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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The SHROB rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single homozygous recessive trait, designated faK, and is allelic with the Zucker fatty trait (fa), but of distinct origin. The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. The SHROB are glucose intolerant compared to heterozygous or wild-type SHR, but retain fasting euglycemia even on a high sucrose diet, suggesting that diabetes requires polygenic interaction with additional modifier genes. Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Increased activity of the sympathetic nervous system may be a common factor leading by separate pathways to hypertension and to insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in SHROB. Moxonidine (8 mg/kg/day), a selective I1-imidazoline receptor agonist, not only reduced blood pressure but also ameliorated glucose intolerance. Moxonidine reduced fasting insulin by 47% and plasma free fatty acids by 30%. Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. Thus, central sympatholytic therapy not only counters hypertension but also insulin resistance, glucose tolerance, and hyperlipidemia in the SHROB model of Syndrome X.
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PMID:Molecular pathology in the obese spontaneous hypertensive Koletsky rat: a model of syndrome X. 1084 68

The cellular mechanisms for the insulin resistance of pregnancy and gestational diabetes mellitus (GDM) are unknown. The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. Subjects (n = 6 for each group) were similar in age and degree of obesity (body fat >30%). IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. No significant differences were evident in basal insulin receptor tyrosine phosphorylation or IRTK activity in the three groups. After maximal insulin (10(-7) mol/l) stimulation, IRTK activity measured with the artificial substrate poly(Glu,Tyr) increased in all subjects but was lower in women with GDM by 25% (P < 0.05) and 39% (P < 0.001) compared with pregnant and nonpregnant control subjects, respectively. Similarly, insulin receptor tyrosine phosphorylation was significantly decreased in subjects with GDM (P < 0.05) compared with pregnant and nonpregnant control subjects. Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). PC-1 content in muscle from GDM subjects was increased by 63% compared with pregnant control subjects (P < 0.05) and by 206% compared with nonpregnant control subjects (P < 0.001). PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. These changes worsen in women with GDM when controlling for obesity. These postreceptor defects in insulin signaling may contribute to the pathogenesis of GDM and the increased risk for type 2 diabetes later in life.
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PMID:Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. 1087 Nov 98

The molecular mechanism whereby tumor necrosis factor-alpha (TNF-alpha) induces insulin resistance in obesity is not well understood. Previously, we have shown that inhibition of TNF-alpha improved hepatic insulin sensitivity in obese Zucker rats without altering the tyrosine phosphorylation of liver insulin receptors (IRs), which indicates that the TNF-alpha and insulin-signaling cascades interact distally to the IR. To assess the effects of TNF-alpha on signaling molecules downstream from the IR, we analyzed the tyrosine phosphorylation patterns of liver homogenate proteins from TNF-alpha-neutralized fa/fa rats and showed that focal adhesion kinase (FAK) was consistently hyperphosphorylated (4.5-fold). Moreover, intravenous insulin increased hepatic FAK phosphorylation in a time-dependent manner in Sprague-Dawley rats, which suggests that TNF-alpha may induce hepatic insulin resistance by preventing FAK phosphorylation in response to insulin treatment. To explore the cellular mechanism whereby TNF-alpha regulates phosphorylation of FAK in the liver, we measured c-Src kinase activity and the abundance of 3 major protein tyrosine phosphatases (PTPs) (PTP-1B, leukocyte antigen-related tyrosine phosphatase [LAR], and src homology 2 domain-containing protein-tyrosine phosphatase [SHPTP-2]) in liver homogenates from obese Zucker rats after TNF-alpha blockade. Hepatic c-Src kinase activity was unaltered, but LAR protein was reduced by 75%. In addition, TNF-alpha blockade reduced hepatic PTP activity toward tyrosine phosphorylated FAK by 70%, and this was accounted for by immunodepletion of LAR. Incubation of HepG2 cells with TNF-alpha increased LAR protein levels in a dose-dependent manner. Additionally, pretreatment with TNF-alpha abolished insulin-stimulated tyrosine phosphorylation of FAK in HepG2 cells but had no effect on IR tyrosine phosphorylation or expression. These data suggest that TNF-alpha promotes LAR expression and thus prevents insulin-mediated tyrosine phosphorylation of FAK. This probably represents the interface between TNF-alpha and insulin signaling in the liver.
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PMID:Tumor necrosis factor-alpha induces hepatic insulin resistance in obese Zucker (fa/fa) rats via interaction of leukocyte antigen-related tyrosine phosphatase with focal adhesion kinase. 1090 91

