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Cited by 45Metabolism, Diabetes, and CancerPI3K/AKT/mTOR signaling in cancerNatural Antidiabetic Agents Studies

Convergence of IPMK and LKB1-AMPK Signaling Pathways on Metformin Action

Open access
Bang, Sookhee, Chen, Yong, Ahima, Rexford S., Kim, Sangwon F.·2014·Molecular Endocrinology
DOI 10.1210/me.2014-1134PMC PMC4075158
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Abstract

Metformin is a biguanide drug that is widely prescribed for type 2 diabetes. Metformin suppresses hepatic gluconeogenesis and increases fatty acid oxidation. Although studies have suggested that metformin acts, at least in part, via activation of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, the specific molecular mechanisms underlying metformin's regulation of glucose and lipid metabolism have not been well delineated. Recently, we have shown that inositol polyphosphate multikinase (IPMK) plays an important role in cellular energy metabolism and glucose-mediated AMPK regulation. Here we investigated the role of IPMK in metformin-induced AMPK activation. We observed that metformin-mediated activation of AMPK was impaired in the absence of IPMK. Overexpression of wild-type IPMK was sufficient to restore LKB1-AMPK activation by either metformin or AICAR in IPMK−/− murine embryonic fibroblast cells, suggesting that IPMK may act as an upstream regulator of LKB1-AMPK signaling in response to metformin. Moreover, this regulation was mediated by protein-protein interaction between IPMK and LKB1 as a dominant-negative peptide, which abrogates this interaction, attenuated metformin's ability to activate AMPK. Our data demonstrate that IPMK plays an important role in LKB1/AMPK signaling and may be targeted for treatment of metabolic diseases.

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  • IPMK is implicated in neurodegeneration, cancer, and inflammation.

    “Over two decades, multidisciplinary research has unveiled its far-reaching biological roles and implications in diverse diseases, including neurodegeneration, cancer, and inflammation.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [30]

    The Abstract (page unavailable) describes IPMK as a multifunctional signaling protein and reports its involvement in pathways including Akt, mTOR and AMPK. It does not link IPMK to neurodegeneration, cancer or inflammation; its discussion of a cancer syndrome concerns LKB1, not IPMK. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • IPMK depletion impairs AMPK activation.

    “IPMK depletion impairs AMPK activation [30], which is crucial for glucose sensing and metabolism.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [30]

    In “Deletion of IPMK impairs metformin-mediated activation of LKB1/AMPK,” IPMK-depleted cells show reduced AMPK activation after metformin or AICAR treatment. The same section reports that IPMK deletion does not affect AMPK phosphorylation induced by a calcium ionophore, so the unqualified claim is broader than the finding. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • IPMK is involved in inflammatory disorders, obesity, Alzheimer's disease, inflammatory bowel disease, and intestinal neuroendocrine tumors.

    “Over the past two decades, research utilizing animal models and human mutation analyses has revealed IPMK’s involvement in a wide array of human diseases, including inflammatory disorders [28,29], obesity [30,31], Alzheimer’s disease [32], inflammatory bowel disease [33,34], and intestinal neuroendocrine tumors [35].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [30]

    The Discussion links IPMK to glucose metabolism, familial type 2 diabetes, and metformin-responsive AMPK signaling, but does not establish its involvement in obesity. Searches for obesity and the other listed diseases found no passage connecting IPMK to them; the reference to obese mice concerns a metformin study, not an IPMK finding. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cites

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Cited by

Sorted by citations

Authors
Bang, S., Chen, Y., Ahima, R. S., & Kim, S. F.
Affiliations
University of Pennsylvania (US)
Corresponding author
Kim, Sangwon F.
ORCID
Venue
Molecular Endocrinology
Publisher
The Endocrine Society
Published
2014-07-01
Volume
28
Issue
7
Pages
1186-1193
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
DOI
10.1210/me.2014-1134
PMC
PMC4075158
OpenAlex
W1983690350
Cited by
45
References
7
Citations by year
2026: 1 · 2025: 2 · 2024: 4 · 2022: 6 · 2021: 1 · 2020: 5 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 7 · 2015: 3 · 2014: 1
FWCI
2.19
Type
journal article
Language
en
Open access
Locations
  • Molecular Endocrinology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Diabetes Association (7-13-BS-004)
  • University of Pennsylvania
  • National Alliance for Research on Schizophrenia and Depression
  • National Institutes of Health
  • National Cancer Institute (P30CA016520)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK084336, DK084336)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords
metformin, inositol polyphosphate multikinase, LKB1, AMPK, AMPK activation, protein-protein interaction, type 2 diabetes, glucose metabolism, energy metabolism, AICAR, hepatic gluconeogenesis, fatty acid oxidation
MeSH terms
Aminoimidazole Carboxamide, Animals, Diabetes Mellitus, Type 2, Energy Metabolism, Fatty Acids, Gluconeogenesis, Glucose, HeLa Cells, Humans, Hypoglycemic Agents, Liver, Metformin, Oxidation-Reduction, Phosphorylation, Ribonucleotides, Protein Serine-Threonine Kinases, Phosphotransferases (Alcohol Group Acceptor), Cell Line, Tumor, Lipid Metabolism, Mice, AMP-Activated Protein Kinases, Gene Knockout Techniques, HEK293 Cells

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