No direct effect of SGLT2 activity on glucagon secretion

Abstract

Aims/hypothesis Sodium-glucose cotransporter (SGLT) 2 inhibitors constitute a new class of glucose-lowering drugs, but they increase glucagon secretion, which may counteract their glucose-lowering effect. Previous studies using static incubation of isolated human islets or the glucagon-secreting cell line α-TC1 suggested that this results from direct inhibition of alpha cell SGLT1/2-activity. The aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting. Methods We explored the effect of SGLT2 activity on glucagon secretion using isolated perfused rat pancreas, a physiological model for glucagon secretion. Furthermore, we investigated Slc5a2 (the gene encoding SGLT2) expression in rat islets as well as in mouse and human islets and in mouse and human alpha, beta and delta cells to test for potential inter-species variations. SGLT2 protein content was also investigated in mouse, rat and human islets. Results Glucagon output decreased three-to fivefold within minutes of shifting from low (3.5 mmol/l) to high (10 mmol/l) glucose (4.0 ± 0.5 pmol/15 min vs 1.3 ± 0.3 pmol/15 min, p < 0.05). The output was unaffected by inhibition of SGLT1/2 with dapagliflozin or phloridzin or by addition of the SGLT1/2 substrate α-methylglucopyranoside, whether at low or high glucose concentrations (p = 0.29-0.99). Insulin and somatostatin secretion (potential paracrine regulators) was also unaffected. Slc5a2 expression and SGLT2 protein were marginal or below detection limit in rat, mouse and human islets and in mouse and human alpha, beta and delta cells. Conclusions/interpretation Our combined data show that increased plasma glucagon during SGLT2 inhibitor treatment is unlikely to result from direct inhibition of SGLT2 in alpha cells, but instead may occur downstream of their blood glucoselowering effects.

Sodium Glucose Co-Transporter 2 Inhibition Does Not Favorably Modify the Physiological Responses to Dietary Counselling in Diabetes-Free, Sedentary Overweight and Obese Adult Humans

“…SGLT2 inhibition has been suggested to promote endogenous glucose production in response to increased pancreatic secretion of glucagon [41,42], thus potentially masking, or blunting the benefits of SGLT2 inhibition. Our data, consistent with recent reports from animal studies of isolated perfused rat pancreas [43], and human studies describing inter-individual heterogeneity of SGLT2 expression and function in pancreatic islets [44], showed that glucagon concentration was unaffected by SGLT2 inhibition.…”

Dynamic alterations in early intestinal development, microbiota and metabolome induced by in ovo feeding of L-arginine in a layer chick model

“…Another series of putative annotated metabolites involved in galactose metabolism were differentially abundant. In fact, Arg plays an important role in regulating energy metabolism [56], which can stimulate the release of hormones, such as glucagon, to accelerate the conversion of galactose to glucose [57,58], and then may reduce the synthesis of oligosaccharides. In addition, a negative correlation between the levels of serum oligosaccharides and the abundance of Ruminococcaceae (R = − 0.588, P = 0.035 for raffinose and R = − 0.555, P = 0.040 for stachyose) was also observed.…”

<p>Extraglycemic Effects of SGLT2 Inhibitors: A Review of the Evidence</p>

“…61 Moreover, some studies have suggested that SGLT2i may exert a direct stimulatory effect on alfa cells, 62,63 although this finding is controversial and has not been consistently replicated in all studies. 64,65 Oxidation of ketone bodies produces more amounts of ATP per molecule of oxygen than glucose or fatty acids oxidation does and may provide a more efficient energy source for the myocardium. 61 In fact, enhanced production of ketone bodies has been proposed as one mechanism driving protection from cardiovascular death and heart failure observed during SGLT2i therapy.…”