Cited by 169Regulation of Appetite and ObesityPancreatic function and diabetesDiabetes Management and Research

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Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes

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Gelling, Richard W., Morton, Gregory J., Morrison, Christopher D., Niswender, Kevin D., Myers, Martin G., Rhodes, Christopher J., Schwartz, Michael W.·2006·Cell Metabolism

DOI 10.1016/j.cmet.2005.11.013

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Abstract

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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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: Gelling, Richard W.
Morton, Gregory J.
Morrison, Christopher D.
Myers, Martin G.
Rhodes, Christopher J.
Schwartz, Michael W.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2006-01
Volume: 3
Issue: 1
Pages: 67-73
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2005.11.013
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3245 d)
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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Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes

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