2 days before my gastro- and endocrinology exam - perfect!! Even after having lectures and reading in my pharma book about SGLT2i, I still learned a lot of new stuff from you. Especially the mechanisms, gotta love them, and they are rarely explained in lectures atleast. One question though, SGLT2i are not really used in Type 1 Diabetes in my country, as I understand it, because of fear of ketoacidosis. Apparently, T1D are in danger because if they only measure blood glucose and not ketones, blood glucose can be in range on SGLT2i, but they are actually beta-oxidizing and creating ketonebodies. Does that sound right to you and, is that because the low glucose is a reflection of increased glucose in urin and therefore not inside the cells, which then have to beta oxidize? Im sure the T1D patients would love the cardiac and renal benefits of SGLT2i also :D Sorry for making up my own questions and answers, I have just been wondering.
Hi. thank you very much. In case of DM1 the problem is euglycemia ( due to loss of glucose into urine - blood glucose level = normal) They need to increase insulin dosage, but they do not do it - cause blood glucose level will be normal. Actually both patients with DM type 1 and type 2 on SGLT2 inhibitors are at risk of euglycemic ketoacidosis simply because SGLT2 inhib cause lose of glucose into the urine. The loss of urinary glucose again creates a state of carbohydrate starvation and volume depletion, increasing the glucagon/insulin ratio and resulting in a state of severe dehydration and ketosis. www.ncbi.nlm.nih.gov/books/NBK554570/ In the setting of SGLT-2 inhibition, fasting glucose can be maintained at reasonable levels despite very low portal insulin because of urinary glucose loses. This may predispose to ketosis and, most importantly, may uncouple ketosis from the finding of severe hyperglycemia. www.ncbi.nlm.nih.gov/pmc/articles/PMC4542270/#B17 I think the reason why eug ketoacidosis is more common in DM1 - is that this patients are more predisposed to ketone bodies production compared to DM2. In Type 2 diabetes, serum levels of total ketone bodies did not exceed 2.0 mmol/l even if the patients were untreated or poorly controlled. In Type 1 diabetic subjects, treated with once or twice daily injections of insulin, morning serum levels of acetoacetate, 3-hydroxybutyrate and total ketone bodies were significantly elevated by four-, ten- and sevenfold, respectively. pubmed.ncbi.nlm.nih.gov/6376243/ So from 1 point - eugl ketoacidosis is more common in DM type 1 - and it's the reason why they highlight this effect. And it's the reason why they do not recommend them in this case. from 2nd point - we are generally more concern about ketoacidosis in type 1 diabetes. So SGLT2 inhib in patients with DM2 can be potentially even more dangerous because we do not expect ketoacidosis to develop (cause the incidence in DM2 is lower compared to DM1) especially with normal blood glucose level. Also i think the ratio of insulin / glucagon in case of DM1 is far more disbalanced. Ketogenesis is considered to be controlled by the islet hormones, insulin and glucagon (20). Insulin strongly inhibits ketosis, predominantly by reducing lipolysis in adipocytes and reducing the supply of free fatty acids, the substrate for ketone body production. In addition, insulin may have direct effects at the level of the hepatocyte by lowering intracellular cAMP (21). In contrast, glucagon potently increases cAMP in hepatocytes, a signal that has been tied to both lipid and glucose metabolism (22). Consequently, the plasma insulin-to-glucagon ratio has long been purported to dictate the rates of ketogenesis (23). www.ncbi.nlm.nih.gov/pmc/articles/PMC7171961/ I think the usage of SGLT2i in DM1 is just a matter of time, cause clinical trials with them in DM1 patients are ongoing.)
Very interesting, thanks!!! The glucagon coupeling with insulin and disconnect in diabetes is super interesting, unfortunately after tomorrow it's on to the next subject.. But for sure I will revisit this later. @@Foxterrier 🙏
@@Foxterrier Our first real clinical experience, 8 semesters in.... 4 weeks in neurological department and 4 weeks in general surgery. Looking very much forward to it ;)
Great video as always, love the integration of review papers which often explain things better than some standard textbooks.
Thank you very much. Yes in 99% information in articles describes problem in more details and is more up to date )
2 days before my gastro- and endocrinology exam - perfect!! Even after having lectures and reading in my pharma book about SGLT2i, I still learned a lot of new stuff from you. Especially the mechanisms, gotta love them, and they are rarely explained in lectures atleast.
