Serotonin (5-HT) drives diabetes and liver disease, blocking it is therapeutic

[haidut]

After more than a decade of doing research in bioenergetics, I have come to the conclusion that there is hardly a disease (both acute and chronic) where 5-HT is not involved as a causal factor. Out of all those conditions, the ones with the biggest public health impacts are probably obesity, diabetes, and liver disease and those are usually present together (i.e. co-morbidities) in a patient. Despite official claims that the cause of these widespread conditions is eating too much (and especially sugar) and moving too little, the fact that even wild animals living close to humans are getting fat and diabetic virtually guarantees that the cause is environmental. Putting the eternal villain PUFA aside, another ubiquitous environmental factor is the usage of serotonergic drugs, as well as the presence of chronic stress - both resulting in increased serotonergic tone by themselves and greatly synergistic in combination. The study below demonstrates that elevated 5-HT leads to hyperglycemia, hyperlipidemia, insulin resistance, and hepatic steatosis/inflammation/fibrosis through the activation of the 5-HT2 receptor. Conversely, lowering 5-HT synthesis by administration of an inhibitor of tryptophan hydroxylase (TPH, rate-limiting step in serotonin synthesis) and/or blocking the 5-HT2 receptor (with a serotonin antagonist) lead to amelioration (and even reversal) of most of these pathologies. Btw, it is probably just a "coincidence" that despite medicine continuing to gaslight the public about 5-HT being the "happiness" hormone, behind the scenes many companies are running clinical trials with TPH inhibitors or serotonin receptor antagonists as curative treatments for a host of incurable conditions including pulmonary/cardiac fibrosis, as well as the more "benign" but much more widespread conditions collectively known as the metabolic syndrome.

5-HT 2 receptor mediates high-fat diet-induced hepatic steatosis and very low density lipoprotein overproduction in rats - PubMed

Up-regulation of hepatic 5-HT₂R and 5-HT synthesis by HFD is crucial for HFD-induced overproduction of hepatic triglycerides and VLDL with hyperlipidemia.

pubmed.ncbi.nlm.nih.gov

Crucial Roles of 5-HT and 5-HT2 Receptor in Diabetes-Related Lipid Accumulation and Pro-Inflammatory Cytokine Generation in Hepatocytes

"...These effects of the 5-HT system were also detected in palmitic acid- or high glucose-treated PMHs and regulated multiple inflammatory signaling pathways. In diabetic mice, co-treatment with antagonists of both 5-HT synthesis and 5-HT2R significantly abolished hepatic steatosis, inflammation, and fibrosis as well as hyperglycemia and dyslipidemia. Conclusion: Activation of the hepatocellular 5-HT system plays a crucial role in inducing diabetes-related hepatic dysfunction and is a potential therapeutic target."

"...Numerous patients with T2DM develop NAFLD with inflammatory complications, namely, NASH. However, the mechanisms underlying these processes are not understood entirely. We revealed that the 5-HT system, including 5-HT synthesis and 5-HT2R, is activated in the hepatocytes of a T2DM mouse model, which crucially affected the occurrence of hepatic steatosis and inflammation with fibrosis. 5-HT2R activation in hepatocytes regulates PKCε activation with the subsequent phosphorylation of Akt, mTOR, and ERK1/2, ultimately resulting in ELS, including de novo lipogenesis, and TG and VLDL synthesis with LDA, whereas the activation of both 5-HT synthesis and 5-HT2R modulates oxidative stress with the activation of NF-κB and inflammatory signaling molecules, including p38, JNK, and STAT3, resulting in PICG."

"...We found that the levels of dopamine, another molecule synthesized by AADC, were very low and unchanged in the liver and serum of Ctrl and T2DM mice with or without CDP treatment (data not shown), whereas 5-HT levels were significantly elevated in the liver and serum of T2DM mice, and were obviously reduced by CDP treatment; hepatic 5-HT levels were also inhibited by Sar (Fig. 8a). The expression of hepatic Tph1, AADC, 5-HT2AR, and 5-HT2BR was up-regulated in T2DM mice compared to Ctrl mice (Fig. 8a). T2DM mice exhibited PKCε activation with increased phosphorylation of Akt, mTOR, and ERK1/2, upregulated ACC, GPAT1, and MTTP expression (Fig. 8b), and increased TG and VLDL levels (Fig. 8c) in the liver; they also showed hepatic oxidative stress and inflammation with up-regulated MAO-A expression, increased H2O2 and MDA levels, NF-κB activation, increased phosphorylation of p38, JNK, and STAT3, and increased TNF-α and IL-1β levels (Fig. 8b and c). These alterations were remarkably inhibited by Sar and CDP in a synergistic manner."

