Improving Type 2 Diabetes Through a Distinct Adrenergic Signaling Pathway Involving mTORC2 That Mediates Glucose Uptake in Skeletal Muscle

Sato, Masaaki; Dehvari, Nodi; Öberg, Anette I.; Dallner, Olof S.; Sandström, Anna L.; Olsen, Jessica M.; Csikasz, Robert I.; Summers, Roger J.; Hutchinson, Dana S.; Bengtsson, Tore

doi:10.2337/db13-1860

Cited by 110 publications

(171 citation statements)

References 55 publications

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“…Potentially, as discussed above, skin microcirculation does not adequately represent muscle microcirculation, where the largest part of glucose utilization occurs. Interestingly, in a recent study in rats and mice, stimulation of β2-adrenoreceptors in skeletal muscle cells increased glucose uptake independent of the insulin signaling pathway, 33 which could explain the lack of effect on microvascular perfusion. Because we only measured glucose levels, and not muscle glucose uptake, additional studies are needed to assess whether the inverse association between neurogenic activity and glucose levels is mediated by increased glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Smits

Tonneijck

Muskiet

et al. 2016

ATVB

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Objective— To assess the effects of glucagon-like peptide (GLP)-1–based therapies (ie, GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) on microvascular function in patients with type 2 diabetes mellitus. Approach and Results— We studied 57 patients with type 2 diabetes mellitus (mean±SD age: 62.8±6.9 years; body mass index: 31.8±4.1 kg/m 2 ; HbA 1c [glycated hemoglobin] 7.3±0.6%) in an acute and 12-week randomized, placebo-controlled, double-blind trial conducted at the Diabetes Center of the VU University Medical Center. In the acute study, the GLP-1 receptor agonist exenatide (therapeutic concentrations) or placebo (saline 0.9%) was administered intravenously. During the 12-week study, patients received the GLP-1 receptor agonist liraglutide (1.8 mg daily), the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg daily), or matching placebos. Capillary perfusion was assessed by nailfold skin capillary videomicroscopy and vasomotion by laser Doppler fluxmetry, in the fasting state and after a high-fat mixed meal. In neither study, treatment affected fasting or postprandial capillary perfusion compared with placebo ( P >0.05). In the fasting state, acute exenatide infusion increased neurogenic vasomotion domain power, while reducing myogenic domain power (both P <0.05). After the meal, exenatide increased endothelial domain power ( P <0.05). In the 12-week study, no effects on vasomotion were observed. Conclusions— Despite modest changes in vasomotion, suggestive of sympathetic nervous system activation and improved endothelial function, acute exenatide infusion does not affect skin capillary perfusion in type 2 diabetes mellitus. Twelve-week treatment with liraglutide or sitagliptin has no effect on capillary perfusion or vasomotion in these patients. Our data suggest that the effects of GLP-1–based therapies on glucose are not mediated through microvascular responses.

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Section: Discussionmentioning

confidence: 99%

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Smits

Tonneijck

Muskiet

et al. 2016

ATVB

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“…The underlying mechanisms for these effects in SM remain to be elucidated; a recently newly identified adrenergic signaling pathway involving MTORC2 (38) or signaling molecules secreted by brown adipocytes (39) might play a role in this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

Short-term Cold Acclimation Recruits Brown Adipose Tissue in Obese Humans

et al. 2015

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Recruitment of brown adipose tissue (BAT) has emerged as a potential tool to combat obesity and associated metabolic complications. Short-term cold acclimation has been shown not only to enhance the presence and activity of BAT in lean humans but also to improve the metabolic profile of skeletal muscle to benefit glucose uptake in patients with type 2 diabetes. Here we examined whether short-term cold acclimation also induced such adaptations in 10 metabolically healthy obese male subjects. A 10-day cold acclimation period resulted in increased cold-induced glucose uptake in BAT, as assessed by [18F]fluorodeoxyglucose positron emission tomography/computed tomography. BAT activity was negatively related to age, with a similar trend for body fat percentage. In addition, cold-induced glucose uptake in BAT was positively related to glucose uptake in visceral white adipose tissue, although glucose uptake in visceral and subcutaneous white adipose tissue depots was unchanged upon cold acclimation. Cold-induced skeletal muscle glucose uptake tended to increase upon cold acclimation, which was paralleled by increased basal GLUT4 localization in the sarcolemma, as assessed through muscle biopsies. Proximal skin temperature was increased and subjective responses to cold were slightly improved at the end of the acclimation period. These metabolic adaptations to prolonged exposure to mild cold may lead to improved glucose metabolism or prevent the development of obesity-associated insulin resistance and hyperglycemia.

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“…mTOR modulates cellular processes such as protein synthesis and energy metabolism (10,37) and has distinct functions depending on whether it is part of mTOR complex (mTORC)1 or mTORC2. In the developing and adult heart mTORC1 activity is associated with protein synthesis and physiological hypertrophy, and mTORC2 may modulate glucose uptake, as demonstrated previously in skeletal muscle (35,40,57). Increased glucose uptake is critical for the survival of cardiomyocytes during the acute phase of ischemic injury, when lipid metabolism will become not only insufficient for the energy demands of the heart but will also lead to a significant increase in oxidative stress (3,46,72).…”

mentioning

confidence: 91%

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

Pentassuglia

Heim

Lebboukh

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Nrg1β is critically involved in cardiac development and also maintains function of the adult heart. Studies conducted in animal models showed that it improves cardiac performance under a range of pathological conditions, which led to its introduction in clinical trials to treat heart failure. Recent work also implicated Nrg1β in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1β acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1β on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1β enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1β causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr861), Akt (Thr308 and Ser473), and its effector AS160 (Thr642). Knockdown of ErbB2 or ErbB4 reduces Akt phosphorylation and blocks the glucose uptake. The Akt inhibitor VIII and the PI3K inhibitors LY-294002 and Byl-719 abolish Nrg1β-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1β-induced increases in Akt-p-Ser473 but does not modify AS160-p-Thr642 or the glucose uptake responses to Nrg1β. In conclusion, our study demonstrates that Nrg1β enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kα, and Akt. Furthermore, although Nrg1β activates mTORC2, the resulting Akt-Ser473 phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1β regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure.

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Improving Type 2 Diabetes Through a Distinct Adrenergic Signaling Pathway Involving mTORC2 That Mediates Glucose Uptake in Skeletal Muscle

Cited by 110 publications

References 55 publications

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

GLP-1–Based Therapies Have No Microvascular Effects in Type 2 Diabetes Mellitus

Short-term Cold Acclimation Recruits Brown Adipose Tissue in Obese Humans

Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes

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