Patient and family expectations of beta-cell replacement therapies in type 1 diabetes

ABSTRACT

Background: New methods of beta-cell replacement have been developed to maintain excellent glycemic control, improve quality of life, and even eliminate insulin injections in patients with type 1 diabetes mellitus (T1DM). Previously, we demonstrated that being insulin-free is the strongest motivation for accepting a newly developed therapy. Multiple allogeneic islet transplantations with immunosuppression using a human donor is the best option to be insulin-free, but the necessity for immunosuppression and donor shortage are major issues. However, these issues have been improved with scientific progress. The aim of this study was to investigate the opinions of patients and their families about the current progress. Methods: We conducted a questionnaire survey of T1DM patients (n = 47) and their family members (n = 49) about newly developed therapies: single and multiple allogeneic islet transplantation, single and multiple encapsulated allogeneic islet transplantation, single and multiple xenogeneic islet transplantation, and induced pluripotent stem cell therapy. Results: More than 90% of respondents wished to be insulin-free and have stable glycemic control. More than 90% of respondents accepted at least one of the new therapies. The current standard treatment multiple allogeneic islet transplantation was not well accepted or favored. Conclusions: The next generation of treatments, including xenotransplantation and induced pluripotent stem cell therapy, were more acceptable and favorable. Even though the majority of patients wish to become insulin-free, it is not sufficiently strong motivation for accepting newly developed treatments.

Introduction

Type 1 diabetes (T1DM) patients with great difficulty in achieving stable glycemic control using conventional insulin replacement therapy are constantly menaced by disabling hypoglycemia and life-threatening complications derived from chronic hyperglycemia. To resolve these problems, allogeneic islet transplantation (AIT) has been developed since the 1970s and has become a standard therapy for T1DM patients with labile glycemic metabolism.^1,2 While AIT appears to be a promising therapeutic option, there are still major limitations to its widespread use, including severe donor shortage, subsequent long waiting period, low rate of achieving insulin-free status, and ineluctability of the use of immunosuppressive agents.

To overcome these problems, various newly developed beta-cell replacement therapies have become clinically available. Encapsulated allogeneic islet transplantation (Encapsulated AIT), that is, AIT using an immunoisolating membrane or hydrogel to encapsulate islet cells in order to prevent immunorejection, can eliminate the use of immunosuppressant agents. Xenogeneic islet transplantation (XIT), which is bio-artificial islet transplantation using animal islets, in particular, encapsulated porcine islets in this survey, could resolve both the shortage of donors and the need for immunosuppression. Regenerative therapy using embryonic stem cells and induced pluripotent stem (iPS) cells is also expected to be applicable in this field. The transplantation of human iPS-derived islet-like cells (IPS) might also overcome both donor shortage and the necessity for immunosuppression. Of note, since T1DM is an autoimmune disease, the general concept that iPS cells from own cells do not need immunosuppression is not applicable for T1DM. Moreover, each therapy is comprised of two approaches: single transplantation and multiple transplantation. In single transplantation, infusion is conducted only once from a single donor; the latest outcomes show a low rate of achieving insulin-independence, but newly developed protocols have improved this rate.³ In contrast, the multiple transplantation approach, that is, multiple allogeneic islet transplantation (multiple AIT), multiple encapsulated allogeneic islet transplantation (multiple encapsulated AIT) and multiple xenogeneic islet transplantation (multiple XIT), can provide a sufficient number of islets and can be a reliable plan to achieve insulin-independence. Among these new therapies, AIT, encapsulated AIT, and XIT have been applied in the clinical setting, whereas IPS remains at the basic research stage.⁴

It is important that these new therapies meet the desires and aims of patients. Patients’ quality of life is a fundamental endpoint of successful treatment. To provide an optimal therapy to improve quality of life, we should understand how patients feel about the advantages and disadvantages of new therapies, what they are hoping for, and what they are worried about.

Previously, we conducted a questionnaire survey to investigate the opinions of T1DM patients and their family members about newly developed therapies. We reported that achieving an insulin-free status was a more important motivator than avoiding hypoglycemia for patients to accept newly developed therapies,⁵ while the major goal of the currently available beta-cell replacement therapies is to eliminate the occurrence of severe hypoglycemia.^6,7 This previous survey revealed discrepancies between the patients’ demands and therapeutic intention. Conversely, with the current progress of research into therapies for T1DM patients, achieving insulin-free status with multiple AIT has become more likely, encapsulation technology has eliminated the fear of the side effects of immunosuppression, and IPS and XIT could alleviate donor shortage issues.

