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

Although mRNAs encoding insulinlike growth factor (IGF) binding proteins (BPs) are present in adult rat liver and IGF BP-1 circulates at elevated levels in diabetic animals, there is little knowledge of the metabolic regulation of IGF BPs in normal tissues. We examined the release of IGF BPs by adult rat hepatocytes maintained in primary culture. When cultured for 2 days in the absence of added insulin, hepatocytes released a BP identified as BP-1 on the basis of approximately 30,000-Mr on ligand blotting and reactivity with antiserum to human BP-1 in immunoblotting and immunoprecipitation studies. Release of BP-1 was sensitive to insulin with suppression of 24 +/- 4, 73 +/- 5, and 64 +/- 14% at 10(-10), 10(-8), and 10(-6) M insulin, respectively; ED50 was approximately 1.7 x 10(-9) M, which is within the physiological range. Suppression by insulin was reversible and began within 3 h. Because normal hepatocytes in primary culture exhibit insulin-responsive release of both BP-1 and IGF-1, this system may be an ideal model for studies of molecular mechanisms of metabolic regulation.
Diabetes 1991 Jul
PMID:Nutrition and somatomedin. XXV. Regulation of insulinlike growth factor binding protein 1 in primary cultures of normal rat hepatocytes. 171 86

Impaired growth in diabetic humans occurs despite increased growth hormone and normal insulinlike growth factor I (IGF-I). Because IGF-I circulates complexed to binding proteins (BPs), we asked whether diabetes-related changes in IGF BPs could be associated with alterations in free unbound IGF-I--presumably the active form. Rats were given streptozocin (STZ) in increasing doses to produce graded severity of diabetes. IGF BP-1 and BP-3 were measured by ligand blotting, total IGF-I was determined by radioimmunoassay after separation from BPs by isocratic high-performance liquid chromatography (HPLC) at pH 3.9, and free IGF-I was estimated operationally as immunoreactivity with molecular weight equal to native IGF-I after HPLC at pH 7. Animals given 36 mg/kg STZ exhibited a glucose level of 9.74 mM and impaired weight gain, with little alteration in IGF BPs or total or free IGF-I. In contrast, animals given 72 mg/kg STZ (glucose level 24.64 mM and weight loss) had insignificant changes in total IGF-I and BP-3 but a 300% increase in BP-1 and a 50% fall in free IGF-I (both P less than 0.005). With 144 and 288 mg/kg STZ, animals had further metabolic decompensation and weight loss, with progressive fall in BP-3 and rise in BP-1; total and free IGF-I fell to 10-20% of control (both P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1991 Aug
PMID:Nutrition and somatomedin. XXVII. Total and free IGF-I and IGF binding proteins in rats with streptozocin-induced diabetes. 171 63

Insulin-like growth factor I (IGF I) is an endocrine hormone that mediates most of the effects of pituitary growth hormone. Other important regulatory factors of serum IGF I levels are insulin and nutrition. Most of the circulating IGF I is bound to three IGF binding proteins (BP), mostly IGFBP-3, BP-2 and BP-1. IGF I is also produced by many cells in the body where it exerts autocrine and/or paracrine effects. IGF I has a specific receptor on most cells, the so-called type 1 IGF receptor. When IGF I is administered intravenously as a bolus it leads to acute hypoglycaemia in a similar way to insulin and mainly with the insulin receptor. Chronic administration of IGF I to hypophysectomized or diabetic rats leads to prominent anabolic effects and growth. In this manuscript, metabolic and endocrine effects of recombinant IGF I are discussed. Recombinant IGF I therapy increases energy expenditure and lipid oxidation and decreases proteolysis and protein oxidation. These effects occur despite a partial inhibition of insulin and growth hormone secretion. The therapeutic spectrum of recombinant IGF I, consisting of inhibition of catabolism, stimulation of anabolism, decreases of triglyceride and cholesterol levels and a striking increase in insulin sensitivity, renders IGF I a very interesting, powerful tool for insulin-resistant states such as non-insulin-dependent diabetes mellitus.
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PMID:Recombinant human insulin-like growth factor-I: a therapeutic challenge for diabetes mellitus. 782 34

