On the mechanism of impaired insulin secretion in chronic renal failure.
It has been suggested that a sustained rise in resting levels of cytosolic calcium [Ca2+]i of pancreatic islets is responsible for impaired insulin secretion in chronic renal failure (CRF). Evidence for such an event is lacking and the mechanisms through which it may affect insulin secretion are not known. Studies were conducted in normal, CRF, and normocalcemic, parathyroidectomized (PTX) CRF rats to answer these questions. Resting levels of [Ca2+]i of islets from CRF rats were higher (P less than 0.01) than in control of CRF-PTX rats. [3H]2-deoxyglucose uptake and cAMP production by islets were not different in the three groups. Insulin content of, and glucose-induced insulin secretion by islets from CRF rats was lower (P less than 0.01) than in control and CRF-PTX rats. In contrast, glyceraldehyde-induced insulin release by CRF islets was normal. Basal ATP content, both glucose-stimulated ATP content and ATP/ADP ratio, net lactic acid output, Vmax of phosphofructokinase-1, and Ca2+ ATPase of islets from CRF rats were lower (P less than 0.02-less than 0.01) than in normal or CRF-PTX animals. Data show that: (a) Glucose but not glyceraldehyde-induced insulin secretion is impaired in CRF; (b) the impairment in glucose-induced insulin release in CRF is due to a defect in the metabolism of glucose; (c) this latter defect is due to reduced ATP content induced partly by high [Ca2+]i of islets; and (d) the high [Ca2+]i in islets of CRF rats is due to augmented PTH-induced calcium entry into cells and decreased calcium extrusion from the islets secondary to reduced activity of the Ca2+ ATPase.
Fadda
G Z
GZ
Division of Nephrology and Geriatric Medicine, University of Southern California School of Medicine, Los Angeles 90033.
Hajjar
S M
SM
Perna
A F
AF
Zhou
X J
XJ
Lipson
L G
LG
Massry
S G
SG
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002118:Calcium / Q000032:analysis; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000097:blood; D016105:Parathyroidectomy; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains
D007328:Insulin; D010281:Parathyroid Hormone; D015221:Potassium Channels; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium