Diabetes, Vol 44, Issue 8 947-953, Copyright © 1995 by American Diabetes Association

ARTICLES

Kinetics of insulin action in vivo. Identification of rate-limiting steps

PD Miles, M Levisetti, D Reichart, M Khoursheed, AR Moossa and JM Olefsky
Department of Surgery, University of California, San Diego, USA.

To examine the kinetic steps in insulin's in vivo action, we have assessed the temporal relationship between arterial insulin, interstitial insulin, glucose disposal rate (GDR), and insulin receptor kinase (IRK) activity in muscle and between portal insulin, hepatic glucose production (HGP), and IRK activity in liver. Interstitial insulin, as measured by lymph-insulin concentration (muscle only), and IRK activity were used as independent methods to determine the arrival of insulin at its tissue site of action. Euglycemic clamps were conducted in seven mongrel dogs and consisted of an activation phase with a venous insulin infusion (7.2 nmol.kg-1.min-1, 100 min) and a deactivation phase. Liver and muscle biopsies were taken to assess IRK activity. Arterial, portal, and lymph insulin rose to 636 +/- 12, 558 +/- 18, and 402 +/- 24 pmol/l, respectively. GDR increased from 13.9 +/- 0.6 to 41.7 +/- 2.8, and HGP declined from 14.4 +/- 0.6 to 1.1 +/- 0.6 mumol.kg-1.min-1. Muscle and liver IRK activity increased significantly from 5.9 +/- 0.9 to 14.6 +/- 0.6 and 5.5 +/- 0.7 to 23.7 +/- 1.9 fmol P/fmol insulin receptor (IR), respectively. The time to half-maximum response (t1/2a) for stimulation of GDR (19.8 +/- 4.8 min) and suppression of HGP (21.5 +/- 3.7 min) were similar. The t1/2a for stimulation of GDR, muscle IRK, and rise in lymph insulin were not significantly different from one another and were all markedly greater than that for the approach to steady state of arterial insulin (2.3 +/- 1.2 min, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. D. Chiu, J. M. Richey, L. N. Harrison, E. Zuniga, C. M. Kolka, E. Kirkman, M. Ellmerer, and R. N. Bergman Direct Administration of Insulin Into Skeletal Muscle Reveals That the Transport of Insulin Across the Capillary Endothelium Limits the Time Course of Insulin to Activate Glucose Disposal Diabetes, April 1, 2008; 57(4): 828 - 835. [Abstract] [Full Text] [PDF]

				H. Wang, A. X. Wang, Z. Liu, and E. J. Barrett Insulin Signaling Stimulates Insulin Transport by Bovine Aortic Endothelial Cells Diabetes, March 1, 2008; 57(3): 540 - 547. [Abstract] [Full Text] [PDF]

				E. M. Eggleston, L. A. Jahn, and E. J. Barrett Hyperinsulinemia Rapidly Increases Human Muscle Microvascular Perfusion but Fails to Increase Muscle Insulin Clearance: Evidence That a Saturable Process Mediates Muscle Insulin Uptake Diabetes, December 1, 2007; 56(12): 2958 - 2963. [Abstract] [Full Text] [PDF]

				H. Wang, Z. Liu, G. Li, and E. J. Barrett The vascular endothelial cell mediates insulin transport into skeletal muscle Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E323 - E332. [Abstract] [Full Text] [PDF]

				H. P.M.M. Lauritzen, T. Ploug, C. Prats, J. M. Tavare, and H. Galbo Imaging of insulin signaling in skeletal muscle of living mice shows major role of T-tubules. Diabetes, May 1, 2006; 55(5): 1300 - 1306. [Abstract] [Full Text] [PDF]

				J. B. Meigs, C. J. O'Donnell, G. H. Tofler, E. J. Benjamin, C. S. Fox, I. Lipinska, D. M. Nathan, L. M. Sullivan, R. B. D'Agostino, and P. W.F. Wilson Hemostatic Markers of Endothelial Dysfunction and Risk of Incident Type 2 Diabetes: The Framingham Offspring Study Diabetes, February 1, 2006; 55(2): 530 - 537. [Abstract] [Full Text] [PDF]

				B. Thorand, J. Baumert, L. Chambless, C. Meisinger, H. Kolb, A. Doring, H. Lowel, W. Koenig, and for the MONICA/KORA Study Group Elevated Markers of Endothelial Dysfunction Predict Type 2 Diabetes Mellitus in Middle-Aged Men and Women From the General Population Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 398 - 405. [Abstract] [Full Text] [PDF]

				Z. Liu, W. Long, D. A. Fryburg, and E. J. Barrett The Regulation of Body and Skeletal Muscle Protein Metabolism by Hormones and Amino Acids J. Nutr., January 1, 2006; 136(1): 212S - 217S. [Abstract] [Full Text] [PDF]

				M. J.M. Serlie, J. H. de Haan, C. J. Tack, H. J. Verberne, M. T. Ackermans, A. Heerschap, and H. P. Sauerwein Glycogen Synthesis in Human Gastrocnemius Muscle Is Not Representative of Whole-Body Muscle Glycogen Synthesis Diabetes, May 1, 2005; 54(5): 1277 - 1282. [Abstract] [Full Text] [PDF]

				K. Sydow, C. E Mondon, and J. P Cooke Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA Vascular Medicine, May 1, 2005; 10(2_suppl): S35 - S43. [Abstract] [PDF]

				M. A. Vincent, L. H. Clerk, J. R. Lindner, A. L. Klibanov, M. G. Clark, S. Rattigan, and E. J. Barrett Microvascular Recruitment Is an Early Insulin Effect That Regulates Skeletal Muscle Glucose Uptake In Vivo Diabetes, June 1, 2004; 53(6): 1418 - 1423. [Abstract] [Full Text] [PDF]

				J. B. Meigs, F. B. Hu, N. Rifai, and J. E. Manson Biomarkers of Endothelial Dysfunction and Risk of Type 2 Diabetes Mellitus JAMA, April 28, 2004; 291(16): 1978 - 1986. [Abstract] [Full Text] [PDF]

				M. Hamilton-Wessler, M. Ader, M. K. Dea, D. Moore, M. Loftager, J. Markussen, and R. N. Bergman Mode of Transcapillary Transport of Insulin and Insulin Analog NN304 in Dog Hindlimb: Evidence for Passive Diffusion Diabetes, March 1, 2002; 51(3): 574 - 582. [Abstract] [Full Text] [PDF]

				A. D. Pradhan, J. E. Manson, N. Rifai, J. E. Buring, and P. M. Ridker C-Reactive Protein, Interleukin 6, and Risk of Developing Type 2 Diabetes Mellitus JAMA, July 18, 2001; 286(3): 327 - 334. [Abstract] [Full Text] [PDF]