due to deficient insulin levels or simply to lack of available circulating binding protein. Alternative or altered molecular forms of circulating GH in diabetes seem unlikely on present evidence. That GH has an effect on glycaemic control is most evident from the abnormal glucose tolerance seen in acromegalics, but is also seen with physiological GH variations such as during the pubertal growth spurt. In diabetics the derangements to the GH/IGF-I axis, caused by poor metabolic control, leads to aggravation of the metabolic problems. Altered GH/IGF-I levels have been implicated in the long-term complications associated with diabetes, and whilst GH/IGF-I are not essential for the early changes involved in these complications they may still play an important role in their development, especially proliferative retinopathy.
 ...
PMID:The role of growth hormone in diabetes mellitus. 305 58

The concentrations of somatomedins/insulin-like growth factors were measured by a specific radioimmunoassay for insulin-like growth factor-I and a specific radioreceptor assay for insulin-like growth factor-II in sera of term normal and Type 1 (insulin-dependent) diabetic pregnant women and in various cord sera of their newborn infants. Serum insulin-like growth factor-I levels in normal (non-diabetic) maternal serum were higher than in non-pregnant women (486 +/- 26 versus 215 +/- 26 ng/ml). The normal pregnancy-induced increment of insulin-like growth factor-I was markedly reduced in diabetic pregnancy. It was not different in patients with good or poor glycaemic control, as judged by normal or elevated blood levels of haemoglobin A1c content. Insulin-like growth factor-I levels in cord serum of infants of diabetic women with good glycaemic control (86 +/- 11 ng/ml) and poor glycaemic control (91 +/- 19 ng/ml) were significantly higher (p less than 0.01) than in infants of non-diabetic women (43 +/- 42 ng/ml). The fetal birth weight ratios were not significantly correlated with insulin-like growth factor-I levels in cord serum. Serum insulin-like growth factor-II levels in maternal and cord serum in diabetic and normal pregnancy were not different from each other or from normal non-pregnant women. The increment in insulin-like growth factor-I levels in maternal serum in pregnancy may influence placental structure and function. Lack of this increment in maternal diabetes may have direct implication in placental abnormalities in diabetes and indirect implications on fetal development and metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Insulin-like growth factors (IGF) I and II in diabetic pregnancy: suppression of normal pregnancy-induced rise of IGF-I. 381 36

Preexposure of IM-9 lymphocytes to the somatomedin peptide insulin-like growth factor-I (IGF-I) results in a time- and concentration-dependent reduction in specific receptors for IGF-I. Since insulin and proinsulin are structurally homologous to IGF-I, we investigated the ability of insulin analogues to compete for occupancy and to directly modulate IGF-I receptor concentrations. IGF-I binds rapidly and reversibly to IM-9 cells at 15 degrees C, with half-maximal displacement of 125I-I-IGF-I at IGF-I concentrations of 3.6 X 10(-9) M and insulin concentrations of 5 x 10(-7) M. Preexposure of cells at 37 degrees C to either IGF-I or insulin produced a concentration-dependent reduction in binding of 125I-IGF-I. A 50% decrease in binding was observed following preincubation of cells with IGF-I at 2.5 x 10(-9) M and insulin at 2 x 10(-7) M. At higher insulin concentrations (10(-6)-10(-5) M), up to 70% reduction in 125I-IGF-I binding occurred. Bovine proinsulin and guinea pig insulin competed less potently than porcine insulin for the IGF-I receptor, and produced receptor loss in proportion to their ability to occupy the IGF-I receptor. Scatchard analysis indicated that at all insulin concentrations, the decrease in binding was secondary to loss of available IGF-I receptors, with no change in affinity. Receptor loss was evident following 1-2 h preexposure to insulin, with a t1/2 of 4 h and maximal receptor loss within 10 h. Similarly, IGF-I and IGF-II competed for occupancy of the IM-9 insulin receptor, with 50% displacement of 125I-insulin occurring at peptide concentrations of 3.5 x 10(-9) M (insulin), 3.5 x 10(-8) M (IGF-II), and 3 x 10(-7) M (IGF-I). Preexposure of cells to these peptides at 37 degrees C for 20 h resulted in a concentration-dependent reduction in binding of 125I-insulin, with the order of analogue effectiveness being insulin greater than IGF-II greater than IGF-I. These data emphasize the structural and functional homology of insulin and the somatomedin peptides, IGF-I and II, as well as their respective receptors. Additionally, the data support the conclusion that the insulin and somatomedin peptides not only bind to both receptors, but downregulate each receptor in proportion to their ability to occupy that receptor.
Diabetes 1982 May
PMID:Insulin-induced loss of insulin-like growth factor-I receptors on IM-9 lymphocytes. 629 57

