Verapamil corrects abnormal metabolism of pancreatic islets and insulin secretion in phosphate depletion.
Phosphate depletion (PD) causes impaired insulin secretion and metabolic derangements in pancreatic islets. We studied PD, pair-weighed (PW), and PD and PW rats treated with verapamil (PD-V and PW-V) to examine the mechanisms of these derangements. Cytosolic calcium ([Ca2+]i) in PD islets was higher than that in PW, PD-V, and PW-V islets, and the values in the latter three groups were not different. Both basal and stimulated ATP in PD islets were lower than those in PW, PW-V, or PD-V islets. The maximum velocity (Vmax) of Ca(2+)-ATPase and the Km and Vmax of Na+,K(+)-ATPase were reduced in PD islets. In both PD-V and PW-V, the Vmax of Ca(2+)-ATPase was higher than that in PD, but lower than that in PW. Both initial and second phases of insulin secretion by PD islets were lower than those by PW and PW-V islets. In PD-V rats, insulin secretion was greater than that in PD rats, but only the second phase was significantly higher. The data are consistent with either of the following possibilities: 1) PD causes a change in the permeability of islets, allowing increased entry of Ca2+ into them and a fall in ATP of islets; the latter would impair the activity of both ATPases, leading to reduced Ca2+ extrusion from islets and, hence, an elevation in their [Ca2+]i; or 2) the primary defect in PD is a reduction in the activities of ATPases of islets due to the fall in ATP secondary to phosphorus deficiency. The decreased Ca2+ extrusion that ensues, even in the face of normal Ca2+ entry, will result in high [Ca2+]i. In either of these scenarios the rise in [Ca2+]i would inhibit mitochondrial oxygen consumption and ATP production, further lowering the ATP content of the islets. The higher [Ca2+]i and low ATP of PD underlie the impaired insulin secretion. Verapamil, by blocking normal or augmented Ca2+ entry into the islets, mitigates or prevents the derangements in islet function and metabolism.
Fadda
G Z
GZ
Division of Nephrology, University of Southern California School of Medicine, Los Angeles 90033.
Hajjar
S M
SM
Zhou
X J
XJ
Massry
S G
SG
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000032:analysis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010710:Phosphates / Q000097:blood / Q000172:deficiency*; D051381:Rats; D011919:Rats, Inbred Strains; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis; D014700:Verapamil / Q000494:pharmacology*
D007328:Insulin; D010710:Phosphates; D000255:Adenosine Triphosphate; D014700:Verapamil; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium