Deficiency in phosphorylase phosphatase activity despite elevated protein phosphatase type-1 catalytic subunit in skeletal muscle from insulin-resistant subjects.

Nyomba, B. L. Grégoire; Brautigan, David L.; Schlender, Keith K.; Wang, Wei; Bogardus, Clifton; Mott, David M.

doi:10.1172/jci115464

Cited by 20 publications

(5 citation statements)

References 42 publications

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“…However, the present study shows that first-degree relatives of NIDDM patients also have increased basal GLUT-4 mRNA concentrations, provided they are insulin resistant and not insulin sensitive. This is in accordance with the finding of increased expression of protein phosphatase 1 and insulin receptor substrate i in the basal state in skeletal muscle of insulin-resistant subjects [23,24]. In fact, a tendency towards high basal GLUT-4 mRNA levels in NIDDM patients was also shown by Garvey et al [14].…”

Section: Discussionsupporting

confidence: 90%

Effect of insulin on GLUT-4 mRNA and protein concentrations in skeletal muscle of patients with NIDDM and their first-degree relatives

Schalin-J�ntti

Yki-J�rvinen

Koranyi³

et al. 1994

Diabetologia

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We examined whether insulin resistance, i.e. impaired insulin stimulated glucose uptake in NIDDM patients and their first-degree relatives is associated with alterations in the effect of insulin on the expression of the GLUT-4 gene in skeletal muscle in vivo. Levels of GLUT-4 mRNA and protein were measured in muscle biopsies taken before and after a euglycaemic insulin clamp from 14 NIDDM patients, 13 of their first-degree relatives and 17 control subjects. Insulin stimulated glucose uptake was decreased in the diabetic subjects (19.8 +/- 3.0 mumol.kg LBM-1.min-1, both p < 0.001) compared with control subjects (44.1 +/- 2.5 mumol.kg LBM-1.min-1) and relatives (39.9 +/- 3.3 mumol.kg LBM-1.min-1). Basal GLUT-4 mRNA levels were significantly higher in diabetic subjects and relatives compared to control subjects (99 +/- 8 and 108 +/- 9 pg/micrograms RNA vs 68 +/- 5 pg/micrograms RNA; both p < 0.01). Insulin increased GLUT-4 mRNA levels in all control subjects (from 68 +/- 5 to 92 +/- 6 pg/micrograms RNA; p < 0.0001), but not in the diabetic patients (from 99 +/- 8 to 90 +/- 8 pg/micrograms RNA, NS), or their relatives (from 94 +/- 9 to 101 +/- 11 pg/micrograms RNA, NS). In the relatives, individual basal GLUT-4 mRNA concentrations varied between 55 and 137 pg/micrograms RNA.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 90%

Effect of insulin on GLUT-4 mRNA and protein concentrations in skeletal muscle of patients with NIDDM and their first-degree relatives

Schalin-J�ntti

Yki-J�rvinen

Koranyi³

et al. 1994

Diabetologia

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“…Activity of PP1 was shown to be reduced in skeletal muscle of insulin-resistant Pima Indians (39,40), but not in type 2 diabetic subjects (15). H o w e v e r, no differences in expression of PP1 catalytic subunit were found in insulin-resistant subjects (41). Thus, impaired activity of PP1 could be expected to result from derangement in control of its activity by regulatory subunits.…”

Section: Discussionmentioning

confidence: 99%

Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes.

