Murase, N

Starzl, TE

Tai, J

Tzakis, A

Tze, WJ

PubMed

Name not available

Effect of FK 506 on glucose metabolism and insulin secretion in normal rats

D-Scholarship@Pitt

11\ ' .1 I I ' : 11 ' , ii' , 1i I: j 'j !I " i! I .1 . '"j. "j ,;1 , .' :: I EFFECTS ON PANCREATIC FUNCTION Effect of FK 506 on Glucose Metabolism and Insulin Secretion in Normal Rats W.J. Tze, J. Tai, N. Murase, A. Tzakis, and T.E. Starzl FK 506 is a powerful immunosuppressant currently being investigated in clinical transplantation. I In vivo administration of this drug resulted in the prolongation of skin, liver, kidney, and heart allografts in large and small animal models.2•3 The immunosuppressive effect has also been shown recently to be effective in the prevention of development of diabetes in BB rats.4 In baboons. treat-ment with FK 506 to prolong kidney allograft survival resulted in hyperglycemia in recipient animals.5 In vitro. it has been demonstrated that FK 506 does not affect insulin secretion from rat and human islets.6•7 Such observations suggest that the affect of FK 506 on pancreatic islet cells needs closer examination. The present study was under-taken to assess the in vivo effects of FK 506 treatment on glucose metabolism and insulin secretion by the ~ cells in normal rats. MATERIALS AND METHODS Inbred male ACI rats (Harlan Sprague Dawley Inc. Indianapolis. Ind) weighing 200 to 300 g were used for all experiments. The animals were provided with rat chow and water ad libitum. Injectable form of FK S06 (Fujisawa Pharmaceutical Co, Tokyo, Japan) was prepared daily in saline and given intramuscularly (1M) at I mglkg per day for 14 consecutive days in ACI rats. The control animals received saline 1M. A standard intravenous (IV) glucose tolerance test (IVGTI I g1kg body weight of 2S% dextrose) was performed in overnight fasted animals prior to, at I week during, and immediately after the 2-week course of FK S06 treatment and following discontin-uation of FK S06 injections at 2, 4, and 8 weeks. Blood was taken at 0; I, 3, S, 10, IS, 30, 4S, 60, 90, and 120 minutes for blood glucose (Beckman Glucose Analyzer, Beckman Instruments) and insulin (Pharmacia RIA Kit, Montreal) determination. In addition, an oral glucose tolerance test (OGTI, 2 gIkg body weight of 20% dextrose) was also performed I day after the IVGTI in some animals. Blood was taken at 0, IS, 30, 60, 90, and 120 minutes for glucose determination. Rat insulin standard was a generous gift from E. Lilly Co, Indianapolis, Ind. Data were analyzed statistically by Student's t test with the level of significance set at P < .OS. RESULTS Fig 1 shows that the glucose tolerance curve in normal ACI rats became abnormal after 1 week of FK 506 injections, and worsened after the second week of injections. Fig 2 shows that there was improvement in glucose 700 600 .... 'a , 500 a E • • 400 0 u .li! 300 CI 'a 0 200 .2 III 100 0 -20 0 20 40 80 80 100 120 140 Mlnut •• Fig 1. Effect of the duration of FK 506 treatment (1 mg/kg per day 1M) on glucose tolerance curves following IVGTT (1 g/kg body weight) in ovemight-fasted ACI rats (l\-l\ before treatment, n = 14, mean :t: SEM; V-V 1 week, n = 8; and 0-0 2 weeks, n = 14 of FK 506). tolerance by 2 weeks after the stoppage of FK 506 injec-tions and a near normal curve was obtained after 1 montr Four groups of rats were tested showing insignifica~I variation in results among the groups. The overall resui[ would indicate that it required approximately I month for normalization of the glucose tolerance curve following discontinuation of the medication. Fig 3 shows the oorr glucose curves in ACI rats treated with 1 mglkg per day for 2 weeks. The glucose tolerance curve was abnormal following FK 506 treatment in these animals, and it worsened after 2 weeks of discon-tinuation of medication. However. a normal glucose curve returned 4 weeks after stoppage of FK 506 treatment. From the Department of Pediatrics and Pathology, University of British Columbia, Vancouver, British Columbia, Canada; and the Depilrtment of Surgery, University of Pittsburgh, Pittsburgh, Penn-sylvania. Address reprint requesIS to Wah Jun Tze, MD, FRCPC, Profes-sor of Pediatrics, University of ee, ee's Children's Hospital, 4480 Oak St, Room 1 Me, Vancouver, ee, Canada V6H 3V4. © 1991 by Appleton & Lange 0041-13451911$3.001+0 3158 Transplantation Proceedings, Vol 23, No 6 (December), 1991: pp 3158-3160 EFFECT OF FK 506 ON GLUCOSE METABOLISM 600 500 '6 " ~ 400 II • 0 () a § .. • II) 300 200 100 0 -20 0 20 40 60 80 100 120 140 Minute. Fig 2. Effect of FK 506 treatment (1 mg/kg per day 1M for 2 weeks) on glucose tolerance curves following IVGTT (1 g/kg BW) in overnight-fasted ACI rats (0-0 before treatment, n = 35, mean::!: SEM; t:"-t:,, 2 weeks of FK 506, n = 33; V-V 2 weeks, n = 14; and <J-<J 4 weeks, n == 16, after discontinuation of FK 506). Fig 4 summarizes the effect of 2 weeks of FK 506 treatment at 1 mg/kg per day on the insulin profiles in ACI rats following IVOn. Before FK 506 treatment, two insulin peaks were observed. The initial peak at 1 minute was significantly higher than the second peak at 15 minutes and then the insulin levels gradually declined to above basal level at 2 hours. After the 2-week course of FK 506 treatment, the first insulin peak in response to IVOn was similar to the controls, while the second peak disappeared. Complete normalization of insulin profile was observed when the animals were retested 8 weeks after discontinu-ation of FK 506 treatment. 