Modulation of Insulin Secretion by Targeting a Novel Pancreatic Hyperpolarization-activated Current Via Pharmacological Intervention and/or Somatic Gene Transfer

An estimated 16 million people in the US alone suffer from diabetes, a disorder of glucose metabolism involving the hormone insulin. Indeed, diabetes is a leading cause of death. Conventional treatments of type-2 diabetes include drugs that improve insulin action and those that enhance insulin secretion. Drugs currently used to enhance insulin secretion target the KATP channel complex; inhibition of this complex stimulates insulin secretion by depolarizing pancreatic ?cells to trigger insulin release, with side effects (e.g. KATP inhibitors mask ischemic electrocardiographic ST elevation, a clinical hallmark of heart attack, of susceptible diabetic patients). Since conventional drugs that enhance insulin action or insulin secretion often fail, periodic injection of insulin is often used as a last resort, which is also associated with its own complications (e.g. hypoglycemia), inconvenience and cost. Therefore, it is highly desirable to be able to modulate or "custom-tailor" the insulin-secreting activities in vivo by targeting proteins other than the KATP channel complex.JHU researchers have discovered a novel hyperpolarization-activated membrane ionic current, encoded by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel gene family, in insulin-secreting pancreatic ?cells. In silico analysis indicates that glucose-induced rhythmic electrical activities of pancreatic ?cells, which underlie their subsequent insulin secretion, could be modulated by manipulating the activity of this gene. This novel pancreatic ionic current, when inhibited by a selective blocker, significantly reduces the secretion of insulin. This pancreatic ionic current could be genetically inhibited by a genetic suppressor or could be augmented by genetic overexpression of HCN channels. Description (Set) Proposed Use (Set) This invention can be easily extrapolated to provide for a potential treatment of diabetes that negates the need of tedious routine insulin injection. This novel method to modulate the insulin secretion level can be achieved by pharmacological intervention and/or by somatic gene transfer of particular classes of ion channels and/or their modulatory subunits

Inventor(s): Li, Ronald A.

Type of Offer: Licensing



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