Augmentation of Ca2+-stimulated insulin release by glucose and long-chain fatty acids in rat pancreatic islets: free fatty acids mimic ATP-sensitive K+ channel-independent insulinotropic action of glucose.
Glucose augments Ca2+-stimulated insulin release from the pancreatic beta-cell in an ATP-sensitive K+ channel (K(ATP) channel)-independent manner. In studying the mechanisms underlying this action, we used rat pancreatic islets and examined the effects of exogenous free fatty acids (FFAs), which are precursors of long-chain acyl-CoA (LC-CoA), on KCl-induced Ca2+-stimulated insulin release. Myristate, palmitate, and stearate augmented insulin release induced by 50 mmol/l KCl in the presence of 2.8 mmol/l glucose. Added acutely, their potency was weak compared with that of glucose-induced augmentation. The FFA-induced augmentation became much greater, however, when islets were preincubated with FFAs under stringent Ca2+-free conditions (with 1 mmol/l EGTA) before the KCl stimulation. Under these conditions, 16.7 mmol/l glucose augmented 13-fold insulin release induced by 50 mmol/l KCl, whereas palmitate or myristate (both at a free concentration of 10 micromol/l) produced 5.8- and 5.2-fold augmentations. Effects of FFAs and glucose were concentration-dependent. The temporal profiles of augmentation induced by 11.1 mmol/l glucose and 10 micromol/l palmitate were similar. Glucose and palmitate caused almost identical augmentation patterns for the initial 10 min of stimulation; subsequently, glucose augmentation was better sustained than palmitate augmentation. This suggests the existence of a longer-term glucose-specific signaling moiety that cannot be mimicked by FFAs. Our results provide direct evidence that FFAs can mimic the K(ATP) channel-independent action of glucose. Taking these results together with previous results, we conclude that glucose augments Ca2+-stimulated insulin release, at least in part, by increasing malonyl-CoA and cytosolic LC-CoA. However, one or more other glucose-specific signaling molecules are required for the full expression of augmentation.
Komatsu
M
M
Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, Matsumoto, Japan. mitsu@neco.or.jp
Yajima
H
H
Yamada
S
S
Kaneko
T
T
Sato
Y
Y
Yamauchi
K
K
Hashizume
K
K
Aizawa
T
T
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology; D004338:Drug Combinations; D005110:Extracellular Space / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D019814:Myristic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D004338:Drug Combinations; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D015221:Potassium Channels; D019814:Myristic Acid; D019308:Palmitic Acid; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D005947:Glucose; D003981:Diazoxide; D002118:Calcium