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

The expression and regulation of IGF-I is tissue-specific in diabetes mellitus in the rat. These studies were designed to examine if similar tissue specificity exists for IGF-BPs in the diabetic milieu. Diabetes mellitus was induced by a single i.p. injection of STZ (100 mg/kg body weight). Rats were treated with either vehicle--insulin, vanadate, or phlorizin for 7-14 days. Tissues were analyzed for IGF-BPs by ligand blotting and by affinity cross-linking and immunoprecipitation. In liver tissue from nondiabetic control rats, multiple forms of IGF-BPs were noted, ranging from 48,000 to 25,000 M(r). In diabetic rat liver tissue, the 25,000-M(r) form was unchanged, whereas the higher M(r) forms (48,000-42,000 M(r)) were decreased, and the 30,000-M(r) form was increased. Insulin therapy of diabetic rats decreased all forms to below control levels. In the kidney tissue of control rats, faint IGF-BP bands were seen at 30,000 and 25,000 M(r). In diabetic rat kidney tissue, the 30,000-M(r) form again was increased (as in liver) and restored to control levels with insulin therapy. In contrast, only a 30,000-M(r) band was seen in control pituitary tissue, which was slightly increased in the diabetic rats and also was decreased below control levels by insulin. In hypothalamus and cerebral cortex tissue, bands at 30,000 and 25,000 M(r) were noted, and neither was altered by diabetes or insulin treatment. Treatment of diabetic rats with vanadate and phlorizin resulted in comparable blood glucose levels, which were only slightly higher than those achieved with insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Dec
PMID:Differential tissue regulation of insulin-like growth factor binding proteins in experimental diabetes mellitus in the rat. 128 Feb 36

We studied the influence of fasting serum from nine insulin-dependent diabetic children and adolescents under insufficient metabolic control on normal human bone cells in vitro compared with serum from eight sex- and age-matched controls. Cell number 24 h after plating was significantly less under diabetic serum, indicating impaired cell attachment, spreading and initiation of cell proliferation. Cell number after five days was reduced by 1% diabetic serum, while higher serum concentrations had diverging effects on osteoblast proliferation. Collagen synthesis of human osteoblasts was significantly reduced by 8% diabetic serum compared to 8% control serum, while synthesis of non-collagenous proteins was not affected. Duration of diabetes (several weeks up to 12 years) had no influence on these parameters. The serum from one patient, which was studied a second time under excellent metabolic control three months later, however, had lost its inhibitory influence on collagen synthesis of osteoblasts. The pattern of the interstitial collagen types I, III and V was not altered by diabetic serum. These results indicate that defective regulation of proliferation and collagen synthesis of osteoblasts by components present in human diabetic serum may be an important factor in the development of diabetic osteopenia. The negative influence might be explained in part by reduced levels of IGF-I and elevated levels of IGF binding protein-1 in the diabetic sera.
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PMID:Defective stimulation of proliferation and collagen biosynthesis of human bone cells by serum from diabetic patients. 128 77

AGEs are nonenzymatically glycosylated adducts of proteins that accumulate in vascular tissues with aging and at an accelerated rate in people with diabetes; AGEs are closely linked to tissue damage due to their high reactivity in protein cross-linking. A macrophage-monocyte receptor system for AGE moieties is shown to mediate the uptake of AGE-modified proteins by a process that also induces cachectin-TNF, IL-1, IGF-I, and PDGF secretion. Thus, in addition to removing senescent glucose-modified proteins and cells, AGE-mediated release of growth-promoting factors may represent a mechanism by which macrophages signal mesenchymal cells the need for replacement of senescent proteins. The age of the macrophage correlates inversely with the binding and removal capacity of the AGE receptor, possibly preventing the clearance of cross-linked proteins and the compounding aging-related tissue damage. In addition to monocyte and macrophages, other cells express similar receptors for AGE-proteins, including endothelial cells, fibroblasts, and mesangial cells. Endothelial cell AGE-receptors mediate transcytosis of AGEs to the subendothelium, induce increased permeability, and enhance endothelium-dependent procoagulant activity. Renal mesangial AGE receptors mediate PDGF-dependent extracellular matrix protein production. Fibroblast AGE receptors may influence cellular proliferation by EGF and EGF-receptor regulation. These findings, in connection with the known abundance of AGEs in aged and diabetic tissues, indicate that AGE-ligand-receptor interactions are crucial for the development of age- and diabetes-related vascular tissue and renal pathology.
Diabetes 1992 Oct
PMID:Receptor-mediated interactions of advanced glycosylation end products with cellular components within diabetic tissues. 132 53