"...By hematoxylin and eosin staining (Fig. 8d), we found hepatic steatosis and lobular inflammation with inflammatory cell infiltration and hepatocyte ballooning in the lobes. By Masson’s trichrome staining (Fig. 8e), we found hepatic fibrosis in the periportal and parenchymal regions of T2DM mice. These phenotypes were significantly ameliorated by Sar and CDP, particularly by the combination of both. Additionally, increased hepatic levels of hydroxyproline (Fig. 8c), a marked amino acid in the collagen of fibrous tissue [33], and liver injury with increased activity of serum ALT and AST (Fig. 9c) were also reversed significantly in T2DM mice by Sar and CDP in a synergistic manner."

"...Treatment with Sar and CDP, alone or in combination, reversed the bodyweight loss and reduced the increases in food intake and hepatic index in T2DM mice (Fig. 9a). Whereas there was no significant difference between the three treatments for the amelioration of bodyweight loss, food intake, and hepatic index, suggesting that these effects are not crucial for treating NASH. Sar and CDP treatment (alone or in combination) of T2DM mice also ameliorated dyslipidemia and IR in a synergistic manner, including a reduction of the increased serum levels of TG, FFAs, LDL-c, and VLDL-c, decreased serum levels of HDL-c (Fig. 9b), and increased levels of fasting blood glucose and serum insulin with an increased HOMA-IR index (Fig. 9c). Taken together, our findings show that 5-HT system activation in the liver is a crucial event leading to T2DM-related NASH."

 

[ecstatichamster]

so million dollar question is how to lower serotonin safely....is that carrot salad? Other ideas?

 

[ecstatichamster]

thank you so much for posting this, @haidut so appreciated!

 

[Validus]

After more than a decade of doing research in bioenergetics, I have come to the conclusion that there is hardly a disease (both acute and chronic) where 5-HT is not involved as a causal factor. Out of all those conditions, the ones with the biggest public health impacts are probably obesity, diabetes, and liver disease and those are usually present together (i.e. co-morbidities) in a patient. Despite official claims that the cause of these widespread conditions is eating too much (and especially sugar) and moving too little, the fact that even wild animals living close to humans are getting fat and diabetic virtually guarantees that the cause is environmental. Putting the eternal villain PUFA aside, another ubiquitous environmental factor is the usage of serotonergic drugs, as well as the presence of chronic stress - both resulting in increased serotonergic tone by themselves and greatly synergistic in combination. The study below demonstrates that elevated 5-HT leads to hyperglycemia, hyperlipidemia, insulin resistance, and hepatic steatosis/inflammation/fibrosis through the activation of the 5-HT2 receptor. Conversely, lowering 5-HT synthesis by administration of an inhibitor of tryptophan hydroxylase (TPH, rate-limiting step in serotonin synthesis) and/or blocking the 5-HT2 receptor (with a serotonin antagonist) lead to amelioration (and even reversal) of most of these pathologies. Btw, it is probably just a "coincidence" that despite medicine continuing to gaslight the public about 5-HT being the "happiness" hormone, behind the scenes many companies are running clinical trials with TPH inhibitors or serotonin receptor antagonists as curative treatments for a host of incurable conditions including pulmonary/cardiac fibrosis, as well as the more "benign" but much more widespread conditions collectively known as the metabolic syndrome.