et al. 2000

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Glycogen synthase (GS) activity is reduced in skeletal muscle of type 2 diabetes, despite normal protein expression, consistent with altered GS regulation. Glycogen synthase kinase-3 (GSK-3) is involved in regulation (phosphorylation and deactivation) of GS. To access the potential role of GSK-3 in insulin resistance and reduced GS activity in type 2 diabetes, the expression and activity of GSK-3 were studied in biopsies of vastus lateralis from type 2 and nondiabetic subjects before and after 3-h hyperinsulinemic (300 mU · m -2 · m i n -1 )-euglycemic clamps. The specific activity of G S K-3 did not differ between nondiabetic and diabetic muscle and was decreased similarly after 3-h insulin infusion. However, protein levels of both a n d isoforms of GSK-3 were elevated (~30%) in diabetic muscle compared with lean (P < 0.01) and weightmatched obese nondiabetic subjects (P < 0.05) and were unchanged by insulin infusion. Thus, both basal and insulin-stimulated total GSK-3 activities were elevated by approximately twofold in diabetic muscle. GSK-3 expression was related to in vivo insulin action, as GSK-3 protein was negatively correlated with maximal insulin-stimulated glucose disposal rates. In summ a r y, GSK-3 protein levels and total activities are 1) elevated in type 2 diabetic muscle independent of obesity and 2) inversely correlated with both GS activity and maximally insulin-stimulated glucose disposal. We conclude that increased GSK-3 expression in diabetic muscle may contribute to the impaired GS activity and skeletal muscle insulin resistance present in t y p e 2 diabetes. D i a b e t e s 4 9 :2 6 3-271, 2000

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“…The phosphorylated GPa was separated from remaining [γ-$$P]ATP by Ultrafree-MC filters (10 000 NMWL Filter Unit) in an Eppendorf centrifuge. The rotor was operated for 60 min at 4 mC and 2000 g. Radiolabelled substrate [$$P]GPa was dephosphorylated according to Nyomba et al [29]. Dephosphorylation was carried out by incubating the radiolabelled GPa with 0.1 unit of rabbit skeletal-muscle PP1 for 5 min at 30 mC in a buffer containing 50 mM Tris, 1.0 mM EDTA, 12.5 mM β-mercaptoethanol and 0.5 mg\ml BSA (pH 7.0-7.5) in a final volume of 70 µl.…”

Section: Phosphatase Activitymentioning

confidence: 99%

Inhibition of glycogenolysis in primary rat hepatocytes by 1,4-dideoxy-1,4-imino-D-arabinitol

Andersen

Rassov

Westergaard

et al. 1999

Biochemical Journal

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1,4-Dideoxy-1,4-imino-d-arabinitol (DAB) was identified previously as a potent inhibitor of both the phosphorylated and non-phosphorylated forms of glycogen phosphorylase (EC 2.4.1.1). In the present study, the effects of DAB were investigated in primary cultured rat hepatocytes. The transport of DAB into hepatocytes was dependent on time and DAB concentration. The rate of DAB transport was 192 pmol/min per mg of protein per mM DAB(medium-concentration). In hepatocytes, DAB inhibited basal and glucagon-stimulated glycogenolysis with IC(50) values of 1.0+/-0.3 and 1.1+/-0.2 microM, respectively. The primary inhibitory effect of DAB on glycogenolysis was shown to be due to inhibition of glycogen phosphorylase but, at higher concentrations of DAB, inhibition of the debranching enzyme (4-alpha-glucanotransferase, EC 2.4.1.25) may have an effect. No effects on glycogen synthesis were observed, demonstrating that glycogen recycling does not occur in cultured hepatocytes under the conditions tested. Furthermore, DAB had no effects on phosphorylase kinase, the enzyme responsible for phosphorylation and thereby activation of glycogen phosphorylase, or on protein phosphatase 1, the enzyme responsible for inactivation of glycogen phosphorylase through dephosphorylation.

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Deficiency in phosphorylase phosphatase activity despite elevated protein phosphatase type-1 catalytic subunit in skeletal muscle from insulin-resistant subjects.

Cited by 20 publications

References 42 publications

Effect of insulin on GLUT-4 mRNA and protein concentrations in skeletal muscle of patients with NIDDM and their first-degree relatives

Effect of insulin on GLUT-4 mRNA and protein concentrations in skeletal muscle of patients with NIDDM and their first-degree relatives

Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes.

Inhibition of glycogenolysis in primary rat hepatocytes by 1,4-dideoxy-1,4-imino-D-arabinitol

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