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Cited by 186Metabolism, Diabetes, and CancerPancreatic function and diabetesLiver Disease Diagnosis and Treatment

Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis

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Perry, Rachel J., Zhang, Dongyan, Guerra, Mateus T., Brill, Allison L., Goedeke, Leigh, Nasiri, Ali R., Rabin-Court, Aviva, Wang, Yongliang +12 more·2020·Nature
DOI 10.1038/s41586-020-2074-6PMC PMC7101062
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Abstract

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes 1-3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation-all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment-reversing hepatic steatosis and glucose intolerance-were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.

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  • A 4-week study in humans with type 2 diabetes suggested greater reductions in liver lipid content and glycogen levels with cotadutide vs liraglutide and placebo despite comparable weight loss and fasting glucose reduction.

    “Furthermore, a 4-week study in humans with type 2 diabetes comparing the effects of the combined GLP-1/glucagon RA cotadutide versus the GLP-1 RA liraglutide and placebo suggested greater reductions in liver lipid content and glycogen levels despite comparable weight loss and reduction in fasting glucose levels with cotadutide and liraglutide [136].”

    From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [136]

    The paper’s Abstract reports reduced hepatic lipids and glycogen after chronic glucagon infusion in high-fat-fed rats, with lower fasting glucose and similar body weight. It does not report a four-week study in humans with type 2 diabetes or compare cotadutide with liraglutide and placebo, so the clinical comparison is unsupported. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Perry, R. J., Zhang, D., Guerra, M. T., Brill, A. L., Goedeke, L., Nasiri, A. R., Rabin-Court, A., Wang, Y., Peng, L., Dufour, S., Zhang, Y., Zhang, X.-M., Butrico, G. M., Toussaint, K., Nozaki, Y., Cline, G. W., Petersen, K. F., Nathanson, M. H., Ehrlich, B. E., & Shulman, G. I.
Affiliations
Yale University (US)
Corresponding author
Shulman, Gerald I.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-03-04
Volume
579
Issue
7798
Pages
279-283
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-2074-6
PMC
PMC7101062
OpenAlex
W3009231969
Cited by
186
References
3
Citations by year
2026: 25 · 2025: 25 · 2024: 30 · 2023: 38 · 2022: 33 · 2021: 24 · 2020: 11
FWCI
8.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health (1s10od023598-01, UL1TR000142, UL1TR001863)
  • National Heart, Lung, and Blood Institute (K99HL150234)
  • National Cancer Institute (R00CA215315, K99CA215315)
  • National Institute of General Medical Sciences (T32GM007324)
  • National Institute of Diabetes and Digestive and Kidney Diseases (T32DK101019, F32DK114954, R01DK119968, R01DK114793, R01DK112797, R01DK114041, U24DK059635, R01DK116774, R01DK045710, P01DK057751, F31DK118836, R01DK061747, R01DK113984, P30DK034989, T32DK007058, P30DK045735)
  • National Institute of Neurological Disorders and Stroke (R01NS087568)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
glucagon, gluconeogenesis, hepatic lipolysis, adipose triglyceride lipase, hepatic steatosis, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, hepatic glucose metabolism, pyruvate carboxylase, acetyl-CoA
MeSH terms
Acetyl Coenzyme A, Acyltransferases, Adipose Tissue, Animals, Diabetes Mellitus, Type 2, Enzyme Activation, Glucagon, Gluconeogenesis, Lipase, Lipolysis, Liver, Mitochondria, Oxidation-Reduction, Mice, Knockout, Inositol 1,4,5-Trisphosphate Receptors, Non-alcoholic Fatty Liver Disease

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