Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis

Brian T O'Neill; Hans P M M Lauritzen; Michael F Hirshman; Graham Smyth; Laurie J Goodyear; C Ronald Kahn

doi:10.1016/j.celrep.2015.04.037

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Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis

Journal article

Open access

Peer reviewed

Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis

Brian T O'Neill, Hans P M M Lauritzen, Michael F Hirshman, Graham Smyth, Laurie J Goodyear and C Ronald Kahn

Cell reports (Cambridge), Vol.11(8), pp.1220-1235

05/26/2015

DOI: 10.1016/j.celrep.2015.04.037

PMCID: PMC4449334

PMID: 25981038

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Abstract

Insulin and insulin-like growth factor 1 (IGF-1) are major regulators of muscle protein and glucose homeostasis. To determine how these pathways interact, we generated mice with muscle-specific knockout of IGF-1 receptor (IGF1R) and insulin receptor (IR). These MIGIRKO mice showed >60% decrease in muscle mass. Despite a complete lack of insulin/IGF-1 signaling in muscle, MIGIRKO mice displayed normal glucose and insulin tolerance. Indeed, MIGIRKO mice showed fasting hypoglycemia and increased basal glucose uptake. This was secondary to decreased TBC1D1 resulting in increased Glut4 and Glut1 membrane localization. Interestingly, overexpression of a dominant-negative IGF1R in muscle induced glucose intolerance in MIGIRKO animals. Thus, loss of insulin/IGF-1 signaling impairs muscle growth, but not whole-body glucose tolerance due to increased membrane localization of glucose transporters. Nonetheless, presence of a dominant-negative receptor, even in the absence of functional IR/IGF1R, induces glucose intolerance, indicating that interactions between these receptors and other proteins in muscle can impair glucose homeostasis.

Receptor, IGF Type 1 - metabolism

Phosphorylation

Muscle, Skeletal - growth & development

Signal Transduction

Homeostasis

Male

Muscle, Skeletal - metabolism

Mice, Knockout

Animals

Muscle Proteins - metabolism

Glucose - metabolism

Female

Receptor, Insulin - metabolism

Mice

Details

Title: Subtitle: Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis
Creators: Brian T O'Neill - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
Hans P M M Lauritzen - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
Michael F Hirshman - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
Graham Smyth - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
Laurie J Goodyear - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
C Ronald Kahn - Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: c.ronald.kahn@joslin.harvard.edu
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.11(8), pp.1220-1235
DOI: 10.1016/j.celrep.2015.04.037
PMID: 25981038
PMCID: PMC4449334
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Grant note: R01 DK031036 / NIDDK NIH HHS P30 DK036836 / NIDDK NIH HHS R01AR42238 / NIAMS NIH HHS R01 DK033201 / NIDDK NIH HHS K08DK100543 / NIDDK NIH HHS UL1 TR000135 / NCATS NIH HHS U24DK100469 / NIDDK NIH HHS K08 DK100543 / NIDDK NIH HHS R01 AR042238 / NIAMS NIH HHS R37 DK031036 / NIDDK NIH HHS U24 DK100469 / NIDDK NIH HHS P30 DK36836 / NIDDK NIH HHS
Language: English
Date published: 05/26/2015
Academic Unit: Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094551102771

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