A role for protein tyrosine phosphatases in the negative regulation of insulin signaling and a putative involvement in the insulin resistance associated with type 2 diabetes have been postulated since their discovery. The recent demonstration that mice lacking the protein tyrosine phosphatase-1B (PTP-1B) have enhanced insulin sensitivity validates this. Furthermore, when fed a high fat diet, these mice maintained insulin sensitivity and were resistant to obesity, suggesting that inhibition of PTP-1B activity could be a novel way of treating type 2 diabetes and obesity. This commentary reviews our current knowledge of PTP-1B in insulin signaling and its role in diabetes and discusses the development of potent and selective PTP-1B inhibitors.
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PMID:Protein tyrosine phosphatase-1B in diabetes. 1097 95

Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.
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PMID:Decreased Akt kinase activity and insulin resistance in C57BL/KsJ-Leprdb/db mice. 1101 58

Tumor necrosis factor-alpha (TNFalpha) has been implicated as a contributing mediator of insulin resistance observed in pathophysiological conditions such as obesity, cancer-induced cachexia, and bacterial infections. Previous studies have demonstrated that TNFalpha confers insulin resistance by promoting phosphorylation of serine residues on insulin receptor substrate 1 (IRS-1), thereby diminishing subsequent insulin-induced tyrosine phosphorylation of IRS-1. However, little is known about which signaling molecules are involved in this process in adipocytes and about the temporal sequence of events that ultimately leads to TNFalpha-stimulated IRS-1 serine phosphorylation. In this study, we demonstrate that specific inhibitors of the MAP kinase kinase (MEK)1/2-p42/44 mitogen-activated protein (MAP) kinase pathway restore insulin signaling to normal levels despite the presence of TNFalpha. Additional experiments show that MEK1/2 activity is required for TNFalpha-induced IRS-1 serine phosphorylation, thereby suggesting a mechanism by which these inhibitors restore insulin signaling. We observe that TNFalpha requires 2.5-4 h to markedly reduce insulin-triggered tyrosine phosphorylation of IRS-1 in 3T3-L1 adipocytes. Although TNFalpha activates p42/44 MAP kinase, maximal stimulation is observed within 10-30 min. To our surprise, p42/44 activity returns to basal levels well before IRS-1 serine phosphorylation and insulin resistance are observed. These activation kinetics suggest a mechanism of p42/44 action more complicated than a direct phosphorylation of IRS-1 triggered by the early spike of TNFalpha-induced p42/44 activity. Chronic TNFalpha treatment (>> 72 h) causes adipocyte dedifferentiation, as evidenced by the loss of triglycerides and down-regulation of adipocyte-specific markers. We observe that this longer term TNFalpha-mediated dedifferentiation effect utilizes alternative, p42/44 MAP kinase-independent intracellular pathways. This study suggests that TNFalpha-mediated insulin resistance, but not adipocyte dedifferentiation, is mediated by the MEK1/2-p42/44 MAP kinase pathway.
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PMID:Tumor necrosis factor alpha-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. 1104 72

