Skeletal Muscle Insulin Signaling Defects Downstream of Phosphatidylinositol 3-Kinase at the Level of Akt Are Associated With Impaired Nonoxidative Glucose Disposal in HIV Lipodystrophy

Haugaard, Steen B.; Andersen, Ove; Madsbad, Sten; Frank, Christian; Iversen, Johan; Nielsen, Jens; Wojtaszewski, Jørgen F.P.

doi:10.2337/diabetes.54.12.3474

Cited by 27 publications

(29 citation statements)

References 55 publications

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“…2) as previously demonstrated for IRTK to IRS-1-PI3K activity [11] and for IRS-1-PI3K activity to phosphorylation of Akt1 and Akt2 [34]. Of note, the fold changes demonstrated were of similar magnitudes to those in previous studies [11,34,35]. Our results are consistent with: (1) signal Increase from basal (%) * * * Fig.…”

Section: Discussionsupporting

confidence: 82%

Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action

et al. 2010

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Aims/hypothesis Insulin resistance in skeletal muscle is a key factor in the development of type 2 diabetes and although some studies indicate that this could be partly attributed to reduced content and activity of various proximal and distal insulin signalling molecules, consensus is lacking. We therefore aimed to investigate the regulation of proximal insulin signalling in skeletal muscle and its effect on glucose metabolism in a large non-diabetic population.Methods We examined 184 non-diabetic twins with goldstandard techniques including the euglycaemic-hyperinsulinaemic clamp. Insulin signalling was evaluated at three key levels, i.e. the insulin receptor, IRS-1 and V-akt murine thymoma viral oncogene (Akt) levels, employing kinase assays and phospho-specific western blotting. Results Proximal insulin signalling was not associated with obesity, age or sex. However, birthweight was positively associated with IRS-1-associated phosphoinositide 3-kinase (PI3K; IRS-1-PI3K) activity (p=0.04); maximal aerobic capacity ðV Á O 2max Þ, paradoxically, was negatively associated with IRS-1-PI3K (p=0.02) and Akt2 activity (p=0.01). Additionally, we found low heritability estimates for most measures of insulin signalling activity. Glucose disposal was positively associated with Akt-308 phosphorylation (p<0.001) and Akt2 activity (p=0.05), but not with insulin receptor tyrosine kinase or IRS-1-PI3K activity. Conclusions/interpretation With the exception of birthweight, 'classical' modifiers of insulin action, including genetics, age, sex, obesity and V Á O 2max , do not seem to mediate their most central effects on whole-body insulin sensitivity through modulation of proximal insulin signalling in skeletal muscle. We also demonstrated an association between Akt activity and in vivo insulin sensitivity, suggesting a role of Akt in control of in vivo insulin resistance and potentially in type 2 diabetes.

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Section: Discussionsupporting

confidence: 82%

Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action

et al. 2010

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“…Similar to the inconsistent finding of impaired insulin action on AKT phosphorylation (6,7,(11)(12)(13), this probably reflects the large heterogeneity in both type 2 diabetic and obese non-diabetic individuals combined with the relatively small sample sizes often used in such studies. However, the impaired insulin activation of GS and the lack of dephosphorylation of GS at sites 2+2a appear to be consistent findings in type 2 diabetic patients [3,7], as well as in other insulin-resistant conditions such as PCOS [9] and HIV lipodystrophy [37]. Consistently, we have demonstrated that insulin-mediated dephosphorylation of GS at sites 2 + 2a correlates significantly with insulinstimulated NOGM in a large cohort of twins [38].…”