Crucial Roles of 5-HT and 5-HT2 Receptor in Diabetes-Related Lipid Accumulation and Pro-Inflammatory Cytokine Generation in Hepatocytes

"...These effects of the 5-HT system were also detected in palmitic acid- or high glucose-treated PMHs and regulated multiple inflammatory signaling pathways. In diabetic mice, co-treatment with antagonists of both 5-HT synthesis and 5-HT2R significantly abolished hepatic steatosis, inflammation, and fibrosis as well as hyperglycemia and dyslipidemia. Conclusion: Activation of the hepatocellular 5-HT system plays a crucial role in inducing diabetes-related hepatic dysfunction and is a potential therapeutic target."

"...Numerous patients with T2DM develop NAFLD with inflammatory complications, namely, NASH. However, the mechanisms underlying these processes are not understood entirely. We revealed that the 5-HT system, including 5-HT synthesis and 5-HT2R, is activated in the hepatocytes of a T2DM mouse model, which crucially affected the occurrence of hepatic steatosis and inflammation with fibrosis. 5-HT2R activation in hepatocytes regulates PKCε activation with the subsequent phosphorylation of Akt, mTOR, and ERK1/2, ultimately resulting in ELS, including de novo lipogenesis, and TG and VLDL synthesis with LDA, whereas the activation of both 5-HT synthesis and 5-HT2R modulates oxidative stress with the activation of NF-κB and inflammatory signaling molecules, including p38, JNK, and STAT3, resulting in PICG."

"...We found that the levels of dopamine, another molecule synthesized by AADC, were very low and unchanged in the liver and serum of Ctrl and T2DM mice with or without CDP treatment (data not shown), whereas 5-HT levels were significantly elevated in the liver and serum of T2DM mice, and were obviously reduced by CDP treatment; hepatic 5-HT levels were also inhibited by Sar (Fig. 8a). The expression of hepatic Tph1, AADC, 5-HT2AR, and 5-HT2BR was up-regulated in T2DM mice compared to Ctrl mice (Fig. 8a). T2DM mice exhibited PKCε activation with increased phosphorylation of Akt, mTOR, and ERK1/2, upregulated ACC, GPAT1, and MTTP expression (Fig. 8b), and increased TG and VLDL levels (Fig. 8c) in the liver; they also showed hepatic oxidative stress and inflammation with up-regulated MAO-A expression, increased H2O2 and MDA levels, NF-κB activation, increased phosphorylation of p38, JNK, and STAT3, and increased TNF-α and IL-1β levels (Fig. 8b and c). These alterations were remarkably inhibited by Sar and CDP in a synergistic manner."

"...By hematoxylin and eosin staining (Fig. 8d), we found hepatic steatosis and lobular inflammation with inflammatory cell infiltration and hepatocyte ballooning in the lobes. By Masson’s trichrome staining (Fig. 8e), we found hepatic fibrosis in the periportal and parenchymal regions of T2DM mice. These phenotypes were significantly ameliorated by Sar and CDP, particularly by the combination of both. Additionally, increased hepatic levels of hydroxyproline (Fig. 8c), a marked amino acid in the collagen of fibrous tissue [33], and liver injury with increased activity of serum ALT and AST (Fig. 9c) were also reversed significantly in T2DM mice by Sar and CDP in a synergistic manner."

"...Treatment with Sar and CDP, alone or in combination, reversed the bodyweight loss and reduced the increases in food intake and hepatic index in T2DM mice (Fig. 9a). Whereas there was no significant difference between the three treatments for the amelioration of bodyweight loss, food intake, and hepatic index, suggesting that these effects are not crucial for treating NASH. Sar and CDP treatment (alone or in combination) of T2DM mice also ameliorated dyslipidemia and IR in a synergistic manner, including a reduction of the increased serum levels of TG, FFAs, LDL-c, and VLDL-c, decreased serum levels of HDL-c (Fig. 9b), and increased levels of fasting blood glucose and serum insulin with an increased HOMA-IR index (Fig. 9c). Taken together, our findings show that 5-HT system activation in the liver is a crucial event leading to T2DM-related NASH."

Thoughts on omeprazole as a TPH inhibitor? I've always read that proton pump inhibitors should be avoided, because they can impair our cognition....

