Glucose-induced [Ca2+]i abnormalities in human pancreatic islets -: Important role of overstimulation

被引:62
作者
Björklund, A
Lansner, A
Grill, VE
机构
[1] Karolinska Hosp, Karolinska Inst, Dept Mol Med,Endocrine & Diabet Unit, Endocrine Lab L6B 01, S-17176 Stockholm, Sweden
[2] Royal Inst Technol, Dept Numer Anal & Comp Sci, S-10044 Stockholm, Sweden
[3] Norwegian Univ Sci & Technol, Dept Internal Med, N-7034 Trondheim, Norway
关键词
D O I
10.2337/diabetes.49.11.1840
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Chronic hyperglycemia desensitizes beta -cells to glucose. To further define the mechanisms behind desensitization and the role of overstimulation, we tested human pancreatic islets for the effects of long-term elevated glucose levels on cytoplasmic free Ca2+ concentration ([Ca2+](i)) and its relationship to overstimulation. Islets were cultured for 48 h with 5.5 or 27 mmol/l glucose. Culture with 27 mmol/l glucose obliterated postculture insulin responses to 27 mmol/l glucose. This desensitization was specific for glucose versus arginine, Desensitization was accompanied by three major [Ca2+](i) abnormalities: 1) elevated basal [Ca2+](i),) loss of a glucose-induced rise in [Ca2+](i) and 3) perturbations of oscillatory activity with a decrease in glucose-induced slow oscillations (0.2-0.5 min(-1)). Coculture with 0.3 mmol/l diazoxide was performed to probe the role of overstimulation. Neither glucose nor diazoxide affected islet glucose utilization or oxidation, Coculture with diazoxide and 27 mmol/l glucose significantly (P < 0.05) restored postculture insulin responses to glucose and lowered basal [Ca2+](i) and normalized glucose-induced oscillatory activity. However, diazoxide completely failed to revive an increase in [Ca2+](i) during postculture glucose stimulation. In conclusion, desensitization of glucose-induced insulin secretion in human pancreatic islets is induced in parallel with major glucose-specific [Ca2+](i) abnormalities. Overstimulation is an important but not exclusive factor behind [Ca2+](i) abnormalities.
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页码:1840 / 1848
页数:9
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