Treatment with diazoxide causes prolonged improvement of beta-cell function in rat islets transplanted to a diabetic environment.
Prolonged hyperglycemia desensitizes beta cells. A role for hyperglycemia-induced excessive stimulation can be tested by diazoxide, which inhibits glucose-induced insulin secretion. Using diazoxide, we have investigated in a rat transplantation model whether excessive stimulation can induce lasting effects on beta cells. One batch with 150 islets and another with 20 islets isolated from Wistar-Furth rats were transplanted under the left-kidney capsule of syngeneic streptozotocin-diabetic recipients. In a first series, recipients were treated for 8 weeks with or without 0.2% diazoxide in the food. Graft-bearing kidneys were then perfused and excised. Diazoxide treatment increased by 5.5-fold the insulin response to 10 mmol/L arginine, by 4.1-fold the graft insulin content, and by 2.3-fold the preproinsulin mRNA versus nontreated diabetic controls. The persistence of these effects was assessed in a second series in which 8 weeks of diazoxide treatment was followed by 1 week of no treatment. Again, perfusion experiments showed a higher insulin response to arginine in diazoxide-treated rats (136.0 +/- 25.7 v 62.3 +/- 11.8 fmol/min, P < .05). Also, the response to 27.8 mmol/L glucose was increased (54.0 +/- 17.1 v 13.6 +/- 7.8 fmol/min, P < .05). The insulin content was increased (2.2 +/- 0.6 v 1.0 +/- 0.4 pmol/islet, P < .05), as well as the preproinsulin mRNA (0.60 +/- 0.08 v0.22 +/- 0.02 pg/islet, P < .05). In a third series, we tested the impact of diazoxide treatment when given only during the first 2 weeks following transplantation. When tested 6 weeks later, insulin secretion was unaffected, whereas there was a strong tendency for a higher preproinsulin mRNA and insulin content in grafts of diazoxide-treated rats. In conclusion, this study demonstrates that beta-cell function in transplanted islets is improved by diazoxide long after the end of treatment, an effect that is likely due to removal of hyperglycemia-induced excessive stimulation.
Hiramatsu
S
S
Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
Höög
A
A
Möller
C
C
Grill
V
V
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D003981:Diazoxide / Q000627:therapeutic use*; D005260:Female; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D008297:Male; D011384:Proinsulin / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011920:Rats, Inbred WF; D013311:Streptozocin
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D011498:Protein Precursors; D012333:RNA, Messenger; D013311:Streptozocin; C013737:preproinsulin; D011384:Proinsulin; D003981:Diazoxide