Funding agencies: These studies were funded by the National Institutes of Health to MA (DK68596) and RNB (DK29867 and DK27619), and by researcher-initiated studies supported by Janssen Pharmaceutica, Sanofi-Aventis, and Amylin Pharmaceuticals. AVBN was supported by an American Diabetes Association mentor-based fellowship (awarded to RNB).
Hepatic insulin clearance is the primary determinant of insulin sensitivity in the normal dog
Article first published online: 3 DEC 2013
Copyright © 2013 The Obesity Society
Volume 22, Issue 5, pages 1238–1245, May 2014
How to Cite
Ader, M., Stefanovski, D., Kim, S. P., Richey, J. M., Ionut, V., Catalano, K. J., Hucking, K., Ellmerer, M., Van Citters, G., Hsu, I. R., Chiu, J. D., Woolcott, O. O., Harrison, L. N., Zheng, D., Lottati, M., Kolka, C. M., Mooradian, V., Dittmann, J., Yae, S., Liu, H., Castro, A. V. B., Kabir, M. and Bergman, R. N. (2014), Hepatic insulin clearance is the primary determinant of insulin sensitivity in the normal dog. Obesity, 22: 1238–1245. doi: 10.1002/oby.20625
Disclosure: The authors declare no conflict of interest.
Author contributions: MA conceived of the study, designed the experiments, analyzed and interpreted the data, and wrote the manuscript. DS assisted with data and statistical analysis. SPK, JMR, VI, and OOW performed experiments and MRI analysis. KJC, KH, ME, GVC, IRH, JDC, LNH, DZ, ML, CMK, VM, JD, SY, HL, AVBC, and MK performed experiments. RNB conceived of the study, interpreted the data, and assisted with manuscript preparation.
- Issue published online: 1 MAY 2014
- Article first published online: 3 DEC 2013
- Accepted manuscript online: 30 SEP 2013 09:15AM EST
- Manuscript Accepted: 10 SEP 2013
- Manuscript Revised: 15 AUG 2013
- Manuscript Received: 18 APR 2013
Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, nonstimulated conditions.
Metabolic assessment was performed in healthy dogs (n = 90). Whole-body sensitivity from euglycemic clamps (SICLAMP) was the primary outcome variable, and was measured independently by IVGTT (n = 36). Adiposity was measured by MRI (n = 90), and glucose-stimulated insulin response was measured from hyperglycemic clamp or IVGTT (n = 86 and 36, respectively).
SICLAMP was highly variable (5.9-75.9 dl/min per kg per μU/ml). Despite narrow range of body weight (mean, 28.7 ± 0.3 kg), adiposity varied approximately eight-fold and was inversely correlated with SICLAMP (P < 0.025). SICLAMP was negatively associated with fasting insulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (r = 0.53, P < 0.00001), whether calculated from clamp or IVGTT.
These data suggest that insulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose the hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight.