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

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.

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

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.

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

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 155-LB
Author(s):  
CAROLINA SOLIS-HERRERA ◽  
MARIAM ALATRACH ◽  
CHRISTINA AGYIN ◽  
HENRI HONKA ◽  
RUPAL PATEL ◽  
...  
Keyword(s):  
Renal Denervation ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Urinary Glucose Excretion ◽  
Urinary Glucose ◽  
Sglt2 Inhibition ◽  
Endogenous Glucose ◽  
Glucose Excretion

Effect of Glucagon on Nocturnal Rates of Endogenous Glucose Production in Type 2 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 44-OR
Author(s):  
ANANDA BASU ◽  
HUALING ZHAI ◽  
RICKEY CARTER ◽  
RITA BASU
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Endogenous Glucose

Abstract 16107: Combined HbA1c and Systolic Blood Pressure Reduction With Dapagliflozin in Patients With Both Inadequately Controlled Type 2 Diabetes Mellitus and Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Michael A Weber ◽  
James List ◽  
Traci A Mansfield ◽  
Shamik J Parikh ◽  
Agata Ptaszynska
Keyword(s):  
Diabetes Mellitus ◽  
Blood Pressure ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Systolic Blood Pressure ◽  
Enzyme Inhibitor ◽  
Blood Pressure Reduction ◽  
Glucose Lowering ◽  
Urinary Glucose

Background: Hypertension is a common comorbidity in patients with type 2 diabetes mellitus (T2DM). Initial treatment is usually with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), with other antihypertensive therapies (AHTs) added if needed. Dapagliflozin (DAPA) increases urinary glucose excretion accompanied by diuresis and weight loss, which contributes to blood pressure (BP) reduction. Here we evaluate the proportions of patients achieving combined HbA1c and systolic blood pressure (SBP) reduction with DAPA in two studies of patients with both inadequately controlled T2DM and hypertension. Methods: Patients with both inadequately controlled T2DM (HbA1c 7.0-10.5%) and hypertension (seated SBP / diastolic BP: 140-164 / 85-104 mmHg) despite receiving glucose-lowering drugs and an ACEi or ARB (Study 1) plus a 2nd AHT agent (Study 2) were randomized to receive double-blind DAPA 10 mg or placebo for 12 weeks. Primary results have been presented previously; here we present proportions of patients achieving combined changes from baseline (Δ) in HbA1c and SBP. Results: In Study 2, additional AHT drugs were thiazide/thiazide-like diuretics (~44%), calcium channel blockers (~27%), and beta blockers (~27%). Across both studies, 520 and 522 patients had available paired ΔHbA1c and ΔSBP values in the DAPA and placebo groups, respectively. More patients achieved combined ΔHbA1c and ΔSBP reduction with DAPA (n=325; 62.5%) vs placebo (n=190; 36.4%) (Figure - dotted boxes). Considering more stringent thresholds, more patients achieved combined reductions in ΔHbA1c of ≥0.5% and ΔSBP of ≥5 mmHg with DAPA (n=194; 37.3%) vs placebo (n=86; 16.5%) (Figure - solid boxes). Conclusions: In T2DM patients with hypertension on glucose-lowering therapies and an ACEi or ARB ± 1 additional AHT, adding dapagliflozin achieved clinically significant combined HbA1c and SBP reductions over 12 weeks in greater numbers of patients than placebo.

Benefits and limitations of reducing glucagon action for the treatment of type 2 diabetes

2009 ◽  
Vol 296 (3) ◽  
pp. E415-E421 ◽  
Author(s):  
Safina Ali ◽  
Daniel J. Drucker
Keyword(s):  
Type 2 Diabetes ◽  
Therapeutic Potential ◽  
Receptor Gene ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucagon Receptor ◽  
Hepatic Glucose ◽  
Extrahepatic Tissues ◽  
Glucagon Receptor Gene

Glucagon is secreted from the α-cells of the pancreatic islets and regulates glucose homeostasis through modulation of hepatic glucose production. As elevated glucagon levels contribute to the pathophysiology of hyperglycemia in subjects with type 2 diabetes, reduction of glucagon receptor gene (Gcgr) activity represents a potential target for the treatment of T2DM. Herein, we review current concepts of glucagon action in hepatic and extrahepatic tissues and evaluate the therapeutic potential, mechanisms of action, and safety of reducing Gcgr signaling for the treatment of T2DM.

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