A reduced capacity for insulin to elicit increases in glucose uptake and metabolism in target tissues such as skeletal muscle is a common feature of obesity and diabetes. The association between lipid oversupply and such insulin resistance is well established, and evidence for mechanisms through which lipids could play a causative role in the generation of muscle insulin resistance is reviewed. While the effects of lipids may in part be mediated by substrate competition through the glucose-fatty acid cycle, interference with insulin signal transduction by lipid-activated signalling pathways is also likely to play an important role. Thus, studies of insulin resistance in Type 2 diabetes, obesity, fat-fed animals and lipid-treated cells have identified defects both at the level of insulin receptor-mediated tyrosine phosphorylation and at downstream sites such as protein kinase B (PKB) activation. Lipid signalling molecules can be derived from free fatty acids, and include diacylglycerol, which activates isozymes of the protein kinase C (PKC) family, and ceramide, which has several effectors including PKCs and a protein phosphatase. In addition, elevated lipid availability can increase flux through the hexosamine biosynthesis pathway which can also lead to activation of PKC as well as protein glycosylation and modulation of gene expression. The mechanisms giving rise to decreased insulin signalling include serine/threonine phosphorylation of insulin receptor substrate-1, but also direct inhibition of components such as PKB. Thus lipids can inhibit glucose disposal by causing interference with insulin signal transduction, and most likely by more than one pathway depending on the prevalent species of fatty acids.
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PMID:Signalling aspects of insulin resistance in skeletal muscle: mechanisms induced by lipid oversupply. 1108 Jun 10

The orphan receptor, bombesin (Bn) receptor subtype 3 (BRS-3), shares high homology with bombesin receptors (neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R)). This receptor is widely distributed in the central nervous system and gastrointestinal tract; target disruption leads to obesity, diabetes, and hypertension, however, its role in physiological and pathological processes remain unknown due to lack of selective ligands or identification of its natural ligand. We have recently discovered (Mantey, S. A., Weber, H. C., Sainz, E., Akeson, M., Ryan, R. R. Pradhan, T. K., Searles, R. P., Spindel, E. R., Battey, J. F., Coy, D. H., and Jensen, R. T. (1997) J. Biol. Chem. 272, 26062-26071) that [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) has high affinity for BRS-3 and using this ligand showed BRS-3 has a unique pharmacology with high affinity for no known natural Bn peptides. However, use of this ligand is limited because it has high affinity for all known Bn receptors. In the present study we have attempted to identify BRS-3 selective ligands using a strategy of rational peptide design with the substitution of conformationally restricted amino acids into the prototype ligand [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) or its d-Phe(6) analogue. Each of the 22 peptides synthesized had binding affinities determined for hBRS-3, hGRPR, and hNMBR, and hBRS-3 selective ligands were tested for their ability to activate phospholipase C and increase inositol phosphates ([(3)H]inositol phosphate). Using this approach we have identified a number of BRS-3 selective ligands. These ligands functioned as receptor agonists and their binding affinities were reflected in their potencies for altering [(3)H]inositol phosphate. Two peptides with an (R)- or (S)-amino-3-phenylpropionic acid substitution for beta-Ala(11) in the prototype ligand had the highest selectivity for the hBRS-3 over the mammalian Bn receptors and did not interact with receptors for other gastrointestinal hormones/neurotransmitters. Molecular modeling demonstrated these two selective BRS-3 ligands had a unique conformation of the position 11 beta-amino acid. This selectivity was of sufficient magnitude that these should be useful in explaining the role of hBRS-3 activation in obesity, glucose homeostasis, hypertension, and other physiological or pathological processes.
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PMID:Rational design of a peptide agonist that interacts selectively with the orphan receptor, bombesin receptor subtype 3. 1111 77

