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)

Insulin and the insulin-like growth factors IGF-I and IGF-II are thought to exert their mitogenic effects in cultured chick embryo fibroblasts and human skin fibroblasts via IGF receptors rather than via insulin receptors. These effects appear to be mediated by the type I subtype of IGF receptor, which is structurally similar to the insulin receptor and exhibits significant cross-reactivity with insulin. As a first step in our long-range goal of defining those features of the IGF-I and IGF-II molecules that confer enhanced mitogenic activity and reactivity with these mitogenic type I IGF receptors, we have prepared two hybrid insulin-IGF molecules and examined their mitogenic and binding activities: (1) A27-insulin, containing an elongated 27-residue A-chain (in which the 6-residue D-domain of IGF-II was added to the carboxy-terminus of the 21-residue A-chain of insulin) combined with the B-chain of insulin; and (2) A insulin-B IGF-1, containing the A-chain of insulin and the synthetic 30-residue B-domain of IGF-I. Both hybrid molecules stimulated DNA synthesis and inhibited 125I-IGF-I binding to type I IGF receptors in both chick embryo and human fibroblast cultures. A27-insulin had considerably greater mitogenic potency and binding potency than A insulin-B IGF-I. Neither hybrid molecule was more potent in these assays than insulin, indicating that the presence of D IGF-II or B IGF-I by itself was not sufficient to increase the mitogenic potency of insulin in fibroblasts. By contrast, A insulin-B IGF-I showed enhanced reactivity with an antiserum to IGF-I. A27-insulin retained significant insulin-like metabolic activity despite the presence of the D-domain of IGF-II.
Diabetes 1986 Mar
PMID:Mitogenic activity and receptor reactivity of hybrid molecules containing portions of the insulin-like growth factor I (IGF-I), IGF-II, and insulin molecules. 300 95

The effects of recombinant human growth hormone (GH, 1 micrograms/ml) and insulin-like growth factor I (IGF-I, 200 ng/ml) on the production of insulin and glucagon by human fetal islet-like cell clusters (ICCs) were studied in tissue culture. ICCs were derived after collagenase digestion and culture of pancreases from 16 fetuses (mean gestational age 15.6 wk). The ICCs were cultured with or without GH or IGF-I for 7 or 31 days. Basal rates of insulin and glucagon production were not altered by GH during the first 17 days of culture, but the release of both hormones was increasingly augmented by GH during the last 2 wk of culture (131% increase in insulin and 85% in glucagon compared with controls). ICCs cultured for 7 days in the presence of GH secreted more insulin when incubated for 120 min in 20 mM than in 2 mM glucose (2.1-fold response, P less than .05), whereas ICCs maintained in basal medium did not respond to glucose. GH had no effect on DNA and insulin content or insulin biosynthesis. Exogenous IGF-I caused a 28% suppression of insulin release (P less than .05) between days 4 and 10 of culture but induced a 49% increase in the mean secretion rate during the last week (days 25-31, P less than .01). Glucagon release was not affected by exogenous IGF-I. In contrast to GH, exogenous IGF-I induced a twofold increase in the DNA content of the 7-day--cultured ICCs. However, insulin biosynthesis and release were markedly suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1988 Dec
PMID:Effects of growth hormone and insulin-like growth factor I on endocrine function of human fetal islet-like cell clusters during long-term tissue culture. 305 61

