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Deciphering the hypoglycemic glucagon response: development of a graded hyperinsulinemic hypoglycemic clamp technique in female mice.

Malmgren, Siri LU and Ahrén, Bo LU (2015) In Endocrinology 156(10). p.3866-3871
Abstract
Glucose lowering therapy in type 1 and type 2 diabetes is often associated with hypoglycemic events. To avoid this, glucose lowering therapies need to be developed that support the hypoglycemic defense mechanisms. Such development needs a tool for evaluating counterregulatory mechanisms in vivo. A sustained glucagon release during hypoglycemia is of most importance to hypoglycemic defense mechanisms. We have therefore developed a graded hyperinsulinemic hypoglycemic clamp in mice and used it to evaluate counterregulatory glucagon dynamics. Glucose was clamped at narrow intervals aiming at 2.5, 3.5, 4.5 and 6.0 mmol/L. Glucagon levels were increased during hypoglycemia in a glucose-dependent way with a glucagon counterregulatory threshold... (More)
Glucose lowering therapy in type 1 and type 2 diabetes is often associated with hypoglycemic events. To avoid this, glucose lowering therapies need to be developed that support the hypoglycemic defense mechanisms. Such development needs a tool for evaluating counterregulatory mechanisms in vivo. A sustained glucagon release during hypoglycemia is of most importance to hypoglycemic defense mechanisms. We have therefore developed a graded hyperinsulinemic hypoglycemic clamp in mice and used it to evaluate counterregulatory glucagon dynamics. Glucose was clamped at narrow intervals aiming at 2.5, 3.5, 4.5 and 6.0 mmol/L. Glucagon levels were increased during hypoglycemia in a glucose-dependent way with a glucagon counterregulatory threshold between 3.5 and 4.0 mmol/L. Modelling the glucose - glucagon relationship using a hyperbolic curve with the equation: Plasma glucagon=-4.20+90.79/blood glucose showed high correlation. When comparing this method to the insulin tolerance test (ITT) as an approach to study glucagon dynamics in vivo we found that the graded clamp more efficiently evoked a robust, predictable, glucagon response with considerably less variation in blood glucose. In conclusion, we have developed a tool for the study of in vivo glucagon dynamics during hypoglycemia in mice and demonstrated a hyperbolic glucose-counterregulatory glucagon relationship. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Endocrinology
volume
156
issue
10
pages
3866 - 3871
publisher
Endocrine Society
external identifiers
  • pmid:26132921
  • wos:000362235300049
  • scopus:84943645698
ISSN
0013-7227
DOI
10.1210/EN.2015-1314
language
English
LU publication?
yes
id
9a0bd99e-cc8b-4541-ab8c-3f7dda18c996 (old id 7751142)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26132921?dopt=Abstract
date added to LUP
2015-08-01 21:27:46
date last changed
2017-01-01 04:16:22
@article{9a0bd99e-cc8b-4541-ab8c-3f7dda18c996,
  abstract     = {Glucose lowering therapy in type 1 and type 2 diabetes is often associated with hypoglycemic events. To avoid this, glucose lowering therapies need to be developed that support the hypoglycemic defense mechanisms. Such development needs a tool for evaluating counterregulatory mechanisms in vivo. A sustained glucagon release during hypoglycemia is of most importance to hypoglycemic defense mechanisms. We have therefore developed a graded hyperinsulinemic hypoglycemic clamp in mice and used it to evaluate counterregulatory glucagon dynamics. Glucose was clamped at narrow intervals aiming at 2.5, 3.5, 4.5 and 6.0 mmol/L. Glucagon levels were increased during hypoglycemia in a glucose-dependent way with a glucagon counterregulatory threshold between 3.5 and 4.0 mmol/L. Modelling the glucose - glucagon relationship using a hyperbolic curve with the equation: Plasma glucagon=-4.20+90.79/blood glucose showed high correlation. When comparing this method to the insulin tolerance test (ITT) as an approach to study glucagon dynamics in vivo we found that the graded clamp more efficiently evoked a robust, predictable, glucagon response with considerably less variation in blood glucose. In conclusion, we have developed a tool for the study of in vivo glucagon dynamics during hypoglycemia in mice and demonstrated a hyperbolic glucose-counterregulatory glucagon relationship.},
  author       = {Malmgren, Siri and Ahrén, Bo},
  issn         = {0013-7227},
  language     = {eng},
  number       = {10},
  pages        = {3866--3871},
  publisher    = {Endocrine Society},
  series       = {Endocrinology},
  title        = {Deciphering the hypoglycemic glucagon response: development of a graded hyperinsulinemic hypoglycemic clamp technique in female mice.},
  url          = {http://dx.doi.org/10.1210/EN.2015-1314},
  volume       = {156},
  year         = {2015},
}