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- Title
Endocrine Factors Protect ALR Mice From Diabetes.
- Authors
Ize-Ludlow, Diego; Bowman, Thomas A.; Najjar, Sonia M.; O'Doherty, Robert M.; Becker, Dorothy J.; Mathews, Clayton E.
- Abstract
ALR mice, an NOD related swain, which are resistant to autoimmune, chemically-induced, and obesity-induced diabetes. The resistance to diabetes is partially explained by an increased resistance to oxygen radicals. As reduced oxidative burden has been positively correlated with insulin signaling, we hypothesized that endocrine characteristics play a role in the resistance to diabetes in this strain. To assess differences in insulin secretion/action we compared female ALR, C57BL/6 (B6), BALB, and the non-autoimmune NOD.H2b by i.p. glucose tolerance (GTT, 1.5 mg/kg) and insulin tolerance tests (ITT, 0.75U/kg). GTT induced glucose area under the curve (gAUC) was not significantly different between ALR (7502±7004), NOD.H2b (159474±5505), or BALB (14542 ± 3719). However, B6 mice had an increased gAUC (19296±3106 [P<0.01]). 1st phase insulin response (FPIR) as AUC of insulin (iAUC) in the first 10 min was decreased in ALR (1.6+1.1) and B6 (0.87±1.4) compared to NOD.H2b (17.0±6.3 [P<0.001]). To reconcile the disconnect between glucose tolerance and no apparent FPIR in ALR we performed i.v. GTT with diazoxide. In the presence of diazoxide ALR became glucose intolerant. Suggesting glucose tolerance is maintained by insulin secretion but not detectable due to increased insulin clearance. During in vitro perifusion, glucose stimulated iAUC was not different between ALR (55±31) and NOD.H2b (75±21) and was decreased in B6 (18±19). This confirmed that ALR islets have a normal and B6 have deficient insulin secretory capacity. Insulin sensitivity during ITT (AUC glucose) in ALR (-1106±286) was not different from BALB (-1800±733) or NOD (-1556±564) while B6 were more insulin sensitive (-2786±43l, P<0.05]. Yet, ALR mice exhibited a significant increase of insulin clearance from the blood compared to the controls. Insulin receptor signaling pathway by expression microarray and protein levels of CEACAM1, a transmembrane protein involved in insulin endocytosis and degradation, are elevated in ALR liver vs. NOD. These results suggest increased hepatic insulin action in ALR. In conclusion, increased hepatic insulin signaling may be a non-immune factor protecting ALR mice from diabetes. Their apparent in vivo insulin secretion deficiency is explained by rapid insulin clearance. ADA-Funded Research
- Subjects
ENDOCRINE system; DIABETES; LABORATORY mice; BLOOD sugar; INSULIN resistance; PROTEINS
- Publication
Diabetes, 2007, Vol 56, pA675
- ISSN
0012-1797
- Publication type
Article