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Do sodium-glucose co-transporter-2 inhibitors increase plasma glucagon by direct actions on the alpha cell? And does the increase matter for the associated increase in endogenous glucose production?

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@article{67fe56ff885f4ed993779b00dbd57a65,
title = "Do sodium-glucose co-transporter-2 inhibitors increase plasma glucagon by direct actions on the alpha cell?: And does the increase matter for the associated increase in endogenous glucose production?",
abstract = "Sodium-glucose co-transporter-2 inhibitors (SGLT2is) lower blood glucose and are used for treatment of type 2 diabetes. However, SGLT2is have been associated with increases in endogenous glucose production (EGP) by mechanisms that have been proposed to result from SGLT2i-mediated increases in circulating glucagon concentrations, but the relative importance of this effect is debated, and mechanisms possibly coupling SGLT2is to increased plasma glucagon are unclear. A direct effect on alpha-cell activity has been proposed, but data on alpha-cell SGLT2 expression are inconsistent, and studies investigating the direct effects of SGLT2 inhibition on glucagon secretion are conflicting. By contrast, alpha-cell sodium-glucose co-transporter-1 (SGLT1) expression has been found more consistently and appears to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2is does not support interference with SGLT1 during therapy. Paracrine effects mediated by secretion of glucagonotropic/static molecules from beta and/or delta cells have also been suggested to be involved in SGLT2i-induced increase in plasma glucagon, but studies are few and arrive at different conclusions. It is also possible that the effect on glucagon is secondary to drug-induced increases in urinary glucose excretion and lowering of blood glucose, as shown in experiments with glucose clamping where SGLT2i-associated increases in plasma glucagon are prevented. However, regardless of the mechanisms involved, the current balance of evidence does not support that SGLT2 plays a crucial role for alpha-cell physiology or that SGLT2i-induced glucagon secretion is important for the associated increased EGP, particularly because the increase in EGP occurs before any rise in plasma glucagon.",
keywords = "Benzhydryl Compounds, Blood Glucose, Diabetes Mellitus, Type 2/drug therapy, Glucagon, Glucose, Glucosides, Humans, Pharmaceutical Preparations, Sodium, Sodium-Glucose Transporter 2 Inhibitors/therapeutic use, alpha-cell glucose transporters, renal glucose reabsorption, glucose-regulated glucagon secretion, sodium-glucose co-transporter-2 inhibitors, alpha-cell glucose metabolism, hepatic glucose output",
author = "Kuhre, {Rune E} and Deacon, {Carolyn F} and {Wewer Albrechtsen}, {Nicolai J} and Holst, {Jens J}",
note = "{\textcopyright} 2021 John Wiley & Sons Ltd.",
year = "2021",
month = sep,
doi = "10.1111/dom.14422",
language = "English",
volume = "23",
pages = "2009--2019",
journal = "Diabetes, Obesity and Metabolism",
issn = "1462-8902",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "9",

}

RIS

TY - JOUR

T1 - Do sodium-glucose co-transporter-2 inhibitors increase plasma glucagon by direct actions on the alpha cell?

T2 - And does the increase matter for the associated increase in endogenous glucose production?

AU - Kuhre, Rune E

AU - Deacon, Carolyn F

AU - Wewer Albrechtsen, Nicolai J

AU - Holst, Jens J

N1 - © 2021 John Wiley & Sons Ltd.

PY - 2021/9

Y1 - 2021/9

N2 - Sodium-glucose co-transporter-2 inhibitors (SGLT2is) lower blood glucose and are used for treatment of type 2 diabetes. However, SGLT2is have been associated with increases in endogenous glucose production (EGP) by mechanisms that have been proposed to result from SGLT2i-mediated increases in circulating glucagon concentrations, but the relative importance of this effect is debated, and mechanisms possibly coupling SGLT2is to increased plasma glucagon are unclear. A direct effect on alpha-cell activity has been proposed, but data on alpha-cell SGLT2 expression are inconsistent, and studies investigating the direct effects of SGLT2 inhibition on glucagon secretion are conflicting. By contrast, alpha-cell sodium-glucose co-transporter-1 (SGLT1) expression has been found more consistently and appears to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2is does not support interference with SGLT1 during therapy. Paracrine effects mediated by secretion of glucagonotropic/static molecules from beta and/or delta cells have also been suggested to be involved in SGLT2i-induced increase in plasma glucagon, but studies are few and arrive at different conclusions. It is also possible that the effect on glucagon is secondary to drug-induced increases in urinary glucose excretion and lowering of blood glucose, as shown in experiments with glucose clamping where SGLT2i-associated increases in plasma glucagon are prevented. However, regardless of the mechanisms involved, the current balance of evidence does not support that SGLT2 plays a crucial role for alpha-cell physiology or that SGLT2i-induced glucagon secretion is important for the associated increased EGP, particularly because the increase in EGP occurs before any rise in plasma glucagon.

AB - Sodium-glucose co-transporter-2 inhibitors (SGLT2is) lower blood glucose and are used for treatment of type 2 diabetes. However, SGLT2is have been associated with increases in endogenous glucose production (EGP) by mechanisms that have been proposed to result from SGLT2i-mediated increases in circulating glucagon concentrations, but the relative importance of this effect is debated, and mechanisms possibly coupling SGLT2is to increased plasma glucagon are unclear. A direct effect on alpha-cell activity has been proposed, but data on alpha-cell SGLT2 expression are inconsistent, and studies investigating the direct effects of SGLT2 inhibition on glucagon secretion are conflicting. By contrast, alpha-cell sodium-glucose co-transporter-1 (SGLT1) expression has been found more consistently and appears to be more prominent, pointing to an underappreciated role for this transporter. Nevertheless, the selectivity of most SGLT2is does not support interference with SGLT1 during therapy. Paracrine effects mediated by secretion of glucagonotropic/static molecules from beta and/or delta cells have also been suggested to be involved in SGLT2i-induced increase in plasma glucagon, but studies are few and arrive at different conclusions. It is also possible that the effect on glucagon is secondary to drug-induced increases in urinary glucose excretion and lowering of blood glucose, as shown in experiments with glucose clamping where SGLT2i-associated increases in plasma glucagon are prevented. However, regardless of the mechanisms involved, the current balance of evidence does not support that SGLT2 plays a crucial role for alpha-cell physiology or that SGLT2i-induced glucagon secretion is important for the associated increased EGP, particularly because the increase in EGP occurs before any rise in plasma glucagon.

KW - Benzhydryl Compounds

KW - Blood Glucose

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Glucagon

KW - Glucose

KW - Glucosides

KW - Humans

KW - Pharmaceutical Preparations

KW - Sodium

KW - Sodium-Glucose Transporter 2 Inhibitors/therapeutic use

KW - alpha-cell glucose transporters

KW - renal glucose reabsorption

KW - glucose-regulated glucagon secretion

KW - sodium-glucose co-transporter-2 inhibitors

KW - alpha-cell glucose metabolism

KW - hepatic glucose output

UR - http://www.scopus.com/inward/record.url?scp=85106602409&partnerID=8YFLogxK

U2 - 10.1111/dom.14422

DO - 10.1111/dom.14422

M3 - Review

C2 - 33961344

VL - 23

SP - 2009

EP - 2019

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 9

ER -

ID: 67244540