155-LB: The Increase in Endogenous Glucose Production with SGLT2 Inhibition Is Unchanged by Renal Denervation but Highly Correlates to Urinary Glucose Excretion

S<a>odium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i)</a> effectively lower plasma glucose (PG) concentration in patients with type 2 diabetes, but studies suggest that circulating glucagon concentrations and endogenous glucose production (EGP) are increased by SGLT2i, possibly compromising their glucose-lowering ability. To tease out whether and how glucagon may influence the glucose-lowering effect of SGLT2 inhibition, we subjected 12 patients with type 2 diabetes to a randomized, placebo-controlled, double-blinded, crossover, double-dummy study comprising, on four separate days, a liquid mixed meal test preceded by single-dose administration of either 1) placebo, 2) the SGLT2i empagliflozin (25 mg), 3) the glucagon receptor antagonist LY2409021 (300 mg), and 4) the combination <a>empagliflozin+LY2409021</a>. Empagliflozin and LY2409021 individually lowered fasting PG compared to placebo and the combination further decreased fasting PG. Previous findings of increased glucagon concentrations and EGP during acute administration of SGLT2i were not replicated in this study. Empagliflozin reduced postprandial PG via increased urinary glucose excretion. LY2409021 reduced EGP significantly, but gave rise to a paradoxical increase in postprandial PG excursion, which was annulled by empagliflozin during their combination (empagliflozin+LY2409021). In conclusion, our findings do not support that an SGLT2i-induced glucagonotropic effect is of importance for the glucose-lowering property of SGLT2 inhibition.

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Competitive inhibition of SGLT2 by tofogliflozin or phlorizin induces urinary glucose excretion through extending splay in cynomolgus monkeys

AJP Renal Physiology ◽

10.1152/ajprenal.00076.2014 ◽

2014 ◽

Vol 306 (12) ◽

pp. F1520-F1533 ◽

Cited By ~ 9

Author(s):

Takumi Nagata ◽

Masayuki Suzuki ◽

Masanori Fukazawa ◽

Kiyofumi Honda ◽

Mizuki Yamane ◽

...

Keyword(s):

Competitive Inhibition ◽

Fractional Excretion ◽

Dependent Manner ◽

Urinary Glucose Excretion ◽

Cynomolgus Monkeys ◽

Urinary Glucose ◽

Sglt2 Inhibition ◽

Glucose Excretion

Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed a glucose lowering effect in type 2 diabetes patients through inducing renal glucose excretion. Detailed analysis of the mechanism of the glucosuric effect of SGLT2 inhibition, however, has been hampered by limitations of clinical study. Here, we investigated the mechanism of urinary glucose excretion using nonhuman primates with SGLT inhibitors tofogliflozin and phlorizin, both in vitro and in vivo. In cells overexpressing cynomolgus monkey SGLT2 (cSGLT2), both tofogliflozin and phlorizin competitively inhibited uptake of the substrate (α-methyl-d-glucopyranoside; AMG). Tofogliflozin was found to be a selective cSGLT2 inhibitor, inhibiting cSGLT2 more strongly than did phlorizin, with selectivity toward cSGLT2 1,000 times that toward cSGLT1; phlorizin was found to be a nonselective cSGLT1/2 inhibitor. In a glucose titration study in cynomolgus monkeys under conditions of controlled plasma drug concentration, both tofogliflozin and phlorizin increased fractional excretion of glucose (FEG) by up to 50% under hyperglycemic conditions. By fitting the titration curve using a newly introduced method that avoids variability in estimating the threshold of renal glucose excretion, we found that tofogliflozin and phlorizin lowered the threshold and extended the splay in a dose-dependent manner without significantly affecting the tubular transport maximum for glucose (TmG). Our results demonstrate the contribution of SGLT2 to renal glucose reabsorption (RGR) in cynomolgus monkeys and demonstrate that competitive inhibition of cSGLT2 exerts a glucosuric effect by mainly extending splay and lowering threshold without affecting TmG.

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1127-P: SGLT2 Inhibition (SGLT2i) Mediated Urinary Glucose Excretion (UGE) Associations with Metabolic and Renal Hemodynamic Parameters

Diabetes ◽

10.2337/db19-1127-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 1127-P

Author(s):

YULIYA LYTVYN ◽

ANDRIY LYTVYN ◽

ELZA O. MUSCELLI ◽

BRUCE A. PERKINS ◽

DAVID CHERNEY ◽

...

Keyword(s):

Hemodynamic Parameters ◽

Urinary Glucose Excretion ◽

Renal Hemodynamic ◽

Urinary Glucose ◽

Sglt2 Inhibition ◽

Glucose Excretion

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Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001178 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001178 ◽

Cited By ~ 1

Author(s):

Ele Ferrannini ◽

Ricardo Pereira-Moreira ◽

Marta Seghieri ◽

Eleni Rebelos ◽

Aglécio L Souza ◽

...

