Effects of free fatty acids on beta-cell functions: a possible involvement of peroxisome proliferator-activated receptors alpha or pancreatic/duodenal homeobox.
It is well known that acute administration of fatty acids enhances insulin release from beta cells, although chronic exposure to fatty acids inhibits insulin release (lipotoxicity). The mechanism for these reciprocal effects of fatty acids on insulin release remains to be elucidated. The present study was performed to investigate the effects of fatty acids on gene expression related to glucose metabolism or insulin biosynthesis. In islets cultured with palmitate for 8 hours, glucose-induced insulin release was enhanced together with increment of pyruvate carboxylase (PC) mRNA or peroxisome proliferator-activated receptors (PPAR)alpha. In contrast, by extending the culture period up to 48 hours, glucose-induced insulin release or islet insulin content was significantly impaired by the coexistence of palmitate. Concomitantly, PC, PPARalpha, GLUT-2, glucokinase (GK), preproinsulin, or pancreatic/duodenal homeobox-1 (PDX-1) mRNA were significantly suppressed in those islets cultured for 48 hours with palmitate. These data may imply that during short-term culture period palmitate promotes PPARalpha gene expression, which enhances PC mRNA expression leading to the enhancement of insulin release, whereas during long-term culture period, palmitate rather inhibits PPARalpha mRNA, which reduces PC mRNA expression. Furthermore, palmitate reduces GLUT-2, GK, or preproinsulin mRNA expression probably through the inhibition of PDX-1 mRNA.
Yoshikawa
H
H
Department of Medicine and Bioregulatory Science, Graduated School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Tajiri
Y
Y
Sako
Y
Y
Hashimoto
T
T
Umeda
F
F
Nawata
H
H
D000818:Animals; D002478:Cells, Cultured; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005941:Glucokinase / Q000235:genetics; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000503:physiopathology; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D019308:Palmitic Acid / Q000494:pharmacology; D011384:Proinsulin / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D005230:Fatty Acids, Nonesterified; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D019308:Palmitic Acid; C013737:preproinsulin; D011384:Proinsulin; D005941:Glucokinase; D005947:Glucose