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HMGCR and rosuvastatin regulates GLP-1 secretion and expression - a translational study

Miskelly, Michael G LU ; Lindqvist, Andreas LU ; Jujić, Amra ; Hamilton, Alexander LU ; Cowan, Elaine LU orcid ; Raikundalia, Sweta LU ; Dutius Andersson, Anna-Maria LU ; Nergård, Bent J ; Del Giudice, Rita LU and Kryvokhyzha, Dmytro LU orcid , et al. (2026) In The Journal of clinical endocrinology and metabolism 111(5). p.1343-1355
Abstract

CONTEXT: Statin use is associated with increased risk of type 2 diabetes and mild hyperglycemia. The underlying mechanisms are not well studied and the effect of statin treatment on GLP-1 secretion or production are unknown.

OBJECTIVE: To assess the effects of rosuvastatin on GLP-1 secretion and production.

METHODS: We performed association studies in the Malmö Diet and Cancer study cardiovascular cohort (MDCS-CC) re-examination cohort, in vitro investigations using GLUTag cells and acute and chronic studies in female, normoglycemic C57Bl/6j mice.

RESULTS: Studies in the MDCS-CC reexamination cohort(n=3734) revealed that in individuals without type 2 diabetes, statin usage was associated with higher fasting GIP,... (More)

CONTEXT: Statin use is associated with increased risk of type 2 diabetes and mild hyperglycemia. The underlying mechanisms are not well studied and the effect of statin treatment on GLP-1 secretion or production are unknown.

OBJECTIVE: To assess the effects of rosuvastatin on GLP-1 secretion and production.

METHODS: We performed association studies in the Malmö Diet and Cancer study cardiovascular cohort (MDCS-CC) re-examination cohort, in vitro investigations using GLUTag cells and acute and chronic studies in female, normoglycemic C57Bl/6j mice.

RESULTS: Studies in the MDCS-CC reexamination cohort(n=3734) revealed that in individuals without type 2 diabetes, statin usage was associated with higher fasting GIP, insulin, glucose, glucagon and HOMA-IR, but not GLP-1. However, in patients with type 2 diabetes, statin usage was associated with higher fasting GLP-1 levels.Rosuvastatin treatment or Hmgcr knockdown reduced GLP-1 secretion and increased Gcg mRNA in GLUTag cells. Rosuvastatin acutely reduced postprandial GLP-1 secretion, whereas chronic rosuvastatin treatment in mice caused hyperglycemia and increased postprandial GLP-1 levels. The acute effect of Hmgcr KD on GLP-1 secretion could be mimicked by targeting intracellular cholesterol using a PCSK9 inhibitor. Finally, transcriptomic alterations induced by rosuvastatin were limited to genes involved in cholesterol biosynthesis.

CONCLUSIONS: We have established HMGCR as a regulator of GLP-1 secretion and provide a plausible explanation for the clinically observed mild hyperglycemia associated with statin use. Given the negative acute effect on GLP-1 secretion, monitoring of blood glucose levels is recommended after prescribing rosuvastatin."

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of clinical endocrinology and metabolism
volume
111
issue
5
pages
1343 - 1355
publisher
Oxford University Press
external identifiers
  • pmid:41206007
  • scopus:105036535523
ISSN
1945-7197
DOI
10.1210/clinem/dgaf608
language
English
LU publication?
yes
additional info
© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
id
b1dfb0a3-5cde-4cb9-afb4-348cf7f1e5c1
date added to LUP
2025-11-10 08:58:02
date last changed
2026-06-10 09:12:56
@article{b1dfb0a3-5cde-4cb9-afb4-348cf7f1e5c1,
  abstract     = {{<p>CONTEXT: Statin use is associated with increased risk of type 2 diabetes and mild hyperglycemia. The underlying mechanisms are not well studied and the effect of statin treatment on GLP-1 secretion or production are unknown.</p><p>OBJECTIVE: To assess the effects of rosuvastatin on GLP-1 secretion and production.</p><p>METHODS: We performed association studies in the Malmö Diet and Cancer study cardiovascular cohort (MDCS-CC) re-examination cohort, in vitro investigations using GLUTag cells and acute and chronic studies in female, normoglycemic C57Bl/6j mice.</p><p>RESULTS: Studies in the MDCS-CC reexamination cohort(n=3734) revealed that in individuals without type 2 diabetes, statin usage was associated with higher fasting GIP, insulin, glucose, glucagon and HOMA-IR, but not GLP-1. However, in patients with type 2 diabetes, statin usage was associated with higher fasting GLP-1 levels.Rosuvastatin treatment or Hmgcr knockdown reduced GLP-1 secretion and increased Gcg mRNA in GLUTag cells. Rosuvastatin acutely reduced postprandial GLP-1 secretion, whereas chronic rosuvastatin treatment in mice caused hyperglycemia and increased postprandial GLP-1 levels. The acute effect of Hmgcr KD on GLP-1 secretion could be mimicked by targeting intracellular cholesterol using a PCSK9 inhibitor. Finally, transcriptomic alterations induced by rosuvastatin were limited to genes involved in cholesterol biosynthesis.</p><p>CONCLUSIONS: We have established HMGCR as a regulator of GLP-1 secretion and provide a plausible explanation for the clinically observed mild hyperglycemia associated with statin use. Given the negative acute effect on GLP-1 secretion, monitoring of blood glucose levels is recommended after prescribing rosuvastatin."</p>}},
  author       = {{Miskelly, Michael G and Lindqvist, Andreas and Jujić, Amra and Hamilton, Alexander and Cowan, Elaine and Raikundalia, Sweta and Dutius Andersson, Anna-Maria and Nergård, Bent J and Del Giudice, Rita and Kryvokhyzha, Dmytro and Nilsson, Peter M and Juul-Holst, Jens and Torekov, Signe Sørensen and Lagerstedt, Jens O and Gomez, Maria F and Eliasson, Lena and Mulder, Hindrik and Hedenbro, Jan and Magnusson, Martin and Wierup, Nils}},
  issn         = {{1945-7197}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{1343--1355}},
  publisher    = {{Oxford University Press}},
  series       = {{The Journal of clinical endocrinology and metabolism}},
  title        = {{HMGCR and rosuvastatin regulates GLP-1 secretion and expression - a translational study}},
  url          = {{http://dx.doi.org/10.1210/clinem/dgaf608}},
  doi          = {{10.1210/clinem/dgaf608}},
  volume       = {{111}},
  year         = {{2026}},
}