Section: Discussionsupporting

confidence: 71%

Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes

Vind

Birk

Vienberg³

et al. 2012

Diabetologia

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Aims/hypothesis In type 2 diabetes, reduced insulinstimulated glucose disposal, primarily glycogen synthesis, is associated with defective insulin activation of glycogen synthase (GS) in skeletal muscle. Hyperglycaemia may compensate for these defects, but to what extent it involves improved insulin signalling to glycogen synthesis remains to be clarified. Methods Whole-body glucose metabolism was studied in 12 patients with type 2 diabetes, and 10 lean and 10 obese non-diabetic controls by means of indirect calorimetry and tracers during a euglycaemic-hyperinsulinaemic clamp. The diabetic patients underwent a second isoglycaemichyperinsulinaemic clamp maintaining fasting hyperglycaemia. Muscle biopsies from m. vastus lateralis were obtained before and after the clamp for examination of GS and relevant insulin signalling components. Results During euglycaemia, insulin-stimulated glucose disposal, glucose oxidation and non-oxidative glucose metabolism were reduced in the diabetic group compared with both control groups (p<0.05). This was associated with impaired insulin-stimulated GS and AKT2 activity, deficient dephosphorylation at GS sites 2+2a, and reduced Thr308 and Ser473 phosphorylation of AKT. When studied under hyperglycaemia, all variables of insulin-stimulated glucose metabolism were normalised compared with the weightmatched controls. However, insulin activation and dephosphorylation (site 2+2a) of GS as well as activation of AKT2 and phosphorylation at Thr308 and Ser473 remained impaired (p<0.05). Conclusions/interpretations These data confirm that hyperglycaemia compensates for decreased whole-body glucose disposal in type 2 diabetes. In contrast to previous less wellcontrolled studies, we provide evidence that the compensatory effect of hyperglycaemia in patients with type 2 diabetes does not involve normalisation of insulin action on GS or upstream signalling in skeletal muscle.

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“…Patients with HIV lipodystrophy are characterized by having decreased oxidative and nonoxidative glucose disposal (25)(26)(27). During insulin stimulation, nonoxidative glucose metabolism is thought to primarily represent muscle glycogen synthesis (49).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study (27) shows that patients with HIV lipodystrophy have a decreased insulin-stimulated GS activity in skeletal muscle. This defect in insulin action is associated with reduced dephosphorylation on sites 2 ϩ 2a, 3a, and 3a ϩ b, most likely via impaired signaling at the level of glycogen synthase kinase (GSK)-3␣ Ser 21 and GSK-3␤ Ser 9 and Akt but not further upstream at the level of IRS-1-associated phosphatidylinositol-3-kinase activity (27). The present study aimed to explore the mechanisms underlying the increase in insulin sensitivity after acute suppression of lipolysis by acipimox in patients with HIV lipodystrophy and fasting hyperinsulinemia.…”

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confidence: 99%

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Inhibition of Lipolysis Stimulates Peripheral Glucose Uptake but Has No Effect on Endogenous Glucose Production in HIV Lipodystrophy

et al. 2007

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HIV-infected patients with lipodystrophy (HIV lipodystrophy) are insulin resistant and have elevated plasma free fatty acid (FFA) concentrations. We aimed to explore the mechanisms underlying FFA-induced insulin resistance in patients with HIV lipodystrophy. Using a randomized, placebo-controlled, cross-over design, we studied the effects of an overnight acipimox-induced suppression of FFAs on glucose and FFA metabolism by using stable isotopelabeled tracer techniques during basal conditions and a two-stage euglycemic-hyperinsulinemic clamp (20 and 50 mU insulin/m 2 per min, respectively) in nine patients with nondiabetic HIV lipodystrophy. All patients received antiretroviral therapy. Biopsies from the vastus lateralis muscle were obtained during each stage of the clamp. Acipimox treatment reduced basal FFA rate of appearance by 68.9% (95% CI 52.6 -79.5) and decreased plasma FFA concentration by 51.6% (42.0 -58.9) (both, P < 0.0001). Endogenous glucose production was not influenced by acipimox. During the clamp, the increase in glucose uptake was significantly greater after acipimox treatment compared with placebo (acipimox: 26. 85 , decreased phosphorylation of glycogen synthase (GS) site 3a ؉ b, and increased GS activity (percent I-form) in skeletal muscle (P < 0.01). Acipimox decreased phosphorylation of GS (site 3a ؉ b) (P < 0.02) and increased GS activity (P < 0.01) in muscle. The present study provides direct evidence that suppression of lipolysis in patients with HIV lipodystrophy improves insulin-stimulated peripheral glucose uptake. The increased glucose uptake may in part be explained by increased dephosphorylation of GS (site 3a ؉ b), resulting in increased GS activity.

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Skeletal Muscle Insulin Signaling Defects Downstream of Phosphatidylinositol 3-Kinase at the Level of Akt Are Associated With Impaired Nonoxidative Glucose Disposal in HIV Lipodystrophy

Cited by 27 publications

References 55 publications

Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action

Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action

Hyperglycaemia normalises insulin action on glucose metabolism but not the impaired activation of AKT and glycogen synthase in the skeletal muscle of patients with type 2 diabetes

Inhibition of Lipolysis Stimulates Peripheral Glucose Uptake but Has No Effect on Endogenous Glucose Production in HIV Lipodystrophy

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