SSRIs, Insulin, Aspirin

[allblues]

Here's a study on two common SSRIs, paroxetine and sertraline inhibiting cellular response to insulin;

Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases. - PubMed - NCBI

Here we demonstrate that incubation (1 h) of rat hepatoma Fao cells with the SSRIs paroxetine and sertraline, but not with the atypical antipsychotic drug olanzapine, inhibited the insulin-stimulated Tyr phosphorylation of the insulin receptor substrate-1 (IRS-1) with half-maximal effects at approximately 10 microM. This inhibition correlated with a rapid phosphorylation and activation of a number of Ser/Thr (serine/threonine) IRS-1 kinases including JNK, S6K1, ERK and p38 MAPK, but not PKB (Akt). JNK appears as a key player activated by SSRIs because specific JNK inhibitors partially eliminated the effects of these drugs..

.. These results implicate selected SSRIs as inhibitors of insulin signaling and as potential inducers of cellular insulin resistance.

About c-Jun N-terminal kinases (JNKs) from Wikipedia;

c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock.

Another one, which also included fluoxetine. The researchers show even an inhibition of insulin secretion by the SSRIs and not simply insulin resistance. Contains some harsh quotes;

Selective serotonin reuptake inhibitors (SSRIs) inhibit insulin secretion and action in pancreatic β cells. - PubMed - NCBI

Inhibition of IRS-2 action by 30 μM SSRI was associated with a marked inhibition of glucose-stimulated insulin secretion from murine and human pancreatic islets..

.. Prolonged treatment (16 h) of Min6 cells with sertraline resulted in the induction of inducible nitric oxide synthase; activation of endoplasmic reticulum stress, and the initiation of the unfolded protein response, manifested by enhanced transcription of ATF4 and C/EBP homologous protein. This triggered an apoptotic process, manifested by enhanced caspase 3/7 activity, which resulted in β cell death..

..These findings implicate SSRIs as inhibitors of IRS protein function and insulin action through the activation of GSK3β. They further suggest that SSRIs inhibit insulin secretion; induce the unfolded protein response; activate an apoptotic process, and trigger β cell death. Given that SSRIs promote insulin resistance while inhibiting insulin secretion, these drugs might accelerate the transition from an insulin-resistant state to overt diabetes.

Ouch.

Then a study on aspirin showing opposite effects vs the kinases, along with a nice quote to begin the study;

Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine ki... - PubMed - NCBI

The hypoglycemic effects of high dose salicylates in the treatment of diabetes were documented before the advent of insulin... In this study, we analyzed the effects of aspirin (acetylsalicylic acid) on serine phosphorylation of insulin receptor substrate 1 (IRS-1) in cells treated with tumor necrosis factor (TNF)-alpha..

.. Interestingly, aspirin treatment inhibited the phosphorylation of IRS-1 at Ser307 as well as the phosphorylation of JNK, c-Jun, and degradation of IkappaBalpha..

.. Finally, aspirin rescued insulin-induced glucose uptake in 3T3-L1 adipocytes pretreated with TNF-alpha. We conclude that aspirin may enhance insulin sensitivity by protecting IRS proteins from serine phosphorylation catalyzed by multiple kinases.

Also, aspirin improving glucose tolerance by inhibiting inducible nitric oxide synthase, (yet) another point for Ray; Aspirin attenuates insulin resistance in muscle of diet-induced obese rats by inhibiting inducible nitric oxide synthase production and S-nitrosyla... - PubMed - NCBI

In summary, no news for the people of this forum, but if you find difficulty dealing with carbohydrates, coming from a low-carb situation, past use of SSRI or other serotonergic drugs, aspirin could be worth a shot.

 

[SQu]

Thank you! I'm trying a little with coffee in the afternoon when energy is blocked in spite of taking care to eat enough carbs.

 

[charlie]

Another aspirin score!

 

[ecstatichamster]

Fantastic post. Thank you. Had no idea about the ssris

 

[allblues]

Oh, there's also this, had this one tucked away in the archives;

Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake

This study was done on rats genetically modified to express either half or none of the regular amount of serotonin transport protein (SERT).

So, no SSRI involved in this study, but the effects of the SSRI-type drugs is to produce a very similar condition,
antagonizing/blocking/downregulating the serotonin transporter very extensively.
For instance, i've seen studies where sertraline, a common SSRI blocked about 90% of SERT-binding sites, which would be a very similar situation. The study says about the same.

Similarly to the SSRI-studies above, being SERT-deficient (either by drugs or by genetic modification) proved to be really detrimental
the rats' health. From the abstract;

Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity (there's that JNK-guy again) and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity.

And a correlation study;

Obesity and expression of serotonin transporter (SERT) in human platelets

Obesity and related negative health markers go hand in hand with low levels of serotonin transporter binding (SERT) in this study,
echoing the other studies.

The mean Bmax of [3H]paroxetine was significantly lower in OB (obese) than in C (control) (Bmax: 1083.23±276.9 vs 1443.8±242.55 fmol/mg protein, respectively, P<0.005). An inverse correlation was observed between BMI and Bmax values, as assessed by simple linear regression (R=−0.563; P<0.0001). A significant negative correlation was also found between SERT Bmax and waist circumference (P=0.0046; R=−0.424), hip circumference (P=0.0009; R=−0.49), sistolic blood pressure (P=0.0237; R=−0.341), fasting serum glucose (P=0.001; R=−0.479), insulin (P<0.0001; R=−0.626), tryglycerides (P=0.0071; R=−0.4) C reactive protein..

Safe and effective? Mmmmmmmm.