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)

Experimental evidence has suggested that insulin-like growth factor-I (IGF-I) may contribute to diabetic complications. Previously, we and others have shown that normal glomerular mesangial cells have receptors for, synthesize, and exhibit a mitogenic response to IGF-I. We investigated the IGF-I response in cells derived from a genetic model of diabetes, the nonobese diabetic (NOD) mouse. Mesangial cell lines were derived from diabetic (D-NOD) and nondiabetic adult mice. D-NOD cells released more IGF-I into the supernatant and had a decreased binding of IGF-I to surface receptors. Analysis according to Scatchard revealed a decreased number of receptor sites on D-NOD cells, although the structure of the IGF-I receptor visualized by cross-linking was identical for both cell types. Preincubation of D-NOD cells with an antibody to IGF-I resulted in an increase in the number of receptor sites. This suggested that autocrine IGF-I was responsible for the decrease in D-NOD receptor number and that diabetes had resulted in a stable phenotypic change.
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PMID:Mesangial cells from diabetic NOD mice constitutively secrete increased amounts of insulin-like growth factor-I. 769 81

Insulin-like growth factor I (IGF-I) is a useful therapeutic agent in insulin resistant diabetes mellitus due to insulin receptor disease because of its hypoglycaemic effects through the IGF-I receptor. A girl with typical type A insulin resistant syndrome was treated with IGF-I for two years and the treatment was effective in ameliorating hyperglycaemia. Overproduction of testosterone in polycystic ovaries was aggravated with this treatment, however. Therefore, IGF-I treatment may be used for glycaemic control but with caution because of its possible side effect of aggravating hyperandrogenism in these patients.
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PMID:Long-term follow up in type A insulin resistant syndrome treated by insulin-like growth factor I. 794 36

Abnormalities of GH secretion and clearance are well-documented in poorly controlled insulin-dependent diabetes mellitus (IDDM), but the contribution of the receptor (GHR) and the GH-binding protein (GHBP) to these abnormalities has not been defined. We studied the expression of the GHR/GHBP gene in the livers, hearts and kidneys in streptozocin-induced diabetes (STZ-D) in the rat. GHR and GHBP mRNA levels were measured by Northern blot and ribonuclease protection assays. Whereas levels of GHR and GHBP mRNA were significantly decreased in liver and heart of STZ-D rats when compared with the control group (P < 0.01), GHR mRNA was significantly increased in the kidneys of STZ-D rats (P = 0.03). Six days of insulin treatment did not significantly alter the levels of GHR/GHBP mRNA in the liver or heart of STZ-D rats, but significantly decreased GHBP mRNA (P = 0.04) in the kidney. Circulating IGF-I was reduced, as was IGF-I mRNA in the liver and heart of STZ-D rats; only circulating IGF-I was restored by insulin treatment. Neither STZ-D nor insulin treatment affected IGF-I or IGF-I receptor mRNA concentrations in the kidney. We conclude that (1) STZ-D modulates the expression of the GHR/GHBP gene and (2) that these changes in GHR/GHBP mRNA concentrations are tissue-specific; STZ-D decreases GHR/GHBP mRNA in liver and heart tissue but increases GHR mRNA concentrations in the kidney. Our results indicate a role for decreased numbers of hepatic GHRs in the pathogenesis of resistance to GH's actions in terms of IGF-I generation and promotion of linear growth in IDDM. We postulate that increased GHR expression in the kidney may be involved in the renal complications of IDDM.
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PMID:Tissue-specific regulation of the growth hormone receptor gene in streptozocin-induced diabetes in the rat. 796 96

Fetal mesenchyme-derived factors are likely to play an important role in pancreatic islet development and growth. We have used primary cultures of human fetal pancreatic tissue to identify growth factors that have morphogenic, mitogenic, and insulinotropic activity. The formation of islet-like cell clusters (ICCs) during a 6-day culture was stimulated two- to threefold by hepatocyte growth factor/scatter factor (HGF/SF) basic fibroblast growth factor (FGF)-2, and to a lesser extent by keratinocyte growth factor (FGF-7) and insulin-like growth factor-II (IGF-II). In contrast, transforming growth factor-beta (TGF-beta) had a strong inhibitory effect. The ICCs formed during HGF/SF stimulation consisted mainly of epithelial cells, whereas FGF-2-induced ICCs were predominantly nonepithelial. Furthermore, although both FGF-2 and HGF/SF increased the total insulin content of the cultures, only HGF/SF increased the insulin content per DNA. Quantitatively, HGF/SF stimulated a 2.3-fold increase in the proportion of insulin-positive cells and a 3-fold higher number of replicating beta-cells. Blocking of the IGF-I receptor inhibited ICC formation but did not affect their insulin content. Immunoneutralizing TGF-beta resulted in increased cell growth and insulin content, indicating the presence of an endogenous inhibitory TGF-beta activity in the model system. Our results suggest that HGF/SF may be an important component of the fetal mesenchyme-derived factors responsible for pancreatic islet development. HGF/SF also may prove valuable for supporting the in vitro growth of islet cells.
Diabetes 1994 Jul
PMID:Hepatocyte growth factor/scatter factor has insulinotropic activity in human fetal pancreatic cells. 801 61

