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

OBJECTIVE 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 METHODS Fourteen subjects who received a renal transplant (six with T2D [A1C 7.2 ± 0.1%] and eight non-DM [A1C 5.6 ± 0.1%) underwent measurement of EGP with [3-3H]glucose infusion following dapagliflozin (DAPA) 10 mg or placebo. Plasma glucose, insulin, C-peptide, glucagon, and titrated glucose-specific activity were measured. RESULTS Following placebo in T2D, fasting plasma glucose (FPG) (143 ± 14 to 124 ± 10 mg/dL; P = 0.02) and fasting plasma insulin (12 ± 2 to 10 ± 1.1 μU/mL; P < 0.05) decreased; plasma glucagon was unchanged, and EGP declined. After DAPA in T2D, FPG (143 ± 15 to 112 ± 9 mg/dL; P = 0.01) and fasting plasma insulin (14 ± 3 to 11 ± 2 μU/mL; P = 0.02) decreased, and plasma glucagon increased (all P < 0.05 vs. placebo). EGP was unchanged from baseline (2.21 ± 0.19 vs. 1.96 ± 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 ± 0.10 to 1.78 ± 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 = 0.824; P < 0.001) was observed. CONCLUSIONS Renal 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.

[1]  G. Mosconi,et al.  Native kidney function after renal transplantation combined with other solid organs in preemptive patients. , 2010, Transplantation proceedings.

[2]  R. DeFronzo.  Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. , 1988, Diabetes.

[3]  R. DeFronzo,et al.  Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake. , 1989, Metabolism: clinical and experimental.

[4]  R. Steele,et al.  Measurement of size and turnover rate of body glucose pool by the isotope dilution method. , 1956, The American journal of physiology.

[5]  J. Miles,et al.  Hormonal, Metabolic and Hemodynamic Adaptations to Glycosuria in Type 2 Diabetes Patients Treated with Sodium-Glucose Co-Transporter Inhibitors. , 2019, Current diabetes reviews.

[6]  R. DeFronzo.  The Triumvirate: β-Cell, Muscle, Liver: A Collusion Responsible for NIDDM , 1988, Diabetes.

[7]  R. DeFronzo,et al.  Epinephrine-induced insulin resistance in man. , 1980, The Journal of clinical investigation.

[8]  R. DeFronzo,et al.  Renal, metabolic and cardiovascular considerations of SGLT2 inhibition , 2017, Nature Reviews Nephrology.

[9]  L. Groop,et al.  Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. , 1989, The Journal of clinical investigation.

[10]  R. DeFronzo,et al.  Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. , 1996, The Journal of clinical endocrinology and metabolism.

[11]  P. Flakoll,et al.  Effects of hyperglycemia, glucagon, and epinephrine on renal glucose release in the conscious dog. , 2004, Metabolism: clinical and experimental.

[12]  R. DeFronzo,et al.  Regulation of hepatic glucose metabolism in humans. , 1987, Diabetes/metabolism reviews.

[13]  F. Pattou,et al.  Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion , 2015, Nature Medicine.

[14]  G. Reaven,et al.  Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes. , 1988, The Journal of clinical investigation.

[15]  R. DeFronzo,et al.  Dapagliflozin lowers plasma glucose concentration and improves β-cell function. , 2015, The Journal of clinical endocrinology and metabolism.

[16]  Walter Pfaller,et al.  Impact of Culture Conditions, Culture Media Volumes, and Glucose Content on Metabolic Properties of Renal Epithelial Cell Cultures , 1999, Cellular Physiology and Biochemistry.

[17]  A. Cherrington,et al.  Banting Lecture 1997. Control of glucose uptake and release by the liver in vivo. , 1999, Diabetes.

[18]  C. Rabito,et al.  Contribution of native kidney function to total glomerular filtration rate after combined kidney-pancreas transplantation. , 1998, Transplantation.

[19]  R. DeFronzo,et al.  Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. , 2014, The Journal of clinical investigation.

[20]  E. Cersosimo,et al.  Effects of beta-adrenergic blockade on hepatic and renal glucose production during hypoglycemia in conscious dogs. , 1998, The American journal of physiology.

[21]  R. Rizza,et al.  Effect of intermittent endogenous hyperglucagonemia on glucose homeostasis in normal and diabetic man. , 1979, The Journal of clinical investigation.

[22]  E. Cersosimo,et al.  Effects of β-adrenergic blockade on hepatic and renal glucose production during hypoglycemia in conscious dogs. , 1998, American journal of physiology. Endocrinology and metabolism.

[23]  T. Heise,et al.  Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. , 2014, The Journal of clinical investigation.

[24]  D W Neal,et al.  Basal hepatic glucose production is regulated by the portal vein insulin concentration. , 1998, Diabetes.