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Glucose is a major energy source critical for the optimal function and survival of most cellular organisms. However, the availability of glucose fluctuates constantly, influenced by factors like nutrient availability and the organism's feeding state. Gluconeogenesis is a critical metabolic process that evolved to maintain euglycemia during periods of low glucose availability. In mammals, it occurs predominantly in the liver and is activated in response to low blood glucose levels, such as during fasting. This process is hormonally regulated and is primarily stimulated by cortisol and glucagon produced by the adrenal glands and the pancreas, respectively. The secretion of these hormones is also regulated by circadian rhythm, anticipatory to the rhythmic transition between feeding and fasting states. Indeed, gluconeogenic genes like phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6P) exhibit diurnal regulation, aligning with the activity of the master transcription factors CLOCK and BMAL1, which govern the mammalian circadian clock. Recent evidence has highlighted a role for the gut microbiota in regulating host metabolism and metabolic health. 

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SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans

Heeyoung Chae, Robert Augustin, Eva Gatineau, Eric Mayoux, ... Patrick Gilon

Objective

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i), or gliflozins, are anti-diabetic drugs that lower glycemia by promoting glucosuria, but they also stimulate endogenous glucose and ketone body production. The likely causes of these metabolic responses are increased blood glucagon levels, and decreased blood insulin levels, but the mechanisms involved are hotly debated. This study verified whether or not SGLT2i affect glucagon and insulin secretion by a direct action on islet cells in three species, using multiple approaches.

Methods

We tested the in vivo effects of two selective SGLT2i (dapagliflozin, empagliflozin) and a SGLT1/2i (sotagliflozin) on various biological parameters (glucosuria, glycemia, glucagonemia, insulinemia) in mice. mRNA expression of SGLT2 and other glucose transporters was assessed in rat, mouse, and human FACS-purified α- and β-cells, and by analysis of two human islet cell transcriptomic datasets. Immunodetection of SGLT2 in pancreatic tissues was performed with a validated antibody. The effects of dapagliflozin, empagliflozin, and sotagliflozin on glucagon and insulin secretion were assessed using isolated rat, mouse and human islets and the in situ perfused mouse pancreas. Finally, we tested the long-term effect of SGLT2i on glucagon gene expression.

Results

SGLT2 inhibition in mice increased the plasma glucagon/insulin ratio in the fasted state, an effect correlated with a decline in glycemia. Gene expression analyses and immunodetections showed no SGLT2 mRNA or protein expression in rodent and human islet cells, but moderate SGLT1 mRNA expression in human α-cells. However, functional experiments on rat, mouse, and human (29 donors) islets and the in situ perfused mouse pancreas did not identify any direct effect of dapagliflozin, empagliflozin or sotagliflozin on glucagon and insulin secretion. SGLT2i did not affect glucagon gene expression in rat and human islets.

Conclusions

The data indicate that the SGLT2i-induced increase of the plasma glucagon/insulin ratio in vivo does not result from a direct action of the gliflozins on islet cells.