Accessory cells for β‐cell transplantation

Despite recent advances, insulin therapy remains a treatment, not a cure, for diabetes mellitus with persistent risk of glycaemic alterations and life‐threatening complications. Restoration of the endogenous β‐cell mass through regeneration or transplantation offers an attractive alternative. Unfortunately, signals that drive β‐cell regeneration remain enigmatic and β‐cell replacement therapy still faces major hurdles that prevent its widespread application. Co‐transplantation of accessory non‐islet cells with islet cells has been shown to improve the outcome of experimental islet transplantation. This review will highlight current travails in β‐cell therapy and focuses on the potential benefits of accessory cells for islet transplantation in diabetes.     

Aetiology of type 1 diabetes: Physiological growth in children affects disease progression

The prevailing view is that type 1 diabetes (T1D) develops as a consequence of a severe decline in β‐cell mass resulting from T‐cell‐mediated autoimmunity; however, progression from islet autoantibody seroconversion to overt diabetes and finally to total loss of C‐peptide production occurs in most affected individuals only slowly over many years or even decades. This slow disease progression should be viewed in relation to the total β‐cell mass of only 0.2 to 1.5 g in adults without diabetes. Focal lesions of acute pancreatitis with accumulation of leukocytes, often located around the ducts, are frequently observed in people with recent‐onset T1D, and most patients display extensive periductal fibrosis, the end stage of inflammation. An injurious inflammatory adverse event, occurring within the periductal area, may have negative implications for islet neogenesis, dependent on stem cells residing within or adjacent to the ductal epithelium. This could in part prevent the 30‐fold increase in β‐cell mass that would normally occur during the first 20 years of life. This increase occurs in order to maintain glucose metabolism during the physiological increases in insulin production that are required to balance the 20‐fold increase in body weight during childhood and increased insulin resistance during puberty. Failure to expand β‐cell mass during childhood would lead to clinically overt T1D and could help to explain the apparently more aggressive form of T1D occurring in growing children when compared with that observed in affected adults.     

Targeting β‐cell functions in therapy for type 2 diabetes

Recently, Leahy et al. issued a “consensus statement” in regard to targeting β‐cell function in therapy for type 2 diabetes that recommends continued multidisciplinary efforts to realign treatment of type 2 diabetes to preserve β‐cell function by early intervention. This might be applicable not only for obese type 2 diabetes in Europe and America, but also for lean type 2 diabetes in Asia. To establish evidence, development of non‐invasive measurements of β‐cell mass for longitudinal observation during long duration of diabetes is critical. In addition, studies that clarify the development of β‐cell dysfunction with regard to both mass reduction and functional impairment are required for the development of novel strategies to preserve β‐cell function by treatment of type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00117.x, 2011)     

Diagnostic criteria for acute‐onset type 1 diabetes mellitus (2012): Report of the Committee of Japan Diabetes Society on the Research of Fulminant and Acute‐onset Type 1 Diabetes Mellitus

Type 1 diabetes is a disease characterized by destruction of pancreatic β‐cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute‐onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute‐onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3 months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti‐islet autoantibodies are diagnosed with ‘acute‐onset type 1 diabetes mellitus (autoimmune)’. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C‐peptide immunoreactivity <0.6 ng/mL) without verifiable anti‐islet autoantibodies are diagnosed simply with ‘acute‐onset type 1 diabetes mellitus’. Patients should be reevaluated after certain periods in case their statuses of anti‐islet autoantibodies and/or endogenous insulin secretory capacity are unknown.     