Among 43 patients with Laron syndrome followed in our clinic, we were able to study the carbohydrate metabolism from infancy into adult age in 30 patients. During infancy, fasting blood glucose levels were in the hypoglycemic range (mean +/- SD, 3.5 +/- 1.2 mmol/L) and increased at the end of a delayed puberty to 4.6 +/- 0.6 mmol/L. Fasting plasma insulin was higher than expected for concomitant glucose levels, and several of the 20 patients who underwent an oral glucose tolerance test (OGTT) had glucose intolerance and relatively high insulin levels. In adult patients, insulinopenia developed and one 38-year-old patient developed non-insulin-dependent diabetes mellitus (NIDDM) with subsequent need for insulin therapy. Continuous insulin-like growth factor-I (IGF-I) treatment of a pubertal patient with glucose intolerance and hyperinsulinemia normalized both responses. In conclusion, long-term IGF-I deficiency leads to insulin resistance, which is reversed by exogenous IGF-I administration.
 ...
PMID:Carbohydrate metabolism in primary growth hormone resistance (Laron syndrome) before and during insulin-like growth factor-I treatment. 747 3

Synthesis of insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) is altered in diabetes and malnutrition, but underlying processes are poorly understood. To study molecular mechanisms, we examined regulation of IGF-I and IGFBP-1 gene transcription in primary cultures of rat hepatocytes. Transcription of the IGF-I and IGFBP-1 genes was measured as incorporation of [alpha-32P]UTP into preinitiated message in isolated nuclei. IGFBP-1 gene transcription was not sensitive to reduction in amino acid concentration from 5x to 0.5x rat arterial plasma levels. However, IGF-I gene transcription fell 60-70% in response to reduced provision of amino acids. Culture with 10(-9) M insulin lowered IGFBP-1 gene transcription 50% below control levels (10-11 M) but did not affect IGF-I gene transcription; 10(-6) M insulin raised IGF-I gene transcription 2-fold. After an acute reduction in insulin concentration, IGFBP-1 transcription began to rise within 30 min, but IGF-I gene transcription was unchanged over 120 min. Similarly, 3-6 h were required for stimulation of IGF-I gene transcription by insulin, but a 40% decrease in IGFBP-1 gene transcription could be detected within 15 min after adding 10(-6) M insulin, and suppression of IGFBP-1 transcription by insulin was unaffected by the presence of cycloheximide. Effects of insulin on IGFBP-1 gene transcription were not mimicked or antagonized by phorbol ester.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding protein 1 gene transcription by hormones and provision of amino acids in rat hepatocytes. 751 86

Insulin-like growth factor-I (IGF-I) in serum is predominantly bound in a ternary complex, consisting of IGF peptide, IGF-binding protein-3 (IGFBP-3), and an acid-labile subunit, or a binary complex, consisting of IGF peptide and any of the six IGFBPs. In the binary complex, IGF-I is more bioavailable and has a faster turnover rate. Proteolysis of IGFBP-3 may alter the distribution of IGF-I between these complexes by reducing IGFBP-3 affinity for IGF-I and/or acid-labile subunit and may offer an additional mechanism for regulation of IGF availability. In the present study, sera from patients with noninsulin-dependent diabetes mellitus (NIDDM) were found to have significantly higher IGFBP-3 proteolytic activity than sera from age-matched healthy subjects (188 +/- 12% vs. 104 +/- 6% of a control serum pool; P < 0.001). The mean (+/- SE) of serum IGFBP-3 levels determined by Western ligand blotting was lower in NIDDM patients than in healthy control subjects (61.5 +/- 5% and 79 +/- 5% of a control serum pool, respectively; P < 0.01). However, IGFBP-3 concentrations determined by RIA did not differ. This discrepancy could be explained by IGFBP-3 proteolysis, resulting in IGFBP-3 fragments that are detectable by RIA, but not by Western ligand blotting. Western immunoblotting of sera with or without prior treatment with endoglycosidase-F demonstrated that a glycosylated 29-kilodalton (kDa) IGFBP-3 form with a protein core of 20 kDa was present in sera from healthy controls, and this fragment was increased in NIDDM and term pregnancy sera, suggesting that it is produced by endogenous proteolysis. The presence of the 29-kDa IGFBP-3 proteolytic fragment at about 130-150 kDa after neutral size chromatography of pooled sera may suggest that 29-kDa IGFBP-3 participates in ternary complex formation. Further studies are required to determine whether the avidity of ternary complex formation with the 29-kDa IGFBP-3 fragment is reduced and whether the resulting increased IGF turnover can explain the reduced IGF-I levels (z scores) observed in NIDDM patients compared to healthy subjects (-0.81 +/- 0.32 SD vs. +0.26 +/- 0.17 SD; P < 0.001). Neutral size-chromatography of sera demonstrated that IGFBP-3 protease activity in the approximately 130- to 150-kDa mol wt range is regulated by NIDDM and pregnancy in parallel with that of unfractionated sera.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Increased proteolysis of insulin-like growth factor-binding protein-3 (IGFBP-3) in noninsulin-dependent diabetes mellitus serum, with elevation of a 29-kilodalton (kDa) glycosylated IGFBP-3 fragment contained in the approximately 130- to 150-kDa ternary complex. 751 16

