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

Authors:
Masaaki Sato at Monash University (Australia)
Masaaki Sato
Nodi Dehvari at Stockholm University
Nodi Dehvari
Anette I Oberg
Anette I Oberg
Anette I Oberg
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Olof S Dallner at The Rockefeller University
Olof S Dallner
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Abstract

Type 2 diabetes is an increasing worldwide epidemic that poses major health problems. We have identified a novel physiological system that increases glucose uptake in skeletal muscle but not in white adipocytes. Activation of this system improves glucose tolerance in Goto-Kakizaki rats or mice fed a high fat diet, which are established models for type 2 diabetes. The pathway involves activation of β2-adrenoceptors that increase cAMP levels and activate PKA that phosphorylates mammalian target of rapamycin complex 2 (mTORC2) at S2481. The active mTORC2 causes translocation of GLUT4 to the plasma membrane and glucose uptake without the involvement of Akt or AS160. Stimulation of glucose uptake into skeletal muscle following activation of the sympathetic nervous system is likely to be of high physiological relevance since mTOR complex 2 activation was observed at the cellular, tissue and whole animal level in rodent and human systems. This signaling pathway provides new opportunities for the treatment of type 2 diabetes.
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Masaaki Sato,
1,2,3
Nodi Dehvari,
1
Anette I. Öberg,
2,3
Roger J. Summers,
2,3
Dana S. Hutchinson,
2,3
and Tore Bengtsson
1
RESPONSE TO COMMENT ON SATO ET AL.
Improving Type 2 Diabetes
Through a Distinct Adrenergic
Signaling Pathway Involving
mTORC2 That Mediates Glucose
Uptake in Skeletal Muscle.
Diabetes 2014;63:4115–4129
Diabetes 2014;63:e22–e23 | DOI: 10.2337/db14-1283
We thank Xiang et al. (1) for their comments on our article
published in Diabetes (2) that shows for the first time that
activation of b
2
-adrenoceptors promotes GLUT4-translocation
and glucose uptake in skeletal muscle via a specific pathway
dependent on mammalian target of rapamycin (mTOR) com-
plex 2 (mTORC2). Because this pathway bypasses several of
the proteins used in the insulin pathway, which are down-
regulated and desensitized in type 2 diabetes, we hypothesize
that this pathway may be used to regulate glucose uptake and
blood glucose in diabetic patients.
However, Xiang et al. (1) raise important concerns re-
garding the use of b
2
-adrenoceptor agonists to treat type
2 diabetes. As they point out, systemic activation of b
2
-
adrenoceptors can lead to an acute rise in blood glucose
levels by increasing hepatic glucose output, and this could
be detrimental for diabetic patients. Stimulation of b
2
-
adrenoceptors can regulate both glucose output from the
liver and its uptake into skeletal muscle. However, our
novel finding makes it feasible to develop compounds
that specifically enhance glucose uptake into skeletal mus-
cle without activating glucose output from the liver.
There are several ways in which the b
2
-adrenergic pathway
could be used to develop new medicines to treat type 2 di-
abetes. An emerging paradigm in pharmacology is the recog-
nition of biased ligands that can stimulate a preferred subset
of signaling pathways activated by the receptor (3). Another
possibility would be to directly activate specificproteinsinthe
novel b
2
-adrenergic pathway. Both approaches could pro-
mote glucose uptake in skeletal muscle without accompany-
ing side effects in the liver and other tissues.
Furthermore, the rise in blood glucose after sympathetic
stimulation is a short-term effect, as illustrated in another
article by Xiang et al. (4) in which orthopedic trauma in-
duced an increase in blood glucose that peaked after 2 h. In
contrast, the long-term effect of b
2
-adrenoceptor agonist
treatment is an improvement of glucose tolerance (2),
suggesting that glucose uptake into skeletal muscle out-
weighs glucose release from the liver.
Afinal concern raised by Xiang et al. (1) is that our study
does not directly show that the mTORC2 pathway is involved
in the improvement of glucose tolerance in type 2 diabetes.
