Effect of SGLT2 inhibitors on glucagon secretion in pancreatic alpha cells

[Speaker] Suguru Nakayama:1
[Co-author] Licht Miyamoto:1, Koichiro Tsuchiya:1
1:Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan

Insulin resistance and secretion failure are the major causes of type 2 diabetes. In recent years, however, dysregulation of glucagon secretion has attracted in recent years attention because elevated glucagon levels could be a more important cause of diabetes. SGLT 2, expressed in kidney nephron of kidney, prevents glucose excretion by inhibiting glucose reabsorptions. Therefore, inhibitors against SGLT2 show a hypoglycemic effect. Recent clinical study have shown that dapagliflozin could be responsible for hyperglucagonemia. In addition, it has been discussed that inhibition of SGLT2 in alpha cells directly affects glucagon secretion through KATP channel activation by using human pancreatic alpha cells. Thus, in order to clarify the importance of SGLT2 in glucagon regulation, we examined the effect of SGLT2 inhibition by various inhibitors in mouse glucagonoma, alpha-TC cells.
Mouse glucagonoma, alpha-TC cells were used. Dapaglifrozin, Empaglifrozin, Phlorhizin were used as SGLT2 inhibitor. Cytochalasin B, which inhibits the GLUT family, was used as a glucose uptake inhibitor. Glucose uptake and glucagon secretion after treatment with the inhibitors were measured. The Glucose uptake was measured using 2-deoxy-D-glucose labeled with tritium. Glucagon levels in the medium were measured by a sandwich detection method of N- and C-terminus.
SGLT2 inhibitors reduced glucose uptake by 25%, indicating that SGLT2 functions in alpha-TC cells. However, glucagon secretion did not change at this time. Cytochalasin B markedly inhibited glucose uptake compared to SGLT2 inhibitors, but glucagon secretion was not increased in contrast to the SGLT2 inhibitors. Therefore, it was suggested that strong inhibition or glucose uptake promotes glucagon secretion, but weak glucose uptake inhibition e.g. SGLT2 inhibitor had little effect on glucagon secretion. On the other hand, stimulation by alpha-TC cells with nateglinide did not alten either glucose uptake or glucagon secretion, so the KATP channel was not considered to be involved in the regulation of glucagon secretion.
SGLT2 glucose transporter is suggested to function in alpha cells, but it seems not to competent enough to affect glucagon secretion.
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