Dynamic pathology of islet endocrine cells in type 2 diabetes: β‐Cell growth,death, regeneration and their clinical implications

Diabetes is defined as a disease of hyperglycemic metabolic disorder caused by impaired insulin action or low insulin secretion, resulting in the occurrence of vascular complications. Based on this definition, diabetes therapy has long been oriented to correct hyperglycemia against the specific complications of diabetes. This definition has posed some difficulties, however, in understanding of the pathophysiology of this complicated disease and as such in the establishment of an effective treatment. With continuing efforts to explore the structural basis for diabetes onset and methodological development of immunohistochemistry, progressive decline of β‐cells is now established as a salient feature of type 2 diabetes. Accordingly, diabetes therapy has now turned out to protect β‐cells concurrently with the correction of hyperglycemia. Together with this effort, exploration of the means to regenerate β‐cells or to supply new β‐cells by, for example, induced pluripotential stem cells, are vigorously made with the search for the mechanism of β‐cell decline in diabetes. In the present review, we describe the advances in the islet pathology in type 2 diabetes with special reference to the dynamic alterations of islet endocrine cells in the milieu of maturation, obesity, aging and ethnic differences. The effect of amyloid deposition is also discussed. We hope it will help with understanding the pathophysiology of diabetes, and suggest the future direction of diabetes treatment.     

The environment and the origins of islet autoimmunity and Type 1 diabetes

Type 1 diabetes involves the specific destruction of the pancreatic islet β‐cells, eventually resulting in a complete dependency of exogenous insulin. The clinical onset of diabetes is preceded by the appearance of autoantibodies against β‐cell antigens. The human leukocyte antigen (HLA) region is the single most important genetic determinant of Type 1 diabetes susceptibility, yet variability in the HLA region has been estimated to explain only approximately 60% of the genetic influence of the disease. Over 50 identified non‐HLA genetic polymorphisms support the notion that genetics alone cannot explain Type 1 diabetes. Several lines of evidence indicate that environmental triggers may be integral in inducing the onset of islet autoimmunity in genetically susceptible individuals. The association between environmental factors and the clinical onset is complicated by observation that the rate of progression to clinical onset may be affected by environmental determinants. Hence, the environment may be aetiological as well as pathogenic. Putative inductive mechanisms include viral, microbial, diet‐related, anthropometric and psychosocial factors. Ongoing observational cohort studies such as The Environmental Determinants of Diabetes in the Young (TEDDY) study aim to ascertain environmental determinants that may trigger islet autoimmunity and either speed up or slow down the progression to clinical onset in subjects with persistent islet autoimmunity.     

Oral therapy for type 1 diabetes mellitus using a novel immunomodulator,FTY720 (fingolimod), in combination with sitagliptin,a dipeptidyl peptidase‐4 inhibitor,examined in non‐obese diabetic mice

Aims/Introduction: The therapeutic effectiveness against type 1 diabetes mellitus of a novel immunomodulator, FTY720 (fingolimod), in combination with sitagliptin, a dipeptidyl peptidase‐4 inhibitor, was examined in the non‐obese diabetic (NOD) mouse model. Materials and Methods: Female NOD mice that had developed type 1 diabetes mellitus spontaneously were divided into four groups according to which therapy they received: (i) FTY720 (0.1 mg/kg, orally, six times a week) plus sitagliptin (1 mg/kg, orally, six times a week); (ii) FTY720 (0.1 mg/kg, orally, six times a week); (iii) sitagliptin (1 mg/kg, orally, six times a week); and (iv) the vehicle (water) alone. Therapeutic efficacy was evaluated in terms of survival rate, ratio of insulin‐positive β‐cells/total islet area, extent of islet inflammation (insulitis score) and blood‐glucose level. Results: The therapeutic administration of FTY720 plus sitagliptin significantly improved survival (83% at 70 days after onset, P < 0.05) compared with sitagliptin alone (17%) or vehicle alone (0%). The fasting‐blood glucose level, the ratio of insulin‐positive β‐cells/total islet area and the insulitis score in the surviving mice, which had been treated with FTY720 plus sitagliptin, were improved to the normal levels as in age‐matched NOD mice with normoglycemia. Conclusions: Combination therapy with FTY720 and sitagliptin is a promising candidate for type 1 diabetes mellitus treatment, and might allow the treatment of type 1 diabetes mellitus with only oral agents. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00218.x , 2012)     