400 '6 300 " IJ> E II • 0 200 () a E :J C 100 II) o L-__ ~ __ L-__ L-__ ~ __ ~ __ ~ __ ~~ -20 0 20 40 60 80 100 120 140 Minute. Fig 3. Effect of FK 506 treatment (1 mg/kg per day 1M for 2 weeks) on glucose tolerance curves following OGTT (2 g/kg body weight) in overnight-fasted ACI rats (0-0 normal controls, n = 24, mean ::!: SEM; t:"-t:,, 2 weeks of FK 506, n == 8; V-V 2 weeks; and <J-<J 4 weeks after discontinuation of FK 506). 3159 100 80 ~ " ::l ::II .5 60 'S • .5 40 E 2 • II) 20 o L-__ ~~~~ __ ~ __ ~ __ ~ __ ~ __ ~ -20 0 20 40 60 80 100 120 140 Minute. Fig 4. Effect of FK 506 treatment (1 mg/kg per day for 2 weeks) on insulin profiles following IVGTT (1 g/kg body weight) in over-night-fasted ACI rats (0-0 before treatment, n == 10, mean ::!: SEM; t:"-t:,, 2 weeks of FK 506, n == 9; V-V 4 weeks; n == 13; and <1-<18 weeks, n == 8, after discontinuation of FK 506). DISCUSSION FK 506 is a powerful immunosuppressant which has been used in a clinical trial in organ transplantation, and also found to be effective in the prevention of the development of diabetes in BB rats. 1.4 The biological activities of this drug are similar to CyA, and CyA at high doses is known to affect the glucose metabolism of recipients. 8 It was previously reported that rats on oral form of FK 506 between I and 4 mg/kg per day for 34 days tend to have high blood glucose levels but no detailed study was con-ducted.9 This observed side effect would be more impor-tant when FK 506 is used as immunosuppressant in the treatment of newly diagnosed type I diabetics and as a antirejection agent in islet cell transplantation. We pres-ently observed that FK 506 treatment at I mg/kg per day for 2 weeks did not significantly affect the basal glucose and insulin levels in the treated ACI rats. However, this treatment with FK 506 altered their glucose tolerance. The derangement of glucose metabolism in the rats treated with FK 506 was not permanent. Glucose profiles following IVOn were nearly normalized by about 4 weeks after stoppage of the agent, and return to normality was ob-served when the animals were retested by 8 weeks. The normalization of BG profile preceded that of insulin profile by 2 to 4 weeks. The mechanism underlying the effect of FK 506 on glucose metabolism remains to be determined. The insulin profiles following IVGn in the treated rats would support the view that the effect was most likely due to decreased insulin release from {3 cells. This study confirmed that FK 506, at high doses, can affect glucose metabolism in rats in vivo. This would support the in vitro observation that FK 506 affected islet insulin synthesis and response to glucose challenge in vitro at a high concentration.6 The FK 506 treatment regimen is currently being used in our laboratory for islet allotrans-3160 plantation studies. It was found to be effective in the prolongation of allografts across a major histocompatibility bamer. The present duta showed that FK 506 given 1M at 1 mglkg per day for up to 2 weeks can cause temporary deterioration of the glucose metabolism in the recipients. This effect on carbohydrate metabolism is reversible and will not limit the value of FK 506 in transplantation. REFERENCES I. StanI TE, Todo S, Fung J, et al: Lancet ii:IOOO. 1989 2. Thomson A W: Immunol Today 10:6. 1989 TZE, TAl. MURASE ET Al 3. Murase N. Kim DG. Todo S. et al: Transplant Proc 22(suppl 1):74. 1990 4. Murase N. Lieberman 1. Na1esnik MA. et al: Diabetes 39:1584.1990 5. Thiru S. Collier DSTJ. Caine R: Transplant Proc 19(suppl 6):98. 1987 6. Tze WI. Tai I. Cheung S: Transplantation 49:1172. 1990 7. Leonard DK. Landry AS. Sollinger HW. et al: Diabetes 38(suppl I): 172. 1989 8. Teraoka S. Kawai T. Yamaguchi Y. et a1: Transplant Proc 21:2774. 1989 9. Nalesnik MA. Todo S. Murase N. et al: Transplant Proc 19(suppl 6):89. 1987 10. Murase N. Todo S. Lee P-H. et al: Transplant Proc 19(suppl 6):71. 1987 

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Effect of FK 506 on glucose metabolism and insulin secretion in normal rats

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