Insulin and insulin-like growth factor I (IGF-I) are structurally related peptides capable of stimulating a variety of metabolic and mitogenic processes. In this study, we investigated the interaction between these peptides and their receptor-mediated pathways in an untransformed cell line. Cultured bovine fibroblasts specifically bound IGF-I and insulin, and each peptide could stimulate DNA synthesis and cell replication through its own receptor. Preincubation of bovine fibroblasts with concentrations of insulin that did not bind to the IGF-I receptor resulted in complete but reversible cellular desensitization to IGF-I-stimulated mitogenesis. Preincubation with as little as 0.1 nM insulin was sufficient to inhibit subsequent IGF-I action. Various insulin analogs produced desensitization in direct relation to the affinity of the insulin for the insulin receptor. Desensitization required > 4 h of cell exposure to insulin and was blocked in the presence of cycloheximide. Neither serum-stimulated mitogenesis nor IGF-I-stimulated glucose uptake were affected by insulin pretreatment. 125I-labeled IGF-I affinity cross-linking experiments indicated that preincubation with insulin did not affect labeling of the 130,000-M(r) alpha-subunit of the IGF-I receptor, but was associated with the loss of IGF-I- and insulin-inhibitive bands at M(r) = 100,000, 85,000, 58,000, and 34,000. These studies suggest that insulin, via interaction with insulin receptors on bovine fibroblasts, regulates IGF-I action at a step distal to IGF-I receptor binding and are consistent with desensitization occurring at an intracellular step in the mitogenic pathway shared by insulin and IGF-I.
Diabetes 1994 Sep
PMID:Physiological concentrations of insulin induce cellular desensitization to the mitogenic effects of insulin-like growth factor I. 807 Jun 13

Endothelial cells are likely to play an important role in the development of diabetic vascular diseases, since they are exposed directly to the abnormal circulating metabolites of diabetes and may be easily damaged early in the natural course of vascular complications. In this study, aortic endothelial cells were cultured from diabetic BB rats. Their binding and internalization of insulin-like growth factor-I (IGF-I) were measured. IGF-I binding was higher in cells of diabetic rats than of control rats at both 37 degrees C (4.5% +/- 1.6% v 2.74% +/- 0.9% per mg protein, P < .05) and 4 degrees C (20.6% +/- 5.6% v 13.7% +/- 4.6% per mg protein, P < .01). Internalization of IGF-I also increased (1.62% +/- 0.2% v 0.74% +/- 0.15% of total count at 37 degrees C after 60 minutes, P < .05). Cross-linking studies showed that in cells from diabetic rats, the major band of 140 kd corresponding to the alpha-subunit of the IGF-I receptor increased in density by 50% compared with those from control rats. The IGF-I-stimulated tyrosine kinase activity (TKA) of partially purified receptor from cells of diabetic rats, measured using poly-glu-tyr as substrate, was normal. Since the biological effects of IGF-I are initiated by its binding to the IGF-I receptor, which is able to transduce mitogenic and metabolic signals, our results support the hypothesis that the IGF-I receptor is involved in the development of diabetic vascular complications.
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PMID:Insulin-like growth factor-I receptor increases in aortic endothelial cells from diabetic rats. 823 30

Glomerular hypertrophy is reported in several endocrine disorders such as acromegaly and diabetes mellitus, where abnormalities of growth hormone and insulin-like growth factor (IGF-I) have been reported. In the present report, we have cultured bovine and human glomerular endothelial cells, and bovine glomerular epithelial and mesangial cells, and characterized the expression of IGF-I mRNA and its receptor in these cells. High affinity, specific receptors for IGF-I were identified in all three types of cells by radioreceptor assays. Receptor number (Ro) derived by Scatchard analysis revealed an unusually high number of Type I IGF receptors, approx. 1.2 x 10(5) receptors/cell in glomerular endothelial cells. Affinity crosslinking studies and immunoprecipitation with antibodies against the Type I IGF receptor identified the alpha-subunit of the IGF-I receptor as having a molecular mass of 140 kDa. Biologically, IGF-I was more potent than insulin or IGF-II in stimulating DNA synthesis in glomerular endothelial cells. Northern blot analysis showed that glomerular and aortic endothelial cells expressed IGF-1 mRNA of 1.7 kb. In contrast, renal glomeruli showed several IGF-1 mRNAs of 7.5, 1.7 and 1.2 kb. Thus, the demonstration of both a prepondence of Type I IGF receptors coupled with the growth promoting effects of IGF-I in glomerular endothelial and epithelial cells, as well as the local production of IGF-I mRNA suggests that IGF-I serves an important role as an autocrine or paracrine regulator of the growth of renal glomeruli.
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PMID:Characterization of type I IGF receptor and IGF-I mRNA expression in cultured human and bovine glomerular cells. 826 20

