fig2

Figure 2. Top: endocrine pancreas with its GABA ergic controls OFF. This leads to a leakage of insulin rendering differentiated cells resistant to insulin; in addition, GABA fails to block glucagon release when insulin is released, sending a hybrid catabolic-anabolic hormonal message. The GABA deficiency increases epinephrine release from adrenals, which inhibits delta cells and somatostatin, activating growth hormone. The first cell is a new mitotic stem cell with new insulin receptors it receives the dual catabolic - anabolic message. PKA, Src are activated closing pyruvate kinase and pyruvate dehydrogenase and the glycolytic supply of acetyl CoA; but the increase of IP3 and calcium mediated by insulin, boosts glycolysis until the pyruvate kinase bottle neck, by increasing the fructose 2-6 bis Phosphate activator. Indeed, calcium stimulates a phosphodiesterase that decreases cAMP, cancelling its inhibitory effect on fructose 2-6 bis Phosphate synthesis. Note that growth hormone activates the production of DAG via ATGL, which stimulates PKC and CPI 17, inhibiting PP1 phosphatase, which maintains the glycolytic bottle neck, in spite of the conversion of DAG into triglycerides. Insulin elicits fatty acid synthesis by inhibiting via PKB, AMP kinase, which suppresses the inhibition of acetyl CoA carboxylase; the automatic increase of malonyl CoA closes the fatty acid transporter and the fatty acid source of acetyl CoA. Since the glycolytic source of acetyl CoA was off as well, the stem cell becomes dependent of ketone bodies reconverted into acetyl CoA to feed their citrate condensation, and support the synthesis of fatty acid and lipids for new mitotic cells. Note the supply of amino acids the synthesis of proteins, the transamination, and the release of lactic acid. The next cell is a liver cell resistant to insulin; it receives the catabolic glucagon part of the pancreatic message and is programmed for making glucose and ketone bodies. The fatty acid synthesis is OFF (ACC inhibition by AMP kinase) while fatty acid supplied by adipocytes, form acetyl CoA by beta oxidation, the decreased citrate condensation inhibited by NADH, leaves more acetyl CoA for the ketogenic pathway. The increased NADH comes from a lower oxygen supply and reduction. PKC-CPI17 is stimulated by DAG coming from ATGL stimulated by growth hormone. Muscle, provides amino acids supporting neoglucogenesis, note the transamination the urea cycle. The bottom cell is a muscle cell, also insulin resistant, while receiving the catabolic message (through epinephrine). Muscle activity releases calcium in the cytosol stimulating a phosphodiesterase hydrolyzing cAMP, which cancels the inhibition of fructose 2-6 bis Phosphate formation, activating glycolysis. The glycolytic bottle neck, is maintained because the inhibitor CPI17 of PP1 is again formed via PKC stimulation by DAG, produced by ATGL activated by growth hormone. The citrate condensation is not inhibited by NADH (the latter decreases since lactic acid and myoglobin pull more oxygen). The citric acid cycle turns, activity lowers the ATP/AMP ratio. Cortisol activates proteolysis providing amino acids to the liver. Doted lines are interrupted pathways. Blocks adjacent to each cell indicate the switch compound levels. DAG: diacyl glycerol; PK: pyruvate kinase; PDH: pyruvate dehydrogenase; GH: growth hormone; ATGL: adipose triglyceride lipase