title: Metabolic function of a suboptimal transplanted islet mass in nonhuman primates on rapamycin monotherapy.
abstract: Although islet transplantation may restore insulin independence to individuals with type 1 diabetes mellitus, most have abnormal glucose tolerance. We asked whether the defective glucose tolerance is due to inadequate β-cell mass or to impaired insulin sensitivity. We performed  metabolic studies on four cynomolgus primates before inducing diabetes with streptozotocin (STZ), then again 2-3 weeks after restoring insulin independence via intrahepatic islet transplantation utilizing a calcineurin inhibitor-free immunosuppressive regimen (induction with rabbit  antithymocyte globulin and maintenance therapy with rapamycin). Engrafted β-cell mass was assessed by acute insulin and C-peptide responses to glucose (AIR(glu) and ACR(glu)) and arginine (AIR(arg) and ACR(arg)). Insulin sensitivity (S(I))  was determined in naive and transplanted primates from an intravenous glucose tolerance test using the minimal model. α-Cell function was determined by the acute glucagon response to arginine (AGR(arg)). Glucose tolerance (K(g)) decreased from 4.1 ± 0.5%/min  in naive primates to 1.8 ± 0.3%/min in transplanted primates (p < 0.01). Following transplantation, AIR(glu) was 28.7 ± 13.1 μU/ml compared to 169.9 ± 43.1 μU/ml (p < 0.03) in the naive condition, ACR(glu) was 14.5 ± 6.0  ng/ml compared to 96.5 ± 17.0 ng/ml naive (p < 0.01), AIR(arg) was 29.1 ± 13.1 μU/ml compared to 91.4 ± 28.2 μU/ml naive (p < 0.05), and ACR(arg) was 1.11 ± 0.51 ng/ml compared to 2.79 ± 0.77 ng/ml naive (p  < 0.05). S(I) did not differ from naive to posttransplant states. AGR(arg) was reduced in transplanted primates (349 ± 118 pg/ml) when compared to both naive (827 ± 354 pg/ml) and post-STZ diabetic primates (1020 ± 440 pg/ml) (p < 0.01 for  both comparisons). These data suggest that impaired glucose tolerance observed in islet transplant recipients is secondary to low functional β-cell mass and not to insulin resistance shortly after transplant. Furthermore, improved glycemic control achieved via islet transplantation over  the diabetic state might be attained, in part, via reduced glucagon secretion.
authors.affiliation: Islet and Autoimmunity Branch, NIDDK, NIH, Bethesda, MD, USA. scott.soleimanpour@uphs.upenn.edu
authors.forename: Scott A
authors.initials: SA
authors.lastname: Soleimanpour
authors.forename: Boaz
authors.initials: B
authors.lastname: Hirshberg
authors.forename: David J
authors.initials: DJ
authors.lastname: Bunnell
authors.forename: Anne E
authors.initials: AE
authors.lastname: Sumner
authors.forename: Marilyn
authors.initials: M
authors.lastname: Ader
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Kristina I
authors.initials: KI
authors.lastname: Rother
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rickels
authors.forename: David M
authors.initials: DM
authors.lastname: Harlan
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D005934:Glucagon / Q000378:metabolism; D005951:Glucose Tolerance Test; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008252:Macaca fascicularis; D020123:Sirolimus / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007166:Immunosuppressive Agents; D007328:Insulin; D005934:Glucagon; D001120:Arginine; D020123:Sirolimus
references.citation: Transplantation. 2003 Dec 15;76(11):1623-5
references.pmid: 14702535
references.citation: Cell Transplant. 2009;18(10):1247-59
references.pmid: 20003758
references.citation: Cell Transplant. 2009;18(8):833-45
references.pmid: 19500470
references.citation: Am J Transplant. 2002 Apr;2(4):381-5
references.pmid: 12118862
references.citation: Comput Methods Programs Biomed. 1986 Oct;23(2):113-22
references.pmid: 3640682
references.citation: Diabetes. 1988 Apr;37(4):413-20
references.pmid: 3288530
references.citation: Am J Transplant. 2005 Jun;5(6):1529-36
references.pmid: 15888064
references.citation: Diabetes. 2002 Jul;51(7):2148-57
references.pmid: 12086945
references.citation: JAMA. 2005 Feb 16;293(7):830-5
references.pmid: 15713772
references.citation: Diabetes. 2009 May;58(5):1175-84
references.pmid: 19228810
references.citation: Endocrinology. 2004 Feb;145(2):467-74
references.pmid: 14551233
references.citation: Diabetes. 2001 Feb;50(2):277-82
references.pmid: 11272137
references.citation: PLoS One. 2011 Jan 25;6(1):e16096
references.pmid: 21283589
references.citation: Radiology. 2004 Jan;230(1):163-8
references.pmid: 14695391
references.citation: Ups J Med Sci. 2000;105(2):107-23
references.pmid: 11095108
references.citation: Lipids. 2010 Dec;45(12):1089-100
references.pmid: 21042876
references.citation: J Gerontol A Biol Sci Med Sci. 2004 Oct;59(10):1007-14
references.pmid: 15528768
references.citation: World J Surg. 2001 Apr;25(4):509-15
references.pmid: 11344405
references.citation: Diabetes. 1993 Nov;42(11):1663-72
references.pmid: 8405710
references.citation: Diabetes. 1989 Dec;38(12):1512-27
references.pmid: 2684710
references.citation: Diabetes. 2002 Jul;51(7):2135-40
references.pmid: 12086943
references.citation: Diabetes. 2006 Aug;55(8):2324-32
references.pmid: 16873697
references.citation: Transplantation. 2007 Mar 15;83(5):532-8
references.pmid: 17353769
references.citation: J Clin Invest. 1970 Apr;49(4):837-48
references.pmid: 4986215
references.citation: J Am Soc Nephrol. 2005 Oct;16(10):3128-35
references.pmid: 16107580
references.citation: Diabetes Obes Metab. 2010 Nov;12(11):994-1003
references.pmid: 20880346
references.citation: Diabetes Res Clin Pract. 1985 Oct;1(3):131-7
references.pmid: 3915260
references.citation: Diabetes. 2003 Nov;52(11):2731-9
references.pmid: 14578291
references.citation: Cell Metab. 2009 Apr;9(4):350-61
references.pmid: 19356716
references.citation: Transplantation. 2003 Jul 15;76(1):55-60
references.pmid: 12865786
references.citation: J Clin Endocrinol Metab. 2006 Jun;91(6):2138-44
references.pmid: 16569741
references.citation: J Clin Endocrinol Metab. 2002 Dec;87(12):5424-9
references.pmid: 12466330
references.citation: J Biol Chem. 2010 Dec 17;285(51):40050-9
references.pmid: 20943662
references.citation: N Engl J Med. 1975 May 8;292(19):985-9
references.pmid: 804137