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


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.
Department of Medicine, Columbia University, New York, New York, USA.
Hua V
HV
Lin
Hongxia
H
Ren
Varman T
VT
Samuel
Hui-Young
HY
Lee
Taylor Y
TY
Lu
Gerald I
GI
Shulman
Domenico
D
Accili
D000273:Adipose Tissue / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002153:Calorimetry, Indirect; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D007328:Insulin; D011972:Receptor, Insulin; D005947:Glucose
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