Cholinergic regulation of fuel-induced hormone secretion and respiration of SUR1-/- mouse islets.
Neural and endocrine factors (i.e., Ach and GLP-1) restore defective glucose-stimulated insulin release in pancreatic islets lacking sulfonylurea type 1 receptors (SUR1(-/-)) (Doliba NM, Qin W, Vatamaniuk MZ, Li C, Zelent D, Najafi H, Buettger CW, Collins HW, Carr RD, Magnuson MA, and Matschinsky FM. Am J Physiol Endocrinol Metab 286: E834-E843, 2004). The goal of the present study was to assess fuel-induced respiration in SUR1(-/-) islets and to correlate it with changes in intracellular Ca(2+), insulin, and glucagon secretion. By use of a method based on O(2) quenching of phosphorescence, the O(2) consumption rate (OCR) of isolated islets was measured online in a perifusion system. Basal insulin release (IR) was 7-10 times higher in SUR1(-/-) compared with control (CON) islets, but the OCR was comparable. The effect of high glucose (16.7 mM) on IR and OCR was markedly reduced in SUR1(-/-) islets compared with CON. Ach (0.5 microM) in the presence of 16.7 mM glucose caused a large burst of IR in CON and SUR1(-/-) islets with minor changes in OCR in both groups of islets. In SUR1(-/-) islets, high glucose failed to inhibit glucagon secretion during stimulation with amino acids or Ach. We conclude that 1) reduced glucose responsiveness of SUR1(-/-) islets may be in part due to impaired energetics, as evidenced by significant decrease in glucose-stimulated OCR; 2) elevated intracellular Ca(2+) levels may contribute to altered insulin and glucagon secretion in SUR1(-/-) islets; and 3) The amplitudes of the changes in OCR during glucose and Ach stimulation do not correlate with IR in normal and SUR1(-/-) islets suggesting that the energy requirements for exocytosis are minor compared with other ATP-consuming reactions.
Doliba
Nicolai M
NM
Dept. of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. nicolai@mail.med.upenn.edu
Qin
Wei
W
Vatamaniuk
Marko Z
MZ
Buettger
Carol W
CW
Collins
Heather W
HW
Magnuson
Mark A
MA
Kaestner
Klaus H
KH
Wilson
David F
DF
Carr
Richard D
RD
Matschinsky
Franz M
FM
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics*; D000109:Acetylcholine / Q000494:pharmacology; D000110:Acetylcholinesterase / Q000235:genetics; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology*; D002799:Cholinergic Fibers / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D051273:Glucose Transporter Type 2 / Q000235:genetics; D005905:Glyburide / Q000494:pharmacology; D006728:Hormones / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051664:Kv1.3 Potassium Channel; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D010101:Oxygen Consumption / Q000187:drug effects; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000109:Acetylcholine; D000110:Acetylcholinesterase; D000596:Amino Acids; D002118:Calcium; D005934:Glucagon; D005947:Glucose; D051273:Glucose Transporter Type 2; D005905:Glyburide; D006728:Hormones; D007328:Insulin; D051664:Kv1.3 Potassium Channel; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577508:Abcc8 protein, mouse; C494838:Kcnab1 protein, mouse; C495682:Slc2a2 protein, mouse