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 thiazolidinediones are a class of novel antidiabetic compounds that enhance the response of target tissues to insulin. Pioglitazone, a thiazolidinedione analog, lowers blood glucose and insulin levels in rodent models of non-insulin-dependent diabetes mellitus. We have studied the effect of pioglitazone on 3T3-L1 cells, a cell line that undergoes differentiation from a preadipocyte fibroblastic morphology to that of an adipocyte. Pioglitazone treatment of preadipocytes enhanced the insulin- or insulin-like growth factor-1 (IGF-I)-regulated differentiation (monitored by the rate of lipogenesis or triglyceride accumulation), whereas treatment of the cells in the absence of insulin or IGF-I resulted in no apparent change in the cellular phenotype. Pioglitazone caused both a leftward shift and enhanced maximum response for the IGF-I-regulated differentiation of the cells, consistent with the idea that the drug enhances the sensitivity of cells to polypeptide hormones. A series of pioglitazone analogs were tested in this system, and variations in activity relative to that of the parent compound were observed. A study of the time required for the drug to exert an effect on differentiation revealed that an increased rate of lipogenesis occurred 16-24 hr after drug treatment in appropriately staged cells. An increased rate of glucose transport and increased activity of lipogenic enzymes were noted in a time frame that correlated with the change in lipogenesis. Analysis of mRNA abundance for Glut-4, lipoprotein lipase, and glucose-6-phosphate dehydrogenase showed that pioglitazone enhanced the insulin induction of these mRNA species. Thus, pioglitazone, in combination with insulin or IGF-I, appears to be exerting effects on the cellular phenotype by eliciting changes in the expression of genes that regulate metabolic pathways leading to the acquisition of the differentiated phenotype.
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PMID:Enhancement of adipocyte differentiation by an insulin-sensitizing agent. 153 16

Congenital anomalies occur up to four times more frequently in diabetic pregnancy than in the nondiabetic population. Although past work has shown that maternal hyperglycemia and hyperketonemia may increase embryonic abnormalities, recent experimental evidence suggests that low insulin levels may also contribute to diabetic embryopathy. This study investigated the effects of guinea pig serum (whose insulin is inactive in rat systems) on rat embryonic growth and development in culture. Supplementation of guinea pig serum with pork insulin at low (1 ng/ml) and high (5 ng/ml) physiological concentrations and insulinlike growth factors (IGF) I and II were also studied. Culture of rat embryos from the early headfold stage in guinea pig serum resulted in poor embryonic growth and development with a 92% rate of anomalies. Supplementation of guinea pig serum with zinc-binding pork insulin significantly improved rat embryonic growth and development (46% anomaly rate) especially between the first 5 and 21 h of the period of organogenesis. This evidence supports our most recent findings that low insulin levels, as encountered in untreated diabetic pregnancy, may contribute to the increased risk of congenital abnormality. Insulin at low physiological concentrations improved growth, whereas higher physiological concentrations were required to increase growth and development. IGF-I or IGF-II supplementation improved rat embryonic growth and development but failed to match that of the controls, indicating that other growth factors including insulin may also be required.
Diabetes 1992 Mar
PMID:Insulin and insulinlike growth factors in embryonic development. Effects of a biologically inert insulin (guinea pig) on rat embryonic growth and development in vitro. 155 91

Five IDD patients achieved strict preconception glycemic control and then underwent nine IVF-ET cycles. All patients had high E2 response with an adequate number of preovulatory oocytes retrieved and normal fertilization and cleavage rates; one conceived. Follicular fluid analysis revealed similar E2, P, A, hCG, PRL, and IGF-I levels to non-IDD controls. The source of the insulin detected in the FF of IDD patients was probably from the insulin doses administered intensively during the tight diabetes management; insulin was absent in non-IDD participants. It seems that patients with IDD have conventional responses to gonadotropin stimulation for IVF and their follicular milieu resembles that of non-IDD patients. Nevertheless, in view of the significant advantages of preconceptional diabetes control in regard to pregnancy outcome, they should be allowed to participate in IVF programs only after tight preconception metabolic control has been obtained.
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PMID:In vitro fertilization and embryo transfer in well-controlled, insulin-dependent diabetics. 163 16