We recently reported that insulin inhibits basal and cortisone- and T3-stimulated GH secretion by GH3 rat pituitary tumor cells. The effects of purified semisynthetic human insulin were therefore tested on long-term GH secretion in normal pituitary cells. Primary monolayer cultures derived from male rat pituitaries were grown in serum-free defined medium. Insulin (7 nM) maximally inhibited basal GH secretion by almost 60% after 72 h, with 50% of maximal GH suppression occurring with 1.75 nM insulin. Insulin receptor antiserum blocked the suppression of GH by 7 nM insulin, but had no effect on the suppression of GH by IGF-I (3.25 nM). GRF (100 pM) stimulated GH two- to threefold during 48 h. Insulin (7 nM) prevented the stimulation of GH induced by up to 1 nM GRF (P less than 0.01) and this suppression was also selectively blocked by insulin receptor antiserum. The inhibition of GRF-stimulated GH required a lag period of 48 h and the dose of insulin required for 50% inhibition of GRF stimulation was 3.5 nM. Insulin did not alter the degradation rate of 125I-GH in these cultures and medium glucose concentrations were not different in control or insulin-treated wells for up to 72 h of incubation. The insulin-induced suppression of GH was also observed when cells were grown in glucose-free medium. Insulin did not nonselectively suppress cell secretion, as PRL secretion was mildly stimulated (P less than 0.01) by insulin in the same cultures. Fibroblast growth factor, epidermal growth factor, and insulin A-chain at similar doses did not alter basal or GRF-stimulated GH secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1986 Apr
PMID:Effects of insulin on rat anterior pituitary cells. Inhibition of growth hormone secretion and mRNA levels. 308

Plasma concentrations of insulin like growth factor-I in the adolescent diabetic remain controversial. IGF-I levels were determined by radioimmunoassay in 81 insulin dependent adolescent diabetics (49 boys and 32 girls) and compared with 75 puberty stage matched normal controls. Plasma somatomedin bioactivity was determined by cartilage bioassay in a smaller group of 10 normal and 25 diabetic subjects. IGF-I concentrations increased in the normals during puberty and there were no observed differences between the sexes. (P1, 0.77 +/- 0.08; P2, 1.33 +/- 0.2; P3, 1.59 +/- 0.16; P4, 1.76 +/- 0.16; P5, 2.24 +/- 0.09). IGF-I also increased in the diabetics reaching a peak level at stage three in both girls and boys. Combining the data from both sexes the diabetics had significantly lower levels of IGF-I compared to controls at stages; (P1, 0.67 +/- 0.05, ns. P2, 0.92 +/- 0.1, p less than 0.05; P3, 1.16 +/- 0.09, p less than 0.01; P4, 0.73 +/- 0.11, p less than 0.001; P5, 1.13 +/- 0.11, p less than 0.001). Plasma somatomedin bioactivity was elevated in the normals but inhibitory responses were observed in all but two of the diabetic subjects, highlighting the presence of inhibitory factors in diabetic plasma. HbA1C levels rose in the diabetics during puberty, however using covariance analysis there was no relationship between IGF-I and HbA1C when changes relating to puberty were excluded. The importance of controlling for pubertal stage as opposed to age is noted when assessing IGF-I status in the diabetic adolescent.
Diabetes Res 1988 Dec
PMID:Somatomedin-C/IGF-I measured by radioimmunoassay and somatomedin bioactivity in adolescents with insulin dependent diabetes compared with puberty matched controls. 324 65

Little is known about hormonal regulation of substrate transport and metabolism in the mucosal lining of the small intestine. Because insulin regulates these functions in other tissues by binding to its receptor, we have investigated the presence of insulin receptors in canine small intestinal mucosa with basolateral membranes (BLM) and brush border membranes (BBM) prepared by sorbitol density centrifugation. A14-[125I]iodoinsulin was used to study binding and structural characteristics of specific insulin receptors in BLM. Analysis of receptors in BLM identified binding sites with high affinity (Kd 88 pM) and low capacity (0.4 pmol/mg protein) as well as with low affinity (Kd 36 nM) and high capacity (4.7 pmol/mg protein). Binding was time, temperature, and pH dependent, and 125I-labeled insulin dissociation was enhanced in the presence of unlabeled insulin. Cross-reactivity of these receptors to proinsulin, IGF-II, and IGF-I was 4, 1.8, and less than 1%, respectively. Covalent cross-linking of labeled insulin to BLM insulin receptors with disuccinimidyl suberate revealed a single 135,000-Mr band that was completely inhibited by unlabeled insulin. There was a 16-fold greater specific binding of insulin to BLM (39.0 +/- 2.4%) than to BBM (2.5 +/- 0.6%). These results demonstrate the presence of a highly specific receptor for insulin on the vascular, but not the luminal, surface of the small intestinal mucosa in dogs, and suggest that insulin may play an important role in the regulation of gastrointestinal physiology.
Diabetes 1987 Oct
PMID:Identification and characterization of insulin receptors in basolateral membranes of dog intestinal mucosa. 330 83

