Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets.
Uncoupling protein 2 (UCP2) negatively regulates insulin secretion. UCP2 deficiency (by means of gene knockout) improves obesity- and high glucose-induced beta cell dysfunction and consequently improves type 2 diabetes in mice. In the present study, we have discovered that the small molecule, genipin, rapidly inhibits UCP2-mediated proton leak. In isolated mitochondria, genipin inhibits UCP2-mediated proton leak. In pancreatic islet cells, genipin increases mitochondrial membrane potential, increases ATP levels, closes K(ATP) channels, and stimulates insulin secretion. These actions of genipin occur in a UCP2-dependent manner. Importantly, acute addition of genipin to isolated islets reverses high glucose- and obesity-induced beta cell dysfunction. Thus, genipin and/or chemically modified variants of genipin are useful research tools for studying biological processes thought to be controlled by UCP2. In addition, these agents represent lead compounds that comprise a starting point for the development of therapies aimed at treating beta cell dysfunction.
Zhang
Chen-Yu
CY
Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA.
Parton
Laura E
LE
Ye
Chian Ping
CP
Krauss
Stefan
S
Shen
Ruichao
R
Lin
Cheng-Ting
CT
Porco
John A
JA
Lowell
Bradford B
BB
D000255:Adenosine Triphosphate / Q000378:metabolism; D000447:Aldehydes / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels; D057889:Iridoid Glycosides; D039823:Iridoids; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000187:drug effects* / Q000378:metabolism; D008968:Molecular Conformation; D009765:Obesity / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011522:Protons; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D000071246:Uncoupling Protein 2
C512409:1,10-anhydrogenipin; D000447:Aldehydes; D004365:Drugs, Chinese Herbal; D006575:Heterocyclic Compounds, 3-Ring; D007328:Insulin; D007473:Ion Channels; D057889:Iridoid Glycosides; D039823:Iridoids; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D015221:Potassium Channels; D011522:Protons; D011714:Pyrans; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; C007834:genipin; D005947:Glucose; C027576:4-hydroxy-2-nonenal