Our study clearly shows that there is a novel b
2
-adrenoceptor
signaling pathway that involves mTORC2 and promotes glu-
cose uptake in skeletal muscle. This was shown in vitro, ex
vivo, and in vivo. It is thus very likely that the novel pathway
also mediates some or all of the beneficial effects and im-
provement of glucose tolerance induced by b
2
-adrenoceptor
stimulation in type 2 diabetes, although further studies are
required to fully understand this mechanism. These studies
should dissect different parts of the physiological response,
focusing particularly on glucose uptake in skeletal muscle,
to better understand how this can best be used for the de-
velopment of new medicines. Although b
2
-adrenoceptor
stimulation of glucose uptake in skeletal muscle has been
1
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm
University, Stockholm, Sweden
2
Department of Pharmacology, Monash University, Clayton, Victoria, Australia
3
Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences,
Monash University, Parkville, Victoria, Australia
Corresponding author: Tore Bengtsson, tore.bengtsson@su.se.
M.S., N.D., and A.I.Ö. contributed equally to the response.
© 2014 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for profit, and
the work is not altered.
e22 Diabetes Volume 63, December 2014
e-LETTERS –COMMENTS AND RESPONSES
a neglected area of research, we believe that our study clearly
identifies novel targets that can be exploited in the search
for new treatments for type 2 diabetes.
Duality of Interest. No potential conflicts of interest relevant to this article
were reported.
References
1. Xiang L, Mittwede PN, Hester RL. Comment on Sato et al. Improving type 2
diabetes through a distinct adrenergic signaling pathway involving mTORC2 that
mediates glucose uptake in skeletal muscle. Diabetes 2014;63:4115–4129 (Letter).
Diabetes 2014;63:e20. DOI: 10.2337/db14-1187
2. Sato M, Dehvari N, Öberg AI, et al. Improving type 2 diabetes through
a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose
uptake in skeletal muscle. Diabetes 2014;63:4115–4129
3. Evans BA, Sato M, Sarwar M, Hutchinson DS, Summers RJ. Ligand-directed
signalling at b-adrenoceptors. Br J Pharmacol 2010;159:1022–1038
4. Xiang L, Lu S, Mittwede PN, Clemmer JS, Husband GW, Hester RL. b
2
adrenoreceptor blockade improves early post-trauma hyperglycemia and
pulmonary injury in obese rats. Am J Physiol Heart Circ Physiol 2014;307:
H621–H627.
diabetes.diabetesjournals.org Response e23
... One such response, β 2 -AR mediated glucose uptake in skeletal muscle, is attenuated by inhibition of PKA/AC and mimicked by cyclic adenosine monophosphate (cAMP) analogs. [2][3][4] In skeletal muscle, cAMP levels rise rapidly in response to high efficacy β 2 -AR agonists such as isoprenaline 5 before cAMP is degraded by phosphodiesterases, whereas β 2 -AR mediated glucose uptake by isoprenaline increases more slowly and the effect is sustained for up to 20 h. 5 This suggests that the transient nature of the β 2 -AR cAMP response may occur in parallel with an alternative mechanism that maintains increased glucose uptake, highlighting the importance of understanding the molecular mechanisms involved. ...
... Transcriptional regulation may also be a factor considering the differences in time courses observed but isoprenaline-mediated glucose uptake in skeletal muscle is independent of both transcription and translation, at least 2 h post-receptor stimulation. 4,5 In addition, partial agonists such as BRL37344 produce only modest cAMP responses yet have similar efficacy to isoprenaline for glucose uptake. ...
... Our previous work has involved investigating the mechanism whereby β 2 -ARs increase skeletal muscle glucose uptake. [2][3][4][5]22 We and others have shown that activation of β 2 -ARs increases glucose uptake in skeletal muscle using cell lines (mouse C 2 C 12 , rat L6 skeletal muscle, human skeletal muscle cells) and isolated skeletal muscle strips, and that β 2 -AR agonist administration in vivo improves glucose tolerance in diabetic rats and obese mice. 4 A level of complexity arises from in vivo studies in rodents using BRL37344 as it is a dual rodent β 2 −/β 3 -AR agonist and its beneficial effects at least in rodents are most likely due to its action at adipocyte β 3 -ARs and skeletal muscle β 2 -ARs. ...
