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- Hotamisligil, GS, et al.
(författare)
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Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance
- 1997
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 46:3, s. 451-455
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that tumor necrosis factor (TNF)-α production from adipose tissue is elevated in rodent and human obesity and plays an important role in insulin resistance in experimental animal models. In this study, we examined the adipose expression of both TNF receptors (TNFR1 and TNFR2) in human obesity and demonstrated that obese female subjects express approximately twofold more TNFR2 mRNA in fat tissue and approximately sixfold more soluble TNFR2 in circulation relative to lean control subjects. In contrast, TNFR1 expression and protein levels were similar in these subjects. TNFR2 expression levels in adipose tissue were strongly correlated with BMI (r = 0.65, P < 0.001) and level of hyperinsulinemia (P < 0.001), an indirect measure of insulin resistance, as well as level of TNF-α mRNA expression in fat tissue (r = 0.56, P < 0.001). These results suggest that TNFR2 might play a role in human obesity by modulating the actions of TNF-α.
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| 2. |
- Krook, A, et al.
(författare)
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Improved glucose tolerance restores insulin-stimulated Akt kinase activity and glucose transport in skeletal muscle from diabetic Goto-Kakizaki rats
- 1997
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 46:12, s. 2110-2114
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Tidskriftsartikel (refereegranskat)abstract
- The serine/threonine kinase Akt (protein kinase B [PKB] or related to A and C protein kinase [RAC] has recently been implicated to play a role in the signaling pathway to glucose transport. However, little is known concerning the regulation of Akt activity in insulinsensitive tissues such as skeletal muscle. To explore the role of hyperglycemia on Akt kinase activity in skeletal muscle, normal Wistar rats or Goto-Kakizaki (GK) diabetic rats were treated with phlorizin. Phlorizin treatment normalized fasting blood glucose and significantly improved glucose tolerance (P < 0.001) in GK rats, whereas in Wistar rats, the compound had no effect on glucose homeostasis. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) Akt kinase activity was reduced by 68% (P < 0.01) and glucose transport was decreased by 39% (P < 0.05), compared with Wistar rats. Importantly, the defects at the level of Akt kinase and glucose transport were completely restored by phlorizin treatment. There was no significant difference in Akt kinase protein expression among the three groups. At a submaximal insulin concentration (2.4 nmol/l), activity of Akt kinase and glucose transport were unaltered. In conclusion, improved glucose tolerance in diabetic GK rats by phlorizin treatment fully restored insulin-stimulated activity of Akt kinase and glucose transport. Thus, hyperglycemia may directly contribute to the development of muscle insulin resistance through alterations in insulin action on Akt kinase and glucose transport.
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| 3. |
- Sjoholm, A
(författare)
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Glucose stimulates islet beta-cell mitogenesis through GTP-binding proteins and by protein kinase C-dependent mechanisms
- 1997
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 46:7, s. 1141-1147
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Tidskriftsartikel (refereegranskat)abstract
- Glucose is a cardinal secretory and mitogenic stimulus for the insulin-producing pancreatic ö-cell both in vitro and in vivo, but the mechanisms by which the sugar acts mitogenically remain largely elusive. In this study, the intracellular pathways that convey glucose-induced mitogenic and secretory signaling in ö-cells were investigated. For this purpose, fetal rat pancreatic islets enriched in ö-cells were cultured in 3.3 or 16.7 mmol/l glucose for 3 days. It was found that glucose stimulated ö-cell replication, insulin secretion, and cAMP content. These effects were mimicked by agonists of cAMP-dependent protein kinases but not by guanosine- 3′,5′-cyclic monophosphate (cGMP). Antagonists of cAMP-dependent protein kinases failed to block the glucose-induced increments in β-cell replication and insulin secretion. Glucose is known to activate protein kinase C, and a protein kinase C–activating phorbol ester was found to promote β-cell mitogenesis and insulin secretion. Conversely, when protein kinase C was inhibited, the mitogenic (but not secretory) response to glucose was attenuated. There were no additive or synergistic effects on β-cell replication when cAMP and phorbol ester were combined, whereas insulin secretion was potentiated by this combination. Artificially causing Ca2+ inlet by glibenclamide or ionomycin did not result in a stimulated mitogenic response, and preventing Ca2+ influx by blocking plasma membrane Ca2+ channels did not abolish the mitogenicity of glucose, although it reduced insulin secretion. Pretreatment of islets with pertussis toxin, known to regulate transduction of signals through heterotrimeric GTP-binding proteins, completely prevented the stimulatory effect of glucose on +-cell mitogenesis but not on insulin secretion. We conclude that specific activation of protein kinase C or cAMP synthesis is sufficient to increase β-cell mitogenesis and insulin secretion, whereas cGMP appears not to affect these processes. However, cAMP does not seem to mediate the mitogenicity or secretory action of glucose. The results instead suggest that signaling through GTP-binding proteins and protein kinase C activation is required for transduction of the mitogenic, but not secretory, message of the sugar in the β-cell.
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