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.
Diabetes Res Clin Pract 1991 Nov
PMID:Insulin-like growth factor-I expression is not increased in the retina of diabetic BB/W-rats. 166 64

Circulating insulin-like growth factor (IGF) bioactivity is reduced in animals and patients with diabetes mellitus. We sought to determine whether the availability and levels of specific IGF binding proteins (BPs) are altered in animals with experimental diabetes, and might contribute to changes in circulating IGF bioactivity in experimental diabetes. Female Sprague-Dawley rats were administered streptozotocin or citrate buffer iv, and then killed either 3 days later, or else after 4-day insulin treatment (7.5 U/kg human NPH twice daily), or 2 days after insulin was discontinued. Serum [125I]IGF-I binding activity was markedly increased in diabetic animals compared to controls when analyzed by Sephacryl S-200 chromatography, dot blot, and affinity labeling techniques, due to increased binding to low mol wt BPs (81 +/- 4% of ligand eluting with low mol wt BPs in diabetic serum vs. 22 +/- 3% in control, P less than 0.001). In contrast, activated charcoal removed ligand from these BPs and underestimated the availability of BPs in diabetes. Serum binding activity fell toward control levels during insulin therapy, then rose again after insulin was withdrawn, corresponding to changes in metabolic status. To distinguish changes in specific BPs, serum proteins were separated by 13% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, then transferred to nitrocellulose. Ligand blotting with [125I]IGF-I demonstrated that serum levels of a 32 K mol wt IGF BP are markedly increased in diabetic rats and decline during insulin therapy. Levels of this 32 K IGF BP rose again after insulin was discontinued, demonstrating regulation in accordance with changes in insulin and metabolic status. Western analysis and affinity labeling with immunoprecipitation revealed that this 32 K protein is distinct from the 34 K fetal rat BP, and is immunologically related to the type 1 human IGF BP. We conclude that circulating [125I]IGF-I binding activity is markedly increased in animals with acute streptozotocin-induced diabetes, due to changes in low mol wt proteins, including a 32 K type 1 IGF BP that is regulated by changes in insulin and/or metabolic status. Regulation of low mol wt IGF BPs by insulin, and perhaps other factors, may play an important role in the modulation of tissue growth factor bioactivity in metabolic disease.
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PMID:Regulation of low molecular weight insulin-like growth factor binding proteins in experimental diabetes mellitus. 169

Binding proteins for the insulin-like growth factors (IGFBP) are important modulators of the biological actions of IGF-I and IGF-II. Concentrations of one of these proteins, IGFBP-1, in human plasma and IGFBP-1 mRNA in rat liver are markedly altered in diabetes and fasting. We now examine the regulation of IGFBP-1 and IGFBP-I mRNA in H4-II-E cells, a rat cell line derived from the minimal deviation H35 Reuber hepatoma previously reported to synthesize IGFBP-1 as its predominant IGF-binding protein. Confluent H4-II-E cells in serum-free medium were incubated with different hormones for 48 h, and the conditioned medium was analyzed by ligand blotting. Dexamethasone (10(-6) M) increased levels of 30-kDa IGFBP-1 approximately 10-fold; stimulation was half-maximal at 6 x 10(-9) M dexamethasone. No stimulation was seen with progesterone, testosterone, IGF-I, or rat GH, whereas insulin gave a small inhibition. Immunoblot analysis using a monoclonal antibody to human IGFBP-1 confirmed that the 30-kDa IGFBP induced by dexamethasone was IGFBP-1. IGFBP-1 mRNA was increased to a similar extent (7-fold), as determined by Northern blot hybridization using human or rat IGFBP-1 cDNA probes. The stimulation of IGFBP-1 mRNA was observed within 3 h after the addition of dexamethasone; IGFBP-1 in the medium increased more slowly. After withdrawal of dexamethasone from stimulated cells, IGFBP-1 mRNA decreased by 80% after 48 h; IGFBP-1 decreased more slowly. The increased abundance of IGFBP-1 mRNA in dexamethasone-treated cells primarily reflected increased transcription rather than increased mRNA stability.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dexamethasone stimulates transcription of the insulin-like growth factor-binding protein-1 gene in H4-II-E rat hepatoma cells. 170 85

