Hope vs hype: where are we in type 1 diabetes?
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Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research.
KeywordsAutomated insulin delivery Immune intervention Islet regeneration Islet replacement therapy Review Stem cells Type 1 diabetes
Artificial endocrine pancreas
- BB rat
Glucagon-like peptide-1 receptor agonists
Human embryonic stem cell
Islet neogenesis-associated protein
Induced pluripotent stem cell
Trial to Reduce IDDM in the Genetically at Risk
The issue of hope vs hype is not unique to type 1 diabetes. In a search of PubMed conducted for the purposes of this article, there were 427 articles identified when the search term was ‘hope and hype’, and this number was reduced to 24 for the search term ‘hope and hype and diabetes’. Several discussed ‘hope or hype’ or ‘hype and hope’, while others addressed going ‘from hype to hope’, and at least one talked of ‘hype, hope and reality’. The point is that the scientific community needs to be cautious about how provocative findings are communicated. Journals, too, need to be cautious when issuing press releases about articles that are appearing in them. This applies also to academic institutions and research organisations that issue press releases.
Headline: transplants offer hope for diabetes
Islet replacement therapy: reality
The modern era of pancreas transplantation began with a report from the University of Minnesota in 1967 . The field expanded such that 15 years later it was touted as an important approach to type 1 diabetes that resulted in durable control of blood glucose . This was further enhanced by the demonstration that pancreas transplantation reduced the recurrence of renal disease in patients also receiving kidney transplants . Moreover, the 10 year patient and kidney graft survival rates were higher in individuals having a kidney transplant together with a pancreas transplant than in those having a kidney transplant alone, regardless of whether the kidney donor was deceased or living .
A problem with pancreas transplantation is the associated morbidity, including acute rejection, graft thrombosis resulting in the need for allograft pancreatectomy, the need for chronic immunosuppression, infectious complications and the relatively high rates of haematological cancers . Nonetheless, as surgical techniques have been refined, accompanied by better immunosuppression, there have been improved pancreas graft survival rates and lower acute rejection rates . An unexpected but important finding has been the recurrence of autoimmunity without evidence of rejection in the setting of chronic immunosuppressive therapy .
Organ procurement has been a limiting factor, as there are only a limited number of organ donors and not all have a pancreas suitable for transplantation. Initially, this was a major problem. Somewhat surprisingly, however, in the USA there has been a progressive decline in pancreas transplantation over the past 10–15 years . This is somewhat of a paradox in that pancreas transplantation is a definitive therapy with improving success rates over time but one that is applied less often. Moreover, the continued limited number of organ donors means some patients barely surviving the waiting list for a transplant. Intriguingly, it is also now possible to perform pancreas transplantation using a laparoscopic robotic approach . One criticism is the lack of randomised clinical trials to establish the actual risk, benefit and cost effectiveness of pancreas transplantation .
Transplantation of islets, rather than whole pancreas, was first reported in rodents in 1972 , and in human beings in 1977 . Progress in the field was markedly facilitated by improvements in islet isolation and purification, including the development of the Ricordi chamber, reported in 1989 . Using the Edmonton protocol, involving a glucocorticoid-free immunosuppressive regimen, insulin independence was achieved in most patients, giving great hope to the field . However, an international trial using that protocol did not have equivalent success , perhaps related to differences in sites in experience both with the complex preparation of human islets for transplantation and clinical experience in the routine management of immunosuppressive therapies . Nonetheless, there has been a progressive improvement in outcomes , and the Clinical Islet Transplantation Consortium has completed a Phase III trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycaemia . Compared with pancreas transplantation, the procedure is less invasive and is associated with less morbidity, but the requirement for chronic immunosuppression remains. Another problem is that islets often fail to continue to produce insulin, requiring a second islet transplant or a return to insulin therapy. According to the most recent report from the Collaborative Islet Transplant Registry, between 1999 and 2013, worldwide a total of 1011 individuals received islet transplantation, 25–30% of whom were insulin independent after 5 years and 40–55% had significant C-peptide production . Interestingly, at least 40 islet transplant recipients have had to undergo pancreas transplant after the islets failed . Moreover, even if the procedure were highly successful, the limitation of cadaveric organ donors would preclude wide-scale use. Ideally, being an organ donor should be the default position, with individuals having to opt out of organ donation rather than having to opt in.
Headline: stem cells can cure diabetes
There has been enormous progress in our understanding of the development of islets , thus permitting the generation of islets from human embryonic stem cells (hESCs) . The hope has been that this would provide an unlimited source of islets suitable for replacement therapy. Indeed, formal clinical trials were initiated with encapsulated hESCs, the capsules designed to obviate the need for immunosuppression . Unfortunately, there was inadequate vascularisation and a foreign body reaction that has led to a new trial with a modified encapsulation device but the need for immunosuppression . A limitation of the preclinical programme for these trials was that they were conducted in immunodeficient rodents [24, 25], since it was known that the original encapsulation device would not stop a xenograft reaction and the embryonic stem cells were human in origin.