Insulin-like growth factor-I (IGF-I) has been inversely associated with low-density lipoprotein (LDL) cholesterol in normal women with slightly elevated cholesterol levels and hypothyroid women. More than 95% of IGF-I circulates bound to binding proteins (IGFBPs); of these IGFBP-1 is of particular interest as it is inversely regulated by insulin and is thought to inhibit the action of IGF-I and IGF-II. We examined the relationship between IGFBP-1 and LDL cholesterol in 41 healthy adult subjects. LDL cholesterol correlated with the body mass index (r = 0.40, P < 0.01), sex (r = 0.51, P < 0.001) and IGFBP-1 levels (r = 0.36, P < 0.02). LDL cholesterol did not correlate with age (r = 0.25, P = not significant) or IGF-I (r = 0.06, P = not significant). Upon multivariate regression analysis, sex, body mass index and IGFBP-1 were all independent predictors of LDL cholesterol (all P < 0.05). Elevated IGFBP-1 levels have been associated with an inhibition of serum IGF-I bioactivity in children with insulin-dependent diabetes. IGFBP-1 also appears to inhibit IGF-I hexose-stimulated uptake. IGFBP-1 may also be inhibiting the effect of IGFs on the cellular metabolism of LDL cholesterol.
 ...
PMID:Insulin-like growth factor-binding protein-1 is correlated with low density lipoprotein cholesterol in normal subjects. 751 6

Glucagon (1-1.5 mg) was administrated iv as a bolus dose to healthy individuals (n = 7), patients with GH deficiency (n = 14), and patients with insulin-dependent diabetes mellitus (IDDM; n = 6). Thereafter, blood samples for determination of serum glucose, insulin, insulin-like growth factor-binding protein-1 (IGFBP-1), GH, and insulin-like growth factor-I (IGF-I) concentrations were collected for 180 min. IGFBP-1 concentrations increased significantly in response to glucagon, with maximal values observed at 90 min [in healthy subjects from 36 +/- 6 to 58 +/- 10 micrograms/L (P < 0.05), in GH-deficient patients from 36 +/- 4 to 54 +/- 6 micrograms/L (P < 0.001), and in IDDM patients from 115 +/- 18 to 167 +/- 27 micrograms/L (P < 0.05)]. The IGFBP-1 elevation was delayed in relation to the glucagon-induced increase in glucose and insulin concentrations. When the groups were combined, the individual IGFBP-1 peak value observed at 90 min was inversely correlated to the individual peak value of insulin observed at 15-30 min (r = -0.743; P < 0.001). In GH-deficient patients, serum GH concentrations remained undetectable (< 0.2 micrograms/L), and IGF-I concentrations were unchanged after the glucagon injection. In healthy subjects and IDDM patients, mean GH levels did not change significantly, whereas mean IGF-I concentrations decreased slightly at 30 min. In conclusion, glucagon increased serum IGFBP-1 concentrations in spite of increases in glucose and insulin. These results suggest that glucagon is a stimulator of IGFBP-1.
 ...
PMID:Glucagon stimulates insulin-like growth factor binding protein-1 secretion in healthy subjects, patients with pituitary insufficiency, and patients with insulin-dependent diabetes mellitus. 752 39

Insulin-dependent diabetes can be associated with low insulin-like growth factor-I (IGF-I) levels despite normal or even high GH secretion. The basis of the diabetic abnormalities in GH-IGF dynamics that contribute to insulin resistance and impaired fuel metabolism are not well understood. To further investigate these matters, this study evaluated baseline IGF system parameters and responses to recombinant human IGF-I in four diabetic adolescents and six pubertal stage-matched controls. Spontaneous overnight and arginine-stimulated GH secretion, insulin, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), and IGFBP-3 levels were measured before, during, and after daily 10-h sc infusions of saline or IGF-I (20 micrograms/kg.h). Baseline overnight GH secretion and IGFBP-1 and -3 levels were not significantly different in the two groups, but IGF-I levels were significantly lower and IGF-II levels were higher in diabetic subjects. IGF-I infusion produced a 3-fold increase in serum IGF-I levels and a reciprocal profound reduction in IGF-II levels in both groups. IGFBP-1 levels increased dramatically in diabetics and modestly in normal subjects in response to IGF-I infusion, but IGFBP-3 levels were not significantly altered. Spontaneous overnight and arginine-stimulated GH secretion were suppressed by about 50% in both groups after IGF-I infusion. Insulin requirements were substantially reduced in diabetics receiving IGF-I, and insulin secretion was suppressed in normal subjects, with no evidence of a change in insulin half-life. Blood glucose remained stable in both groups throughout saline and IGF-I infusions, and no hypoglycemia or other adverse effect occurred during IGF-I infusions. Further studies are necessary to determine whether the addition of IGF-I to insulin replacement therapy may stably reduce the insulin requirement, maintain normal GH levels, and perhaps achieve better metabolic and anabolic balance in the treatment of insulin-dependent diabetes.
 ...
PMID:The effects of subcutaneous insulin-like growth factor-I infusion in insulin-dependent diabetes mellitus. 752 24


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>