Insulin binding to mouse oocytes and preimplantation embryos was assessed by light-microscopic autoradiography. Significant insulin binding was present on the cells of morulae and increased twofold at the blastocyst stage of development. Insulin binding was markedly decreased by native insulin and to a lesser extent by insulin-like growth factors (IGFs). No specific insulin binding was detected on oocytes or embryos throughout the eight-cell stage. Specific binding of IGF-I and IGF-II was also observed on the cells of blastocyst outgrowths. The findings demonstrate that specific binding of insulin and IGF is temporally expressed on the cells of pre- and peri-implantation mouse embryos. These results confirm and extend our previous immunofluorescence study.
Diabetes 1988 May
PMID:Autoradiographic evidence for insulin and insulin-like growth factor binding to early mouse embryos. 336 Feb 16

The regulation of DNA replication by growth hormone and the production of somatomedin C/insulin-like growth factor I (SM-C/IGF-I) and insulin by fetal rat islets in culture has been studied. Islets were cultured for 3 days in medium containing 2.7 or 16.7 mM glucose, various concentrations of fetal calf serum (FCS), and 100-1000 ng/ml human growth hormone (GH). DNA replication was determined by incorporation of [3H]thymidine into islet DNA; SM-C/IGF-I and insulin secreted into the medium were measured by specific radioimmunoassays. Glucose caused a twofold stimulation of islet DNA replication in medium containing greater than or equal to 1% FCS but failed to stimulate DNA replication at lower serum concentrations. In the presence of 16.7 mM glucose, GH (100-1000 ng/ml) stimulated DNA replication at all serum concentrations. In medium containing 2.7 mM glucose, GH was stimulatory only in the presence of 1% FCS. Somatomedin C/IGF-I release into the culture medium could be detected in all experimental groups. Glucose alone did not affect SM-C/IGF-I release, and in serum concentrations less than 0.1% FCS, GH also failed to increase the release of the peptide. In medium containing 1% FCS and 16.7 mM glucose, 100-1000 ng/ml GH caused a 50-100% increase in SM-C/IGF-I release into the medium. Addition of 100 ng/ml exogenous SM-C/IGF-I to medium containing 16.7 mM glucose and 0.1-1.0% FCS caused a twofold stimulation of the islet DNA replication. This effect could be abolished by the addition of an antibody to SM-C/IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1987 Mar
PMID:Growth hormone regulation of somatomedin C/insulin-like growth factor I production and DNA replication in fetal rat islets in tissue culture. 354 51

