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)

Diabetes mellitus in the rat is associated with loss of pulsatile GH secretion. An interplay between hypothalamic GH-releasing factor (GRF) and inhibitory factor [somatostatin (SRIF)] secretion is thought to account for episodic pituitary GH release. An increase in SRIF tone/action or a decrease in GRF release/response in diabetic rats could account for the suppressed GH levels. Pituitaries from streptozotocin-diabetic rats contained less GH than controls (15.9 +/- 2.5 vs. 29.5 +/- 4.6 micrograms/mg; P less than 0.05) despite normal somatotrope representation, as demonstrated using immunofluorescence studies. Basal GH secretion from monolayer culture of dispersed anterior pituitary (AP) cells from diabetic rats was proportionately decreased (150 +/- 10 vs. 103 +/- 10 ng/10(5) cells; P less than 0.005). GRF (10(-11)-10(-8) M)-induced release of GH from AP cells was decreased in diabetic rats (maximum response to 10(-8) M GRF, 401 +/- 60 vs. 618 +/- 41 ng/10(5) cells; P less than 0.01); however, sensitivity to GRF was unchanged (EC50, 79 +/- 41 vs. 128 +/- 67 pM). By contrast, SRIF (10(-7)-10(-10)-induced inhibition of GRF (10(-8) M)-mediated GH release was impaired in AP cells of diabetic rats compared to that in controls (IC50, 112 +/- 33 vs. 55 +/- 31 pM; P less than 0.05) associated with a decrease in AP plasma membrane SRIF receptor concentration (63.4 +/- 15.6 vs. 160.3 +/- 13.7 fmol/mg protein; P less than 0.05), with no change in affinity. These findings are consistent with chronic exposure to increased hypothalamic SRIF influence. GH synthesis has been shown to be independent of SRIF regulation; however, insulin-like growth factor-I and GRF inhibit and stimulate GH synthesis, respectively. In diabetic rats insulin-like growth factor-I levels were decreased, appropriate to low GH status, in serum (290 +/- 66 vs. 1662 +/- 92 ng/ml; P less than 0.001) and hypothalamus (6.8 +/- 1.0 vs. 13.0 +/- 0.4 pg/mg wet wt; P less than 0.001) and, thus, did not seem to account for the low AP GH content. Hypothalamic GRF content in diabetic rats (1.11 +/- 0.10 ng/hypothalamus) did not differ from that in controls (1.16 +/- 0.17 ng/hypothalamus). GRF mRNA levels, however, were reduced by 80% in diabetic rats compared to controls. Taken together these data support a combined role for decreased hypothalamic GRF and increased SRIF in mediating alterations of GH synthesis and secretion in streptozotocin-induced diabetes.
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PMID:Altered pituitary growth hormone (GH) regulation in streptozotocin-diabetic rats: a combined defect of hypothalamic somatostatin and GH-releasing factor. 196 64

Insulinopenic diabetes mellitus in the rat is associated with reduced circulating levels of insulin-like growth factor-I (IGF-I), resulting primarily from decreased IGF-I synthesis in liver and extrahepatic sites. Plasma GH levels in these animals are also suppressed, with loss of episodic secretion and decreased pituitary synthesis. Intrapituitary IGF-I has been postulated to exert local autocrine/paracrine negative feedback regulation on GH synthesis and secretion. The present studies were designed to examine regulation of pituitary IGF-I peptide content and gene expression in insulinopenic streptozotocin (STZ)-diabetic rats compared to that in liver and testis. Serum IGF-I levels were reduced by 86% in STZ-diabetic rats together with reduction of IGF-I content in liver (53%) and testis (74%; all P less than 0.001 vs. control). Concomitantly, liver and testicular IGF-I mRNA levels were reduced by 90% (P less than 0.001 vs. control). Insulin treatment restored IGF-I peptide levels in serum, liver, and testis toward normal, with a partial but significant increase in liver IGF-I mRNA. In contrast, pituitary IFG-I peptide content increased by 69% in STZ-diabetic rats (P less than 0.001 vs. control), with no change in IGF-I gene expression. Insulin treatment completely reversed the rise of pituitary IGF-I peptide content. These results demonstrate a novel discordance in the regulation of IGF-I gene expression and peptide content between pituitary and other tissues in STZ-induced diabetic rats. Elevated IGF-I levels in the pituitaries of these animals may partly explain the suppressed GH synthesis and secretion seen in STZ-diabetic rats and provide further evidence for a potential autocrine or paracrine role of pituitary IGF-I in GH regulation.
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PMID:Pituitary insulin-like growth factor-I content and gene expression in the streptozotocin-diabetic rat: evidence for tissue-specific regulation. 198 70