Membrane-associated tyrosine phosphatase activities were studied in two distinct states of insulin resistance: diabetes and pregnancy. Using a novel immunoenzymatic assay with intact insulin-like growth factor-I (IGF-I) and insulin receptors as substrates, we show that phosphotyrosine-protein phosphatases (PTP-ases) from normal rat tissues induce a decrease in tyrosine phosphorylation of both receptors. Membrane fractions from kidney, brain, and liver contain the highest PTP-ase activity toward the insulin receptor. After 20-day streptozotocin-induced diabetes, PTP-ase activities are increased by 70% in the placenta, reduced by 40-50% in liver and skeletal muscle, and remained unchanged in the nonclassical insulin target tissues, kidney and brain. In general, the dephosphorylation of IGF-I receptor follows a pattern similar to that of insulin receptor except in red skeletal muscle in which it is not modified. Pregnancy also induces alterations of liver PTP-ases similar to those elicited by diabetes with a 50% reduction of insulin and IGF-I receptor dephosphorylation. This effect of pregnancy is further potentiated by diabetes. The alterations in the activity of hepatic PTP-ases from diabetic and pregnant rats are associated with a decreased autophosphorylation of the insulin receptor, suggesting that the diminution of phosphatase activity might be associated to the state of receptor phosphorylation and activation. Our data demonstrate that alterations of PTP-ases in insulin target tissues are found in two insulin-resistant states, one characterized by hyperinsulinemia, pregnancy and one by insulinopenia, streptozotocin-diabetes. These observations suggest a possible relationship between the defective activity of receptor tyrosine kinases and membrane-associated phosphatases from insulin responsive tissues.
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PMID:Alteration of phosphotyrosine phosphatase activity in tissues from diabetic and pregnant rats. 841 48

Linear growth retardation is common in uncontrolled insulin-deficient diabetes, but individual organs such as kidney may hypertrophy. To explore whether this heterogeneity of response might be mediated by differential local insulin-like growth factor-I (IGF-I) gene regulation, we injected rats with ip saline, 65, 120, or 175 mg/kg streptozotocin (STZ). Diabetics were untreated or received daily insulin. Animals were killed 24, 48, or 72 h after documentation of diabetes, and liver, kidney, and lung messenger RNA (mRNA) content analyzed by solution hybridization/RNase protection assay. Untreated diabetics had 10- to 100-fold reductions in hepatic IGF-I mRNA apparent as early as 24 h, and the magnitude of these changes varied directly with the severity of diabetes. In contrast, kidney IGF-I mRNA content increased by 400-500% at 24 h in untreated diabetics given 175 mg/kg STZ, and by 100-200% at 48 h in those given 120 mg/kg STZ, with return to control levels by 72 h. Renal IGF-I mRNA levels actually decreased by 250-350% at 24 h in rats injected with 65 mg/kg STZ, returning to supranormal values by 72 h. These results suggest that severity and/or duration of the metabolic abnormality qualitatively and quantitatively affect this response in the kidney. Liver and kidney IGF-I mRNA levels approached normal with insulin therapy and were similar to controls in rats which received STZ but did not develop diabetes. Lung IGF-I mRNA levels were minimally altered in all experimental groups. At the time point and STZ dosage at which liver IGF-I mRNA changes were most dramatic, little change in liver alpha-tubulin mRNA was noted. At the time point and STZ dosages at which kidney IGF-I mRNA induction was most dramatic, renal IGF-I receptor mRNA was only minimally changed, and renal alpha-tubulin mRNA was modestly reduced. In summary: 1) hepatic IGF-I mRNAs are dramatically reduced, and renal IGF-I mRNAs are significantly increased soon after the onset of insulin-deficient diabetes in STZ-treated rats; 2) insulin therapy restores IGF-I mRNA levels toward normal; and 3) these changes in IGF-I mRNA content are specific and are not the result of hepatic or renal STZ toxicity. These data suggest that IGF-I gene expression is regulated in a discordant, organ-specific manner in diabetes, and that metabolic factors in addition to GH may differentially modulate the endocrine and paracrine effects of IGF-I on growth.
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PMID:Discordant, organ-specific regulation of insulin-like growth factor-I messenger ribonucleic acid in insulin-deficient diabetes in rats. 842 71

Renal hypertrophy is a characteristic and early manifestation of diabetes in human and experimental animals. We examined the precise distribution of insulin-like growth factor-I (IGF-I) receptor mRNA in the experimental diabetic rat kidney using a nonradioactive in situ hybridization technique. Expression of IGF-I receptor mRNA was rarely seen in the glomeruli of control rats. IGF-I receptor mRNA was detected after induction of diabetes in glomerular mesangial, visceral epithelial, and parietal epithelial cells. The number of IGF-I receptor mRNA-positive cells in a glomerulus increased significantly at 4 weeks as compared with the control rats. Overexpression of IGF-I receptor in glomerular cells may contribute to the glomerular hypertrophy in diabetic nephropathy.
J Diabetes Complications
PMID:Upregulation of insulin-like growth factor receptor gene in experimental diabetic rat glomeruli. 857 42


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