Increase in Endogenous Glucose Production With SGLT2 Inhibition Is Unchanged by Renal Denervation and Correlates Strongly With the Increase in Urinary Glucose Excretion

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibition causes an increase in endogenous glucose production (EGP). However, the mechanisms are unclear. We studied the effect of SGLT2 inhibitors on EGP in subjects with type 2 diabetes (T2D) and without diabetes (non-DM) in kidney transplant recipients with renal denervation. RESEARCH DESIGN AND METHODSFourteen subjects who received a renal transplant (six with T2D [A1C 7.2 6 0.1%] and eight non-DM [A1C 5.6 6 0.1%) underwent measurement of EGP with [3-3 H]glucose infusion following dapagliflozin (DAPA) 10 mg or placebo. Plasma glucose, insulin, C-peptide, glucagon, and titrated glucose-specific activity were measured. RESULTSFollowing placebo in T2D, fasting plasma glucose (FPG) (143 6 14 to 124 6 10 mg/dL; P 5 0.02) and fasting plasma insulin (12 6 2 to 10 6 1.1 mU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 6 15 to 112 6 9 mg/dL; P 5 0.01) and fasting plasma insulin (14 6 3 to 11 6 2 mU/mL; P 5 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 6 0.19 vs. 1.96 6 0.14 mg/kg/ min) in T2D (P < 0.001 vs. placebo). In non-DM following DAPA, FPG and fasting plasma insulin decreased, and plasma glucagon was unchanged. EGP was unchanged from baseline (1.85 6 0.10 to 1.78 6 0.10 mg/kg/min) after DAPA, whereas EGP declined significantly with placebo. When the increase in EGP production following DAPA versus placebo was plotted against the difference in urinary glucose excretion (UGE) for all patients, a strong correlation (r 5 0.824; P < 0.001) was observed. CONCLUSIONSRenal denervation in patients who received a kidney transplant failed to block the DAPA-mediated stimulation of EGP in both individuals with T2D and non-DM subjects. The DAPA-stimulated rise in EGP is strongly related to the increase in UGE, blunting the decline in FPG.

Increase in endogenous glucose production with SGLT2 inhibition is attenuated in individuals who underwent kidney transplantation and bilateral native nephrectomy

“…In a recent study we showed that, in kidney transplanted individuals with and without type 2 diabetes, administration of a single dose of dapagliflozin was associated with a compensatory increase in EGP [6]. This is indicative of a minor role for kidney innervation in modulating the liver adaptative response.…”

“…Kidney transplantation offers another model of kidney denervation. We have recently assessed the effect of administration of 10 mg dapagliflozin or placebo after an overnight fasting in 14 individuals (six with type 2 diabetes and eight without diabetes) who received a renal transplant [6]. In both diabetic and non-diabetic transplanted individuals, SGLT2 inhibitor-mediated stimulation of EGP was still fully apparent.…”

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

“…Increases in rates of endogenous glucose production, which have been documented in rodents (53,89,90) and humans (50,51,91,92), are an expected consequence of the increases in plasma glucagon concentrations that have been documented following acute and chronic SGLT2 inhibitor treatment. The increase in plasma glucagon following treatment with an SGLT2 inhibitor, which data reviewed in the previous section argue does not occur due to a direct effect on the a-cell, has been attributed to the glucoselowering effect of these drugs (94) and may also be attributable to a direct effect of SGLT2 inhibition in the ventromedial hypothalamus (VMH), the activity of which has been shown to be critical to the hormonal counterregulatory response to hypoglycemia (95).…”

“…WAT lipolysis promotes ketone production by supplying fatty acids which generate bhydroxybutyrate, acetoacetate and acetone as they are oxidized, and increase gluconeogenesis due to increased supply of both glycerol [a gluconeogenic precursor that drives gluconeogenesis by a substrate push mechanism (79-81)] and acetyl-CoA [the end product of boxidation and an allosteric activator of the ratecontrolling gluconeogenic enzyme pyruvate carboxylase (82)(83)(84)]. Given that both ketogenesis (44,53,(85)(86)(87)(88) and increased rates of endogenous glucose production (51)(52)(53)(89)(90)(91)(92) are observed after SGLT2 inhibitor treatment in humans and rodents, increased rates of lipolysis are a logical upstream explanation of both phenomena. Indeed, in a recent study, we observed that dapagliflozin more than doubled rates of in vivo WAT lipolysis in awake rats (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

“…Recently, Solis‐Herrera et al 24 showed a positive correlation between elevated EGP and UGE after a single dose of dapagliflozin in post‐renal transplant patients with and without type 2 diabetes. An animal study consistently demonstrated a positive association between EGP and UGE 25 .…”