Diabetes-associated renal enlargement is more marked in postpubertal than prepubertal rats, and in the postpubertal rat, is associated with increased kidney insulin-like growth factor-I (IGF-I) levels for the first 2 days. In order to determine whether local IGF-I production is the cause of this increase in tissue levels, IGF-I mRNA levels were determined in pre- and postpubertal Sprague-Dawley rats made diabetic with streptozotocin (STZ) and in control rats. RNA was extracted from kidneys and livers of rats at 0 h, 6 h, 12 h and days 1, 2, 3 and 7 after STZ injection. After Northern blotting and hybridization with an oligonucleotide probe complementary to an E domain of the IGF-I cDNA, four distinct bands (7.4, 4.8, 1.8 and 1.0 kb) were found. Densitometric analyses of the most prominent bands (7.4 and 1.0 kb), after normalization for 18S ribosomal RNA content, revealed a 50-100% increase in the kidneys of postpubertal diabetic rats compared with postpubertal controls 12 h after STZ injection (P less than 0.05, diabetes vs control). Between days 2 and 7, kidney IGF-I mRNA levels in postpubertal diabetic rats fell to approximately 50% of control levels (P less than 0.05, diabetes vs control). In contrast, kidney IGF-I mRNA levels in the prepubertal diabetic rats remained unchanged over the 7 days. Liver IGF-I mRNA levels did not rise during the first 24 h and fell to approximately 60% of control levels by day 7 in both pre- and postpubertal diabetic rats (P less than 0.05, diabetes vs control). Increased local IGF-I production may underlie the initiation of renal enlargement associated with diabetes mellitus.
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PMID:Kidney insulin-like growth factor-I mRNA levels are increased in postpubertal diabetic rats. 203 Mar 29

Diabetes is associated with a fall in serum insulin-like growth factor-I (IGF-1) and a rise in somatomedin inhibitor, a circulating factor(s) of approximately 30,000 MW that is released by the liver and can antagonize both somatomedin and insulin action. Levels of inhibitor correlate with levels of glucose, beta-hydroxybutyrate, and weight loss. To study pathways that could underlie the fall in IGF-1 and rise in inhibitor, the effects of metabolic inhibitors on circulating metabolic fuels, serum IGF-1, and serum somatomedin inhibitor activity were studied. Rats given streptozotocin exhibited weight loss of 14% +/- 0.1%, glucose 457 +/- 26 mg/dL, and beta-hydroxybutyrate (BOHB) 6.3 +/- 0.5 mmol/L. Somatomedin inhibitor was separated from IGF-1 by size exclusion HPLC at pH 3; IGF-1 was measured by RIA, and somatomedin inhibitor by cartilage bioassay. Diabetic animals exhibited a fall in IGF-1 to 76% of normal (P less than .02) and a rise in inhibitor to 270% of normal (P less than .01). 3-Mercaptopicolinic (3-MPA) acid, an inhibitor of gluconeogenesis, lowered glucose to 68 +/- 2 mg/dL and BOHB to 0.96 +/- 0.09 mmol/L (both P less than .01 v diabetic), but levels of inhibitor did not fall. Nicotinic acid, an inhibitor of lipolysis, did not affect glucose but reduced BOHB to 0.42 +/- 0.02 mmol/L; somatomedin inhibitor fell 19% below diabetic levels (NS) but remained above normal (P less than .01). In contrast, inhibition of fatty acid oxidation with methyl-2-tetradecylglycidate reduced glucose to 191 +/- 18 mg/dL but lowered BOHB to normal, 0.16 +/- 0.02 mmol/L, accompanied by normalization of somatomedin inhibitor levels (152% +/- 33% of normal, NS). Below 1.0 mmol/L BOHB, somatomedin inhibitor and BOHB were strongly correlated (r = .67, P less than .001); no comparable relation was found with glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nutrition and somatomedin. XXI. Insulin-like growth factor-I and somatomedin inhibitor in streptozotocin-diabetic rats: relation to ketogenesis and gluconeogenesis. 240 22