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... mTORC2 will then on its turn phosphorylate AKT at Ser473, resulting in full AKT activation [63,64]. Additional stimuli that can trigger mTORC2 activation include adrenergic signaling via G-protein coupled receptors (GPCR), such as the β2-adrenoceptor, which stimulates cAMP accumulation and activation of cAMP-dependent protein kinase (PKA), leading to phosphorylation of mTORC2 [65]. Also, AMPK appears to be sufficient to increase mTORC2 catalytic activity towards AKT in an mTORC1-independent manner [66]. ...
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Comment on Sato et al. Improving Type 2 Diabetes Through a Distinct Adrenergic Signaling Pathway Involving mTORC2 That Mediates Glucose Uptake in Skeletal Muscle. Diabetes 2014;63:4115-4129
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Article
  • Nov 1984
Chronic treatment of rats with the ß2-adrenergic agonists clenbuterol and fenoterol over 16–19 d raised energy intake, expenditure, and body weight gain but did not affect fat or energy deposition, and body protein gain was increased by 50 and 18%, respectively. Both drugs increased the protein content and mitochondrial GDP-binding capacity of brown adipose tissue. Clenbuterol did not affect plasma insulin, growth hormone, or triiodothyronine levels, although insulin levels were reduced by fenoterol. Both drugs caused hypertrophy of skeletal muscle (gastrocnemius), and muscle protein synthesis in vivo (fractional rate) was elevated by 34 and 26% in clenbuterol and fenoteroltreated rats, respectively.
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Adrenergic receptors in rat skeletal muscle
Article
  • May 1986
Sarcolemma-enriched preparations from muscles rich in slow oxidative red fibres contained specific binding sites for the α1 antagonist, prazosin (e.g. soleus Kd 0.13 nM, Bmax 29 fmol/mg protein). Binding sites for prazosin were almost absent from white muscle. Displacement of prazosin binding from sarcolemma of soleus muscle (phentolamine>phenylephrine>idazoxan>yohimbine) suggested that the receptors were α1. Binding sites for dihydroalprenolol (β antagonist) were also more concentrated on red than white muscle and outnumbered prazosin sites by approx. 10:1. Binding sites for idazoxan (α2 antagonist) were undetectable. Contamination of sarcolemma-enriched preparations by endothelial tissue indicated by the activity of angiotensin converting enzyme did not correlate with prazosin binding. It is concluded that post-synaptic α1 adrenergic receptors are present on the sarcolemma of slow oxidative red fibres of rat skeletal muscle. The presence provides the mechanistic basis for apparent α-adrenergic effects to increase glucose and oxygen uptake in perfused rat hindquarter.
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Chronic β2 adrenergic agonist, but not exercise, improves glucose handling in older type 2 diabetic mice
Article
  • Mar 2012
  • CELL MOL NEUROBIOL
Insulin resistant type 2 diabetes mellitus in the obese elderly has become a worldwide epidemic. While exercise can prevent the onset of diabetes in young subjects its role in older diabetic people is less clear. Exercise stimulates the release of the β(2)-agonist epinephrine more in the young. Although epinephrine and β(2)-agonist drugs cause acute insulin resistance, their chronic effect on insulin sensitivity is unclear. We fed C57BL/6 mice a high fat diet to induce diabetes. These overweight animals became very insulin resistant. Exhaustive treadmill exercise 5 days a week for 8 weeks had no effect on their diabetes, nor did the β(2)-blocking drug ICI 118551. In contrast, exercise combined with the β(2)-agonist salbutamol (albuterol) had a beneficial effect on both glucose tolerance and insulin sensitivity after 4 and 8 weeks of exercise. The effect was durable and persisted 5 weeks after exercise and β(2)-agonist had stopped. To test whether β(2)-agonist alone was effective, the animals that had received β(2)-blockade were then given β(2)-agonist. Their response to a glucose challenge improved but their response to insulin was not significantly altered. The β(2)-agonists are commonly used to treat asthma and asthmatics have an increased incidence of obesity and type 2 diabetes. Although β(2)-agonists cause acute hyperglycemia, chronic treatment improves insulin sensitivity, probably by improving muscle glucose uptake.
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