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

ergetic sensor for the metabolic control of the whole organism. Insulin
demand is increased under different physiological and pathological
conditions, such as pregnancy, obesity or aging (1, 2). These various
conditions enforce the ß cell mass to adapt to higher insulin synthe-
sis and secretion requirements. Thus, ß cell plasticity can be accom-
plished by an increase in ß cell mass, which is the net result of both
cell hyperplasia and cell hypertrophy (3). The failure of these com-
pensatory mechanisms results in an insulin deficiency that leads to
hyperglycemia and clinical manifestations of type 2 diabetes (3).

Autocrine insulin signaling on ß cells has shown to be essential in
these compensatory mechanisms (4). On this regard, downstream ef-
fectors of insulin signaling such as Akt and the 70-kDa ribosomal pro-
tein S6 kinase (p70S6K) have proven to be positive key regulators of
ß cell mass (5, 6).

Glucose is the main effector of insulin secretion in ß cells, but it
also plays a role in ß cell proliferation. Mice haploinsufficient for glu-
cokinase are unable to increase ß cell mass in response to high-fat
diet (7). Furthermore, glucose has been found to stimulate ERK 1/2
activation (8, 9). This activation is independent of insulin signaling as
seen in IR -/- ß cells (10). Glucose directly increases ATP/AMP ratio
inhibiting AMP-activated protein kinase (AMPK) activity.

The TSC1-TSC2 complex is located in the crossroad of this sig-
naling network, integrating different signals to determine the cellu-
lar fate through regulation of protein synthesis, cell size and prolif-
eration (11). The GTPase-activating protein (GAP) activity of TSC2
towards Ras homolog enriched in brain (Rheb) negatively regulates
mTORC1 signaling. Akt and ERK directly phosphorylates TSC2 lead-
ing to an increase in mTORC1 signaling (12, 13). In contrast, AMPK
activation has been found to phosphorylate TSC2 and stabilize the
TSC1-TSC2 complex, leading to a diminished mTORC1 activity un-
der low energetic states (14). TSC/mTORC1/p70S6K signaling path-
way is tightly regulated. Although a diminished mTORC1/p70S6K
activity can lead to a decrease in ß cell mass and diabetes, its hy-
peractivity induces an insulin resistance state by a negative feedback
loop on IRS-1/2 (15). As the key regulator of protein synthesis,
mTORC1 hyperactivity can also lead to endoplasmic reticulum as-
sociated stress (ER stress) (16). ß cell ER has a high capacity of pro-

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