In the present study, we sought to elucidate the differences in the acceptance of patients and their families of each beta-cell replacement therapy and to clarify the characteristics of those who accept them under the current state of scientific progress.

Results

We conducted questionnaire survey of T1DM patients and their family members to investigate their opinions about AIT and multiple AIT, encapsulated AIT and multiple encapsulated AIT, XIT and multiple XIT, and IPS. Ninety-six questionnaires were collected, 47 from patients and 49 from family members. The basic characteristics of the respondents are shown in Table 1. The patients’ data include the answers from family members. Some incomplete answers and missing values were excluded from the analysis of each question.

Table 1.

Characteristics of the participants.

Standpoint	Total (n = 96)
Patient	47
Family	49
Age of patient, years† (range)	34.8 ± 20.2 (17–69)
Age of family member, years† (range)	45.8 ± 10.9 (24–75)
Gender of patient
Male	25 (26.0%)
Female	63 (65.6%)
Onset age, years† (range)	26.5 ± 18.0 (2–69)
Disease duration, years† (range)	9.1 ± 13.4 (0–49)

†Data are the mean ± SD.

Approximately 90% of the respondents wished to be insulin-free and have more stable glycemic control. In particular, 72.9% of family members strongly wished that the patients would be insulin-free, which was higher than for the patients (44.7%) (Table 2).

Table 2.

Results of questionnaire items.

	Total	Patient	Family	P-value (Patient: Family)
My/The patient’s present glycemic control is stable	56 (58.3%)	27 (57.4%)	29 (59.1%)	0.528
I feel fear of hypoglycemia/The patient feels fear of hypoglycemia	78 (81.2%)	37 (78.7%)	41 (83.6%)	0.590
I wish to be insulin-free/I wish the patient to be insulin-free†	88 (91.6%)	41 (87.2%)	47 (95.9%)	0.059
I strongly wish to be insulin-free/I strongly wish the patient to be insulin-free‡	56 (58.9%)	21 (44.7%)	35 (72.9%)	0.006
I want my glycemic control to be more stable/I want the patient’s glycemic control to be more stable†	91 (94.8%)	44 (93.6%)	47 (95.9%)	1.000
I strongly want my glycemic control to be more stable/I strongly want the patient’s glycemic control to be more stable‡	66 (68.7%)	29 (61.7%)	37 (75.5%)	0.253

†Classified into the wish group (strongly wish/agree, wish/agree) and no wish group (do not wish/agree strongly do not wish/strongly do not agree)

‡Classified into the strongly wish group (strongly wish) and group of others (wish, do not wish, strongly do not wish)

More than 90% of the respondents accepted at least one or more of the new therapies. Family members were more favorable of the new therapies than the patients and there were significant differences for AIT, encapsulated AIT, multiple encapsulated AIT, XIT, and multiple XIT between the family members and patients (Figure 1).

Figure 1.

Comparison between patients and family members about acceptance of new therapies. AIT, allogeneic islet transplantation; XIT, xenogeneic islet transplantation; IPS, induced pluripotent stem cell therapy. *P < 0.05.

Approximately 80% of the patients had a fear of hypoglycemia, and 36.7% of them accepted AIT; however, none of the patients who did not fear hypoglycemia accepted AIT (Figure 2(a)).

Figure 2.

Comparison between patients with and without (A) fear of hypoglycemia. (B) strong wish to be insulin-free. (C) stable glycemic control. (D) strong wish to have more stable glycemic control. AIT, allogeneic islet transplantation; XIT, xenogeneic islet transplantation; IPS, induced pluripotent stem cell therapy. *P < 0.05.

The patients’ opinions about their wish to be insulin-free, the stability of their present glycemic control (Figure 2(b)), and wish for more stable glycemic control did not have a significant influence on their acceptance of any of the new therapies.

