PMID- 26492646
OWN - NLM
STAT- MEDLINE
DCOM- 20151201
LR  - 20211203
IS  - 0031-7144 (Print)
IS  - 0031-7144 (Linking)
VI  - 70
IP  - 9
DP  - 2015 Sep
TI  - Chronic rapamycin treatment exacerbates metabolism and does not down-regulate 
      mTORC2/Akt signaling in diabetic mice induced by high-fat diet and 
      streptozotocin.
PG  - 604-9
AB  - Rapamycin, a classical inhibitor of the mammalian target of rapamycin (mTOR), has 
      been intensively studied for its role in metabolism and verified to induce 
      metabolic defects through mTORC2/Akt pathway. However, disparity of the results 
      exists depending on the differences of the animal models or the detailed 
      procedures. Moreover, data regarding the effect of rapamycin treatment in 
      diabetic models are sparse. Therefore, we investigated its influence on glucose 
      and lipid metabolism, and further analyzed its effect on the mTORC2/Akt pathway 
      in a high-fat diet- and streptozotocin-induced diabetic mice model. Three-weeks 
      old C57BL/6J mice were fed with a high fat diet (60 kcal% fat) and 
      intraperitoneally injected with streptozotocin (100 mg/kg) at 6 weeks of age. 
      Rapamycin (2 mg/kg) was orally given to the mice daily for consecutive 6 weeks. 
      Body weight, blood lipid parameters and HbA(1c)% values were evaluated. Oral 
      glucose test and insulin tolerance test were performed. Furthermore, western blot 
      assay was applied to investigate the protein epression levels of Akt and PKCalpha, 
      two key targets of the mTORC2/Akt pathway. Rapamycin-treated diabetic mice 
      demonstrated less weight gain, more profound symptoms of polydipsia, polyphagia 
      and polyuria, significant liver fat accumulation and exacerbated metabolic 
      disorders including insulin resistance, hyperglycemia and dyslipidemia. Contrary 
      to what have been expected, though significantly inhibiting mTORC1/S6K1 
      signaling, chronic rapamycin treatment failed to down-regulate mTORC2/Akt 
      pathway. Our findings provide evidence that chronic rapamycin treatment may 
      exacerbate metabolism in diabetic subjects and does not down-regulate mTORC2/Akt 
      signialing in a high-fat diet- and streptozotocin-induced diabetic mice model.
FAU - Wang, Yan
AU  - Wang Y
FAU - He, Zhi
AU  - He Z
FAU - Li, Xianhui
AU  - Li X
FAU - Chen, Wenwei
AU  - Chen W
FAU - Lu, Jiewen
AU  - Lu J
FAU - Chen, Xiangping
AU  - Chen X
FAU - Cao, Liang
AU  - Cao L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Pharmazie
JT  - Die Pharmazie
JID - 9800766
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Multiprotein Complexes)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Anti-Bacterial Agents/*pharmacology
MH  - Body Weight/drug effects
MH  - Diabetes Mellitus, Experimental/*drug therapy
MH  - *Diet, High-Fat
MH  - Drinking
MH  - Eating/drug effects
MH  - Glucose Tolerance Test
MH  - Lipid Metabolism/drug effects
MH  - Liver/pathology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Multiprotein Complexes/*drug effects
MH  - Proto-Oncogene Proteins c-akt/*drug effects
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*drug effects
EDAT- 2015/10/24 06:00
MHDA- 2015/12/15 06:00
CRDT- 2015/10/24 06:00
PHST- 2015/10/24 06:00 [entrez]
PHST- 2015/10/24 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PST - ppublish
SO  - Pharmazie. 2015 Sep;70(9):604-9.