"Results showed that the best-selling, over-the-counter proton pump (H+/K+-ATPase) inhibitor, omeprazole, inhibited TPH1 and TPH2 in the low micromolar range and displayed excellent selectivity over the other closely related aromatic amino acid hydroxylases, i.e.; TH and PAH. Proton pump inhibitors are used clinically for the treatment of gastroesophageal reflux disease and peptic ulcer disease (Herszenyi et al., 2020). These compounds are prodrugs which are absorbed from the gastro-intestinal tract and converted into their active sulfonamide form, which irreversibly binds and inhibits H+/K+-ATPase, in the acidic canaliculi of the gastric parietal cells (Howden, 1991). Proton pump inhibitors are sold without prescription in many countries and are considered among the safest classes of drugs, generally being well tolerated. Interestingly, the S-enantiomer of omeprazole; esomeprazole, was recently reported to inhibit MAO-A (Petzer et al., 2013). In order to gain more insight into the serotonergic profiles of proton pump inhibitors, we characterized the inhibitory effects of omeprazole, esomeprazole, and their commercially available analogues on TPH1 and TPH2. The activities of omeprazole and its analogues at MAO-A were also assessed. Finally, the effect of omeprazole on in vivo 5-HT levels in brain and serum, as well as behavior, was evaluated."

Inhibition of Tryptophan Hydroxylases and Monoamine Oxidase-A by the Proton Pump Inhibitor, Omeprazole—In Vitro and In Vivo Investigations

Serotonin (5-HT) is a hormone and neurotransmitter that modulates neural activity as well as a wide range of other physiological processes including cardiovascular function, bowel motility, and platelet aggregation. 5-HT synthesis is catalyzed by tryptophan hydroxylase (TPH) which exists as two...

www.frontiersin.org

 

[sunny]

Curious also on safest way to inhib. Husband is T2. Has insulin pump to keep level during day. Also to warn of blood sugar heading low as he has a job that is high physical activity.

Interestingly, before Peat, when he was doing some fasting, and more specifically a juicing- but he was juicing mostly veges (pufa)with some apple in it I think - his blood sugar numbers normalized. So I think the low fat was responsible. He thinks the calorie restriction was responsible. I keep wondering what would have happened if he was juicing fruit.

So he is back to insulin.

Anyway, I am Peat, and he tolerates what I say we need to eat or not eat, lol, and he still does some crap food and crap carbs.

I read everything haidut posts on diabetes and metabolic syndrome, trying to decide what I could have hubs try- @haidut , do you think inhibited serotonin is really where t2d need to be focused?

 

[Morten]

After more than a decade of doing research in bioenergetics, I have come to the conclusion that there is hardly a disease (both acute and chronic) where 5-HT is not involved as a causal factor. Out of all those conditions, the ones with the biggest public health impacts are probably obesity, diabetes, and liver disease and those are usually present together (i.e. co-morbidities) in a patient. Despite official claims that the cause of these widespread conditions is eating too much (and especially sugar) and moving too little, the fact that even wild animals living close to humans are getting fat and diabetic virtually guarantees that the cause is environmental. Putting the eternal villain PUFA aside, another ubiquitous environmental factor is the usage of serotonergic drugs, as well as the presence of chronic stress - both resulting in increased serotonergic tone by themselves and greatly synergistic in combination. The study below demonstrates that elevated 5-HT leads to hyperglycemia, hyperlipidemia, insulin resistance, and hepatic steatosis/inflammation/fibrosis through the activation of the 5-HT2 receptor. Conversely, lowering 5-HT synthesis by administration of an inhibitor of tryptophan hydroxylase (TPH, rate-limiting step in serotonin synthesis) and/or blocking the 5-HT2 receptor (with a serotonin antagonist) lead to amelioration (and even reversal) of most of these pathologies. Btw, it is probably just a "coincidence" that despite medicine continuing to gaslight the public about 5-HT being the "happiness" hormone, behind the scenes many companies are running clinical trials with TPH inhibitors or serotonin receptor antagonists as curative treatments for a host of incurable conditions including pulmonary/cardiac fibrosis, as well as the more "benign" but much more widespread conditions collectively known as the metabolic syndrome.