The liver is an epithelioid organ that can regenerate following partial hepatectomy. Although it is composed mainly of hepatocytes, it has a complex, multicellular architecture, implying that intercellular communications must exist during regeneration. As in other mitogen-stimulated cells, immediate-early growth response genes induced in the absence of prior protein synthesis are likely to play an important regulatory role in the regenerative process. Through differential screening of regenerating liver cDNA libraries, we found that one of the most highly expressed immediate-early genes in liver regeneration encodes the rat homolog of the low-molecular-weight insulinlike growth factor (IGF)-binding protein (IGFBP-1). This protein has been implicated in enhancing the mitogenic effect of IGF on tissues. IGFBP-1 gene induction is transcriptionally mediated and specific to regenerating liver, as the gene is not expressed in mitogen-stimulated fibroblasts. IGFBP-1 expression has been shown to increase under low-insulin conditions such as diabetes, and the complex regulation of expression is indicated by our finding that insulin treatment of H35 rat hepatoma cells, which induces proliferation, also causes a rapid decrease in transcription and expression of the IGFBP-1 gene. Of note, IGFBP-1 mRNA is abundant in fetal rat liver, implying that it participates in normal liver growth and development. Although regenerating liver cells continue to produce IGF-I, we did not detect IGF-I receptor mRNA during the first 24 h after hepatectomy. However, some IGFBPs may act to enhance the activity of IGF-I independently of IGF-I receptors. Thus, IGF-1 and IGFBPs may interact with hepatocytes or nonparenchymal liver cells, through either IGF-I or novel receptors. In this way, IGFBP-I and IGF-I could act in a paracrine and/or autocrine fashion in maintaining normal liver architecture during regeneration.
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PMID:The gene encoding rat insulinlike growth factor-binding protein 1 is rapidly and highly induced in regenerating liver. 170 4

Neovascularisation is the biological process of forming new blood vessels. Many conditions can initiate neovascularisation including trauma or chronic ischaemia produced by diseases such as diabetes. Neovascularisation proceeds through a series of steps beginning with destruction of the basement membrane surrounding the microvascular endothelial cells, which allows endothelial cells to extend cytoplasmic buds in the direction of chemotactic factors. Migrating endothelial cells elongate, divide and eventually form tube structures which join to form mature new capillaries. Results of in vitro experiments, in vivo experiments, and clinical studies suggest that peptide growth factors can play key regulatory roles in each step of neovascularisation through both direct and indirect actions. At sites of vascular injuries, degranulating platelets release PDGF, IGF-I, EGF, and TGF-beta. Macrophages and neutrophiles drawn into the ischaemic or injured areas synthesise and release TGF-alpha, TGF-beta, and PDGF, and wounded endothelial cells secrete FGF. These peptide growth factors can stimulate migration, mitosis and differentiation of endothelial cells in culture and can induce neovascularisation in animal models. Clinical correlations suggest that peptide growth factors in the vitreous such as IGF-I and bFGF may promote diabetic retinopathy. As the biological mechanisms of neovascular growth factors become better understood, it may be possible to develop therapeutic approaches to selectively inhibit the peptide growth factors which regulate neovascular diseases.
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PMID:Neovascular growth factors. 171 36