The etiology of the low renin state in DM is not clear. To assess the role of certain growth and regulatory factors in this process, we studied the effects of insulin, IGF-I, and IGF-II on the renin-angiotensin system in normal and 8-wk STZ-induced diabetic rats. Renin secretion was studied both in static incubations and by perifusion of rat renal cortical slices. In diabetic rats, both plasma renin activity (0.65 +/- 1.6 vs. 4.0 +/- 1.2 ng ANG I.ml-1.h-1) and tissue renin concentrations (27 +/- 5 vs. 51 +/- 8 ng ANG I.mg tissue-1.h-1) were reduced. Insulin (0.1-1.0 mu/ml) and IGF-I (10(-9) to 4 x 10(-9) M) stimulated renin secretion in normal tissue (control, 95 +/- 3%; insulin [0.5 mu/ml], 134 +/- 7%; IGF-I [4 x 10(-9) M], 149 +/- 7%). IGF-I stimulated renin secretion in perifusions as early as 30 min, whereas IGF-II had no effect. However, in diabetic renal tissue, neither insulin (0.1-1.0 mu/ml) nor IGF-I (10(-9) to 4 x 10(-9) M) had an effect on renin. This lack of effect was overcome by adding up to 100-fold higher concentrations of these growth factors. ANG II (10(-10) M-10(-8) M) had an exaggerated inhibitory effect on renin secretion in diabetic tissue. This study suggests that the low renin state in DM may be explained by the enhanced inhibitory effect of ANG II and the resistance to the secretogogue actions of insulin and IGF-I.
Diabetes 1992 Sep
PMID:Altered regulation of renin secretion by insulinlike growth factors and angiotensin II in diabetic rats. 138 18

The presence of type I insulin-like growth factor (IGF-I) receptors on placental membranes led to the hypothesis that these receptors might play a critical role in the rapid growth of this organ. Diabetes induces feto-placental overgrowth, but it is not known whether it modifies IGF-I receptor activity in fetal and/or placental tissues. To answer this question, we have partially purified and characterized placental receptors from normal and streptozotocin-induced diabetic rats. In normal rats, binding of 125I-IGF-I to a 140 kDa protein corresponding to the alpha subunit of the receptor was observed in cross-linking experiments performed under reducing conditions. Stimulation by IGF-I induces the autophosphorylation of a 105 kDa phosphoprotein representing the beta subunit of the receptor. In rats made hyperglycaemic and insulinopenic by streptozotocin injection on day 1 of pregnancy, placental IGF-I receptor-binding parameters were not different from controls on day 20 of pregnancy. In contrast, the autophosphorylation and kinase activity of IGF-I receptors of diabetic rats were increased 2-3-fold in the basal state and after IGF-I stimulation. The present study indicates that the rat placental IGF-I receptor possesses structural characteristics similar to that reported for fetal-rat muscle, and suggests that the high-molecular-mass beta subunit could represent a type of receptor specifically expressed during prenatal development. In addition, it clearly demonstrates that diabetes induces functional alterations in IGF-I receptor kinase activity that may play a major role in the placental overgrowth in diabetic pregnancy.
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PMID:Functional alterations of type I insulin-like growth factor receptor in placenta of diabetic rats. 144 71

