Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues

Hua V. Lin, Hongxia Ren, Varman T. Samuel, Hui Young Lee, Taylor Y. Lu, Gerald I. Shulman, Domenico Accili

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

OBJECTIVE - Impaired insulin-dependent glucose disposal in muscle and fat is a harbinger of type 2 diabetes, but murine models of selective insulin resistance at these two sites are conspicuous by their failure to cause hyperglycemia. A defining feature of muscle and fat vis-à-vis insulin signaling is that they both express the insulin-sensitive glucose transporter Glut4. We hypothesized that diabetes is the result of impaired insulin signaling in all Glut4-expressing tissues. RESEARCH DESIGN AND METHODS - To test the hypothesis, we generated mice lacking insulin receptors at these sites ("GIRKO" mice), including muscle, fat, and a subset of Glut4-positive neurons scattered throughout the central nervous system. RESULTS - GIRKO mice develop diabetes with high frequency because of reduced glucose uptake in peripheral organs, excessive hepatic glucose production, and β-cell failure. CONCLUSIONS - The conceptual advance of the present findings lies in the identification of a tissue constellation that melds cell-autonomous mechanisms of insulin resistance (in muscle/fat) with cell-nonautonomous mechanisms (in liver and β-cell) to cause overt diabetes. The data are consistent with the identification of Glut4 neurons as a distinct neuroanatomic entity with a likely metabolic role.

Original languageEnglish (US)
Pages (from-to)700-709
Number of pages10
JournalDiabetes
Volume60
Issue number3
DOIs
StatePublished - Mar 1 2011

Fingerprint

Insulin
Muscles
Fats
Glucose
Insulin Resistance
Neurons
Facilitative Glucose Transport Proteins
Liver
Insulin Receptor
Adipocytes
Hyperglycemia
Type 2 Diabetes Mellitus
Research Design
Central Nervous System

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Lin, H. V., Ren, H., Samuel, V. T., Lee, H. Y., Lu, T. Y., Shulman, G. I., & Accili, D. (2011). Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues. Diabetes, 60(3), 700-709. https://doi.org/10.2337/db10-1056

Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues. / Lin, Hua V.; Ren, Hongxia; Samuel, Varman T.; Lee, Hui Young; Lu, Taylor Y.; Shulman, Gerald I.; Accili, Domenico.

In: Diabetes, Vol. 60, No. 3, 01.03.2011, p. 700-709.

Research output: Contribution to journalArticle

Lin, HV, Ren, H, Samuel, VT, Lee, HY, Lu, TY, Shulman, GI & Accili, D 2011, 'Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues', Diabetes, vol. 60, no. 3, pp. 700-709. https://doi.org/10.2337/db10-1056
Lin, Hua V. ; Ren, Hongxia ; Samuel, Varman T. ; Lee, Hui Young ; Lu, Taylor Y. ; Shulman, Gerald I. ; Accili, Domenico. / Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues. In: Diabetes. 2011 ; Vol. 60, No. 3. pp. 700-709.
@article{8ec05a1622ee4a82a8e4dad993bda171,
title = "Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues",
abstract = "OBJECTIVE - Impaired insulin-dependent glucose disposal in muscle and fat is a harbinger of type 2 diabetes, but murine models of selective insulin resistance at these two sites are conspicuous by their failure to cause hyperglycemia. A defining feature of muscle and fat vis-{\`a}-vis insulin signaling is that they both express the insulin-sensitive glucose transporter Glut4. We hypothesized that diabetes is the result of impaired insulin signaling in all Glut4-expressing tissues. RESEARCH DESIGN AND METHODS - To test the hypothesis, we generated mice lacking insulin receptors at these sites ({"}GIRKO{"} mice), including muscle, fat, and a subset of Glut4-positive neurons scattered throughout the central nervous system. RESULTS - GIRKO mice develop diabetes with high frequency because of reduced glucose uptake in peripheral organs, excessive hepatic glucose production, and β-cell failure. CONCLUSIONS - The conceptual advance of the present findings lies in the identification of a tissue constellation that melds cell-autonomous mechanisms of insulin resistance (in muscle/fat) with cell-nonautonomous mechanisms (in liver and β-cell) to cause overt diabetes. The data are consistent with the identification of Glut4 neurons as a distinct neuroanatomic entity with a likely metabolic role.",
author = "Lin, {Hua V.} and Hongxia Ren and Samuel, {Varman T.} and Lee, {Hui Young} and Lu, {Taylor Y.} and Shulman, {Gerald I.} and Domenico Accili",
year = "2011",
month = "3",
day = "1",
doi = "10.2337/db10-1056",
language = "English (US)",
volume = "60",
pages = "700--709",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "3",

