Mechanisms of impaired insulin secretion after chronic excess of parathyroid hormone.
Excess parathyroid hormone (PTH) in presence or absence of chronic renal failure impairs insulin release from pancreatic islets. This abnormality has been attributed to PTH-induced accumulation of Ca in the cytosol of the islets. Direct evidence for the latter phenomenon is lacking. This study examined the effect of chronic administration of PTH to rats with normal renal function on resting cytosolic Ca of the islets and evaluated the mechanisms through which a rise in resting cytosolic Ca may inhibit insulin secretion. After 42 days of PTH administration, glucose-induced insulin secretion was impaired, and this defect was corrected by the use of D-glyceraldehyde as secretagogue for insulin. Resting cytosolic Ca of islets from PTH-treated rats was markedly increased compared with that of islets from normal animals (288 +/- 27.1 vs. 135 +/- 3.7 nM, P less than 0.01), and their content of ATP in the presence of both 2.8 and 16.7 mM D-glucose was reduced (2.8 mM D-glucose, 4.6 +/- 0.17 vs. 6.0 +/- 0.42 pmol/islet, P less than 0.01; and 16.7 mM D-glucose, 6.9 +/- 0.25 vs. 11.1 +/- 0.95 pmol/islet, P less than 0.01). D-Glyceraldehyde increased ATP content in islets of PTH-treated rats from 4.6 +/- 0.17 to 8.8 +/- 0.71 pmol/islet. Glucose uptake by the islets, their insulin content, and both the Vmax and the apparent Km for fructose 6-phosphate of phosphofructokinase 1 (EC 2.7.1.11) in PTH-treated rats were not different from normal. The two major cellular derangements in the islets of PTH-treated rats were a reduction in ATP content and a rise in resting cytosolic Ca.(ABSTRACT TRUNCATED AT 250 WORDS)
Perna
A F
AF
Division of Nephrology, University of Southern California School of Medicine, Los Angeles 90033.
Fadda
G Z
GZ
Zhou
X J
XJ
Massry
S G
SG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010732:Phosphofructokinase-1 / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D007328:Insulin; D010281:Parathyroid Hormone; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D010732:Phosphofructokinase-1; D005947:Glucose