One question though, SGLT2i are not really used in Type 1 Diabetes in my country, as I understand it, because of fear of ketoacidosis. Apparently, T1D are in danger because if they only measure blood glucose and not ketones, blood glucose can be in range on SGLT2i, but they are actually beta-oxidizing and creating ketonebodies.
Does that sound right to you and, is that because the low glucose is a reflection of increased glucose in urin and therefore not inside the cells, which then have to beta oxidize?
Im sure the T1D patients would love the cardiac and renal benefits of SGLT2i also :D
Sorry for making up my own questions and answers, I have just been wondering.
Hi. thank you very much.
In case of DM1 the problem is euglycemia ( due to loss of glucose into urine - blood glucose level = normal) They need to increase insulin dosage, but they do not do it - cause blood glucose level will be normal.
Actually both patients with DM type 1 and type 2 on SGLT2 inhibitors are at risk of euglycemic ketoacidosis simply because SGLT2 inhib cause lose of glucose into the urine.
The loss of urinary glucose again creates a state of carbohydrate starvation and volume depletion, increasing the glucagon/insulin ratio and resulting in a state of severe dehydration and ketosis.
www.ncbi.nlm.nih.gov/books/NBK554570/
In the setting of SGLT-2 inhibition, fasting glucose can be maintained at reasonable levels despite very low portal insulin because of urinary glucose loses. This may predispose to ketosis and, most importantly, may uncouple ketosis from the finding of severe hyperglycemia.
www.ncbi.nlm.nih.gov/pmc/articles/PMC4542270/#B17
I think the reason why eug ketoacidosis is more common in DM1 - is that this patients are more predisposed to ketone bodies production compared to DM2.
In Type 2 diabetes, serum levels of total ketone bodies did not exceed 2.0 mmol/l even if the patients were untreated or poorly controlled. In Type 1 diabetic subjects, treated with once or twice daily injections of insulin, morning serum levels of acetoacetate, 3-hydroxybutyrate and total ketone bodies were significantly elevated by four-, ten- and sevenfold, respectively.
pubmed.ncbi.nlm.nih.gov/6376243/
So from 1 point - eugl ketoacidosis is more common in DM type 1 - and it's the reason why they highlight this effect. And it's the reason why they do not recommend them in this case.
from 2nd point - we are generally more concern about ketoacidosis in type 1 diabetes. So SGLT2 inhib in patients with DM2 can be potentially even more dangerous because we do not expect ketoacidosis to develop (cause the incidence in DM2 is lower compared to DM1) especially with normal blood glucose level.
Also i think the ratio of insulin / glucagon in case of DM1 is far more disbalanced.
Ketogenesis is considered to be controlled by the islet hormones, insulin and glucagon (20). Insulin strongly inhibits ketosis, predominantly by reducing lipolysis in adipocytes and reducing the supply of free fatty acids, the substrate for ketone body production. In addition, insulin may have direct effects at the level of the hepatocyte by lowering intracellular cAMP (21). In contrast, glucagon potently increases cAMP in hepatocytes, a signal that has been tied to both lipid and glucose metabolism (22). Consequently, the plasma insulin-to-glucagon ratio has long been purported to dictate the rates of ketogenesis (23).
www.ncbi.nlm.nih.gov/pmc/articles/PMC7171961/
I think the usage of SGLT2i in DM1 is just a matter of time, cause clinical trials with them in DM1 patients are ongoing.)
By the way i made video for Hepatorenal syndrome, but with work can't pull myself together to make audio )))
Very interesting, thanks!!! The glucagon coupeling with insulin and disconnect in diabetes is super interesting, unfortunately after tomorrow it's on to the next subject.. But for sure I will revisit this later.
@@Foxterrier 🙏
Which topics do you have next ?
@@Foxterrier Our first real clinical experience, 8 semesters in....
4 weeks in neurological department and 4 weeks in general surgery. Looking very much forward to it ;)
thank you so much for this
Thank you for feedback )
Nice video as always ,I wonder what is the dream job to you? I think you should be a university professor
Thanks. I am teaching in university, but i am not a professor )