Thanks. His paper refers to canagliflozin as an SGLT2 inhibitor. But adds at the end:
Among commonly used SGLT2i, Cana has the least specificity and can potentially inhibit both SGLT1 and SGLT2 transporters (Ohgaki et al., 2016). SGLT1 and SGLT2 have been detected in many areas of the brain (Głuchowska et al., 2021). Brain expression of SGLT2 is lower than SGLT1 but was detected in the microvessels of the blood–brain barrier, hippocampus pyramidal and granular cells, and astrocytes in the ventromedial hypothalamus (Poppe et al., 1997; Enerson & Drewes 2006; Fan et al., 2015; Tahara et al., 2016; Koepsell 2020; Nguyen et al., 2020). Thus, while Cana’s effects on CNS can be indirect, secondary to peripheral changes, or mediated via the activity of autonomic inputs to the hypothalamus (Spallone & Valensi 2021), it is plausible that Cana can attenuate hypothalamic gliosis directly via binding to the SGLT1 or SGLT2. Additional studies will be required to address this question.
It’s also entirely possible for me that the positive effects of these drugs are not related to SGLTi but other unknown targets (USP30 is one of them).
I have to say a big thank you to you guys (@adssx@Neo ) who are chasing down these details on sglt2 inhibitors. I should have known that the rabbit hole goes deep. There are no easy answers. And wrong guesses can have negative consequences for health.
I don’t recall which aging researcher said it but the effort to guess at benefit by imagining mechanisms is fraught with peril. Studies on mice have many challenges when translating to people but it’s better than hand waving at mechanisms that we (or maybe just I) really don’t have any way to understand.
Fortunately there are lots of human studies on sglt2 inhibitors. The sglt1 inhibition benefits vs risks seems more unknown than known at this point. I don’t plan to take any leaps of faith here just yet.
Sure, probably - 1450 Rupees equals about $17 US (83 rupees to the US$), for what I assume is a box of 30 (3 “stripes” of 10 pills each) for a price per tablet of about $0.58.
Thanks @Joseph_Lavelle. Table 1 is interesting and suggests canagliflozin and empagliflozin might be best for neuroprotection, with more data on empagliflozin regarding BNDF. However it’s not a great journal and it doesn’t come out of great research institutions either.
Among the 19 studies, 5 were bioinformatic studies investigating the docking of SGLT2i with molecules involved in the pathophysiology of AD, such as AChE. For example, Shaikh et al.22 found that the docking energy between dapagliflozin and SGLT2, and between dapagliflozin and the CAS domain of AChE, were similar, which suggested that dapagliflozin may be a dual inhibitor of SGLT2 and AChE. Similarly, canagliflozin was found to have significant interactions with the S203 and H447 amino acid moieties of AChE.23 Overall, all SGLT2 inhibitors formed stable complexes with AChE in these five docking studies. Alafnan24 expanded upon these findings by revealing strong bonds between SGLT2i and other molecular targets implicated in the amyloidogenic and phosphorylation pathways of AD.
@adssx Thanks. I’m convinced that sglt2 inhibitors are a good thing. I’m glad I’m taking one (Farxiga / dapagliflozen). I started on it to get weight loss and lower blood sugar; I didn’t get either. But maybe I’m getting these other benefits.
You might be getting lower spikes and less variation in your blood sugar. And hence less AGEs and also less insulin. Do you have data on your insulin on and pre SGLTi?
Might also be lowering your IGF-1 - Do you have data on that on vs pre SGLTi?
No data from before sglt2. My insulin and HOMA-IR are normal post sglt2 so what you say is possible. My HbA1c did not improve significantly until Akkermansia.
Yes, but logically you must see some effect on blood glucose.
I’m a non- diabetic and I have trace/nil amount of urinary glucose (as measured using urinalysis reagent strip) but when I take an SGLT2 inhibitor I see a massive increase in urinary glucose of 500+ mg/dL.
If the body is excreting that amount of glucose it must surely have some effect on blood glucose
I did the urine test because I wanted to reassure myself that the meds I was sent were SGLT2 inhibitors
That’s logical but blood glucose is also affected by the liver adding glucose to the blood. I have always suspected that my liver adds more glucose than it needs to (based on my HbA1c). On the other hand, my blood sugar is always good when I am exercising hard for long periods of time. Other people bonk while I can keep going at a high level. So maybe my liver is optimized for performance vs longevity…?
Yes you’re right about the liver’s gluconeogenesis contribution to blood glucose.
Sorry, my bad, but I forgot to mention I’m on 2g of metformin a day, so I think my liver gluconeogenesis shouldn’t be contributing much to my blood glucose.
I’ve gone back and forth on this one for awhile. I’m not diabetic, but my morning fasting glucose is pretty high (105) unmedicated. hba1c was 5.2 this time, which is good for me I think it was 5.7 before. I did trial after trial on dapag and even used metformin for awhile trying to fix this. On average it does pretty well, I can’t say it always works.
I did sign up for the Cana thing and have my phone call tomorrow morning. Maybe I can learn something from them.
Like you my morning glucose level is always a little high, ~105, while my HbA1C is ~5.4%.
Because of my love/hate relationship with metformin, I stopped taking metformin for a while and tried taking Ceylon cinnamon and chromium. I had tried this in the past but it didn’t work.
After some further reading, I decided the dose and length of time I took it was too small and too short.
N=1 experiment: I am taking 3 grams of cinnamon in the morning and 3 grams+chromium in the evening before meals. After doing this for a week my fasting glucose levels are always below 100. I will stop taking the chromium in a few weeks to see if the cinnamon alone does the trick.
This is thought to work by raising insulin sensitivity.
The studies are small. No RTCs.
Yes, using cinnamon in your breakfast was one of the 10 glucose hacks from the GG video. I’m going to try that starting from tomorrow. I’m also considering an apple cider vinegar beverage before breakfast and dinner to cut down spikes. I’ll also eat my veggies first at dinner and add walnuts to my morning oatmeal.
Now, is there a good veggie to eat in the morning for breakfast? Cucumbers?