We have shown previously that the antioxidant alpha-lipoic acid (ALA) can stimulate glucose transport and can enhance the stimulation of this process by insulin in skeletal muscle from insulin-resistant obese Zucker rats. As insulin can also acutely activate general protein synthesis and inhibit net protein degradation in skeletal muscle, we hypothesized that ALA could directly affect protein turnover and also increase the effect of insulin on protein turnover in isolated skeletal muscle from developing obese Zucker rats. In epitrochlearis muscles isolated from obese Zucker rats, insulin (2 mU/ml) significantly (p < 0.05) increased in vitro protein synthesis (phenylalanine incorporation into protein) and decreased net protein degradation (tyrosine release), whereas a racemic mixture of ALA (2 mM) had no effect on either process. Interestingly, rates of protein synthesis in muscle from obese Zucker rats were substantially lower compared to those values observed in age-matched insulin-sensitive Wistar rats, whereas rates of protein degradation were comparable. Obese Zucker rats were also treated chronically with either vehicle or ALA (50 mg/kg/d for 10 d). Again, insulin significantly increased net protein synthesis and decreased net protein degradation in epitrochlearis muscles isolated from vehicle-treated obese Zucker rats; however, this stimulatory effect of insulin was not improved by prior in vivo ALA treatment. These results indicate that the previously described effect of the antioxidant ALA to increase insulin-stimulated glucose transport in skeletal muscle of obese, insulin-resistant rats does not apply to another important insulin-regulatable process, protein turnover. These findings imply that the cellular mode of action for ALA is restricted to signaling factors unique to the activation of glucose transport, and does not involve the pathway of stimulation of general protein synthesis and net protein degradation.
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PMID:Antioxidant alpha-lipoic acid and protein turnover in insulin-resistant rat muscle. 1118 93

Insulin resistance is a change in physiologic regulation such that a fixed dose of insulin causes less of an effect on glucose metabolism than occurs in normal individuals. The normal compensatory response to insulin resistance is an increase in insulin secretion that results in hyperinsulinemia. If the hyperinsulinemia is sufficient to overcome the insulin resistance, glucose regulation remains normal; if not, type 2 diabetes ensues. Associated with insulin resistance, however, is a cluster of other metabolic abnormalities involving body fat distribution, lipid metabolism, thrombosis and fibrinolysis, blood pressure regulation, and endothelial cell function. This cluster of abnormalities is referred to as the insulin resistance syndrome or the metabolic syndrome. It is causally related not only to the development of type 2 diabetes but also to cardiovascular disease. A major unresolved issue is whether there is a single underlying cause of this syndrome and, if so, what might it be? Several promising hypotheses have been proposed. There are some data to support the hypothesis that fetal malnutrition imprints on metabolic regulatory processes that, in later adult life, predispose to the development of the insulin resistance syndrome. Visceral obesity also has been a candidate for the cause of the syndrome. Whatever mechanism is ultimately found to be responsible, it will undoubtedly have both genetic and environmental components. Among the biochemical mediators that are likely to be responsible for the interference with insulin's effects on intermediary metabolism are free fatty acids and other products from adipose tissue. Recent data suggest that the substances stimulate serine phosphorylation of molecules involved in the initial steps of insulin action, thereby blocking the ability of these molecules to be tyrosine phosphorylated and initiate the subsequent steps of the insulin action cascade. The thiazolidinediones are a new class of agents that have been developed to treat type 2 diabetic patients. These drugs act as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Following their binding to the receptor, the heterodimer molecule that contains the binding site is activated. The activated complex binds to the response elements of specific genes that regulate molecules that effect insulin action and lipid metabolism. These genes are either activated or inhibited. Specifically, the thiazolidinediones improve insulin action and decrease insulin resistance. The exact mechanism by which these agents decrease insulin resistance is not clear but they do decrease the elevated free fatty acid levels present in insulin-resistant patients and they appear to change the body distribution of adipose tissue. Treatment of insulin-resistant type 2 diabetic patients with thiazolidinediones not only improves glycemic control and decreases insulin resistance, it also improves many of the abnormalities that are part of the insulin resistance syndrome.
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PMID:Insulin resistance and its treatment by thiazolidinediones. 1123 17


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