Amylin-induced in vivo insulin resistance in conscious rats: the liver is more sensitive to amylin than peripheral tissues (original) (raw)

Summary

Amylin is a polypeptide of 37 amino acids, predominantly synthesized in pancreatic Beta cells. The peptide was suggested to be dysregulated in Type 2 (non-insulin-dependent) diabetes mellitus and it antagonized certain actions of insulin in vitro in rat muscle. This led to speculation that amylin is involved in the pathogenesis of Type 2 diabetes. We have examined the in vivo effects of rat amylin, amidated at the carboxy-terminus, on insulin-mediated carbohydrate metabolism in conscious rats, using the hyperinsulinaemic (±1 nmol/l) euglycaemic (6 mmol/l) clamp technique combined with [3-3H]-glucose infusion. Basal plasma amylin levels were ≤75 pmol/l. Applied amylin levels of 220±75 pmol/l (infusion rate of 12.5 pmol/min) antagonized only the insulin action on liver, resulting in a 100% increase of hepatic glucose output. Amylin levels of 4750±750 pmol/l (infusion rate of 125 pmol/min) induced a 250% increase of insulin-inhibited hepatic glucose output and, in addition, a 30% decrease of insulin-stimulated peripheral glucose uptake. Amylin did not affect: 1) the metabolic clearance rate of insulin, 2) the levels of plasma glucagon, epinephrine, norepinephrine, and corticosterone, 3) in vitro insulin binding and insulin-stimulated receptor autophosphorylation. This suggests that amylin antagonizes insulin action via binding to a yet unknown receptor. In conclusion: amylin causes in vivo insulin resistance and the liver seems the predominant organ regulated by this hormone. The in vivo effects of amylin mimic the pathophysiological abnormalities of insulin action in Type 2 diabetes.

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Authors and Affiliations

1. Department of Endocrinology and Metabolic Diseases, University Hospital, Leiden
   S. J. Koopmans, H. M. J. Krans, J. K. Radder & M. Frölich
2. Laboratory for Physiological Chemistry, State University, Utrecht, The Netherlands
   A. D. M. van Mansfeld & H. S. Jansz
3. Department of Psychophysiology, State University, Utrecht, The Netherlands
   S. F. de Boer
4. Pfizer Central Research, Groton, Connecticut, USA
   D. K. Kreutter & G. C. Andrews
5. Department of Medical Biochemistry, Sylvius Laboratories, Leiden, The Netherlands
   J. A. Maassen

Authors

1. S. J. Koopmans
2. A. D. M. van Mansfeld
3. H. S. Jansz
4. H. M. J. Krans
5. J. K. Radder
6. M. Frölich
7. S. F. de Boer
8. D. K. Kreutter
9. G. C. Andrews
10. J. A. Maassen

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Koopmans, S.J., van Mansfeld, A.D.M., Jansz, H.S. et al. Amylin-induced in vivo insulin resistance in conscious rats: the liver is more sensitive to amylin than peripheral tissues.Diabetologia 34, 218–224 (1991). https://doi.org/10.1007/BF00405079

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• Received: 27 April 1990
• Revised: 23 November 1990
• Issue date: April 1991
• DOI: https://doi.org/10.1007/BF00405079

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