The presence of somatomedin-C/insulin-like growth factor I (SM-C/IGF-I) was investigated in human fetal pancreatic glands obtained after prostaglandin-induced abortion at 14-17 wk of gestation. Pancreatic explants were cultured in medium containing 11.1 or 22.2 mM glucose and 20% fetal calf serum for 8-10 days. During this period they were exposed, on two separate occasions, to serum-free culture medium for 24 h. SM-C/IGF-I and insulin were measured radioimmunologically in the serum-free media and in acid-ethanol-extracted homogenates of the cultured explants. SM-C/IGF-I was measurable in the conditioned media only after extraction by reverse-phase chromatography to remove somatomedin-binding proteins. On gel filtration at neutral pH of extracted medium samples, the immunoreactive SM-C/IGF-I was recovered in the region of the homogeneous peptide with an apparent molecular weight of 7000-8000. Explants cultured in 22.2 mM glucose contained more SM-C/IGF-I and had a tendency to release more of the peptide into the culture medium than explants cultured in 11.1 mM. There was no difference in insulin content or release between the two groups. By immunocytochemistry, SM-C/IGF-I was localized to the beta-cells of the endocrine pancreas in both freshly fixed tissue and cultured explants. We conclude that the human fetal pancreas contains SM-C/IGF-I and secretes the peptide during tissue culture. The presence of SM-C/IGF-I in the islets of Langerhans may contribute to the growth and development of the insulin-producing beta-cell.
Diabetes 1987 Apr
PMID:Somatomedin-C in human fetal pancreas. Cellular localization and release during organ culture. 354 47

Despite reports of reduced serum insulin-like growth factor (IGF) levels in experimentally diabetic animals, human diabetic patients have been reported to have decreased, normal, or even elevated levels. This study was a cross-sectional examination of the effect of age on immunoreactive IGF-I levels in adult patients with insulin-dependent or noninsulin-dependent diabetes mellitus (IDDM and NIDDM) attending a diabetes out-patient clinic. The patients and normal subjects studied were divided into the age ranges 21-30, 31-40, 41-50, 51-60, and over 60 yr. For all ages combined, the mean IGF-I level (+/- SD) was 0.84 +/- 0.26 U/ml (202 +/- 62 ng/ml) in 133 normal subjects, significantly reduced to 0.41 +/- 0.17 U/ml in 121 IDDM patients, and 0.49 +/- 0.19 U/ml in 46 NIDDM patients (both P less than 0.001). In both groups there was a marked decline in IGF-I with increasing age (P less than 0.01). Except for NIDDM patients aged 21-30 yr (only two patients), IGF-I levels in both IDDM and NIDDM patients were significantly lower in every age range than those in age-matched normal subjects, but did not differ between the two diabetic groups. Glycosylated hemoglobin levels correlated inversely with IGF-I levels only in younger patients with IDDM (r = -0.486; P less than 0.05 for patients aged 21-40 yr). We conclude that factors common to IDDM and NIDDM, perhaps related to relative nutritional deficiency at the cellular level, cause a reduction in serum IGF-I levels, and that this reduction occurs independently of age-related changes in IGF-I.
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PMID:Serum insulin-like growth factor I levels in adult diabetic patients: the effect of age. 373 35

GH secretion is stimulated by hypothalamic GH-releasing factor (GHRH) and inhibited by somatostatin. Since GH induces the production of insulin-like growth factors (IGF) in liver and other tissues, it is of interest to learn whether IGF alters GH release through long loop feedback inhibition. Pituitary adenomas which had been removed from six acromegalic patients were processed for dispersed cell cultures and/or cell membrane preparations. Binding studies using 125I-labeled IGF-I, IGF-II, and insulin revealed specific hormone binding for each ligand to cell membranes derived from four somatotropinomas. A partially purified somatomedin preparation inhibited basal and/or GHRH-stimulated GH release from cultured pituitary cells derived from three of four adenomas; there was no effect of somatomedin in one tumor. In a single tumor, insulin also partially inhibited GHRH-stimulated GH release. Additionally, in one nonadenomatous pituitary removed from a patient with diabetes mellitus, insulin and somatomedin inhibited GHRH-stimulated GH release, and insulin inhibited basal GH secretion. These results indicate that specific cell membrane receptors for somatomedin peptides and insulin may be found on cell membranes from GH-secreting tumors, and that somatomedins and insulin can inhibit GH release in cultured human somatotropinoma cells. Thus, these data suggest that somatomedins may exert feedback inhibition of GH secretion in some patients with acromegaly.
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PMID:Regulation of growth hormone release from cultured human pituitary adenomas by somatomedins and insulin. 388 29


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