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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The kidney is a site of insulin-like growth factor I (IGF-I) production and IGF-I mediates effects on kidney growth and function. Diabetes is associated with kidney growth in man and the rat and, in the latter, commences within 48 h of induction of diabetes. Levels of kidney IGF-I are increased during the first 2-3 days of diabetes and this is at least partially due to increased production. Additionally, IGF-I binding is increased in diabetic rat kidney, due to increased binding to the IGF-I receptor and induction of proximal tubular binding protein expression. These changes are attenuated in prepubertal rats suggesting hormonal regulation. Further studies suggest that the changes are partly GH-dependent but independent of direct sex steroid effects. As kidney growth has been implicated in the subsequent development of diabetic nephropathy, further exploration of the close association between diabetes-related kidney growth and IGF-I accumulation may lead to an improved understanding of this complication.
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PMID:IGF-I and IGF binding proteins in diabetes-related kidney growth. 128 98

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 effects of continuous or acute administration of insulin or insulin-like growth factor-I (IGF-I) on IGF-I mRNA and IGF-I receptor mRNA were studied in the skeletal muscle (gastrocnemius), heart muscle and vascular smooth muscle (aorta) of non-diabetic and diabetic rats using a solution hybridization assay. The levels of IGF-I mRNA in the different types of muscle markedly decreased by diabetes, whereas changes in IGF-I receptor mRNA were less consistent. Continuous infusion of diabetic rats with insulin (28 or 35 nmol/day) for 4 days normalized the altered levels of IGF-I mRNA and IGF-1 receptor mRNA. Infusion of equimolar concentrations of IGF-I did not affect IGF-I mRNA, but decreased the level of IGF-I receptor mRNA in skeletal muscle. In acute experiments, rats were injected with equipotent blood glucose-lowering doses of insulin (14 nmol) or IGF-I (107 nmol). Insulin did not significantly affect levels of IGF-I mRNA, but decreased levels of IGF-I receptor mRNA in skeletal muscle and aorta. IGF-I increased levels of IGF-I mRNA in heart muscle, and markedly decreased levels of IGF-I receptor mRNA in skeletal muscle and heart muscle from non-diabetic and diabetic rats. In conclusion, exogenous IGF-I and insulin can increase IGF-I mRNA and decrease IGF-I receptor mRNA, indicating that both insulin and IGF-I can act as regulators of the IGF-I system in muscle in vivo.
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PMID:In-vivo regulation of messenger RNA encoding insulin-like growth factor-I (IGF-I) and its receptor by diabetes, insulin and IGF-I in rat muscle. 147 27

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

Mauriac syndrome (MS) consists of a triad of poorly controlled diabetes, profound growth retardation, and hepatomegaly. The mechanisms involved in the growth retardation of those patients are not well understood. In an attempt to determine whether the growth retardation was secondary to somatroph secretory failure, abnormal pulsatile secretion, deletion of the growth hormone (GH) receptor, inadequate insulin-like growth factor I (IGF-I) generation, or abnormal IGF-I binding proteins (IGFBPs) two patients with MS were studied and their results compared with those of age-matched diabetic boys of similar glycemic control who were growing well. Overnight GH profiles in the MS and normally growing diabetics were analyzed by the CLUSTER program. The mean 12-hour GH concentrations, pulse amplitude, and pulse frequency were not different in either group of patients and did not change during acute normalization of the serum glucose overnight in the MS patients. The GH-binding proteins (GHBPs) relative binding were found to be the same in both groups of patients and did not differ from normal nondiabetic sera (62% +/- 8.0% relative specific binding in MS patients, v 53% +/- 4.3% in diabetic controls). The IGF-I concentrations were normal and comparable in both groups of patients (1.1 +/- 0.1 U/mL MS, v 1.1 +/- 0.3 diabetic controls). The IGFBPs were comparable in both groups of patients as well. One of the patients with MS had no meaningful increase in his growth velocity after 1 year on GH therapy despite good compliance. In conclusion, our data show normal hypothalamic-pituitary function, normal GHBP, IGF-I generation, and IGFBPs in two patients with MS when compared with normally growing diabetic children. These data, and the lack of linear growth in response to exogenous GH therapy in one patient, suggest a GH-resistant state, either secondary to impaired bioactivity of IGF-I, or a defect at or distal to the IGF-I receptor.
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PMID:Function of the growth hormone-insulin-like growth factor I axis in the profoundly growth-retarded diabetic child: evidence for defective target organ responsiveness in the Mauriac syndrome. 171 38