The insulin-like growth factor I receptor (IGF-I-R) gene is expressed in most body tissues. The levels of IGF-I-R mRNA, however, are regulated by a number of physiological conditions (development, differentiation, and hormonal milieu) as well as in certain pathological states (diabetes and tumors). To understand the molecular mechanisms which control the transcription of the IGF-I-R gene, we have cloned the promoter of the rat receptor gene and have characterized its activity by transient expression assays. Different fragments of the 5'-flanking region (subcloned upstream of a luciferase reporter gene) were transfected into buffalo rat liver 3A cells (a cell line with a low number of IGF-I binding sites) and Chinese hamster ovary cells (a cell line with a higher number of cell-surface receptors). In both cell lines, most of the promoter activity was located in the proximal 416 base pairs of 5'-flanking region. However, further dissection of this proximal fragment revealed a cell type-specific pattern of promoter activity. Thus, in buffalo rat liver 3A cells, subfragments of this region each contributed to total activity, suggesting that contiguous cis-elements can act together to activate transcription. In Chinese hamster ovary cells, on the other hand, subfragments of the proximal promoter region partially substituted for the proximal 416 base pairs of 5'-flanking region. Coexpression studies using an IGF-I-R promoter reporter construct together with an Sp1 expression vector (under the control of an ADH promoter) were performed in SL2 cells, a Drosophila cell line which lacks endogenous Sp1. The results obtained showed that Sp1 can trans-activate the IGF-I-R promoter in vivo. Transient transfection assays were complemented with gel-retardation assays and DNase I footprinting experiments, which showed that transcription factor Sp1 is potentially an important regulator of IGF-I-R gene expression.
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PMID:Structural and functional analysis of the insulin-like growth factor I receptor gene promoter. 144 10

The influence of insulin on plasma and bone mineral homeostasis was studied in the BB rat model, which develops an autoimmune form of diabetes at the age of about 100 days. Untreated diabetes of short duration resulted in hypercalciuria and intestinal calcium malabsorption despite increased free concentrations of serum 1,25-dihydroxyvitamin D. The concentrations of two vitamin D-dependent calcium-binding proteins were also decreased: a low duodenal calbindin-D 9K concentration corresponding to the low intestinal active calcium absorption and a low serum osteocalcin concentration, corresponding to a low bone formation and highly correlated with serum IGF-I concentration. Indeed, on bone histology a very low number of osteoblasts and low osteoblast activity (osteoid formation and mineral apposition rate) were observed. Similar abnormalities persisted in rats with long-standing diabetes resulting in markedly decreased bone mass and increased brittleness of bone. Diabetes therefore resulted in low-turnover osteoporosis. Several hormones (testosterone, growth hormone and 1,25-dihydroxyvitamin D) and growth factors (IGF-I and its binding proteins) with known effects on bone were markedly decreased in diabetic rats. A continuous infusion of testosterone, GH or 1,25-(OH)2D3 for 14 d by miniosmotic pumps could not improve the biochemical or histomorphometric abnormalities. Insulin infusion for 2 weeks, however, rapidly increased and overcorrected the number of osteoblasts, normalized serum osteocalcin and IGF-I concentrations but could not yet normalize bone mineralization. Continuous infusion of IGF-I alone did not improve the osteoblast number of osteocalcin but markedly stimulated bone mineralization. From these data we can conclude that both insulin and IGF-I are potent bone growth factors but with different mode of action. In human type 1 diabetes, a similar decrease in serum osteocalcin and IGF-I was observed. A reduction of regional bone mass, both in long and trabecular bones, is frequently observed in human diabetes. Cumulative data from case control studies indicate that the life-time fracture risk is increased in diabetes.
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PMID:Diabetic bone disease. Low turnover osteoporosis related to decreased IGF-I production. 146 60

There is evidence that the hormonal control of hepatic IGF-I production is mediated by GH and insulin. To elucidate the role of these hormones further we administered s.c. or i.p. insulin (at 2.5 and 5.0 IU/day) and/or GH (0.8 IU/day) to rats made diabetic with streptozotocin 16 days previously. Hepatic IGF-I production was then assessed by quantifying hepatic IGF-I mRNA levels by autoradiography of Northern blots. Diabetes resulted in a fivefold reduction in hepatic IGF-I mRNA levels (optical density (OD) of the 0.7-1.1 kb band: controls, 1.3 +/- 0.09; diabetics, 0.28 +/- 0.08; P < 0.01), which was not significantly changed by treatment with s.c. insulin (OD: low dose, 0.55 +/- 0.05; high dose, 0.58 +/- 0.05) or low dose i.p. insulin (OD: 0.40 +/- 0.03). High dose i.p. insulin enhanced hepatic IGF-I mRNA levels (OD: 0.93 +/- 0.23) compared with diabetic rats (P < 0.01) and those given high dose s.c. insulin (P < 0.04), despite the blood glucose values being similar in the treated groups (i.p., 4.72 +/- 0.29 mmol/l; s.c., 3.32 +/- 0.03 mmol/l). Administration of GH alone partially restored the hepatic IGF-I mRNA level (OD: GH-treated, 1.00 +/- 0.05; diabetic, 0.28 +/- 0.08; P < 0.01), whilst having no effect on blood glucose values (diabetic, 36.35 +/- 0.45 mmol/l; GH-treated, 38.65 +/- 2.39 mmol/l). Additional administration of s.c. insulin completely restored IGF-I mRNA levels to those of controls (OD: low dose, 1.35 +/- 0.14; high dose, 1.27 +/- 0.18).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intraperitoneal insulin is more potent than subcutaneous insulin at restoring hepatic insulin-like growth factor-I mRNA levels in the diabetic rat: a functional role for the portal vascular link. 147 13

