PMID- 37894760
OWN - NLM
STAT- MEDLINE
DCOM- 20231030
LR  - 20240210
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 20
DP  - 2023 Oct 11
TI  - mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic 
      Cardiomyopathy.
LID - 10.3390/ijms242015078 [doi]
LID - 15078
AB  - Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity 
      characterized by cardiac dysfunction and heart failure, without predisposing 
      hypertensive or atherosclerotic conditions. Metabolic insulin resistance, 
      promoting hyperglycemia and hyperlipidemia, is the primary cause of 
      diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has 
      shed light on the importance of identifying a unified target paradigm for both 
      the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies 
      have indicated hyperactivation of the mammalian target of rapamycin (mTOR), 
      specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by 
      promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and 
      stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown 
      significant benefits in diabetes and related cardiac dysfunction. Recently, 
      FDA-approved anti-hyperglycemic sodium-glucose co-transporter 2 inhibitors 
      (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, 
      even acknowledging the absence of SGLT2 channels in the heart. Recent studies 
      have proposed SGLT2-independent drug mechanisms to ascertain their 
      cardioprotective benefits by regulating sodium homeostasis and mimicking energy 
      deprivation. In this review, we systematically discuss the role of mTORC1 as a 
      unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize 
      whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic 
      cardiomyopathy. Further studies are warranted to establish the underlying 
      cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective 
      inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR 
      complex 2) signaling.
FAU - Saha, Sumit
AU  - Saha S
AUID- ORCID: 0000-0002-4031-4608
AD  - Department of Biochemistry and Molecular Biology, Virginia Commonwealth 
      University, Richmond, VA 23298, USA.
FAU - Fang, Xianjun
AU  - Fang X
AD  - Department of Biochemistry and Molecular Biology, Virginia Commonwealth 
      University, Richmond, VA 23298, USA.
FAU - Green, Christopher D
AU  - Green CD
AD  - Department of Biochemistry and Molecular Biology, Virginia Commonwealth 
      University, Richmond, VA 23298, USA.
FAU - Das, Anindita
AU  - Das A
AUID- ORCID: 0000-0003-4422-7277
AD  - Division of Cardiology, Pauley Heart Center, Department of Internal Medicine, 
      Virginia Commonwealth University, Richmond, VA 23298, USA.
LA  - eng
GR  - R01 HL134366/HL/NHLBI NIH HHS/United States
GR  - R01 CA229812/CA/NCI NIH HHS/United States
GR  - RO1HL158951/NH/NIH HHS/United States
GR  - R01 HL158951/HL/NHLBI NIH HHS/United States
GR  - R01 CA266124/CA/NCI NIH HHS/United States
GR  - RO1HL134366/NH/NIH HHS/United States
GR  - 1R01CA266124/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Review
DEP - 20231011
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - 0 (Sodium-Glucose Transporter 2)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - 9NEZ333N27 (Sodium)
SB  - IM
MH  - Humans
MH  - *Diabetes Mellitus, Type 2/complications/drug therapy/metabolism
MH  - *Sodium-Glucose Transporter 2 Inhibitors/pharmacology/therapeutic use
MH  - *Diabetic Cardiomyopathies/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Sodium-Glucose Transporter 2
MH  - *Insulin Resistance
MH  - Mechanistic Target of Rapamycin Complex 2/metabolism
MH  - Sodium/metabolism
MH  - *Hyperlipidemias/drug therapy
PMC - PMC10606418
OTO - NOTNLM
OT  - AMPK
OT  - SGLT2i
OT  - diabetes
OT  - diabetic cardiomyopathy
OT  - mTORC1/2
COIS- The authors declare no conflict of interest.
EDAT- 2023/10/28 11:45
MHDA- 2023/10/30 06:47
PMCR- 2023/10/11
CRDT- 2023/10/28 01:17
PHST- 2023/09/01 00:00 [received]
PHST- 2023/09/27 00:00 [revised]
PHST- 2023/10/04 00:00 [accepted]
PHST- 2023/10/30 06:47 [medline]
PHST- 2023/10/28 11:45 [pubmed]
PHST- 2023/10/28 01:17 [entrez]
PHST- 2023/10/11 00:00 [pmc-release]
AID - ijms242015078 [pii]
AID - ijms-24-15078 [pii]
AID - 10.3390/ijms242015078 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Oct 11;24(20):15078. doi: 10.3390/ijms242015078.