Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats.

Abstract

To determine whether defects in the insulin signal transduction pathway to glucose transport occur in a muscle fiber type-specific manner, post-receptor insulin-signaling events were assessed in oxidative (soleus) and glycolytic (extensor digitorum longus [EDL]) skeletal muscle from Wistar or diabetic GK rats. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) glucose transport was significantly decreased, compared with that of Wistar rats. In EDL muscle from GK rats, maximal insulin-stimulated glucose transport was normal, while the submaximal response was reduced compared with that of Wistar rats. We next treated diabetic GK rats with phlorizin for 4 weeks to determine whether restoration of glycemia would lead to improved insulin signal transduction. Phlorizin treatment of GK rats resulted in full restoration of insulin-stimulated glucose transport in soleus and EDL muscle. In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. In EDL muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and Wistar rats. Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). Here, we show that in EDL muscle from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment. In conclusion, functional defects in IRS-1 and PI 3-kinase in skeletal muscle from diabetic GK rats are fiber-type-specific, with alterations observed in oxidative, but not glycolytic, muscle. Furthermore, regardless of muscle fiber type, downstream steps to PI 3-kinase (i.e., Akt and glucose transport) are sensitive to changes in the level of glycemia.

Divergent regulation of Akt1 and Akt2 isoforms in insulin target tissues of obese Zucker rats.

“…In vivo in all tissues, insulin action on Akt isoforms is better preserved than insulin action on PI3K, and in some tissues, activity of Akt1 or Akt2 is even increased. Similar discrepancies in PI3K and Akt activities have recently been reported with insulin infusion in obese humans with type 2 diabetes (20) and in several insulin-resistant models in rats (39,40,42). These findings suggest the presence of either PI3K-independent pathways that regulate Akt activity in insulin-resistant states or regulatory steps distal to the activation of PI3K.…”

“…Unlike in adipocytes, in skeletal muscle of obese rats, insulin-stimulated activities of Akt1 and Akt2 are reduced 30%. This reduction is unlikely to impair insulin-stimulated glucose transport, since recent studies in models of insulin resistance induced with hyperglycemia in vivo (39) or in vitro (40) show that an ~40% reduction in insulin-stimulated Akt activation in skeletal muscle is associated with no defect in insulin-stimulated glucose transport. On the other hand, glucose metabolism to glycogen is impaired (40), potentially indicating differential dependency of glucose transport and glycogen synthesis on Akt activation.…”

“…Insulin infusion in obese humans with type 2 diabetes normally activates all Akt isoforms in muscle in spite of 50% reduced activation of PI3K (20). In rats, however, hyperglycemia may interfere with insulin activation of Akt in muscle (39,40). The regulation of Akt in states of hyperinsulinemia without hyperglycemia has not been investigated.…”

Expression of the skeletal muscle dystrophin–dystroglycan complex and syntrophin-nitric oxide synthase complex is severely affected in the type 2 diabetic Goto–Kakizaki rat

“…Severe pathophysiological symptoms including defects in insulin secretion and peripheral insulin resistance usually occur by 4 weeks of age (Abdel-Halim et al, 1994;Portha et al, 1991). GK skeletal muscles appear to exhibit a reduced percentage of oxidative fibres (Yasuda et al, 2002) and also show fibre type-specific defects, with IRS1 and PI3K activity decreased primarily in oxidative muscles (Song et al, 1999). Activities of insulin signalling intermediates including PI3K, PKB/Akt and ERK were found to be impaired in GK muscle (Steiler et al, 2003;Krook et al, 1997).…”

Effects of Rexinoids on Glucose Transport and Insulin-mediated Signaling in Skeletal Muscles of Diabetic (db/db) Mice

“…Several independent lines of evidence have shown that decreased insulin-dependent Akt phosphorylation is associated with a variety of insulin-resistant states (33)(34)(35)(36), and interventions that increase the level of Akt phosphorylation in muscle cells and other tissues lead to increased insulin-stimulated glucose transport (35,36). An interesting feature of the effect of rexinoids on Akt phosphorylation is that it was similar in both the slow-twitch soleus muscle as well as in muscle such as EDL that is primarily composed of fast-twitch myofibers.…”