Encapsulation devices have been under development for many years . Recent improvements in approaches to encapsulation may yet eliminate the need for immunosuppression [27, 28]. Unfortunately, this has not yet proved to be the case in human beings. Another approach for production of cells is to differentiate human induced pluripotent stem cells (iPSCs) into insulin-secreting beta cells [29, 30]. If allogenic iPSCs are used, these, too, will require encapsulation and/or immunomodulation, as is the case for hESCs. Alternatively, autologous iPSCs could be used, which would be given to the same individual from which they were derived, which would obviate rejection but not necessarily recurrent autoimmunity . A similar approach, known as transdifferentiation, has been used in which liver cells are obtained by biopsy and differentiated in vitro into beta cells and re-implanted in the individual from whom the cells were obtained . However, any autologous approach would require the site at which the procedure was performed to have a specialised laboratory for differentiating the cells, rather than a single manufacturing site making allogenic cells.
Another issue that needs to be considered is that pure beta cells might not be the answer, as one of the benefits of islet transplantation has been the prevention of severe hypoglycaemia, which involves improvement of alpha cell function and effective paracrine interactions within the islet .
Headline: peptide can make new beta cells
A potentially exciting approach to recovering islet function is in vivo treatment with a substance that causes islets or beta cells to regenerate or reawaken. In rodent islets, glucagon-like peptide-1 receptor agonists (GLP-1RA) were found to increase both neogenesis and proliferation of beta cells while inhibiting beta cell apoptosis . In contrast, in human islets, GLP-1RA inhibits beta cell apoptosis, but only stimulates beta cell proliferation in very young islets . An interesting experiment in human type 2 diabetes was to test whether exenatide, a GLP-1RA, could increase beta cell mass . Although beta cell function was improved, the improvement was not sustained after withdrawal of exenatide. The interpretation was that beta cell mass was thus not increased. Another interpretation could be that beta cell function is improved with exposure to a GLP-1RA, and that the drug must be continued indefinitely in an attempt to maintain increased beta cell function. The use of a GLP-1RA could also be studied in type 1 diabetes.
Many other substances, including small molecules, growth factors, hormones and nutrients, have been found to induce robust beta cell replication in rodent or other eukaryotic models . Some have been widely claimed to be of potential importance, such as islet neogenesis-associated protein (INGAP)  (or its human counterpart, human proislet peptide ), gastrin  and betatrophin . INGAP failed in clinical trials . In the case of betatrophin, the experiments could not be reproduced [43, 44], and the initial paper was subsequently retracted . Again, much of the problem in regeneration is that success in animal models does not translate into success in human beings.
Headline: new approach prevents type 1 diabetes
Prevention of type 1 diabetes
There have been literally hundreds of treatments that prevent autoimmune diabetes in animal models such as the NOD mouse  and the Bio-Breeding (BB) rat . However, to date, none of several tested interventions has been successful in preventing type 1 diabetes in human beings [48, 49]. Most of the studies have been conducted in relatives of people with type 1 diabetes, who have an increased risk of the disease. The participants in trials for secondary prevention are recruited from screening programmes that identify individuals with beta cell autoimmunity. Yet, this requires screening tens of thousands of individuals, since 95% of relatives will not have antibodies. Moreover, most tested interventions have focused on antigen-based immune deviation using various forms of insulin or GAD, or benign substances such as the vitamin nicotinamide . It may very well be that antigen-based immune deviation needs to be initiated prior to the development of antibodies if it is to be successful. This may require population-based genetic screening to select an appropriate cohort for testing primary prevention of disease. One study in primary prevention, the Trial to Reduce IDDM in the Genetically at Risk (TRIGR), is evaluating whether an infant formula that uses casein hydrolysate rather than cow’s milk could delay or prevent the development of type 1 diabetes . A pilot study from Finland suggested that such a formula could delay the appearance of diabetes antibodies , but this was not confirmed in the larger TRIGR trial . Screening the general population for high genetic risk of type 1 diabetes may be feasible . The question is: what intervention should be tested?