Insulin resistance may be due directly to genetically programmed disorders of insulin action or acquired defects in which environmental factors influence insulin action. To address the issue of this distinction, we studied the ability of insulin to stimulate colony formation in primary cultures of erythroid progenitors (assumed to retain environmental influences) and immortalized T lymphocytes (presumed to reflect only genetic influences). Four patients with hyperinsulinemia and disturbed glucose metabolism were studied (2 patients with acanthosis nigricans, 1 of whom had circulating anti-insulin-receptor antibodies, 1 with partial lipodystrophy, and 1 with Cushing's syndrome). The mean colony-forming ability of their erythroid progenitor cells in response to insulin stimulation (less than or equal to 1.6 pM) was significantly blunted compared with control cells (P less than 0.05). The mean responsiveness of their immortalized T-lymphoblast cell lines to similar insulin concentrations was no different than that of control T-lymphocyte lines, consistent with an acquired cause for the observed insulin resistance in each case. A T-lymphocyte line from a patient with leprechaunism, however, showed no stimulation in response to physiological concentrations of insulin. With these same in vitro methodologies, there was normal T-lymphocyte line responsiveness to insulinlike growth factor I (IGF-I) or insulin concentrations greater than 8.6 pM; both of these responses could be completely blocked by preincubation with an antibody to the IGF-I receptor. These findings suggest that, despite resistance to physiological levels of insulin, the high circulating insulin concentrations present in the serum of these patients could mediate unwanted tissue-specific growth through an intact IGF-I receptor-effector mechanism.
Diabetes 1991 Jan
PMID:Use of in vitro clonogenic assays to differentiate acquired from genetic causes of insulin resistance. 184 48

Based on the observation that insulinlike growth factor I (IGF-I) can stimulate glucose utilization in nondiabetic subjects and that the action of the IGF-I receptor is normal in the skeletal muscle of patients with non-insulin-dependent diabetes mellitus (NIDDM), it seems possible that IGF-I might provide an effective acute treatment for the hyperglycemia of NIDDM. Using our recently developed in vitro human muscle preparation, we investigated the hypothesis that IGF-I might be an effective alternative to insulin in stimulating glucose transport in diabetic muscle. Abdominal muscle samples from nonobese nondiabetic, obese nondiabetic, and obese NIDDM patients were obtained during elective abdominal surgery. Plasma levels of IGF-I in diabetic patients were lower than those in either of the nondiabetic groups. Binding studies with wheat-germ-agglutinin-chromatography-purified receptors demonstrated the presence of IGF-I receptors in human muscle, with IGF-I binding being approximately 24% that of insulin. There was no change in IGF-I binding in muscle from obese or diabetic subjects, and the structural characteristics of the IGF-I receptor were not altered, as determined by electrophoretic mobility. IGF-I stimulated glucose transport approximately twofold in incubated muscle from control subjects, but there was no IGF-I stimulation of transport in muscle from obese subjects with or without NIDDM. These results confirm a previous report that human muscle contains receptors for IGF-I and demonstrate for the first time that IGF-I can stimulate glucose transport in human muscle. However, muscle from obese subjects with or without NIDDM is resistant to the action of IGF-I.
Diabetes 1990 Sep
PMID:IGF-I--stimulated glucose transport in human skeletal muscle and IGF-I resistance in obesity and NIDDM. 216 97

