title: Pancreastatin: multiple actions on human intermediary metabolism in vivo, variation in disease, and naturally occurring functional genetic polymorphism.
abstract: BACKGROUND
  The chromogranin A (CHGA) fragment pancreastatin (human CHGA250-301) impairs glucose metabolism, but the role of human pancreastatin in vivo remains unexplored.
  
  
  METHODS
  We studied brachial arterial infusion of pancreastatin (CHGA273-301-amide at approximately 200 nm) on forearm metabolism of glucose, free fatty acids, and amino acids. Plasma pancreastatin was measured in obesity or type 2 diabetes. Systematic discovery of amino acid variation was performed, and the potency of one variant in the active carboxyl terminus (Gly297Ser) was tested.
  
  
  RESULTS
  Pancreastatin decreased glucose uptake by approximately 48-50%; the lack of change in forearm plasma flow indicated a metabolic, rather than hemodynamic, mechanism. A control CHGA peptide (catestatin, CHGA352-372) did not affect glucose. Insulin increased glucose uptake, but pancreastatin did not antagonize this action. Pancreastatin increased spillover of free fatty acids by about 4.5- to 6.4-fold, but not spillover of amino acids. Insulin diminished spillover of both free fatty acids and amino acids, but these actions were not reversed by pancreastatin. Plasma pancreastatin was elevated approximately 3.7-fold in diabetes, but was unchanged during weight loss. Proteolytic cleavage sites for pancreastatin in vivo were documented by matrix-assisted laser desorption ionization/time of flight mass spectrometry. Three pancreastatin variants were discovered: Arg253Trp, Ala256Gly, and Gly297Ser. The Gly297Ser variant had unexpectedly increased potency to inhibit glucose uptake.
  
  
  CONCLUSIONS
  The dysglycemic peptide pancreastatin is specifically and potently active in humans on multiple facets of intermediary metabolism, although it did not antagonize insulin. Pancreastatin is elevated in diabetes, and the variant Gly297Ser had increased potency to inhibit glucose uptake. The importance of human pancreastatin in vivo as well as its natural variants is established.
authors.affiliation: Department of Medicine (9111H), University of California School of Medicine and Veterans Affairs Medical Center, 9500 Gilman Drive, La Jolla, CA 92093-0838, USA. doconnor@ucsd.edu.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
authors.forename: Peter E
authors.initials: PE
authors.lastname: Cadman
authors.forename: Clayton
authors.initials: C
authors.lastname: Smiley
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Joshua
authors.initials: J
authors.lastname: Smith
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Funk
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.forename: Gen
authors.initials: G
authors.lastname: Wen
authors.forename: Laurent
authors.initials: L
authors.lastname: Taupenot
authors.forename: Carmen
authors.initials: C
authors.lastname: Gonzalez-Yanes
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Harper
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.forename: Victor
authors.initials: V
authors.lastname: Sanchez-Margalet
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D001483:Base Sequence; D016022:Case-Control Studies; D053379:Chromogranin A; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005542:Forearm; D014644:Genetic Variation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007270:Injections, Intra-Articular; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009765:Obesity / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000628:therapy; D010187:Pancreatic Hormones / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D011110:Polymorphism, Genetic; D015431:Weight Loss
chemical_list: D000596:Amino Acids; D053379:Chromogranin A; D005230:Fatty Acids, Nonesterified; D010187:Pancreatic Hormones; C050836:pancreastatin; D005947:Glucose