Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro

Insulin resistance occurs in a variety of conditions, including diabetes, obesity and essential hypertension1, but its underlying molecular mechanisms are unclear. In type 2 (non-insulin-dependent) diabetes mellitus, it is insulin-resistance in skeletal muscle, the chief site of insulin-mediated glucose disposal in humans2, that predominantly accounts for the low rates of glucose clearance from the blood, and hence for impaired glucose tolerance3. Human type 2 diabetes is characterized by a decrease in non-oxidative glucose storage (muscle glycogen synthesis)4,5, and by the deposition of amyloid in the islets of Langerhans6,7. Amylin is a 37-amino-acid peptide which is a major component of islet amyloid and has structural similarity to human calcitonin gene-related peptide-2 (CGRP-2; ref.8). CGRP is a neuropeptide which may be involved in motor activity in skeletal muscle9,10. We now report that human pancreatic amylin and rat CGRP-1 are potent inhibitors of both basal and insulin-stimulated rates of glycogen synthesis in stripped rat soleus muscle in vitro. These results may provide a basis for a new understanding of the molecular mechanisms that cause insulin resistance in skeletal muscle.

[1]  G. Greeley,et al.  Effect of calcitonin gene-related peptide on glucose and gastric inhibitory polypeptide-stimulated insulin release from cultured newborn and adult rat islet cells , 1988, Regulatory Peptides.

[2]  R. Heinrikson,et al.  Amino acid analysis by reverse-phase high-performance liquid chromatography: precolumn derivatization with phenylisothiocyanate. , 1984, Analytical biochemistry.

[3]  M. Vranic,et al.  Insulin resistance and decreased insulin response to glucose in lean type 2 diabetics. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[4]  E. Opie.  ON THE RELATION OF CHRONIC INTERSTITIAL PANCREATITIS TO THE ISLANDS OF LANGERHANS AND TO DIABETES MELUTUS , 1901, The Journal of experimental medicine.

[5]  R. Turner,et al.  Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[6]  E. T. Bell.  Hyalinization of the Islets of Langerhans in Diabetes Mellitus , 1952, Diabetes.

[7]  C. Bogardus,et al.  Regulation of glycogen synthase and phosphorylase activities by glucose and insulin in human skeletal muscle. , 1987, The Journal of clinical investigation.

[8]  C. Bogardus,et al.  Muscle Glycogen Synthesis and Disposition of Infused Glucose in Humans With Reduced Rates of Insulin-Mediated Carbohydrate Storage , 1988, Diabetes.

[9]  R. DeFronzo,et al.  Regulation of hepatic glucose metabolism in humans. , 1987, Diabetes/metabolism reviews.

[10]  T. Hökfelt,et al.  Calcitonin gene-related peptide and its binding sites in the human central nervous system and pituitary. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[11]  P. Sawchenko,et al.  Release of the predicted calcitonin gene-related peptide from cultured rat trigeminal ganglion cells , 1984, Nature.

[12]  P. Emson,et al.  Effect of calcitonin gene-related peptide on contraction of striated muscle in the mouse , 1985, Neuroscience Letters.

[13]  W. Whelan,et al.  Carbohydrate metabolism and its disorders , 1968 .

[14]  S. Lillioja,et al.  Correlation between muscle glycogen synthase activity and in vivo insulin action in man. , 1984, The Journal of clinical investigation.

[15]  E. Jéquier,et al.  Modifications of Glucose Storage and Oxidation in Nonobese Diabetics, Measured by Continuous Indirect Calorimetry , 1980, Diabetes.

[16]  O. Kolterman.  The impact of sulfonylureas on hepatic glucose metabolism in type II diabetics. , 1987, Diabetes/metabolism reviews.

[17]  E. Ferrannini,et al.  Insulin resistance in essential hypertension. , 1987, The New England journal of medicine.

[18]  B. F. Becker,et al.  Topics and Perspectives in Adenosine Research , 1987, Springer Berlin Heidelberg.

[19]  E. Newsholme,et al.  The Hormone-Modulatory Effects of Adenosine in Skeletal Muscle , 1987 .

[20]  S. Foord,et al.  Characterization of the human calcitonin-gene-related peptide receptor , 1987 .

[21]  E. Newsholme,et al.  Effects of adenosine deaminase on the sensitivity of glucose transport, glycolysis and glycogen synthesis to insulin in muscles of the rat. , 1988, The International journal of biochemistry.

[22]  P. Cohen,et al.  Antagonistic effects of insulin and beta-adrenergic agonists on the activity of protein phosphatase inhibitor-1 in skeletal muscle of the perfused rat hemicorpus. , 1982, The Journal of biological chemistry.