Regarding the wish for insulin-free status and more stable glycemic control, the sample size of the no wish group was too small to perform any meaningful analysis. In order to identify specific differences influenced by the patients’ opinions, we also classified them into the following two groups: strongly wish group (strongly wish) and group of others (wish, do not wish, and strongly do not wish). Then, as for the question regarding the wish to be insulin-free, only 35.7% of the patients in the strongly wish group accepted multiple AIT, which is the only treatment expected to provide an insulin-free status (Figure 2(c)). Conversely, the strongly wish group for more stable glycemic control showed a higher acceptance rate of all new therapies than those who did not wish for more stable glycemic control, with a statistically significant difference between these groups for encapsulated AIT and multiple encapsulated AIT (Figure 2(d)).

In terms of the most favorable treatment, both the patients and their family members preferred to receive IPS, followed by XIT and multiple XIT (Figure 3). Forty-two percent of the respondents selected either XIT (24%) or multiple XIT (18%) and 35% selected IPS; in contrast, only 1% selected multiple AIT. The acceptance rates of IPS, XIT, and multiple XIT were not positively influenced by any factor such as fear of hypoglycemia, wish for insulin-free status, or present and future glycemic stability.

Figure 3.

Most favorable therapy for all respondents, patients and family members. AIT, allogeneic islet transplantation; XIT, xenogeneic islet transplantation; IPS, induced pluripotent stem cell therapy. *P < 0.05.

Table 3 shows the anxieties related to transplantation. The patients were worried about the expense of hospitalization and expenditure on medicines; in contrast, the family members were more concerned about the complications associated with transplantation and the adverse effects of using immunosuppressants rather than cost.

Table 3.

Main obstacle to transplantation (multiple answers allowed).

	Total (n = 178)	Patient (n = 81)	Family (n = 97)	P-value (Patient: Family)
Complication of transplantation	51 (28.7%)	19 (23.5%)	32 (33.0%)	0.037
Hospitalization expense	31 (17.4%)	19 (23.5%)	12 (12.4%)	0.081
Long waiting period	13 (7.3%)	4 (4.9%)	9 (9.3%)	0.238
Adverse effects of immunosuppressants	42 (23.6%)	15 (18.5%)	27 (27.8%)	0.039
Cost of immunosuppressants	27 (15.2%)	16 (19.8%)	11 (11.3%)	0.178
Others	14 (7.9%)	8 (9.9%)	6 (6.2%)	0.566

The age and gender of the respondents, onset age, and disease duration had no influence on their acceptance of the new therapies.

Discussion

The pathogenesis of T1DM involves a complex autoimmune reaction leading to the complete destruction of the function of beta-cells in the pancreas; therefore, it requires the life-long replacement of insulin. The newly developed beta-cell replacement therapies focused on in the present study could be applied to unstable T1DM patients with severe hypoglycemia and hyperglycemia while maintaining insulin therapy. Our previous report showed that most T1DM patients were reluctant to continue insulin therapy, and other surveys revealed psychological resistance to insulin therapy in diabetic patients.^5,8–10 Conversely, severe hypoglycemia is a common complication of intensive insulin therapy. The occurrence of severe hypoglycemia in T1DM reportedly ranges from 1.4 to 1.7 episodes per patient per year, and hypoglycemia and fear of hypoglycemia adversely affect patients’ health, quality of life, and adherence to therapy.^11–13 Their desire for insulin-free status and concern about the instability of their glycemic control, including hypoglycemia, could influence their acceptance of new therapies. Therefore, we assessed these items as parameters in the present survey.

The family members were more eager for the patients to achieve insulin-free status than the patients themselves and they were more inclined to accept newly developed therapies than the patients. To explain this difference in attitudes between the patients and their family members, it is worth noting that the family members were solicitous about the patient’s health and considered the benefits of the new therapies positively. Interestingly, the family members were worried about the adverse physical effects associated with transplantation; in contrast, the patients were worried about the cost of therapy.

AIT was considered to be a promising therapeutic option for unstable T1DM and has been administered to hundreds of patients. However, some long-term outcome surveys revealed a low rate of achieving insulin-free status with this approach.^6,7,14 Approximately 90% of AIT recipients achieved insulin-independence after one or more islet infusions under the Edmonton protocol, but only 10% remained insulin-independent after 5 years. However, more than 80% of recipients were able to maintain fair glycemic control and be free from severe hypoglycemia⁶; therefore, the avoidance of hypoglycemia has been considered as an appropriate aim for AIT. In addition, a recent survey reported that an improved method of clinical islet isolation and a new protocol for immunosuppressive therapy resulted in an increase in the rate of achieving insulin-free status.¹⁴ Therefore, multiple AIT is the best and only practical option for patients to be insulin-free, and multiple AIT is regarded as the standard method for beta-cell replacement in the clinical setting at the present time.

