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The dual incretin co-agonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice

Pacini, Giovanni and Ahrén, Bo LU (2024) In Peptides 171.
Abstract

Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75 g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50 min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (KG). The 50 min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was... (More)

Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75 g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50 min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (KG). The 50 min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was assessed as AUCinsulin divided by AUCglucose. Insulin sensitivity (SI) and glucose effectiveness (SG) were determined by minimal model analysis of the insulin and glucose data. Tirzepatide glucose-dependently reduced glucose levels and increased insulin levels. The slope for the regression of AUCinsulin versus AUCglucose was increased 7-fold by tirzepatide from 0.014 ± 0.004 with glucose only to 0.099 ± 0.016 (P < 0.001). SI was not affected by tirzepatide, whereas SG was increased by 78% (P < 0.001). The increase in SG contributed to an increase in KG by 74 ± 4% after glucose alone and by 67 ± 8% after glucose+ tirzepatide, whereas contribution by SI times AUCinsulin insulin (i.e., disposition index) was 26 ± 4% and 33 ± 8%, respectively. In conclusion, tirzepatide stimulates both insulin secretion and glucose effectiveness, with stimulation of glucose effectiveness being the prominent process to reduce glucose.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
GIP, GLP-1, Glucose disposal, Glucose tolerance, Insulin sensitivity, Insulin-independent
in
Peptides
volume
171
article number
171117
publisher
Elsevier
external identifiers
  • pmid:37984684
  • scopus:85177879727
ISSN
0196-9781
DOI
10.1016/j.peptides.2023.171117
language
English
LU publication?
yes
additional info
Funding Information: Tina Ovlund at Lund University is gratefully acknowledged for expert technical assistance. This research was funded by the Lund University Medical Faculty (to BA). GP’s former affiliation is Institute of Neurosciences, CNR, Padova, Italy. Funding Information: Tina Ovlund at Lund University is gratefully acknowledged for expert technical assistance. This research was funded by the Lund University Medical Faculty (to BA). GP's former affiliation is Institute of Neurosciences, CNR, Padova, Italy. Publisher Copyright: © 2023 The Authors
id
1b0ae97f-8018-48f8-a3df-77de328e5d4b
date added to LUP
2023-12-20 12:53:04
date last changed
2024-04-18 22:27:16
@article{1b0ae97f-8018-48f8-a3df-77de328e5d4b,
  abstract     = {{<p>Tirzepatide is a dual GIP and GLP-1 receptor co-agonist which is approved for glucose-lowering therapy in type 2 diabetes. Here, we explored its effects on beta cell function, insulin sensitivity and insulin-independent glucose elimination (glucose effectiveness) in normal mice. Anesthetized female C57/BL/6 J mice were injected intravenously with saline or glucose (0.125, 0.35 or 0.75 g/kg) with or without simultaneous administration of synthetic tirzepatide (3 nmol/kg). Samples were taken at 0, 1, 5, 10, 20 and 50 min. Glucose elimination rate was estimated by the percentage reduction in glucose from min 5 to min 20 (K<sub>G</sub>). The 50 min areas under the curve (AUC) for insulin and glucose were determined. Beta cell function was assessed as AUC<sub>insulin</sub> divided by AUC<sub>glucose</sub>. Insulin sensitivity (S<sub>I</sub>) and glucose effectiveness (S<sub>G</sub>) were determined by minimal model analysis of the insulin and glucose data. Tirzepatide glucose-dependently reduced glucose levels and increased insulin levels. The slope for the regression of AUC<sub>insulin</sub> versus AUC<sub>glucose</sub> was increased 7-fold by tirzepatide from 0.014 ± 0.004 with glucose only to 0.099 ± 0.016 (P &lt; 0.001). S<sub>I</sub> was not affected by tirzepatide, whereas S<sub>G</sub> was increased by 78% (P &lt; 0.001). The increase in S<sub>G</sub> contributed to an increase in K<sub>G</sub> by 74 ± 4% after glucose alone and by 67 ± 8% after glucose+ tirzepatide, whereas contribution by S<sub>I</sub> times AUC<sub>insulin</sub> insulin (i.e., disposition index) was 26 ± 4% and 33 ± 8%, respectively. In conclusion, tirzepatide stimulates both insulin secretion and glucose effectiveness, with stimulation of glucose effectiveness being the prominent process to reduce glucose.</p>}},
  author       = {{Pacini, Giovanni and Ahrén, Bo}},
  issn         = {{0196-9781}},
  keywords     = {{GIP; GLP-1; Glucose disposal; Glucose tolerance; Insulin sensitivity; Insulin-independent}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Peptides}},
  title        = {{The dual incretin co-agonist tirzepatide increases both insulin secretion and glucose effectiveness in model experiments in mice}},
  url          = {{http://dx.doi.org/10.1016/j.peptides.2023.171117}},
  doi          = {{10.1016/j.peptides.2023.171117}},
  volume       = {{171}},
  year         = {{2024}},
}