As my poor BG control (A1c 5.8) appears down to excessive gluconeogenesis, I keep looking for ways to ameliorate this. I plan on going on empagliflozin to lower my BG, but I’m worried about my liver just converting glycogen to more BG to compensate for the loss through urine. The paper I cited above seems to say that doesn’t happen, but it’s Chinese and in mice so I don’t trust it.
I was wondering that if the body detects the loss of BG through urine, then the use of a SGLT2i might actually elevate glucagon levels to compensate, which would limit the ability of empagliflozin to lower BG. In fact I found papers that claim exactly this, which was disappointing.
Meanwhile, it appears that two things are true at once - SGLT2i do indeed raise glucagon levels, but the endogenous glucose production happens even before glucagon levels go up. Go figure! Here’s an interesting paper to that effect, which also mentions a fascinating distinction between SGLT2i and SGLT1i (so perhaps canagliflozin to some degree):
Quote:
“Sodium-glucose co-transporter-2 inhibitors (SGLT2is) lower blood glucose and are used for treatment of type 2 diabetes. However, SGLT2is have been associated with increases in endogenous glucose production (EGP) by mechanisms that have been proposed to result from SGLT2i-mediated increases in circulating glucagon concentrations, but the relative importance of this effect is debated, and mechanisms possibly coupling SGLT2is to increased plasma glucagon are unclear. A direct effect on alpha-cell activity has been proposed, but data on alpha-cell SGLT2 expression are inconsistent, and studies investigating the direct effects of SGLT2 inhibition on glucagon secretion are conflicting. By contrast, alpha-cell sodium-glucose co-transporter-1 (SGLT1) expression has been found more consistently and appears to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2is does not support interference with SGLT1 during therapy. Paracrine effects mediated by secretion of glucagonotropic/static molecules from beta and/or delta cells have also been suggested to be involved in SGLT2i-induced increase in plasma glucagon, but studies are few and arrive at different conclusions. It is also possible that the effect on glucagon is secondary to drug-induced increases in urinary glucose excretion and lowering of blood glucose, as shown in experiments with glucose clamping where SGLT2i-associated increases in plasma glucagon are prevented. However, regardless of the mechanisms involved, the current balance of evidence does not support that SGLT2 plays a crucial role for alpha-cell physiology or that SGLT2i-induced glucagon secretion is important for the associated increased EGP, particularly because the increase in EGP occurs before any rise in plasma glucagon.”
There are indeed conflicting findings about SGLT2i and glucagon, as seen in this paper:
https://diabetesjournals.org/diabetes/article/69/12/2619/16248/The-Role-of-Glucagon-in-the-Acute-Therapeutic
Quote:
“Previous findings of increased glucagon concentrations and EGP during acute administration of SGLT2i were not replicated in this study. Empagliflozin reduced postprandial PG through increased urinary glucose excretion.”
This paper is slightly older and in a small number of subjects, but the design seems very good.
Here there’s a study that disassociates both insulin and glucagon from the EPG increase mediated by dapagliflozin:
Quote:
“Collectively, these results indicate that 1 ) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2 ) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.”
I wonder if there are differential effects of increased EGP by different SGLT2i, for example in this study they found that dapagliflozin strongly increases EGP, while in the previous one they found that empagliflozin did not.
