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The MOR-1 Opioid Receptor Regulates Glucose Homeostasis by Modulating Insulin Secretion

Department of Cell Biology and Neuroscience, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854

Address all correspondence and requests for reprints to: Dr. John E. Pintar, Room 359 SPH, 675 Hoes Lane, Piscataway, New Jersey 08854. E-mail: pintar{at}cabm.rutgers.edu.

In addition to producing analgesia, opioids have also been proposed to regulate glucose homeostasis by altering insulin secretion. A considerable controversy exists, however, regarding the contribution of the µ-opioid receptor (MOR-1) to insulin secretion dynamics. We employed congenic C57BL/6J MOR-1 knockout (KO) mice to clarify the role of MOR in glucose homeostasis. We first found that both sexes of MOR-1 KO mice weigh more than wild-type mice throughout postnatal life and that this increase includes preferentially increased fat deposition. We also found that MOR-1 KO mice exhibit enhanced glucose tolerance that results from insulin hypersecretion that reflects increased β-cell mass and increased secretory dynamics in the MOR-1 mutant mice compared with wild type. Analysis of the isolated islets indicated that islet insulin hypersecretion is mediated directly by MOR expressed on islet cells via a mechanism downstream of ATP-sensitive K⁺ channel activation by glucose. These findings indicate that MOR-1 regulates body weight by a mechanism that involves insulin secretion and thus may represent a novel target for new diabetes therapies.

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