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VOL. 76 (3), 357-377, 2010 TSC1-TSC2 COMPLEX ON THE CROSSROAD OF PANCREATIC...

4. DISCUSSION

Recent animal models have pointed out the relevance of TSC1-
TSC2 complex acting as a repressor of mTORC1 for the control of ß
cell mass. Thus, ß cell specific knockout models of TSC1 or TSC2, or
Rheb overexpression results in an augmented ß cell mass, mainly be-
cause of a huge cell hypertrophy (19-22). The importance of mTORC1
functioning in human ß cells is also patent; progressive impairment
in ß cell function was observed in patients who received ß cell trans-
plantation and were treated with rapamycin as an immunosuppres-
sant (32). We previously demonstrated that insulin or glucose inde-
pendently induced proliferation signaling in pancreatic ß cells of fetal
origin (10). Now, we address the important issue of the integration of
both independent signaling in the regulation of ß cells proliferation.

Insulin stimulation mediates TSC2 phosphorylation in a PI3K/Akt-
dependent manner leading to diminished TSC2 activity towards Rheb,
and subsequently producing downstream mTORC1 activation (12).
More importantly, insulin stimulates Akt/TSC2/p70S6K and
MEK/ERKs pathways in either IRA or IRB expressing cell lines. These
results contrast with previous data showing specific signaling for each
of the IR isoforms (33, 34). However, insulin induced a more sustained
signaling in Rec A as compared with Rec B cell lines. In fact, wort-
mannin did not completely block either Akt or TSC2 phosphorylation
in Rec A as compared with Rec B ß cells. These results suggest that
IRA confers a stronger proliferation capability as compared with IRB
in response to insulin, as we recently published in iLIRKO primary
islets (26).

Glucose is an essential proliferation and survival factor for pan-
creatic ß cells (7, 10). Glucose stimulation in vitro is able to induce
ERK 1/2 phosphorylation, independently from insulin secretion in ß
cells (10). ERK 2 directly phosphorylates TSC Ser664 in HEK293T cells
(13), and was increased in several human tumours leading to an up-
regulation of mTORC1 signaling (28). Neither TSC2 Ser939 nor Thr1462
phosphorylation was observed upon glucose stimulation in ß cells.
However, TSC2 Ser664 was stimulated by glucose in a MEK/ERK-de-
pendent manner. Glucose can also exert its effects on mTORC1 sig-
naling by modulation of ATP levels and therefore by AMPK inhibi-
tion. AMPK, on one hand, directly stabilizes TSC1-TSC2 complex (14)

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