However, our survey showed that patients who strongly wished to achieve an insulin-free status had a low acceptance rate of multiple AIT and AIT. AIT involves a long waiting period and has problems related to immunosuppression, both of which are considered negative points. Such disadvantages of AIT have been discussed as much as the advantages of this approach. Besides, next-generation treatments, including XIT and IPS, have become a real possibility thanks to progress in research; accordingly, patients’ intentions also appear to be changing. These might be the reasons why AIT and multiple AIT did not appeal to those patients with a strong wish for insulin-free status, as well as why the acceptance rate of AIT was the lowest among all of the new therapies. From this result, the wish to be insulin-free was not considered sufficiently strong motivation to receive AIT and multiple AIT.

Conversely, it is meaningful that more than 30% of patients with a fear of hypoglycemia accepted AIT, whereas none of the patients without a fear of hypoglycemia accepted it. On the basis of the long-term outcome of AIT, feeling anxious about impending hypoglycemia seems an appropriate indication.

Encapsulated AIT uses an immunoisolating membrane or hydrogel to encapsulate islet cells in order to prevent immunorejection without the need for immunosuppression. Encapsulated AIT was performed clinically on a small number of T1DM patients, but it did not provide insulin-free status; however, blood glucose levels were stabilized, resulting in a reduction in the requirement for exogenous insulin and normalization of HbA1c.^15–17 A greater number of islet donors are required to achieve permanent independence from exogenous insulin because the current encapsulation technology causes a deterioration of graft function and viability due to inflammation and ischemic changes.¹⁸ Encapsulated AIT is different from AIT in that immunosuppression is not required, which is probably why more patients accepted encapsulated AIT than AIT. The acceptance rates of encapsulated AIT and multiple encapsulated AIT were significantly higher in patients who strongly wished for more stable glycemic control than in those who did not. The most common reason for that is encapsulated AIT would provide stable glycemic control without immunosuppression, even though it is still difficult to achieve insulin-free status.

XIT is islet transplantation from other animals, commonly pigs, to humans. XIT would resolve many of the difficulties associated with AIT, including immediate availability and unlimited supply of islets. However, xenografts are associated with immunological rejection and potential risk of the transmission of viral infections. Accordingly, research and clinical applications using islets derived from designated pathogen-free pigs with an immunoisolating membrane or hydrogel have proceeded to minimize the infection risk and prevent immunological rejection. Some clinical trials have already been conducted to assess the effect and safety of clinical pig XIT.^19,20 These trials indicated a certain effect, such as the reduction of unaware hypoglycemia events in unstable T1DM patients; in addition, no transmission of retroviruses and microorganisms was reported. Conversely, because the current encapsulation technology may deteriorate islet function, the main endpoint of achieving insulin-free status has not yet been reached. In this survey, XIT was well accepted and was the second choice option after IPS. Patients reportedly prefer to receive a new organ from a donor of the same species, especially under circumstances in which a human organ was supposed to be unavailable.^21,22 Accurate information about xenotransplantation could help patients to accept these treatments. In our present survey, the advantages of XIT, such as its greater availability, might have appealed to the respondents.

Of all the new therapies we focused on, IPS showed the highest acceptance rate in both patients and family members. Taking account of the fact that of the new therapies examined, only IPS has not been applied in the clinical setting,^4,23,24 some of the risks and disadvantages of this approach have not become apparent. Further clinical development of IPS is expected and it will probably reveal unfavorable issues as well as benefits. There are concerns about the enormous cost of creating beta-cells from patients’ own cells; hence iPS derived islets would be allogeneic which needs immune isolation or immunosuppressive therapy. Moreover, we need to generate more information about the safety of IPS.

The acceptance rates of IPS, XIT, and multiple XIT were not influenced by any factor such as fear of hypoglycemia, wish for insulin-free status, or current and future glycemic stability. A wide range of respondents could accept these treatments regardless of their profile, because the advantages of these treatments such as short waiting time and schedulable surgery could be appealing points for the majority of respondents.

The acceptance rates of multiple transplantations for AIT, encapsulated AIT, and XIT were lower than those for single transplantation, even though multiple injections are more effective for beta-cell replacement therapy because larger amounts of islets can be transplanted, which increases the possibility of achieving insulin-free status. Many patients may place a high importance on the physical and economic burden caused by repetitive treatments.