In this study, food-deprived (18 h) control rats and rats with alloxan-induced diabetes were orally administered saline or the amino acid leucine to assess whether it regulates protein synthesis independently of a change in serum insulin concentrations. Immediately after leucine administration, diabetic rats were infused with insulin (0.0, 4.0, or 20 pmol small middle dot min(-1) small middle dot kg(-1)) for 1 h to examine the role of the hormone in the protein synthetic response to leucine. In control rats, leucine stimulated protein synthesis by 58% and increased phosphorylation of the translational repressor, eukaryotic initiation factor (eIF) 4E-binding protein (BP)-1, 4E-BP1, fivefold. Consequently, association of the mRNA cap-binding protein eukaryotic initiation factor (eIF)4E with 4E-BP1 was reduced to 50% of control values, and eIF4G*eIF4E complex assembly was increased 80%. Furthermore, leucine increased the phosphorylation of the 70-kDa ribosomal protein S6 (rp S6) and the ribosomal protein S6 kinase (S6K1). Diabetes attenuated protein synthesis compared with control rats. Nonetheless, in diabetic rats, leucine increased protein synthesis by 53% without concomitant changes in the phosphorylation of 4E-BP1 or S6K1. Skeletal muscle protein synthesis was stimulated in diabetic rats infused with insulin, but rates of synthesis remained less than values in nondiabetic controls that were administered leucine. Phosphorylation of 4E-BP1 and S6K1 was increased in diabetic rats infused with insulin in a dose-dependent manner, and the response was enhanced by leucine. The results suggest that leucine enhances protein synthesis in skeletal muscle through both insulin-dependent and -independent mechanisms. The insulin-dependent mechanism is associated with increased phosphorylation of 4E-BP1 and S6K1. In contrast, the insulin-independent effect on protein synthesis is mediated by an unknown mechanism.
Diabetes 2002 Apr
PMID:Orally administered leucine enhances protein synthesis in skeletal muscle of diabetic rats in the absence of increases in 4E-BP1 or S6K1 phosphorylation. 1191 9

Leucine performs a signaling role to enhance protein synthesis by phosphorylating eukaryotic initiation factor (eIF) 4E-binding protein 1 (4E-BP1) and 70-kDa ribosomal protein S6 kinase (S6K1), two key regulatory proteins involved in the initiation of mRNA translation. The purpose of the current study was to assess whether the phosphorylation of 4E-BP1 and S6K1 was increased in skeletal muscle and liver by an oral administration of leucine to diabetic rats and to determine the in vivo contribution of insulin to a leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation. Food-deprived (18 h) normal and diabetic rats were orally administered 135 mg/ 100 g body weight L-leucine and sacrificed at 1 h after administration. Leucine administration resulted in enhanced phosphorylation of 4E-BP1 and S6K1 in skeletal muscle and in liver of nondiabetic rats. The stimulatory action of leucine on the phosphorylation of 4E-BP1 and S6K1 in skeletal muscle was not abolished in rats with streptozotocin-induced diabetes. In contrast, leucine administration did not stimulate the phosphorylation of 4E-BP1 and S6K1 in the liver of diabetic rats. These findings suggest that in skeletal muscle, leucine functions as a nutritional signaling molecule that independently regulates the phosphorylation states of 4E-BP1 and S6K1. In contrast to skeletal muscle, insulin is essential in mediating the leucine-dependent induction of 4E-BP1 and S6K1 phosphorylation in liver. leucine, 4E-BP1, S6K1, translation initiation, diabetes
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PMID:Oral administration of leucine stimulates phosphorylation of 4E-bP1 and S6K 1 in skeletal muscle but not in liver of diabetic rats. 1202 90