}

TY - JOUR

T1 - Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues

AU - Lin, Hua V.

AU - Ren, Hongxia

AU - Samuel, Varman T.

AU - Lee, Hui Young

AU - Lu, Taylor Y.

AU - Shulman, Gerald I.

AU - Accili, Domenico

PY - 2011/3/1

Y1 - 2011/3/1

N2 - OBJECTIVE - Impaired insulin-dependent glucose disposal in muscle and fat is a harbinger of type 2 diabetes, but murine models of selective insulin resistance at these two sites are conspicuous by their failure to cause hyperglycemia. A defining feature of muscle and fat vis-à-vis insulin signaling is that they both express the insulin-sensitive glucose transporter Glut4. We hypothesized that diabetes is the result of impaired insulin signaling in all Glut4-expressing tissues. RESEARCH DESIGN AND METHODS - To test the hypothesis, we generated mice lacking insulin receptors at these sites ("GIRKO" mice), including muscle, fat, and a subset of Glut4-positive neurons scattered throughout the central nervous system. RESULTS - GIRKO mice develop diabetes with high frequency because of reduced glucose uptake in peripheral organs, excessive hepatic glucose production, and β-cell failure. CONCLUSIONS - The conceptual advance of the present findings lies in the identification of a tissue constellation that melds cell-autonomous mechanisms of insulin resistance (in muscle/fat) with cell-nonautonomous mechanisms (in liver and β-cell) to cause overt diabetes. The data are consistent with the identification of Glut4 neurons as a distinct neuroanatomic entity with a likely metabolic role.

AB - OBJECTIVE - Impaired insulin-dependent glucose disposal in muscle and fat is a harbinger of type 2 diabetes, but murine models of selective insulin resistance at these two sites are conspicuous by their failure to cause hyperglycemia. A defining feature of muscle and fat vis-à-vis insulin signaling is that they both express the insulin-sensitive glucose transporter Glut4. We hypothesized that diabetes is the result of impaired insulin signaling in all Glut4-expressing tissues. RESEARCH DESIGN AND METHODS - To test the hypothesis, we generated mice lacking insulin receptors at these sites ("GIRKO" mice), including muscle, fat, and a subset of Glut4-positive neurons scattered throughout the central nervous system. RESULTS - GIRKO mice develop diabetes with high frequency because of reduced glucose uptake in peripheral organs, excessive hepatic glucose production, and β-cell failure. CONCLUSIONS - The conceptual advance of the present findings lies in the identification of a tissue constellation that melds cell-autonomous mechanisms of insulin resistance (in muscle/fat) with cell-nonautonomous mechanisms (in liver and β-cell) to cause overt diabetes. The data are consistent with the identification of Glut4 neurons as a distinct neuroanatomic entity with a likely metabolic role.

UR - http://www.scopus.com/inward/record.url?scp=79952428530&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79952428530&partnerID=8YFLogxK

U2 - 10.2337/db10-1056

DO - 10.2337/db10-1056

M3 - Article

C2 - 21266328

AN - SCOPUS:79952428530

VL - 60

SP - 700

EP - 709

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 3

ER -