Keyword(s):

Sodium Excretion ◽

Insulin Infusion ◽

Glucose Production ◽

Whole Body ◽

Glucose Disposal ◽

Sodium Glucose Cotransporter ◽

Urinary Glucose ◽

Patients With Diabetes ◽

Sglt2 Inhibition ◽

Glucose Excretion

IntroductionInsulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known.MethodsWe applied the pancreatic clamp technique in 12 healthy subjects and 13 T2D subjects. Each participant received a somatostatin infusion and a variable glucose infusion to achieve (within 1 hour) and maintain glycemia at 22 mmol/L for 3 hours; next, a constant insulin infusion (240 pmol/min/kg) was added for another 3 hours. Urine was collected separately in each period for glucose and creatinine determination.ResultsDuring saline, glucose excretion was lower in T2D than controls in absolute terms (0.49 (0.32) vs 0.69 (0.18) mmol/min, median (IQR), p=0.01) and as a fraction of filtered glucose (16.2 (6.4) vs 19.9 (7.5)%, p<0.001). With insulin, whole-body glucose disposal rose more in controls than T2D (183 (48) vs 101 (48) µmol/kgFFM/min, p<0.0003). Insulin stimulated absolute and fractional glucose excretion in controls (p<0.01) but not in T2D. Sodium excretion paralleled glucose excretion. In the pooled data, fractional glucose excretion was directly related to whole-body glucose disposal and to fractional sodium excretion (r=0.52 and 0.54, both p<0.01). In another group of healthy controls, empagliflozin was administered before starting the pancreatic clamp to block sodium-glucose cotransporter 2 (SGLT2). Under these conditions, insulin still enhanced both glucose and sodium excretion.ConclusionsAcute exogenous insulin infusion jointly stimulates renal glucose and sodium excretion, indicating that the effect may be mediated by SGLTs. This action is resistant in patients with diabetes, accounting for their increased retention of glucose and sodium, and is not abolished by partial SGLT2 inhibition by empagliflozin.

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The Role of Glucagon in the Acute Therapeutic Effects of SGLT2 Inhibition

10.2337/figshare.13010123 ◽

2020 ◽

Author(s):

Ada Admin ◽

Sofie Hædersdal ◽

Asger Lund ◽

Elisabeth Nielsen-Hannerup ◽

Henrik Maagensen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Therapeutic Effects ◽

Acute Administration ◽

Glucagon Receptor ◽

Glucose Lowering ◽

Urinary Glucose ◽

Sglt2 Inhibition

S<a>odium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i)</a> effectively lower plasma glucose (PG) concentration in patients with type 2 diabetes, but studies suggest that circulating glucagon concentrations and endogenous glucose production (EGP) are increased by SGLT2i, possibly compromising their glucose-lowering ability. To tease out whether and how glucagon may influence the glucose-lowering effect of SGLT2 inhibition, we subjected 12 patients with type 2 diabetes to a randomized, placebo-controlled, double-blinded, crossover, double-dummy study comprising, on four separate days, a liquid mixed meal test preceded by single-dose administration of either 1) placebo, 2) the SGLT2i empagliflozin (25 mg), 3) the glucagon receptor antagonist LY2409021 (300 mg), and 4) the combination <a>empagliflozin+LY2409021</a>. Empagliflozin and LY2409021 individually lowered fasting PG compared to placebo and the combination further decreased fasting PG. Previous findings of increased glucagon concentrations and EGP during acute administration of SGLT2i were not replicated in this study. Empagliflozin reduced postprandial PG via increased urinary glucose excretion. LY2409021 reduced EGP significantly, but gave rise to a paradoxical increase in postprandial PG excursion, which was annulled by empagliflozin during their combination (empagliflozin+LY2409021). In conclusion, our findings do not support that an SGLT2i-induced glucagonotropic effect is of importance for the glucose-lowering property of SGLT2 inhibition.

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Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00545.2012 ◽

2013 ◽

Vol 304 (4) ◽

pp. E414-E423 ◽

Cited By ~ 30

Author(s):

Takumi Nagata ◽

Masanori Fukazawa ◽

Kiyofumi Honda ◽

Tatsuo Yata ◽

Mio Kawai ◽

...

Keyword(s):

Plasma Concentrations ◽

Sglt2 Inhibitor ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption ◽

Urinary Glucose ◽

Sglt2 Inhibition ◽

Renal Glucose Reabsorption

To understand the risk of hypoglycemia associated with urinary glucose excretion (UGE) induced by sodium-glucose cotransporter (SGLT) inhibitors, it is necessary to know the relationship between the ratio of contribution of SGLT2 vs. SGLT1 to renal glucose reabsorption (RGR) and the glycemic levels in vivo. To examine the contributions of SGLT2 and SGLT1 in normal rats, we compared the RGR inhibition by tofogliflozin, a highly specific SGLT2 inhibitor, and phlorizin, an SGLT1 and SGLT2 (SGLT1/2) inhibitor, at plasma concentrations sufficient to completely inhibit rat SGLT2 (rSGLT2) while inhibiting rSGLT1 to different degrees. Under hyperglycemic conditions by glucose titration, tofogliflozin and phlorizin achieved ≥50% inhibition of RGR. Under hypoglycemic conditions by hyperinsulinemic clamp, RGR was reduced by 20–50% with phlorizin and by 1–5% with tofogliflozin, suggesting the smaller contribution of rSGLT2 to RGR under hypoglycemic conditions than under hyperglycemic conditions. Next, to evaluate the hypoglycemic potentials of SGLT1/2 inhibition, we measured the plasma glucose (PG) and endogenous glucose production (EGP) simultaneously after UGE induction by SGLT inhibitors. Tofogliflozin (400 ng/ml) induced UGE of about 2 mg·kg−1·min−1 and increased EGP by 1–2 mg·kg−1·min−1, resulting in PG in the normal range. Phlorizin (1,333 ng/ml) induced UGE of about 6 mg·kg−1·min−1 and increased EGP by about 4 mg·kg−1·min−1; this was more than with tofogliflozin, but the minimum PG was lower. These results suggest that the contribution of SGLT1 to RGR is greater under lower glycemic conditions than under hyperglycemic conditions and that SGLT2-selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.

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