We have measured fasting 0800 h insulin-like growth factor binding proteins (IGFBP)-1 and IGFBP-3, in 52 diabetic adolescents and 74 puberty-matched control subjects with short stature and normal hormonal status. We have also measured overnight hourly profiles of IGFBP-1, glucose, free insulin, and GH in 12 of the diabetic adolescents. With advancing age and pubertal status, IGFBP-1 declined and IGFBP-3 increased significantly in the control, but not the diabetic group. Fasting IGFBP-1 levels were elevated 4-fold compared to controls. Median IGFBP-3 was significantly lower in the diabetic compared to the control group in pubertal stages III and V. Elevated IGFBP-1 was significantly correlated with metabolic control in poorly controlled subjects (mean 12-month glycosylated haemoglobin greater than 8.5%). In the overnight profiles, mean hourly IGFBP-1 was inversely related to insulin, but not glucose. As free insulin levels declined, IGFBP-1 rose, associated with rising predawn blood sugars. The integrated 3-h IGFBP-1 value (0500-0800 h) was significantly correlated with the corresponding glucose integrated value. IGFBP-1 area under the curve for the whole overnight profile was significantly correlated with glycosylated hemoglobin in 11 of the 12 subjects. IGFBP-1 from diabetic adolescents has been shown to inhibit IGF-I bioactivity. We postulate that IGFBP-1 may have a role in growth impairment of poorly controlled diabetes and may contribute to the dawn phenomenon.
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PMID:Abnormal regulation of insulin-like growth factor binding proteins in adolescents with insulin-dependent diabetes. 171 17

The insulin-like growth factor-binding proteins (IGFBPs) are thought to determine the distribution of IGF-I and IGF-II between the blood and tissue compartments and to modulate their biological activities. A dynamic metabolic role for one of the IGFBPs, IGFBP-1, is suggested by the fact that plasma IGFBP-1 was increased after fasting and diabetes and rapidly decreased by refeeding or insulin treatment, respectively. IGFBP-1 mRNA also is increased in the livers of diabetic rats and decreased by insulin treatment. To understand the molecular basis for this regulation, we have examined the effects of insulin on IGFBP-1 and IGFBP-1 mRNA in the H4-II-E cell line derived from the well differentiated H35 rat hepatoma. IGFBP-1, identified by ligand blotting and immunoblotting, is the major IGFBP in H4-II-E cells. Incubation of H4-II-E cells with insulin for 24 h decreased IGFBP-1 in the culture medium by approximately 50%. Inhibition was observed at physiological concentrations of insulin (ED50, less than 0.5 nM), but not at higher concentrations of IGF-II. These results, together with the fact that H4-II-E cells do not possess IGF-I receptors with which insulin might cross-react, suggest that insulin acts via the insulin receptor. Insulin inhibited IGFBP-1 in the medium by 80% in the absence of glucose, suggesting that the inhibition is a direct effect of insulin; glucose exerted a smaller independent effect in the absence of insulin. Insulin decreased IGFBP-1 mRNA in H4-II-E cells by 50% within 1 h and by 90% after 2-12 h of incubation. Nuclear run-on transcription assays indicated a corresponding decrease in the rate of IGFBP-1 gene transcription. Pretreatment of H4-II-E cells with dexamethasone stimulated IGFBP-1 transcription and increased steady state IGFBP-1 mRNA; stimulation was abolished by insulin treatment, indicating that inhibition by insulin was dominant over induction by dexamethasone. Thus, insulin, acting through the insulin receptor, rapidly decreases the abundance of IGFBP-1 mRNA in H4-II-E cells. Regulation occurs at least in part at the level of gene transcription. We propose that regulation of IGFBP-1 synthesis is an important component of the regulation of IGFBP-1 by insulin in vivo.
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PMID:Insulin rapidly inhibits insulin-like growth factor-binding protein-1 gene expression in H4-II-E rat hepatoma cells. 171 86


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