Correspondence
Islet Transplantation
N Engl J Med 2007; 356:963-965March 1, 2007
- Article
To the Editor:
Shapiro et al. (Sept. 28 issue)1 report that in patients with type 1 diabetes who have refractory hypoglycemia, islet transplantation using the Edmonton protocol most often provides endogenous insulin secretion (basal C-peptide secretion, ≥0.3 ng per milliliter) without insulin independence but that this partial beta-cell function provides protection against severe hypoglycemia. Several aspects of this report warrant comment. First, the authors do not state the frequency of hypoglycemia in the recipients before islet transplantation, nor do they report the frequency of hypoglycemia in control subjects. The actual reduction in the risk of severe hypoglycemia is therefore unclear. Second, beta-cell function was not determined under standardized conditions; thus, the minimum number of islets or beta cells necessary for protection against hypoglycemia cannot be ascertained. Third, in previous studies,2-4 islet transplantation consistently failed to improve glucagon responses to hypoglycemia, even when insulin independence was achieved; furthermore, epinephrine responses either did not improve or improved only moderately. The mechanism for the reported protection against severe hypoglycemia is hence uncertain. Further research is needed before islet transplantation can be considered as a form of therapy, even in highly selected patients with severe hypoglycemia, as suggested by the authors.
4 ReferencesChristian Meyer, M.D.
Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ 85012
christian.meyer@med. va. gov 1
Shapiro AMJ ,Ricordi C ,Hering BJ , et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006;355:1318-1330
Full Text | Web of Science | Medline2
Rickels MR ,Schutta MH ,Mueller R , et al. Islet cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes. Diabetes 2005;54:3205-3211
CrossRef | Web of Science | Medline3
Paty BW ,Ryan EA ,Shapiro AMJ ,Lakey JRT ,Robertson RP . Intrahepatic islet transplantation in type 1 diabetic patients does not restore hypoglycemic hormonal counterregulation or symptom recognition after insulin independence. Diabetes 2002;51:3428-3434
CrossRef | Web of Science | Medline4
Meyer C ,Hering B ,Grosmann R , et al. Improved glucose counterregulation and autonomic symptoms after intraportal islet transplants alone in patients with long-standing type I diabetes mellitus. Transplantation 1998;66:233-240
CrossRef | Web of Science | Medline
To the Editor:
In their report, Shapiro et al. describe the effects of islet transplantation on insulin requirements and refractory hypoglycemia in patients with type 1 diabetes mellitus of long duration. They note that “all subjects with residual islet function were completely protected from severe hypoglycemic episodes” up to 1 year after transplantation. However, they do not offer an explanation or discuss the potential implications of this finding. Information about the duration of improvement in hypoglycemia and the effect of islet-cell transplantation in the patients in whom insulin was not detected is not provided. Considering previously published evidence1 concerning the importance of glucagon in preventing hypoglycemia, as well as the relationship between hypoglycemia associated with type 1 diabetes and the lack of appropriate glucagon responses, one might ask whether, in transplanting whole islets (not just beta cells), transplantation of functional alpha cells leads to an improvement in glucagon secretion and thus prevention of hypoglycemia.
1 ReferencesAlina Vaksman, B.A.
New York University School of Medicine, New York, NY 10016
av610@med.nyu. edu 1
Taborsky GJ Jr ,Ahren B ,Havel PJ . Autonomic mediation of glucagon secretion during hypoglycemia: implications for impaired alpha-cell responses in type 1 diabetes. Diabetes 1998;47:995-1005
CrossRef | Web of Science | Medline
To the Editor:
We are interested in the exact criteria used to decide that recurrent neuroglycopenia and glycemic lability warranted transplantation. Did attempts to correct these problems include the use of insulin pumps and continuous glucose monitoring? Since the decision to start insulin was largely determined by daily glucose levels, how often did patients monitor their glucose after transplantation?
The decline in renal function does not agree with our published results.1 In an ongoing study, we are comparing medical management with islet transplantation with respect to the progression of microvascular complications.2 Our patients all have a history of abnormal microalbumin excretion (median ratio of urinary microalbumin to creatinine at entry, 8.0 mg per millimole; overt proteinuria, 30% of patients). In 18 patients followed for a mean (±SD) of 31±8 months since the initial transplantation, there has been no change in either the glomerular filtration rate (measured with both technetium-99m–labeled diethylenetriamine penta-acetic acid and the Cockcroft–Gault formula) or microalbumin excretion. A possible explanation for the difference is that we routinely use tacrolimus and mycophenolate, rather than the more nephrotoxic3 tacrolimus and sirolimus used by Shapiro et al., for maintenance immunosuppression.