In the present study, we identified two different intentions: most of the patients wanted to be insulin-free and many patients did not want to receive multiple transplantations. Considering the latest outcomes, it has been difficult to combine perfectly both the achievement of insulin-free status and a single transplantation. To know their wishes on this point will indicate which method should be developed as a priority, that is, either to pursue glycemic stability by a single transplantation or to set a goal to be insulin-free by multiple transplantations. Patients should be asked which point they give priority to in a future study. Besides, continuous efforts to improve the efficacy of clinical islet transplantation are being made; an improved protocol for single transplantation AIT demonstrated a satisfactory effect equivalent to that of multiple transplantations.³

This survey has some limitations. The respondents’ preferences were inevitably influenced by the contents of the lectures because they answered the questionnaires immediately after listening to them. We did not include embryonic stem (ES) cell derived beta cell in this survey, since we were not able to find a scientist who aims clinical trial of ES cell derived beta cell replacement therapy in Japan. However, since ES cell derived beta cell replacement therapy is already in a clinical stage and less concern about carcinogenesis compared with IPS cells, we speculated ES cell derived beta cell replacement therapy should be accepted by many patients.

Additionally, the respondents attended the symposium by their own free will, so it can be presumed they were interested in newly developed therapies and might be more inclined to accept new therapies than the general T1DM population; furthermore, their intellectual level might also be different from that of the general patient population. In addition, the participants were not selected randomly because choosing random patients is difficult in a practical setting. Nevertheless, this type of survey can provide meaningful information for researchers and healthcare providers, because only a few reports have investigated the perspectives of T1DM patients and their family members toward newly developed therapies. In particular, only a few studies have asked their opinions directly, and such studies are needed because patients themselves must assess their satisfaction with the treatment. It is difficult to make a reproducible and unbiased opinion survey assessing the point of view of patients and their family members, but we think that the present study is the best type of investigation that it is possible to conduct. In addition, considering prior studies,^5,9 more than 50% of patients in all studies answered that they would accept novel treatments such as xenotransplantation, so the outcome is likely to be reproducible.

In this questionnaire, we adopted a subjective assessment method for the respondents because we thought each patient had their own way to judge their condition and they should be responsible for setting each goal. In our previous survey we examined detailed information about hypoglycemia and pointed out that the experience of a hypoglycemic coma could increase the acceptance of new therapies.⁵ Thus, objective glycemic control needs to be examined so we can understand the influence of the quality of glycemic control on patients’ willingness to accept new therapies. On the basis of these points, further research should focus on the relationship between the acceptance of new therapies and respondents’ education level, occupation, and objective indicators of glycemic control such as HbA1c.

As the technology underlying these new therapies will improve further over time, which could increase their efficacy and use in the clinical setting, as well as revealing their disadvantages, it is crucial to investigate updated patients’ perspectives toward these new therapies in order to know what therapies they truly desire, and reflect their opinions effectively in the development of new therapies.

In conclusion, our survey indicated that the current standard cell transplantation therapy for T1DM, that is, multiple AIT, is no longer well accepted or favored by more than half patients or their family members. The next generation of treatments including XIT and IPS are more acceptable and favorable. Although the majority of patients wish to be insulin-free, this is no longer a sufficiently strong motivation to accept the newly developed treatments. There is a growing need to develop IPS and XIT approaches that can be accepted by more patients, which could eliminate the use of immunosuppression and be provided to many patients.

Patients and methods

Ethical guidelines

The institutional ethics committee approved this study, and the questionnaire respondents provided written informed consent to participate in the study. For the respondents who were adolescents, their parents provided written consent.