Crucial Roles of 5-HT and 5-HT2 Receptor in Diabetes-Related Lipid Accumulation and Pro-Inflammatory Cytokine Generation in Hepatocytes

"...These effects of the 5-HT system were also detected in palmitic acid- or high glucose-treated PMHs and regulated multiple inflammatory signaling pathways. In diabetic mice, co-treatment with antagonists of both 5-HT synthesis and 5-HT2R significantly abolished hepatic steatosis, inflammation, and fibrosis as well as hyperglycemia and dyslipidemia. Conclusion: Activation of the hepatocellular 5-HT system plays a crucial role in inducing diabetes-related hepatic dysfunction and is a potential therapeutic target."

"...Numerous patients with T2DM develop NAFLD with inflammatory complications, namely, NASH. However, the mechanisms underlying these processes are not understood entirely. We revealed that the 5-HT system, including 5-HT synthesis and 5-HT2R, is activated in the hepatocytes of a T2DM mouse model, which crucially affected the occurrence of hepatic steatosis and inflammation with fibrosis. 5-HT2R activation in hepatocytes regulates PKCε activation with the subsequent phosphorylation of Akt, mTOR, and ERK1/2, ultimately resulting in ELS, including de novo lipogenesis, and TG and VLDL synthesis with LDA, whereas the activation of both 5-HT synthesis and 5-HT2R modulates oxidative stress with the activation of NF-κB and inflammatory signaling molecules, including p38, JNK, and STAT3, resulting in PICG."

"...We found that the levels of dopamine, another molecule synthesized by AADC, were very low and unchanged in the liver and serum of Ctrl and T2DM mice with or without CDP treatment (data not shown), whereas 5-HT levels were significantly elevated in the liver and serum of T2DM mice, and were obviously reduced by CDP treatment; hepatic 5-HT levels were also inhibited by Sar (Fig. 8a). The expression of hepatic Tph1, AADC, 5-HT2AR, and 5-HT2BR was up-regulated in T2DM mice compared to Ctrl mice (Fig. 8a). T2DM mice exhibited PKCε activation with increased phosphorylation of Akt, mTOR, and ERK1/2, upregulated ACC, GPAT1, and MTTP expression (Fig. 8b), and increased TG and VLDL levels (Fig. 8c) in the liver; they also showed hepatic oxidative stress and inflammation with up-regulated MAO-A expression, increased H2O2 and MDA levels, NF-κB activation, increased phosphorylation of p38, JNK, and STAT3, and increased TNF-α and IL-1β levels (Fig. 8b and c). These alterations were remarkably inhibited by Sar and CDP in a synergistic manner."

"...By hematoxylin and eosin staining (Fig. 8d), we found hepatic steatosis and lobular inflammation with inflammatory cell infiltration and hepatocyte ballooning in the lobes. By Masson’s trichrome staining (Fig. 8e), we found hepatic fibrosis in the periportal and parenchymal regions of T2DM mice. These phenotypes were significantly ameliorated by Sar and CDP, particularly by the combination of both. Additionally, increased hepatic levels of hydroxyproline (Fig. 8c), a marked amino acid in the collagen of fibrous tissue [33], and liver injury with increased activity of serum ALT and AST (Fig. 9c) were also reversed significantly in T2DM mice by Sar and CDP in a synergistic manner."

"...Treatment with Sar and CDP, alone or in combination, reversed the bodyweight loss and reduced the increases in food intake and hepatic index in T2DM mice (Fig. 9a). Whereas there was no significant difference between the three treatments for the amelioration of bodyweight loss, food intake, and hepatic index, suggesting that these effects are not crucial for treating NASH. Sar and CDP treatment (alone or in combination) of T2DM mice also ameliorated dyslipidemia and IR in a synergistic manner, including a reduction of the increased serum levels of TG, FFAs, LDL-c, and VLDL-c, decreased serum levels of HDL-c (Fig. 9b), and increased levels of fasting blood glucose and serum insulin with an increased HOMA-IR index (Fig. 9c). Taken together, our findings show that 5-HT system activation in the liver is a crucial event leading to T2DM-related NASH."

Very inspiring. Any of your idealabs products which will inhibit serotonin?
And If, could they be applied at the navel?