We experienced a 41-year-old acromegalic male (Case 1) in whom the basal plasma GH was extremely high (320-450 ng/mL) but plasma IGF-I was only slightly elevated (2.0-2.8 U/mL). His nutritional condition and associated diabetes mellitus did not appear to be responsible for the relatively low IGF-I level, and a GH-autoantibody in the plasma was absent. We thus performed gel filtration analyses of his plasma and somatotroph adenoma to determine elution patterns of immunoreactive (IR) and receptor active (RA) GH. For comparison, the same studies were carried out on plasmas and somatotroph adenomas obtained from three other acromegalics (Cases 2-4) whose basal plasma GH and IGF-I levels were 22-45 ng/mL and 3.5-6.0 U/mL, respectively. IR GH in Case 1's plasma distributed over an extremely wide range keeping similar titers rather than showing three discernible components (big-big, big, and little GH) as did plasmas and adenomas from Cases 2-4. And, most of the IR GH in Case 1's plasma was eluted in such fractions that contained low levels of RA GH, indicating a minor proportion of biologically active GH. However, interestingly, the chromatographic profile and total GH content of Case 1's adenoma were similar to those of Cases 2-4's adenomas. These results may, at least in part, explain the discrepancy between the plasma GH and IGF-I levels of Case 1. The unexpectedly different GH elution patterns between the plasma and adenoma from this patient, may suggest a contribution of certain plasma factor(s) to the unusual chromatographic profile of plasma GH.
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PMID:A marked molecular heterogeneity of growth hormone (GH) detected in the plasma but not pituitary of a patient with acromegaly: comparison with other acromegalics and an implication for discrepant plasma levels of GH and insulin-like growth factor. 150 22

Growth hormone (GH) hypersecretion is well documented in insulin-dependent diabetes mellitus (IDDM). Somatostatin inhibits GH in acromegalics and healthy subjects although data on its inhibitory effects on high GH levels in IDDM patients are controversial. The effect of treatment with the somatostatin analogue octreotide ("Sandostatin") on GH secretion, IGF1 levels and metabolic control was investigated in insulin-dependent diabetics. Growth hormone and blood glucose were measured at hourly intervals whilst IGF-I was measured every 6 hours during the 24-h period before and after 7 days' treatment with octreotide (200 micrograms subcutaneously three times daily) in 10 C-peptide negative diabetics. Octreotide significantly reduced mean 24 h GH profile (7.2 +/- 0.7 mU/L before; 5.2 +/- 0.5 mU/L on octreotide, p less than 0.01), IGF-I levels (0.62 +/- 0.06 before; 0.47 +/- 0.05 on octreotide, p less than 0.005) mean 24 h blood glucose (14.4 +/- 0.5 mmol/L before; 12.6 +/- 0.4 mmol/L on octreotide, p less than 0.001) and daily insulin requirements (44.8 +/- 3.0 IU before; 37.2 +/- 3.0 IU on octreotide, p less than 0.02). The shape of 24 h GH profile curve changed significantly on octreotide treatment (p less than 0.05) when it consisted of three nadirs and three peaks closely linked with the time of octreotide administration. Moderate (abdominal discomfort) to severe hypoglycaemia) transient side effects have been observed in all treated patients. The results of this study showed that short-term treatment with octreotide given s. c. every eight hours modulates the pattern of GH secretion in C-peptide negative insulin-dependent patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of the somatostatin analogue octreotide on growth hormone secretion in insulin-dependent diabetics without residual insulin secretion. 151 89


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