There is growing evidence for a portal factor, released following a meal, that combined with insulin, induces hepatic glycogen synthesis. We have developed an in vitro model that demonstrates that serotonin could be the portal factor. Using rat primary hepatocyte cultures in 6 well plates with 750,000 cells per well and a 4-hour treatment time, we observed that 0.1 mU/ml of human insulin resulted in generation of 8.8 ± 2.3 ng glycogen/ug total protein compared to 6.7 ± 1.0 ng glycogen/ug total protein, with 5 uM 5HT-serotonin. Interestingly, the combination of 0.1 mU insulin/ml and 5 uM 5HT-serotonin resulted in 22.5 ± 3.8 ng glycogen/ug total protein, a 256% increase in glycogen synthesis compared to insulin alone. In the absence of serotonin, it takes approximately 10-fold greater insulin to achieve the same levels of glycogen synthesis as insulin with serotonin. These data combined with the observation that 95% of serotonin is made in the gut, that gastrointestinal serotonin is released upon food ingestion and the growing evidence that obese subjects have decreasing levels of circulating serotonin, suggest that gastrointestinal serotonin could be the portal factor necessary for efficient hepatic control of system glycemia. These data further suggest that insulin insensitivity is due to loss of a critical co-factor binding, and that this co-factor is serotonin. In summary, type 1 diabetes is due to a deficiency of insulin and type 2 diabetes may be due to a deficiency of its co-factor, portal serotonin.


M.Kiedrowski: None. C.El sanadi: None. M.S.Penn: Consultant; Diasome, Quest Diagnostics. W.Geho: None.

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