Pulsatile Portal Vein Insulin Delivery Enhances Hepatic Insulin Action and Signaling
Open accessAbstract
Insulin is secreted as discrete insulin secretory bursts at ∼5-min intervals into the hepatic portal vein, these pulses being attenuated early in the development of type 1 and type 2 diabetes mellitus (T2DM). Intraportal insulin infusions (pulsatile, constant, or reproducing that in T2DM) indicated that the pattern of pulsatile insulin secretion delivered via the portal vein is important for hepatic insulin action and, therefore, presumably for hepatic insulin signaling. To test this, we examined hepatic insulin signaling in rat livers exposed to the same three patterns of portal vein insulin delivery by use of sequential liver biopsies in anesthetized rats. Intraportal delivery of insulin in a constant versus pulsatile pattern led to delayed and impaired activation of hepatic insulin receptor substrate (IRS)-1 and IRS-2 signaling, impaired activation of downstream insulin signaling effector molecules AKT and Foxo1, and decreased expression of glucokinase (Gck). We further established that hepatic Gck expression is decreased in the HIP rat model of T2DM, a defect that correlated with a progressive defect of pulsatile insulin secretion. We conclude that the physiological pulsatile pattern of insulin delivery is important in hepatic insulin signaling and glycemic control. Hepatic insulin resistance in diabetes is likely in part due to impaired pulsatile insulin secretion.
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- Authors
- Matveyenko, A. V., Liuwantara, D., Gurlo, T., Kirakossian, D., Dalla Man, C., Cobelli, C., White, M. F., Copps, K. D., Volpi, E., Fujita, S., & Butler, P. C.
- Affiliations
- University of California, Los Angeles (US)
- Department of Information Engineering, University of Padova, Padova, Italy
- University of Padua (IT)
- Boston Children's Hospital (US)
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Butler, Peter C.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2012-08-17
- Volume
- 61
- Issue
- 9
- Pages
- 2269-2279
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3425431
- OpenAlex
- W2132083187
- Cited by
- 163
- References
- 51
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 5 · 2023: 14 · 2022: 16 · 2021: 20 · 2020: 9 · 2019: 10 · 2018: 10 · 2017: 12 · 2016: 14 · 2015: 11 · 2014: 17 · 2013: 7 · 2012: 4
- FWCI
- 12.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- National Institutes of Health (5r01dk098655-08)
- Japan Society for the Promotion of Science (22680050)
- National Institute on Aging (P30AG024832)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK078496, R01- DK098655, DK059579, K01DK089003, R01DK038712, R01DK059579, DK089003)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- pulsatile insulin secretion, hepatic insulin signaling, hepatic insulin resistance, IRS-1, insulin receptor substrate 2, Akt, FOXO1, glucokinase, type 2 diabetes, glycemic control
- MeSH terms
- Forkhead Box Protein O1, Insulin Secretion, Animals, Blood Glucose, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Dogs, Glucokinase, Insulin, Insulin Resistance, Liver, Male, Nerve Tissue Proteins, Portal Vein, Signal Transduction, Rats, Sprague-Dawley, Proto-Oncogene Proteins c-akt, Rats, Forkhead Transcription Factors, Insulin Receptor Substrate Proteins
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