Evidence Against an Important Role of Plasma Insulin and Glucagon Concentrations in the Increase in EGP Caused by SGLT2 Inhibitors

Abstract

Sodium-glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-3 H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n 5 26) or placebo (n 5 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (10.66 6 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (10.71 6 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.

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

“…Of note, while the SGLT2i-induced increase in the glucagon/insulin ratio likely contributes to enhanced EGP, it is probably not the only mechanism. This is supported by a recent study showing increased dapagliflozin-induced EGP in humans in conditions in which glucagon and insulin secretions were clamped at basal levels by somatostatin [ 52 ]. There is also an ingrained belief that glucagon exerts strong ketogenic activities, particularly during fasting and insulinopenic conditions.…”

Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks

“…These data suggest that increased plasma glucagon concentrations could contribute to increased rates of gluconeogenesis by stimulating intrahepatic lipolysis (57) in this setting. However, a recent study in which subjects were treated with somatostatin to inhibit pancreatic islet hormone secretion of insulin and glucagon, and given an intravenous infusion of replacement basal insulin and glucagon demonstrated an insulin-and glucagon-independent effect of dapagliflozin to increase EGP in humans with T2D (97). In contrast, either blocking catecholamine and corticosterone action, or saline infusion to prevent dehydration, fully abrogated the effect of dapagliflozin to increase EGP in rats, despite a lack of any difference in plasma glucagon concentrations (53).…”

A decrease in plasma glucose levels is required for increased endogenous glucose production with a single administration of a sodium‐glucose co‐transporter‐2 inhibitor tofogliflozin

“…Nevertheless, the present study showed that EGP levels in each condition seemed to be steady at approximately 180 minutes after SGLT2 inhibitor administration, which is a similar result to a previous study showing that EGP was mostly constant from 180 to 300 minutes after SGLT2 inhibitor administration with isoglycaemic and non-isoglycaemic conditions. 10 Finally, we evaluated changes in metabolite and hormone levels between 0 and 180 minutes. However, we cannot exclude the possibility that slight but chronic changes in metabolite and hormone levels (eg, glucagon, NEFA and 3-hydroxybutyric acids) might contribute to EGP change during this period.…”

“…8,9 However, its mechanism has not yet been elucidated. Very recently, Alatrach et al 10 assessed whether EGP elevation after dapagliflozin administration could occur during isoglycaemic or pancreatic clamp conditions in type 2 diabetes. They showed that administration of dapagliflozin led to higher EGP compared with placebo during both isoglycaemic and pancreatic clamp conditions, and concluded that the dapagliflozin-induced increase in EGP cannot be explained by increased plasma glucagon levels or decreased plasma insulin or glucose concentrations.…”

“…They showed that administration of dapagliflozin led to higher EGP compared with placebo during both isoglycaemic and pancreatic clamp conditions, and concluded that the dapagliflozin-induced increase in EGP cannot be explained by increased plasma glucagon levels or decreased plasma insulin or glucose concentrations. 10 Given that an isoglycaemic clamp is not a normal physiological condition, we hypothesized that reduced PG levels after SGLT2 inhibitor administration somehow suppress insulin secretion and stimulate glucagon secretion in physiological conditions, thus elevating EGP, because insulin and glucagon are the main regulators of EGP. 11 In contrast to the previous study that compared the effect of SGLT2 inhibitors and placebo under conditions of an isoglycaemic clamp (glucose infusion in both placebo and treatment groups), in the present study, we tried to prevent the decrease in glucose induced by SGLT2 inhibitors by mimicking the glucose pattern of time-dependent control under the conditions of no drugs administered.…”