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Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes
Open accessAbstract
To investigate the role of brain insulin action in the pathogenesis and treatment of diabetes, we asked whether neuronal insulin signaling is required for glucose-lowering during insulin treatment of diabetes. Hypothalamic signaling via the insulin receptor substrate-phosphatidylinositol 3-kinase (IRS-PI3K) pathway, a key intracellular mediator of insulin action, was reduced in rats with uncontrolled diabetes induced by streptozotocin (STZ-DM). Further, infusion of a PI3K inhibitor into the third cerebral ventricle of STZ-DM rats prior to peripheral insulin injection attenuated insulin-induced glucose lowering by approximately 35%-40% in both acute and chronic insulin treatment paradigms. Conversely, increased PI3K signaling induced by hypothalamic overexpression of either IRS-2 or protein kinase B (PKB, a key downstream mediator of PI3K action) enhanced the glycemic response to insulin by approximately 2-fold in STZ-DM rats. We conclude that hypothalamic insulin signaling via the IRS-PI3K pathway is a key determinant of the response to insulin in the management of uncontrolled diabetes.
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“Both, peripheral and central insulin signaling are impaired in obese or diabetic states.150, 151, 152, 153, 154”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [154]
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“increasing hypothalamic PI3K signaling, a major intracellular mediator of insulin action, by local overexpression of IRS-2 increases peripheral insulin sensitivity in rats with uDM induced by STZ (65).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [65]
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Metadata
- Authors
- Gelling, R. W., Morton, G. J., Morrison, C. D., Niswender, K. D., Myers, M. G., Rhodes, C. J., & Schwartz, M. W.
- Affiliations
- University of Washington (US)
- University of Michigan (US)
- Corresponding author
- Schwartz, Michael W.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2006-01
- Volume
- 3
- Issue
- 1
- Pages
- 67-73
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2052985185
- Cited by
- 169
- References
- 27
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 4 · 2019: 10 · 2018: 8 · 2017: 9 · 2016: 9 · 2015: 12 · 2014: 8 · 2013: 9 · 2012: 18
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Washington
- National Institutes of Health (2r01dk012829-36, DK‐12829, NS32273)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 12829, R01DK052989, DK68340, DK-52989)
- National Institute of Neurological Disorders and Stroke (NS-32273)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- hypothalamus, insulin signaling, insulin receptor substrate, phosphatidylinositol 3-kinase, Akt, insulin receptor substrate 2, streptozotocin-induced diabetes, insulin resistance, glucose homeostasis
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Blood Glucose, Brain, Chromones, Diabetes Mellitus, Experimental, Insulin, Male, Morpholines, Nerve Tissue Proteins, Rats, Sprague-Dawley, Rats
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