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Israël. J Cancer Metastasis Treat 2019;5:12 I http://dx.doi.org/10.20517/2394-4722.2018.78 Page 5 of 12

Figure 1. Top: endocrine pancreas, the alpha cell releases glucagon; it is turned off by GABA co-released with insulin from beta cells.
In this way when anabolic insulin is ON catabolic hormones are OFF, GABA also inhibits epinephrine release from adrenals. Moreover,
GABA turns off somatostatin release from delta cells, which stimulates growth hormone and IGF. The cell below the pancreas displays
different metabolic finalities that can be reached; these are controlled by a few “switch compounds” themselves controlled by the
endocrine pancreas. These compounds are listed in the boxes below the cell. The yellow pathways represent the nutrition finality forming
glucose and ketone bodies; it is activated by catabolic hormones that control the switch compounds in the yellow box (+ is increase, -
decrease, 0 no change or not relevant). The second and third metabolic finalities represented by the red pathways is the production of
energy from glucose, in the case of glucagon or insulin, note in the corresponding red boxes the difference for diacylglycerol DAG. The
next finality is the production of energy from fatty acids it is represented by the black pathways and the black box for switch compounds.
The last finality represented by the green pathways and green box for the switches, is the anabolic synthesis of new constituents, it is
essential for mitotic cells. The last box in brown shows for comparison the switches for mitotic tumor cells, specially studied in Figure 2.
DAG: diacyl glycerol; PK: pyruvate kinase; PDH: pyruvate dehydrogenase; GH: growth hormone

proteins. Insulin also inhibits the opposite effects: glycogenolysis, neoglucogenesis, lipolysis and proteolysis
mediated by catabolic hormones. Insulin stimulates glucose uptake, facilitating the incorporation of the
glucose transporter. The influx of glucose in cells is also regulated by different affinities of liver glucokinase
lower than the equivalent brain enzyme hexokinase; which serves the brain first with glucose. In parallel,
insulin activates the MAP kinase mitotic and PI3kinase routes, supporting mitosis and cell survival (recall
that each step of these pathways was up-regulated by viral or cellular oncogenes). We have mentioned above,
the downstream stimulation by insulin, of a phospholipase C that generates IP3 and DAG. We recall that
IP3 elicits the release of internal calcium, activating a PDE hydrolyzing cAMP, which cancels the inhibition
of Fruc 2-6 bisP synthesis, leading to an increased glycolysis. Moreover, calcium helps the incorporation of
glucose transporters in cells that have no constitutive transporter in their membrane. But the stimulation