Restoring normal islet mass and function in type 1 diabetes through regenerative medicine and tissue engineering

Summary

Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies.

Introduction

The advent of insulin therapy delivered a medical miracle in the early 20th century, rescuing people with type 1 diabetes from an inexorably progressive and ultimately fatal wasting disease. Since then, numbers of people with type 1 diabetes have steadily increased1, 2 in parallel with a global epidemic of type 2 diabetes over the second half of the 20th century and beyond.³ In 2019, it was estimated that 463 million adults had been diagnosed with diabetes worldwide. This number includes up to 10% with type 1 diabetes, in addition to more than 1·1 million children and adolescents being dependent on insulin replacement therapy.³ Although people with type 2 diabetes and rarer forms of diabetes are not absolutely dependent on insulin replacement, it is now acknowledged that all forms of diabetes are characterised by a suboptimal pancreatic islet cell insulin response.⁴

The dawn of the 21st century heralded β-cell replacement as an alternative to self-administered insulin therapy through seminal success with deceased donor islet transplantation in Edmonton, Canada.⁵ As regenerative medicine begins to deliver unparalleled outcomes across the spectrum of disease, we review its potential for transforming insulin-deficient diabetes.

Unfortunately, as we observe the centenary of insulin treatment, diabetes remains a leading cause of blindness, renal failure, and lower limb amputation,⁶ with increased incidence of myocardial infarction and reduced life expectancy.⁷ This is despite incontrovertible evidence that chronic complications can be prevented by early correction of high blood glucose concentrations.⁸ Achieving this correction with subcutaneously injected or infused insulin is unavoidably associated with risk of hypoglycaemia. Every year, nearly 50% of people with type 1 diabetes of more than 15 years duration require assistance for severe hypoglycaemia, one of the greatest fears of dependence on exogenous insulin.⁹ Great strides have been made in enhancing insulin delivery and glucose testing over the last century, including successful combination in integrated closed-loop systems.¹⁰ In contrast to the physiological β cell, which continuously senses glucose intravascularly with second-to-second control of insulin secretion directly into the portal vein, the wearable bioartifical pancreas has to overcome delays in detecting blood glucose changes due to subcutaneous sensing and in effecting a change in circulating insulin concentrations due to subcutaneous insulin delivery. This process necessitates frequent substantial changes in insulin infusion rate, typically associated with an average of at least 30 minutes each day with glucose less than 4 mmol/L even using the fastest marketed short-acting insulin analogue.¹¹ This approach does not thus provide curative therapy, nor completely removes the burden of glucose uncertainty and unremitting daily self-management.¹²

Transplantation of vascularised whole pancreas from a deceased donor has confirmed that β-cell replacement can immediately normalise blood glucose concentrations in type 1 diabetes and in carefully selected recipients with insulin-treated type 2 diabetes.¹³ Despite established success, applicability to more than a minority is limited by the complexity of the surgery with unavoidable risk of mortality and substantial morbidity, in addition to the limited availability of suitable donor organs.¹⁴

Mechanical and enzymatic dissociation of a donor pancreas has enabled separation of the endocrine cells within the islets of Langerhans from their blood supply and from the digestive enzyme-producing majority of the organ.¹⁵ Islet transplantation is a minimally invasive procedure that was initially undertaken as an autologous procedure following total pancreatectomy for painful pancreatitis.¹⁵ Subsequently, allogeneic islets were infused into the hepatic portal vein with systemic immunosuppression in type 1 diabetes.⁵

Islet transplantation offers prevention of severe hypoglycaemia, stabilisation of blood glucose concentrations, and attainment of optimal HbA_1c (<53 mmol/mol [7·0%]) and is established as standard-of-care for recurrent dangerous hypoglycaemia despite optimised conventional therapy in the integrated UK programme and in other countries around the world.16, 17, 18 However, sustainable insulin independence cannot be reproducibly achieved from a single transplantation procedure, and the requirement for lifelong systemic immunosuppression currently limits recipients to those with life-threatening complications.¹⁹

Portal vein infusion via a percutaneous transhepatic or mini-laparotomy approach is minimally invasive, only very rarely complicated by haemorrhage or thrombosis in experienced centres.16, 17, 18 Intravascularly transplanted cells are, however, subject to an instant blood-mediated inflammatory reaction.²⁰ PET scanning strongly suggests that this thrombotic and innate immune response leads to a substantial loss of transplanted islet mass immediately following infusion.²¹ Moreover, β cells are uniquely sensitive to hypoxia during pancreas retrieval and preservation; during islet isolation, culture, and shipment for transplantation; and within the relatively low oxygen tension portal vein environment before revascularisation from the hepatic artery.²² Transient ex-vivo exposure of primary mouse islets to hypoxia has been shown to lead to upregulation of hypoxia-inducible genes and adaptation enabling β-cell survival but with impaired glucose-stimulated insulin secretion persisting after transplantation.²³ Loss of fully mature end-differentiated phenotype (absence of β-cell urocortin-3 expression) several years after transplantation despite full vascularisation has been reported following clinical islet transplantation.²⁴ Together these limitations have led to maximal engraftment of only approximately 25–40% of normal adult β-cell functional mass despite often repeated transplantations from sequential deceased donors.²⁵ Although this level of functional mass can deliver short-term insulin independence, true physiological endocrine function has not yet been achieved.²⁶

Human islets have been transplanted clinically without encapsulation into alternative sites including skeletal muscle and omentum.²⁷ Although islets might become well vascularised, superior outcomes to portal transplantation have yet to be achieved, potentially due to irreversible adaptation during even short-term ischaemia and unpredictable inflammatory response.

In this Review we consider how the remaining challenges eluding a type 1 diabetes cure might be overcome through regenerative medicine approaches including stem cell-derived β cells, gene therapy, and tissue engineering. The highly vascularised endogenous islet niche and mechanisms for maintenance of β-cell mass and function will be considered as the context for intelligent recapitulation through: (1) generation of an unlimited source of physiologically functional islets; (2) vascularised engraftment of sufficient β-cell mass without tissue ischaemia; and (3) overcoming cell loss through innate and adaptive immune response.