Insulinlike growth factor I (IGF-I) is a mitogenic hormone with important regulatory roles in growth and development. One of the target organs for IGF-I action is the kidney, which synthesizes abundant IGF-I receptors and IGF-I itself. To study the involvement of IGF-I and the IGF-I receptor in the development of nephropathy, one of the major complications of diabetes mellitus, we measured the expression of these genes in the kidney and in other tissues of the streptozocin-induced diabetic rat. The binding of 125I-labeled IGF-I to crude membranes was measured in the same tissues. We observed a 2.5-fold increase in the steady-state level of IGF-I-receptor mRNA in the diabetic kidney, which was accompanied by a 2.3-fold increase in IGF-I binding. In addition to this increase in IGF-I binding to the IGF-I receptor, there was also binding to a lower-molecular-weight material that may represent an IGF-binding protein. No change was detected in the level of IGF-I-peptide mRNA. Similarly, IGF-II-receptor mRNA levels and IGF-II binding were significantly increased in the diabetic kidney. IGF-I- and IGF-II-receptor mRNA levels and IGF-I and IGF-II binding returned to control values after insulin treatment. Because the IGF-I receptor is able to transduce mitogenic signals on activation of its tyrosine kinase domain, we hypothesize that, among other factors, high levels of receptor in the diabetic kidney may also be involved in the development of diabetic nephropathy. Increased IGF-II-receptor expression in the diabetic kidney may be important for the intracellular transport and packaging of lysosomal enzymes, although a role for this receptor in signal transduction cannot be excluded. Finally, the possible role of IGF-binding proteins requires further study.
Diabetes 1990 Dec
PMID:Experimental diabetes increases insulinlike growth factor I and II receptor concentration and gene expression in kidney. 217 8

Insulin and insulin-like growth factor I (IGF-I) are structurally related polypeptides that stimulate DNA synthesis and cellular proliferation, probably through a common pathway. Human arterial smooth muscle cells in culture demonstrated the presence of high-affinity receptors for both these hormones. Insulin and IGF-I both exhibited cross-reactivity to each other's receptors but with an affinity that is 100-fold less than for the homologous receptor. To examine more closely the receptor responsible for producing the growth effects, we used the polyclonal antibody against the insulin receptor, B2, and a monoclonal antibody to the IGF-I receptor, alpha IR3. We studied the growth effects of insulin and IGF-I as measured by stimulation of c-myc, DNA synthesis, and cellular proliferation in the presence and absence of these antibodies. F(ab') fragments of the anti-insulin-receptor antibody at a concentration of 10 micrograms/ml were capable of displacing greater than 90% of the bound insulin, thus establishing an effective insulin-receptor blockade. Under such blockade, insulin and IGF-I were both capable of doubling the amount of DNA synthesis and cell number in cultured human arterial smooth muscle cells. However, in the presence of a 1:2500 dilution of the monoclonal antibody alpha IR3, which caused a 90% displacement of IGF-I bound to its receptor, both the insulin and IGF-I effects on stimulating DNA synthesis or cellular proliferation were inhibited by greater than 90%. These findings demonstrate that the IGF-I receptor is the common pathway for the growth effects of both insulin and IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1989 Jan
PMID:Characterization of induction of protooncogene c-myc and cellular growth in human vascular smooth muscle cells by insulin and IGF-I. 252 Dec 9

We demonstrate the presence of specific insulinlike growth factor I (IGF-I) receptors in human adipocytes. Competition studies with 125I-labeled IGF-I and unlabeled IGF-I, IGF-II, and insulin showed the specificity of 125I-IGF-I binding to the IGF-I receptors in adipocytes, membranes, and partially purified detergent-solubilized extracts. The monoclonal antibody to the IGF-I receptor (alpha-IR3) inhibits 125I-IGF-I binding and immunoprecipitates the IGF-I receptor. In addition, the alpha-subunit of IGF-I receptor is approximately 10,000 Mr larger than the alpha-subunit of insulin receptor, and IGF-I stimulates phosphorylation of the beta-subunit of the IGF-I receptor. IGF-I stimulates basal glucose transport in human adipocytes, but the concentrations of IGF-I required for half-maximal and maximal stimulation of glucose transport are 800- and 1000-fold greater than that of insulin. The possibility of IGF-I stimulating glucose transport by interacting predominantly with insulin receptors is suggested by data showing that 1) IGF-I competes with insulin-binding sites, 2) there is a lack of an additive effect with IGF-I and insulin in stimulating glucose transport, 3) alpha-IR3, which specifically inhibits IGF-I binding, does not inhibit IGF-I or insulin-stimulated glucose transport, 4) insulin-receptor antibody MA-10 inhibits IGF-I and insulin-stimulated glucose transport, and 5) IGF-I stimulates insulin-receptor autophosphorylation, although its effect is markedly decreased compared with insulin. In summary, human adipocytes possess specific IGF-I receptors. However, IGF-I stimulates glucose transport predominantly by interacting with the insulin receptor.
Diabetes 1989 Oct
PMID:Mechanism of IGF-I-stimulated glucose transport in human adipocytes. Demonstration of specific IGF-I receptors not involved in stimulation of glucose transport. 255 60


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