Distinct Mechanisms Responsible for the Increase in Glucose Production and Ketone Formation Caused by Empagliflozin in T2DM Patients

Abstract

OBJECTIVE To examine the mechanisms responsible for the increase in glucose and ketone production caused by empagliflozin in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Twelve subjects with T2DM participated in two studies performed in random order. In study 1, endogenous glucose production (EGP) was measured with 8-h infusion of 6,6,D2-glucose. Three hours after the start of 6,6,D2-glucose infusion, subjects ingested 25 mg empagliflozin (n = 8) or placebo (n = 4), and norepinephrine (NE) turnover was measured before and after empagliflozin ingestion with 3H-NE infusion. Study 2 was similar to study 1 but performed under pancreatic clamp conditions. RESULTS When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (−34 mg/dL) and insulin (−52%) concentrations and increases in plasma glucagon (+19%), free fatty acid (FFA) (+29%), and β-hydroxybutyrate (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate was greater in subjects receiving empagliflozin (+67%) compared with placebo under both fasting and pancreatic clamp conditions. No difference in plasma NE concentration was observed in either study. CONCLUSIONS The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is likely explained by the increase in NE turnover.

The impact of increased hepatic glucose production caused by empagliflozin on plasma glucose concentration in individuals with type 2 diabetes and nondiabetic individuals

“…We previously demonstrated that the increase in HGP is blunted in the denervated kidney, 11 providing evidence of an important role for renal nerves in generating the signal to the liver following SGLT2 inhibition. Consistent with a neural signal, we have shown that the increase in HGP is accompanied by an increase in total body norepinephrine turnover rate within 1–2 h after SGLT2 inhibitor administration, 8 consistent with a role for sympathetic activation in triggering the increase in HGP. Because the magnitude of increase in HGP did not correlate with the amount of glucose excreted in the urine, it is likely that the signal activated by UGE that stimulates HGP is an ON–OFF signal and that the amount of glucose in the urine, as opposed to the acute increase in urinary glucose concentration, is of less importance in activating this signal.…”

“…is calculated using the Steele equation as previously described. [7][8][9] The change in HGP during the last hour of the study (i.e., 240-300 min) from baseline was considered the drug's effect on endogenous glucose production.…”

Association of Glucagon to Insulin Ratio and Metabolic Syndrome in Patients with Type 2 Diabetes

“…As a result, lipolysis is stimulated, and ketone body production increases. Recently, it has been reported that the use of Empagliflozin in patients with T2DM leads to a decrease in serum insulin, an increase in glucagon, and an increase in serum ketone bodies [ 15 ]. Regarding ketone bodies, the “Super-fuel” hypothesis has been proposed, which suggests that serum ketone bodies can serve as an effective energy source for the myocardium, contributing to improved cardiac function in patients with T2DM [ 16 ].…”

Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors

“…This exacerbates the hypovolemic state of DKA, leading to elevated cortisol, epinephrine, and glucagon levels, which in turn further enhance insulin resistance, ketogenesis, and lipolysis 25 48. A recent study has shown an increase in norepinephrine turnover in response to SGLT-2 inhibitor use that can increase hepatic glucose production independent of changes in insulin and glucagon 49…”

“… 25 48 A recent study has shown an increase in norepinephrine turnover in response to SGLT-2 inhibitor use that can increase hepatic glucose production independent of changes in insulin and glucagon. 49 …”