Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling.
Insulin receptor substrates (Irs proteins) mediate the pleiotropic effects of insulin and Igf-1 (insulin-like growth factor-1), including regulation of glucose homeostasis and cell growth and survival. We intercrossed mice heterozygous for two null alleles (Irs1+/- and Irs2+/-) and investigated growth and glucose metabolism in mice with viable genotypes. Our experiments revealed that Irs-1 and Irs-2 are critical for embryonic and post-natal growth, with Irs-1 having the predominant role. By contrast, both Irs-1 and Irs-2 function in peripheral carbohydrate metabolism, but Irs-2 has the major role in beta-cell development and compensation for peripheral insulin resistance. To establish a role for the Igf-1 receptor in beta-cells, we intercrossed mice heterozygous for null alleles of Igf1r and Irs2. Our results reveal that Igf-1 receptors promote beta-cell development and survival through the Irs-2 signalling pathway. Thus, Irs-2 integrates the effects of insulin in peripheral target tissues with Igf-1 in pancreatic beta-cells to maintain glucose homeostasis.
Withers
D J
DJ
Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA.
Burks
D J
DJ
Towery
H H
HH
Altamuro
S L
SL
Flint
C L
CL
White
M F
MF
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism* / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D001786:Blood Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D017526:Receptor, IGF Type 1