Preservation of beta cell function in type 1 diabetes
Many immune intervention studies have been conducted in recent-onset type 1 diabetes . Some have shown no effect. Some have looked promising and have demonstrated a slower decline of beta cell function than the control group. Unfortunately, in most of the latter circumstances, after a transient apparent benefit, there has been a subsequent progressive decline in beta cell function which parallels that in the control group. At least four interventions (the anti-CD3 monoclonal antibodies teplizumab and otelixizumab, a GAD vaccine, and DiaPep277) have actually entered into Phase III trials, all of which failed to meet their primary endpoint . The reasons for failure have been discussed elsewhere . A resulting problem is that public enthusiasm for such trials has waned as apparent failures accumulate. Yet, almost all of the approaches investigated to date have used single agents directed at one or another component of the immune response. However, because some have demonstrated at least a transient response, this suggests their potential for use in a combination therapy approach and/or the potential for consideration for additional course(s) of treatment. It may well be that a different approach is needed, such as blocking innate immunity (inflammation) while inhibiting adaptive immunity (the T-lymphocyte response) and stimulating regulatory immunity, and simultaneously providing a treatment that may improve beta cell health . This may seem radical, but two such trials are listed in ClinicalTrials.gov and should soon be recruiting participants (NCT02586831, NCT03182426). Alternatively, success may require a better understanding of the heterogeneity in disease progression, and the possible need for precision medicine in selection of interventions for different individuals.
One potential problem with some of the immune intervention studies that have been conducted is that there was only transient exposure to the intervention early after enrolment. The hope was that an immune tolerant state would emerge so that the immune system of the person treated would no longer mount an anti-beta cell response. One trial that suggested this was feasible was an early study with otelixizumab in which the treatment lasted only 6 days, and preserved beta cell function was demonstrated 18 months later . Moreover, at 4 years after initial treatment, although beta cell function was not measured, the otelixizumab group required much less insulin than the control group in order to maintain a similar HbA1c . This suggested that the benefit of a 6 day course of treatment could be maintained 4 years later, but there was insufficient data and follow-up to establish tolerance. Yet, immune tolerance may have been too high a bar for autoimmune disease (or organ transplantation), despite the efforts of the Immune Tolerance Network . Tolerance has been achieved in allergy, and can be at least partly or transiently achieved by bone marrow transplantation. However, documented tolerance has yet to be demonstrated in autoimmune diseases, including type 1 diabetes.
Headline: artificial pancreas makes debut
Automated insulin delivery
Closed loop systems
An artificial endocrine pancreas (AEP), or closed loop insulin delivery, or more precisely, a glucose-controlled insulin delivery system, has been a holy grail of type 1 diabetes since the initial reports of development of such systems in the early 1970s [57, 58, 59]. The initial systems involved a bulky bedside apparatus and required intravenous access both for glucose measurement and for insulin delivery. Nonetheless, commercial versions of such systems were introduced and used for research studies and for inpatient management of diabetic ketoacidosis or control of blood glucose during surgery . Later, a glucose-controlled insulin delivery system that used an intravascular glucose sensor and intraperitoneal insulin delivery was tested in clinical trials .
More recently, external glucose-controlled insulin delivery systems have been tested with much fanfare [62, 63]. These involve conventional insulin pumps that are controlled by an algorithm (via computer or smart phone) to deliver insulin, and sometimes glucagon, based on the prevailing level and rate of change of interstitial glucose measured by a glucose sensor . Sensor accuracy and performance, which were previously limiting factors in the development of systems, has dramatically improved over the past decade, thus allowing rapid advancement of the field . Overnight control of basal glucose has readily been achieved, but control of meal-related glucose excursions has been a bigger challenge. Thus, a ‘hybrid’ system has been made commercially available—one that can control overnight glucose but still requires user intervention to control meal excursions .
Onset of insulin action
Part of the reason for difficulty in controlling meal glucose excursions may be that the current generation of ‘rapid-acting’ insulin analogues may be too slow to respond to abrupt increases in glucose following a meal. Newer more rapid analogues are being developed to overcome this issue . Also, refinement of the algorithms controlling insulin delivery may overcome the problem. Control of mealtime glucose was not a problem with intravenous or intraperitoneal insulin delivery, as the pharmacokinetics of insulin produced much quicker insulin excursions.
One potential approach for achieving glucose control is an insulin that can be administered but released in response to prevailing level of glucose, so-called ‘smart’ insulin . The concept dates back to the late 1970s . More recently, several groups have attempted to develop such an insulin , but no clinical trial results have yet been reported.
The author is supported by the Diabetes Research Institute Foundation.
Duality of interest
The author has acted as an advisor to: Adocia, Abvance, AstraZeneca, BD Technologies, Boehringer Ingelheim, Dance Biopharm, Diavacs, Elcelyx Therapeutics, Eli Lilly and Company, Ideal Life, Immunomolecular Therapeutics, Intrexon, Merck, Orgenesis, Sanofi, Servier, Tolerion, vTv Therapeutics, Valeritas LLC and Viacyte. He has had research funding from: NIH, JDRF, Mesoblast and Viacyte. He is a member of the board of directors of: Dexcom Inc., Intarcia Therapeutics and Moerae Matrix. He has equity in: Dance BioPharma, Dexcom Inc., Ideal Life, Intarcia Therapeutics, Intexon, Moerae Matrix and VasoPrep Surgical.
The author was the sole contributor to this paper.
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