Postbinding defects in insulin action were described previously in cultured fibroblasts from six patients with lipoatropic diabetes. To define the contribution of the insulin receptor tyrosine kinase in these defects, we studied autophosphorylation and kinase activity of lectin purified receptors from these six patients and six normal cell lines. The patients' insulin receptors, prepared by precipitation with polyethylene glycol, had normal insulin binding characteristics and autophosphorylation properties, but a 56% decrease in the tyrosine kinase activity toward an exogenous substrate. To identify more subtle qualitative defects in autophosphorylation, insulin receptors were sequentially immunoprecipitated and analyzed for their phosphoaminoacid content. The phosphorylated receptors precipitated with an antiphosphotyrosine antibody contained labeled phosphotyrosine, whereas those in the supernatant, when further precipitated with an antireceptor antibody, contained only phosphoserine. Under these conditions, the insulin-stimulated autophosphorylation of tyrosine was significantly decreased by 54% in the patient receptors compared to normal subjects' receptors. In addition, insulin-like growth factor-I stimulation of autophosphorylation of its receptor was reduced by 59% in the patients' cells compared to those from normal subjects. We conclude that fibroblasts from patients with lipoatropic diabetes have defects in the tyrosine kinase activity of their insulin and their insulin-like growth factor-I receptors that might give rise to the in vitro hormone resistance and be related to the in vivo hormone resistance that occurs in these patients.
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PMID:Tyrosine-kinase defect of the insulin receptor in cultured fibroblasts from patients with lipoatropic diabetes. 254 88

Substrates of the insulin receptor tyrosine kinase have not been identified in skeletal muscle, a major target organ of insulin action. We observed the insulin-stimulated phosphorylation of a 195K protein (pp195) in extracts prepared from rat skeletal muscle and liver. pp195 copurifies with the insulin receptor on wheat germ agglutinin affinity chromatography. pp195 is not related to the insulin receptor, as assessed by lack of recognition by antinsulin receptor antibodies and by phosphopeptide mapping. Reduction of sulfhydryl bonds does not affect its apparent mol wt. Phosphorylation of pp195 has an absolute requirement in vitro for Mn2+ or Mg2+ and for certain basic poly-amino acids, i.e. poly-L-lysine or poly-L-ornithine. In the presence of 1 microM poly-L-lysine insulin stimulates pp195 phosphorylation in a dose-dependent manner (k0.5, approximately 5 x 10(-10) M; maximum approximately 10(-8) M insulin); pp195 phosphorylation by insulin-like growth factor-I requires about 100-fold higher doses. By phosphoamino acid analysis, pp195 is predominantly phosphorylated on tyrosine, and it is recognized by antiphosphotyrosine antibodies. Insulin receptors isolated from rat muscles 5 min after insulin injection induce about 2-fold greater phosphorylation of pp195 in vitro than receptors isolated from saline-injected controls. Streptozotocin-induced diabetes results in marked diminution of insulin-stimulated pp195 phosphorylation in extracts of muscle and liver (approximately 50% when normalized to protein content of wheat germ agglutinin eluates or approximately 80% reduction when normalized to equal receptor number). The defect is reversible by insulin therapy in vivo.
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PMID:Insulin-stimulated phosphorylation of a 195K protein from muscle and liver in the presence of poly-L-lysine. 254 86

Insulin-deficient, streptozotocin-diabetic rats show severe metabolic disturbances and stop growing. Besides insulin, these animals also lack growth hormone and insulin-like growth factor-I. We examined whether or not growth parameters correlate with IGF-I serum levels in young rats with streptozotocin-diabetes of different severity. In the diabetic rats, blood glucose varied between 18.4 and 38.6 mmol/l (healthy controls between 6.1 and 9.3), IGF-I serum levels between 2.6 and 15.6 nmol/l (controls between 19.6 and 26.5), and serum insulin levels between 0.05 and 0.14 nmol/l (controls between 0.36 and 0.55). We found a highly significant linear correlation between IGF-I serum levels and the two investigated growth parameters, tibial epiphyseal width and longitudinal tibial bone growth. The finding that these indices of growth are strongly correlated with IGF-I serum levels in young rats with diabetes of different severity, suggests that IGF-I is a major determinant of growth. This is in keeping with our earlier demonstration that exogenously infused IGF-I promotes growth in diabetic rats.
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PMID:The role of insulin-like growth factor I in growth of diabetic rats. 258 35

