The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition

Abstract

Glucagon is classically described as a counterregulatory hormone that plays an essential role in the protection against hypoglycemia. In addition to its role in the regulation of glucose metabolism, glucagon has been described to promote ketosis in the fasted state. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are a new class of glucose-lowering drugs that act primarily in the kidney, but some reports have described direct effects of SGLT2i on α-cells to stimulate glucagon secretion. Interestingly, SGLT2 inhibition also results in increased endogenous glucose production and ketone production, features common to glucagon action. Here, we directly test the ketogenic role of glucagon in mice, demonstrating that neither fasting- nor SGLT2i-induced ketosis is altered by interruption of glucagon signaling. Moreover, any effect of glucagon to stimulate ketogenesis is severely limited by its insulinotropic actions. Collectively, our data suggest that fasting-associated ketosis and the ketogenic effects of SGLT2 inhibitors occur almost entirely independent of glucagon.

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

“…One mg/kg BW of dapagliflozin induces a plasma C max of ∼500 nM in mice [ 40 ], which is close to the plasma C max of ∼400 nM in humans who are receiving a therapeutic dose of 10 mg [ 41 ]. However, contrary to reports showing increased glucagonemia 6 h or 18 h after dapagliflozin administration [ 14 , 19 ], we did not find any alteration in the glucagon/insulin ratio 16 h after three daily doses (1 mg/kg BW) of dapagliflozin, empagliflozin, or sotagliflozin. This lack of effect might be explained by the relatively rapid clearance of the gliflozins [ 42 , 43 ].…”

“…The gliflozins (dapagliflozin, empagliflozin, and sotagliflozin) tested in this study were very effective, as they strongly increased glucosuria. Several reports have shown that gliflozins increase glucagonemia or decrease insulinemia [ 3 , 8 , 14 , 19 , 23 ]. We replicated these observations as administering dapagliflozin (1–10 mg/kg BW) to fasted mice produced, 1 h later, a dose-dependent increase in glucagonemia and the plasma glucagon/insulin ratio.…”

“…The paradoxical increase in endogenous glucose production (EGP) is a concern, as it diminishes the efficacy of glucosuria-stimulating therapy [ 3 ]. An additional drawback of SGLT2i is the increased incidence of ketoacidosis and the emergence of rare euglycemic diabetic ketoacidosis [ [10] , [11] , [12] , [13] , [14] ]. The rise in ketone body levels results from their increased production rather than decreased renal clearance [ 15 ].…”

“…However, these hypotheses are contested by studies suggesting no SGLT2 expression in α-cells and no effect of gliflozins on glucagon release [ 17 , 26 ] or an inhibition of glucagon release by gliflozins [ 22 , 27 ]. As glucagon and somatostatin strongly influence β-cells, gliflozins might indirectly control insulin secretion, but several reports do not support this mechanism [ 11 , 14 , 19 , 26 , 28 ].…”

Fasting-Induced Natriuresis and SGLT: A New Hypothesis for an Old Enigma

“…Later on, the increased production of ammonium replaces the urinary sodium excretion, maintaining obligatory cation coverage of the metabolically generated anions as a major mechanism responsible for fasting natriuresis (22). Corroborating our initial hypothesis, and in view of the glucagon-ketogenesis pathway, the use of SGLT2-I was consistently associated with an increased risk of euglycemic ketoacidosis in treated diabetic patients (23), and it was recently shown that SGLT2-I in mice act on ketogenesis directly rather than via glucagon (24).…”