Study participants

T1DM patients and their families participated in a symposium that was held in May 2014 by the Japan IDDM network and attended lectures about newly developed therapies presented by experts of each therapy. A summary of the contents of the lectures for each therapy was as follows. AIT: islet transplantation is an attractive treatment for T1DM because of its potential high efficacy and minimal invasive transplantation process. The treatment can effectively control blood glucose. In addition, patients may achieve insulin independence especially after multiple infusions. However, there are still important issues, including difficulty in long-term insulin independence, multiple donor requirements for high efficacy, side effects associated with immunosuppressant drugs, and donor shortage. Encapsulated AIT: human islets are encapsulated and transplanted into the recipient. The capsule can prevent immune attack of the encapsulated islets, so immunosuppressants are not required. However, the efficacy of transplantation may be less than that of standard islet transplantation. In addition, donor shortage is still a problem. XIT: xenogeneic islet transplantation with porcine islets is a promising approach to overcome the shortage of human donors. According to clinical trials, transplantation of encapsulated neonatal porcine islets was safe and resulted in a reduction of unaware hypoglycemia events in unstable T1DM patients. Multiple transplantations of encapsulated porcine islets may be more effective. IPS: human iPS cells are considered a potential source for the generation of insulin-producing pancreatic β-cells. Several researchers have reported that functional iPS cell-derived insulin-producing pancreatic β-cells could restore glycemic control in diabetic mice after transplantation. However, no clinical trials have been performed and their efficacy and safety in humans are still unknown. Table 4 shows the main topics presented at the lectures. After these lectures, the patients and their families completed the questionnaire. The participants included some adolescent T1DM patients, because even though islet transplantation is only available for adults in Japan, adolescents might become candidates for the new therapies in the future. The participants were not assessed for their educational level, but it is quite possible that they have a higher education level than the general public because they attended the symposium under their own free will to gather the latest information about their disease.

Table 4.

Characteristics of each therapy.

Therapy	Donor	Immunosuppressive method	Number of transplants	Efficacy of therapy	Expected effects	Waiting period	Condition of surgery
AIT Clinical stage	Humans	Immunosuppressive agents	Single	Strong	Achieving stable glycemic control; possibility of insulin-free status	Long	Emergency surgery
Multiple AIT Clinical stage	Humans	Immunosuppressive agents	A few times	Strongest	Insulin-free status	Very long	Emergency surgery
Encapsulate AIT Clinical stage	Humans	Immune-isolated membrane (free from immunosuppressive agents)	Single	Average	Achieving stable glycemic control	Long	Emergency surgery
Multiple encapsulate AIT Clinical stage	Humans	Immune-isolated membrane (free from immunosuppressive agents)	A few times	Strong	Achieving stable glycemic control; possibility of insulin-free status	Very long	Emergency surgery
XIT Clinical stage	Sterile donor pigs	Immune-isolated membrane (free from immunosuppressive agents)	Single	Average	Achieving stable glycemic control	Short	Schedulable
Multiple XIT Clinical stage	Sterile donor pigs	Immune-isolated membrane (free from immunosuppressive agents)	A few times	Strong	Achieving stable glycemic control; possibility of insulin-free status	Short	Schedulable
IPS Basic research stage	Medical grade iPS cells	Immune-isolated membrane (free from immunosuppressive agents)	Single	Unknown	Achieving stable glycemic control; possibility of insulin-free status (no data for transplantation to humans)	Short	Schedulable

AIT, allogeneic islet transplantation; XIT, xenogeneic islet transplantation; IPS, induced pluripotent stem cell therapy

Questionnaire

The questionnaire consisted of questions about the degree of stability of present glycemic control, fear of hypoglycemia, wish to be insulin-free, wish to achieve more stable glycemic control, and willingness to receive the newly developed therapies (AIT, multiple AIT, encapsulated AIT, multiple encapsulated AIT, XIT, multiple XIT, and IPS). For these questions, the respondents were allowed to choose one from four ordinal options (strongly wish/agree, wish/agree, do not wish/do not agree, and strongly do not wish/strongly do not agree). The answers were classified into two groups: the wish/agree group (strongly wish/agree, wish/agree) and the no wish/no agree group (do not wish/agree strongly, do not wish/strongly do not agree). The basic characteristics of the respondents (gender, age, onset age, and disease duration) were also collected. In addition, the respondents answered a question regarding their concern about islet transplantation by multiple-choice or free answer. Finally, they selected the best and worst treatment for themselves from seven therapeutic options with the reason for their selection in an open-ended question. We analyzed the acceptance rates of these new therapies based on the above-mentioned factors such as stability of present glycemic control, fear of hypoglycemia, wish for insulin-free status, and more stable glycemic control. We also compared the opinions of the patients and their family members.

Statistical analysis

Fisher’s exact test or an unpaired t-test was performed to analyze the data. Differences were considered significant at a P-value less than 0.05.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors thank the non-profit Japan IDDM network for its cooperation.