The effects of streptozotocin-induced diabetes on weight gain, bone growth and GH secretion have been studied in conscious chronically cannulated male rats. In addition to the classic diabetic symptoms (hyperphagia, polydipsia, polyuria, glycosuria and hyperglycaemia), the slow body weight gain (0.95 +/- 0.5 compared with 2.63 +/- 0.5 g/day in non-diabetic controls) was associated with a reduction in bone growth (from 162 +/- 9 to 48 +/- 4 microns/day) and a reduced pituitary GH content (from 1.5 +/- 0.2 to 0.6 +/- 0.06 mg/gland). Serial blood sampling during the day or overnight showed that the normal male episodic GH secretory pattern was obliterated in the diabetic animals. The constant osmotic stimulation of hyperglycaemia and high fluid turnover was reflected in a significant reduction in pituitary oxytocin and arginine vasopressin (AVP) stores. Intravenous insulin infusions (67-1340 pmol/h for 4 or 7 days) caused a large initial weight gain (greater than 20 g in 2 days) followed by a slower increase, and stimulated tibial bone growth (to 100 +/- 16 and 126 +/- 8 microns/day after 4 or 7 days respectively). Insulin infusion for 7 days also increased pituitary GH content (to 1 +/- 0.15 mg/gland), and the normal episodic GH secretory pattern returned. Intravenous infusions of insulin which reduced, but did not completely normalize, blood glucose levels, allowed the resumption of growth and pulsatile GH secretion. Continuous infusion of recombinant human insulin-like growth factor-I (hIGF-I) at 1110 pmol/h for 54 h also caused a large initial rise in body weight in diabetic rats (17.1 +/- 1.6 compared with 7.5 +/- 2.8 g in saline-infused controls) due primarily to increased fluid retention. This effect of hIGF-I occurred without any significant changes in pituitary GH, AVP, oxytocin, blood glucose or bone growth over this short-term infusion, nor was there any obvious effect on spontaneous GH secretion, monitored over the entire infusion period. We conclude that the diabetic rat is not a good model to study growth stimulation by short-term insulin or IGF-I treatments because the insulin-like effects of these peptides obscure their specific growth-promoting activities in this model.
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PMID:Growth hormone and growth in diabetic rats: effects of insulin and insulin-like growth factor-I infusions. 268

The mechanisms responsible for the elevated levels of circulating GH observed in diabetes mellitus (DM) remain incompletely defined. To assess the episodic fluctuations in serum GH as a reflection of hypothalamic-pituitary activity, we accumulated GH concentration-time series in a total of 48 adult men and women with and without insulin-dependent DM by obtaining serum samples at 10-min intervals over 24 h. Significant pulses of GH release were subsequently identified and characterized by an objective, statistically based pulse detection algorithm (Cluster) and fixed circadian (24-h) periodicities of secretory activity, resolved using Fourier expansion time-series analysis. Compared to those in age-matched controls, integrated 24-h concentrations of GH were 2- to 3.5-fold higher in diabetic men (P = 0.002) and women (P = 0.0005). Both men and women with DM had over 50% more GH pulses per 24 h than their non-DM counterparts. In addition, maximal GH pulse amplitude was markedly elevated in the men and women with DM (P = 0.0019 and 0.0189, respectively). That the increase in maximal pulse amplitude was accounted for by greater baseline levels was documented by a higher interpulse valley mean GH concentration in the diabetics compared to the controls (P = 0.0437 and 0.0056, men and women, respectively) and the absence of any difference in incremental pulse amplitude for either sex (P greater than 0.05). DM men had larger GH pulse areas (P = 0.039) than control men, apparently accounted for by greater pulse width (P = 0.0037). Pulse areas in DM and non-DM women were indistinguishable. Time-series analysis revealed that the 24-h (circadian) rhythms of serum GH concentrations exhibited significantly increased amplitudes in the diabetic group as a whole (compared to the controls, P = 0.011). However, the times of maximal GH concentrations (acrophases) were not significantly different. As a group, serum insulin-like growth factor-I was lower in DM vs. non-DM individuals (P = 0.0014), although when separated by sex this difference did not reach statistical significance in women (P = 0.317). The present data confirm the higher circulating levels of GH previously reported to occur in individuals with poorly controlled DM. The altered frequency of GH pulses together with enhanced interpulse GH concentrations and an amplified circadian GH rhythm are compatible with hypothalamic dysfunction associated with dysregulation of somatostatin and/or GHRH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Alterations in the pulsatile mode of growth hormone release in men and women with insulin-dependent diabetes mellitus. 275 72

Insulin-like growth factor-I (IGF-I) mRNA and GH receptor mRNA levels were analysed in different tissues from rats made diabetic with streptozotocin, fasted rats and rats fed with a protein-reduced diet. Diabetes decreased IGF-I mRNA levels in liver, heart, diaphragm, kidney and aorta, but not in brain. GH receptor mRNA levels were decreased in heart and diaphragm, but not in liver and kidney. Fasting decreased IGF-I mRNA in all tissues studied except brain, and decreased GH receptor mRNA in liver, heart and diaphragm, but not in kidney. A protein-reduced diet decreased hepatic IGF-I mRNA levels but did not significantly affect other tissues, while GH receptor mRNA levels were reduced in liver and diaphragm. In conclusion, both diabetes and limited nutrition affected IGF-I and GH receptor mRNA in different tissues, but the two mRNAs were not co-ordinately regulated in all tissues studied. While reduced GH receptor gene expression may thus be responsible for decreased IGF-I gene expression in some states and tissues, additional regulatory mechanisms may be of importance.
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PMID:Regulation of insulin-like growth factor-I and growth hormone receptor gene expression by diabetes and nutritional state in rat tissues. 280 76


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