Cyclin kinase inhibitor p27(Kip(1)) (p27) has been shown to be upregulated in glomeruli of diabetic animals and mesangial cells cultured under high glucose. This study was an investigation of the role of p27 in the progression of diabetic nephropathy. Mice deficient in p27 (p27 -/-) and wild-type mice (p27 +/+) were studied 12 wk after diabetes induction by streptozotocin. Blood glucose and BP were comparable between diabetic p27 +/+ and p27 -/- mice. The kidney weight to body weight ratio and glomerular volume increased in diabetic p27 +/+ mice. In contrast, these parameters did not change in diabetic p27 -/- mice. Similarly, albuminuria developed in diabetic p27 +/+ mice but not in diabetic p27 -/- mice. The mesangial expansion was significantly milder in diabetic p27 -/- mice than that in diabetic p27 +/+ mice. These changes were associated with a similar increase in glomerular TGF-beta expression in diabetic p27 +/+ and p27 -/- mice. However, glomerular protein expression of fibronectin, a target of TGF-beta, increased only in diabetic p27 +/+ mice. In mesangial cells cultured from p27 +/+ mice, exposure to high glucose caused significant increases in total protein content and [(3)H]-leucine incorporation. On the other hand, high glucose caused a significant reduction in these parameters in cells from p27 -/- mice. Phosphorylation of 4E-BP1, the translation inhibitor, increased after exposure to high glucose in p27 +/+ cells. In p27 -/- cells, the level of phosphorylated 4E-BP1 was higher than that in control p27 +/+ cells and decreased under high glucose conditions. In conclusion, renal hypertrophy, glomerular hypertrophy, and albuminuria did not develop, and mesangial expansion was milder in diabetic p27 -/- mice despite glomerular TGF-beta upregulation. These results suggest that controlling p27 function may ameliorate diabetic nephropathy.
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PMID:The lack of cyclin kinase inhibitor p27(Kip1) ameliorates progression of diabetic nephropathy. 1259 21

Recent literature has shown that circulating levels of insulin-like growth factor I (IGF-I) and/or IGF binding proteins (IGF-BPs) may be of importance in the risk assessment of several chronic diseases including cancer, cardiovascular disease, diabetes mellitus and so on. The present study examined the extent of genetic and environmental influences on the populational variation of circulating IGF-I and IGF-BP-1 in apparently healthy and ethnically homogeneous white families. The plasma levels of each of the studied biochemical indices were determined by enzyme-linked immunoassay in 563 individuals aged 18 to 80 years. Quantitative genetic analysis showed that the IGF-I variation was appreciably attributable to genetic effects (47.1% +/- 9.0%), whereas for IGF-BP-1, only 23.3% +/- 7.8% of the interindividual variation was explained by genetic determinants. Common familial environment factors contributed significantly only to IGF-BP-1 variation (23.3% +/- 7.8%). In addition, we examined the covariations between these molecules and between them and IGF-BP-3 and leptin that were previously studied in the same sample. The analysis revealed that the pleiotropic genetic effects were significant for 2 pairs of traits, namely for IGF-I and IGF-BP-3, and for IGF-BP-1 and leptin. The bivariate heritability estimates were 0.21 +/- 0.04 and 0.15 +/- 0.05. The common environmental factors were consistently a significant source of correlation between all pairs (barring IGF-I and leptin) of the studied molecules; they were the sole predictors of correlation between IGF-I and IGF-BP-1, and between IGF-BP-1 and IGF-BP-3. Our results affirm the existence of specific and common genetic pathways that in combination determine a substantial proportion of the circulating variation of these molecules.
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PMID:Genetic regulation of the variation of circulating insulin-like growth factors and leptin in human pedigrees. 1598 10