3 ReferencesDavid M. Thompson, M.D.
Michelle A. Fung, M.D.
Garth L. Warnock, M.D.
University of British Columbia, Vancouver, BC V5Z 1M9, Canada
david.thompson@vch. ca 1
Thompson DM ,Fung MA ,Kozak RM , et al. A prospective study comparing islet cell transplantation with intensive medical therapy on renal function in patients with type 1 diabetes. Diabetes 2006;55:Suppl 1:A449-A449
Web of Science2
Warnock GL ,Meloche RM ,Thompson D , et al. Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type 1 diabetes mellitus. Arch Surg 2005;140:735-744
CrossRef | Web of Science | Medline3
Mendez R ,Gonwa T ,Yang HC ,Weinstein S ,Jensik S ,Steinberg SA . A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 1 year. Transplantation 2005;80:303-309
CrossRef | Web of Science | Medline
Author/Editor Response
With regard to the comments of Meyer: 97% of subjects enrolled had reduced awareness of hypoglycemia, 56% had metabolic lability or instability, including two or more episodes of severe hypoglycemia, and 53% had progressive secondary complications. Our trial did not directly compare protection from hypoglycemia in transplant recipients with that in controls. A more detailed single-site study using the hypoglycemic score and the lability index showed that subjects enrolled for islet transplantation had severe lability and a high burden of hypoglycemia, as compared with control subjects with type 1 diabetes, and that islet transplantation rapidly brought these scores close to those of normal control subjects without diabetes.1
Both Meyer and Vaksman correctly note that islet transplantation fails to restore hypoglycemic hormonal counterregulation, and glucagon responses remain suppressed.2 We therefore conclude that the protection from hypoglycemia afforded by islet transplantation is the direct result of restoration of at least some endogenous rapidly regulated insulin release from the transplant. Complete protection from severe hypoglycemic episodes in subjects with residual islet function is, in our opinion, the most important positive finding in the trial. Vaksman also asks about detailed follow-up of subjects with failed islet grafts; Figure 2E of our report shows that the mean amplitude of glycemic excursion (MAGE) returned to baseline in subjects with failed grafts. We acknowledge the more limited follow-up in these subjects.
In response to Thompson et al., the criteria used to determine recurrent neuroglycopenia and the severity of glycemic lability for islet transplantation were based on the frequency of hypoglycemic episodes and the MAGE score. At the inception of our trial, in 1999, insulin pumps, continuous glucose monitoring, the Ryan index,1 and the Clarke score3 were not used routinely to assess subjects for transplantation of islets alone. Subjects monitored their own glucose levels at home with blood samples for analysis drawn three times per week for the first week, weekly for the first month, every other week through 4 months, and monthly for the remainder of the first year.
We also acknowledge the comments regarding the potential risk of nephrotoxicity from the combination of sirolimus and tacrolimus. However, as underscored by the long-term data generated by Ojo et al., all recipients of organ transplants who receive long-term calcineurin-inhibitor therapy are at risk for a decline in renal function and, thus, for the need for dialysis.4 We may conclude, therefore, that the immunosuppressive drugs currently used in islet transplantation are far from ideal.
4 ReferencesA.M. James Shapiro, M.D., Ph.D.
University of Alberta, Edmonton, AB T6G 2C8, Canada
shapiro@islet.ca Camillo Ricordi, M.D.
University of Miami, Miami, FL 33136Bernhard J. Hering, M.D.
University of Minnesota, Minneapolis, MN 554551
Ryan EA ,Shandro T ,Green K , et al. Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes 2004;53:955-962
CrossRef | Web of Science | Medline2
Paty BW ,Ryan EA ,Shapiro AMJ ,Lakey JRT ,Robertson RP . Intrahepatic islet transplantation in type 1 diabetic patients does not restore hypoglycemic hormonal counterregulation or symptom recognition after insulin independence. Diabetes 2002;51:3428-3434
CrossRef | Web of Science | Medline3
Clarke WL ,Cox DJ ,Gonder-Frederick LA ,Julian D ,Schlundt D ,Polonsky W . Reduced awareness of hypoglycemia in adults with IDDM: a prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care 1995;18:517-522
CrossRef | Web of Science | Medline4
Ojo AO ,Held PJ ,Port FK , et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003;349:931-940
Full Text | Web of Science | Medline
