Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes. / Kim, Angela; Knudsen, Jakob G.; Madara, Joseph C.; Benrick, Anna; Hill, Thomas G.; Kadir, Lina Abdul; Kellard, Joely A.; Mellander, Lisa; Miranda, Caroline; Lin, Haopeng; James, Timothy; Suba, Kinga; Spigelman, Aliya F.; Wu, Yanling; Macdonald, Patrick E.; Asterholm, Ingrid Wernstedt; Magnussen, Tore; Christensen, Mikkel; Vilsbøll, Tina; Salem, Victoria; Knop, Filip K.; Rorsman, Patrik; Lowell, Bradford B.; Briant, Linford J. B.
I: eLife, Bind 10, e72919, 2021.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes
AU - Kim, Angela
AU - Knudsen, Jakob G.
AU - Madara, Joseph C.
AU - Benrick, Anna
AU - Hill, Thomas G.
AU - Kadir, Lina Abdul
AU - Kellard, Joely A.
AU - Mellander, Lisa
AU - Miranda, Caroline
AU - Lin, Haopeng
AU - James, Timothy
AU - Suba, Kinga
AU - Spigelman, Aliya F.
AU - Wu, Yanling
AU - Macdonald, Patrick E.
AU - Asterholm, Ingrid Wernstedt
AU - Magnussen, Tore
AU - Christensen, Mikkel
AU - Vilsbøll, Tina
AU - Salem, Victoria
AU - Knop, Filip K.
AU - Rorsman, Patrik
AU - Lowell, Bradford B.
AU - Briant, Linford J. B.
N1 - Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved.
PY - 2021
Y1 - 2021
N2 - Insulin-induced hypoglycemia is a major barrier to the treatment of type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon – the body’s principal blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro) and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor(s) that stimulates glucagon secretion remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide, a stable surrogate marker of AVP) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. Exogenous injection of AVP in vivo increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with T1D, hypoglycemia failed to increase both plasma copeptin and glucagon levels. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
AB - Insulin-induced hypoglycemia is a major barrier to the treatment of type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon – the body’s principal blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro) and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor(s) that stimulates glucagon secretion remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide, a stable surrogate marker of AVP) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. Exogenous injection of AVP in vivo increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with T1D, hypoglycemia failed to increase both plasma copeptin and glucagon levels. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
U2 - 10.7554/eLife.72919
DO - 10.7554/eLife.72919
M3 - Journal article
C2 - 34787082
AN - SCOPUS:85120311260
VL - 10
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e72919
ER -
ID: 287118515