Angiotensin (Ang) II is implicated in hypertension, vascular remodeling, and insulin resistance. Peroxisome proliferator-activated receptor (PPAR) gamma activators increase insulin sensitivity and improve Ang II-induced vascular remodeling. We evaluated the effects of the PPAR-gamma activator rosiglitazone on Ang II signaling in aorta and mesenteric arteries. Rats received Ang II by subcutaneous infusion and/or rosiglitazone per os for 7 days. Blood pressure rise in Ang II-infused rats was attenuated by rosiglitazone. Ang II significantly increased Ang II type 1 receptor expression in the mesenteric arteries (P<0.001), whereas that of the aorta was decreased (P<0.05), changes which were reversed by rosiglitazone. Akt activity was increased by Ang II and returned to basal levels under rosiglitazone in both vascular beds. However, Ang II-induced extracellular signal-regulated kinase 1/2 activity increased in aorta but not in mesenteric vessels (P<0.001), where 4E-binding protein 1 activity was significantly increased by Ang II and inhibited by PPAR-gamma activation. In response to Ang II, Src homology (SH) 2-containing inositol phosphatase 2 activity was increased (P<0.05) in both vascular beds. In conclusion, PPAR-gamma activator rosiglitazone attenuated Ang II-induced blood pressure elevation and intracellular signaling on aorta and mesenteric vessels. There was differential inhibition of Ang II type 1 receptor receptors/phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase 1/2 in both vessels. Effects of PPAR-gamma activators on these pathways could contribute to regression of vascular remodeling in models of hypertension and diabetes and, accordingly, in hypertensive diabetic patients.
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PMID:Peroxisome proliferator-activated receptor gamma regulates angiotensin II-stimulated phosphatidylinositol 3-kinase and mitogen-activated protein kinase in blood vessels in vivo. 1634 71

Diabetes mellitus (DM) is associated with pancreatic atrophy and compromised digestion of carbohydrates as a result of exocrine pancreatic insufficiency and lower alpha-amylase synthesis and secretion. The reduced production of digestive enzymes is likely to be caused by deregulated protein metabolism. The relative concentrations and phosphorylation of signaling proteins associated with protein translation, such as PKB, p70S6K1, 4E-BP1, ERK1/2, and also some of those implicated in protein breakdown, such as ubiquitin and NF-kappaB, in the pancreas of streptozotocin (STZ)-induced type I diabetic pancreas were measured using Western blotting. There were significant decreases in the levels of total PKB, p70S6K, 4E-BP1, ERK1/2, and NF-kappaB in the diabetic pancreas compared to control. In contrast, the phosphorylation of p70S6K1, 4E-BP1, ERK1/2, and protein ubiquitination increased significantly compared to controls. Together, these results indicate that STZ-induced DM leads to reduced levels of enzymes mediating protein synthesis while their phosphorylation is actually increased, perhaps in an attempt to maintain protein homeostasis, which is further compromised by heightened ubiquitin-dependent protein breakdown. It is likely that these factors are responsible for pancreatic atrophy, enzyme synthesis, and net protein loss in DM.
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PMID:Signaling proteins associated with diabetic-induced exocrine pancreatic insufficiency in rats. 1715 24

Laminin is a glycoprotein that contributes to renal extracellular matrix expansion in diabetes. We investigated regulation of laminin-beta1 synthesis in murine renal proximal tubular epithelial cells by 30 mmol/l glucose (high glucose), 1 nmol/l insulin (high insulin), and their combination (high glucose+high insulin), simulating conditions observed during progression of type 2 diabetes. Compared with 5 mmol/l glucose and no insulin (control), high glucose alone, high insulin alone, or high glucose+high insulin together increased laminin-beta1 chain protein synthesis within 5 min, lasting for up to 60 min with no change in laminin-beta1 mRNA levels. Cycloheximide, but not actinomycin-D, abrogated increased laminin-beta1 synthesis. High glucose, high insulin, and high glucose+high insulin stimulated phosphorylation of 4E-BP1, a repressor binding protein for eukaryotic initiation factor 4E (eIF4E), that was dependent on activation of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin. High glucose, high insulin, and high glucose+high insulin also promoted release of eIF4E from 4E-BP1, phosphorylation of eIF4E, and increase in eIF4E association with eIF4G, critical events in the initiation phase of mRNA translation. High glucose, high insulin, and high glucose+high insulin increased Erk phosphorylation, which is an upstream regulator of eIF4E phosphorylation, and PD098059, which is a MEK inhibitor that blocks Erk activation, abolished laminin-beta1 synthesis. This is the first demonstration of rapid increment in laminin-beta1 synthesis by regulation of its mRNA translation by cells exposed to high glucose, high insulin, or high glucose+high insulin.
Diabetes 2007 Feb
PMID:High glucose, high insulin, and their combination rapidly induce laminin-beta1 synthesis by regulation of mRNA translation in renal epithelial cells. 1725 94


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