title: Potent humanin analog increases glucose-stimulated insulin secretion through enhanced metabolism in the β cell.
abstract: Humanin (HN) is a 24-aa polypeptide that offers protection from Alzheimer's disease and myocardial infarction, increases insulin sensitivity, improves survival of β cells, and delays onset of diabetes. Here we examined the acute effects of HN on insulin secretion and potential mechanisms through which they are mediated. Effects of a potent HN analog, HNGF6A, on glucose-stimulated insulin secretion (GSIS) were assessed in vivo and in isolated pancreatic islets and cultured murine β cell line (βTC3) in vitro. Sprague-Dawley rats (3 mo old) that received HNGF6A required a significantly higher glucose infusion rate and demonstrated higher insulin levels during hyperglycemic clamps compared to saline controls. In vitro, compared to scrambled peptide controls, HNGF6A increased GSIS in isolated islets from both normal and diabetic mice as well as in βTC3 cells. Effects of HNGF6A on GSIS were dose dependent, K-ATP channel independent, and associated with enhanced glucose metabolism. These findings demonstrate that HNGF6A increases GSIS in whole animals, from isolated islets and from cells in culture, which suggests a direct effect on the β cell. The glucose-dependent effects on insulin secretion along with the established effects on insulin action suggest potential for HN and its analogs in the treatment of diabetes.
authors.affiliation: 2Department of Pediatrics, Golding Bldg. 705, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA. radhika.muzumdar@einstein.yu.edu.
authors.forename: Regina
authors.initials: R
authors.lastname: Kuliawat
authors.forename: Laura
authors.initials: L
authors.lastname: Klein
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Gong
authors.forename: Marianna
authors.initials: M
authors.lastname: Nicoletta-Gentile
authors.forename: Anjana
authors.initials: A
authors.lastname: Nemkal
authors.forename: Lingguang
authors.initials: L
authors.lastname: Cui
authors.forename: Claire
authors.initials: C
authors.lastname: Bastie
authors.forename: Kai
authors.initials: K
authors.lastname: Su
authors.forename: Derek
authors.initials: D
authors.lastname: Huffman
authors.forename: Manju
authors.initials: M
authors.lastname: Surana
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.forename: Norman
authors.initials: N
authors.lastname: Fleischer
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D054411:Receptors, Leptin / Q000235:genetics
chemical_list: D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D054086:KATP Channels; D054411:Receptors, Leptin; C427211:humanin; D005947:Glucose
keywords: diabetes; hyperglycemic clamps; pancreatic islets