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AICAR and Metformin Exert AMPK-dependent Effects on INS-1E Pancreatic β-cell Apoptosis via Differential Downstream Mechanisms.

Dai YL, Huang SL, Leng Y - Int. J. Biol. Sci. (2015)

Bottom Line: Both AICAR and metformin protected INS-1E cells from palmitate-induced apoptosis, as reflected by decreases in both cleaved caspase 3 protein expression and caspase 3/7 activity, and these protective effects were abrogated by AMPK inhibitor compound C.The protective action of AICAR was probably mediated by the suppression of triacylglycerol accumulation, increase in Akt phosphorylation and decrease in p38 MAPK phosphorylation, while metformin might exert its protective effect on INS-1E cells by decreases in both JNK and p38 MAPK phosphorylation.Our results provided new and informative clues for better understanding of the role of AMPK in β-cell apoptosis.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zu Chong Zhi Road 555, Shanghai 201203, China.

ABSTRACT
The role of AMP-activated protein kinase (AMPK) in pancreatic β-cell apoptosis is still controversial, and the reasons for the discrepancies have not been clarified. In the current study, we observed the effects of two well-known AMPK activators 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and metformin, on apoptosis in rat insulinoma INS-1E cells, and further explored their possible mechanisms. Both AICAR and metformin protected INS-1E cells from palmitate-induced apoptosis, as reflected by decreases in both cleaved caspase 3 protein expression and caspase 3/7 activity, and these protective effects were abrogated by AMPK inhibitor compound C. The protective action of AICAR was probably mediated by the suppression of triacylglycerol accumulation, increase in Akt phosphorylation and decrease in p38 MAPK phosphorylation, while metformin might exert its protective effect on INS-1E cells by decreases in both JNK and p38 MAPK phosphorylation. All these regulations were dependent on AMPK activation. However, under standard culture condition, AICAR increased JNK phosphorylation and promoted INS-1E cell apoptosis in an AMPK-dependent manner, whereas metformin showed no effect on apoptosis. Our study revealed that AMPK activators AICAR and metformin exhibited different effects on INS-1E cell apoptosis under different culture conditions, which might be largely attributed to different downstream mediators. Our results provided new and informative clues for better understanding of the role of AMPK in β-cell apoptosis.

No MeSH data available.


Related in: MedlinePlus

Summary for regulations of AICAR and metformin on INS-1E cell apoptosis under palmitate-challenged and standard culture conditions.
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Figure 6: Summary for regulations of AICAR and metformin on INS-1E cell apoptosis under palmitate-challenged and standard culture conditions.

Mentions: In recent years, extensive in vitro and in vivo studies on the role of AMPK in β-cell apoptosis were carried out; however, no definite conclusions have been drawn 2. In the current investigation, we studied the effects of AICAR and metformin on apoptosis under both palmitate-challenged and standard culture conditions in rat insulinoma INS-1E cells. We showed that both AICAR and metformin could exert AMPK-dependent protection against palmitate-induced apoptosis via different downstream mechanisms. AICAR might prevent apoptosis by reversing TG overload, activating Akt and inhibiting p38 MAPK. By contrast, metformin protected INS-1E cells probably through suppression of JNK and p38 MAPK. All these regulations were dependent on activation of AMPK signalling pathway. On the other hand, under standard culture condition, AICAR would induce apoptosis through AMPK-mediated JNK activation; while metformin did not induce apoptosis (Fig. 6). Therefore, we speculated that different culture conditions and differences in downstream mediators were the primary causes for the differential regulations of apoptosis by AICAR and metformin in INS-1E cells. This speculation provided a new insight into the current understanding of the controversies regarding the role of AMPK in β-cell apoptosis.


AICAR and Metformin Exert AMPK-dependent Effects on INS-1E Pancreatic β-cell Apoptosis via Differential Downstream Mechanisms.

Dai YL, Huang SL, Leng Y - Int. J. Biol. Sci. (2015)

Summary for regulations of AICAR and metformin on INS-1E cell apoptosis under palmitate-challenged and standard culture conditions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4582151&req=5

Figure 6: Summary for regulations of AICAR and metformin on INS-1E cell apoptosis under palmitate-challenged and standard culture conditions.
Mentions: In recent years, extensive in vitro and in vivo studies on the role of AMPK in β-cell apoptosis were carried out; however, no definite conclusions have been drawn 2. In the current investigation, we studied the effects of AICAR and metformin on apoptosis under both palmitate-challenged and standard culture conditions in rat insulinoma INS-1E cells. We showed that both AICAR and metformin could exert AMPK-dependent protection against palmitate-induced apoptosis via different downstream mechanisms. AICAR might prevent apoptosis by reversing TG overload, activating Akt and inhibiting p38 MAPK. By contrast, metformin protected INS-1E cells probably through suppression of JNK and p38 MAPK. All these regulations were dependent on activation of AMPK signalling pathway. On the other hand, under standard culture condition, AICAR would induce apoptosis through AMPK-mediated JNK activation; while metformin did not induce apoptosis (Fig. 6). Therefore, we speculated that different culture conditions and differences in downstream mediators were the primary causes for the differential regulations of apoptosis by AICAR and metformin in INS-1E cells. This speculation provided a new insight into the current understanding of the controversies regarding the role of AMPK in β-cell apoptosis.

Bottom Line: Both AICAR and metformin protected INS-1E cells from palmitate-induced apoptosis, as reflected by decreases in both cleaved caspase 3 protein expression and caspase 3/7 activity, and these protective effects were abrogated by AMPK inhibitor compound C.The protective action of AICAR was probably mediated by the suppression of triacylglycerol accumulation, increase in Akt phosphorylation and decrease in p38 MAPK phosphorylation, while metformin might exert its protective effect on INS-1E cells by decreases in both JNK and p38 MAPK phosphorylation.Our results provided new and informative clues for better understanding of the role of AMPK in β-cell apoptosis.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zu Chong Zhi Road 555, Shanghai 201203, China.

ABSTRACT
The role of AMP-activated protein kinase (AMPK) in pancreatic β-cell apoptosis is still controversial, and the reasons for the discrepancies have not been clarified. In the current study, we observed the effects of two well-known AMPK activators 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and metformin, on apoptosis in rat insulinoma INS-1E cells, and further explored their possible mechanisms. Both AICAR and metformin protected INS-1E cells from palmitate-induced apoptosis, as reflected by decreases in both cleaved caspase 3 protein expression and caspase 3/7 activity, and these protective effects were abrogated by AMPK inhibitor compound C. The protective action of AICAR was probably mediated by the suppression of triacylglycerol accumulation, increase in Akt phosphorylation and decrease in p38 MAPK phosphorylation, while metformin might exert its protective effect on INS-1E cells by decreases in both JNK and p38 MAPK phosphorylation. All these regulations were dependent on AMPK activation. However, under standard culture condition, AICAR increased JNK phosphorylation and promoted INS-1E cell apoptosis in an AMPK-dependent manner, whereas metformin showed no effect on apoptosis. Our study revealed that AMPK activators AICAR and metformin exhibited different effects on INS-1E cell apoptosis under different culture conditions, which might be largely attributed to different downstream mediators. Our results provided new and informative clues for better understanding of the role of AMPK in β-cell apoptosis.

No MeSH data available.


Related in: MedlinePlus