The broad clinical phenotype of Type 1 diabetes at presentation

Immune‐mediated (auto‐immune) Type 1 diabetes mellitus is not a homogenous entity, but nonetheless has distinctive characteristics. In children, it may present with classical insulin deficiency and ketoacidosis at disease onset, whereas autoimmune diabetes in adults may not always be insulin dependent. Indeed, as the adult‐onset form of autoimmune diabetes may resemble Type 2 diabetes, it is imperative to test for diabetes‐associated autoantibodies to establish the correct diagnosis. The therapeutic response can be predicted by measuring the levels of autoantibodies to various islet cell autoantigens, such as islet cell antibodies (ICA), glutamate decarboxylase 65 (GAD65), insulin, tyrosine phosphatase (IA‐2) and IA‐2β, and zinc transporter 8 (ZnT8) and evaluating β‐cell function. A high risk of progression to insulin dependency is associated with particular genetic constellations, such as human leukocyte antigen risk alleles, young age at onset, the presence of multiple autoantibodies, including high titres of anti‐GAD antibodies; such patients should be offered early insulin replacement therapy, as they respond poorly to diet and oral hypoglycaemic drug therapy. Hence, considering the broad spectrum of phenotypes seen in adult‐onset diabetes, treatment targets can only be reached by identification of immune‐mediated cases, as their management differs from those with classical Type 2 diabetes.     

Gastrointestinal actions of glucagon‐like peptide‐1‐based therapies: glycaemic control beyond the pancreas

The gastrointestinal hormone glucagon‐like peptide‐1 (GLP‐1) lowers postprandial glucose concentrations by regulating pancreatic islet‐cell function, with stimulation of glucose‐dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP‐1 are at least as important for glucose‐lowering. GLP‐1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP‐1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP‐1 receptor agonists, which mimic the effects of GLP‐1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP‐1 receptor agonists can be broadly categorized as short‐ or long‐acting, with each having unique islet‐cell and gastrointestinal effects that lower glucose levels. Short‐acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long‐acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual β‐cell function.     

Islet antibodies and remaining beta-cell function 8 years after diagnosis of diabetes in young adults: a prospective follow-up of the nationwide Diabetes Incidence Study in Sweden

Objectives. To establish the prevalence of remaining β‐cell function 8 years after diagnosis of diabetes in young adults and relate the findings to islet antibodies at diagnosis and 8 years later. Design. Population‐based cohort study. Setting. Nationwide from all Departments of Medicine and Endocrinology in Sweden. Subjects. A total of 312 young (15–34 years old) adults diagnosed with diabetes during 1987–88. Main outcome measure. Plasma connecting peptide (C‐peptide) 8 years after diagnosis. Preserved β‐cell function was defined as measurable C‐peptide levels. Three islet antibodies – cytoplasmic islet cell antibodies (ICA), glutamic acid decarboxylase antibodies and tyrosine phosphatase antibodies – were measured. Results. Amongst 269 islet antibody positives (ab⁺) at diagnosis, preserved β‐cell function was found in 16% (42/269) 8 years later and these patients had a higher body mass index (median 22.7 and 20.5 kg m^?2, respectively; P = 0.0003), an increased frequency of one islet antibody (50 and 24%, respectively; P = 0.001), and a lower prevalence of ICA (55 and 6%, respectively; P = 0.007) at diagnosis compared with ab⁺ without remaining β‐cell function. Amongst the 241 patients without detectable β‐cell function at follow‐up, 14 lacked islet antibodies, both at diagnosis and at follow‐up. Conclusions. Sixteen per cent of patients with autoimmune type 1 diabetes had remaining β‐cell function 8 years after diagnosis whereas 5.8% with β‐cell failure lacked islet autoimmunity, both at diagnosis and at follow‐up.     

Neutrophils in type 1 diabetes

Type 1 diabetes is an autoimmune disease that afflicts millions of people worldwide. It occurs as the consequence of destruction of insulin‐producing pancreatic β‐cells triggered by genetic and environmental factors. The initiation and progression of the disease involves a complicated interaction between β‐cells and immune cells of both innate and adaptive systems. Immune cells, such as T cells, macrophages and dendritic cells, have been well documented to play crucial roles in type 1 diabetes pathogenesis. However, the particular actions of neutrophils, which are the most plentiful immune cell type and the first immune cells responding to inflammation, in the etiology of this disease might indeed be unfairly ignored. Progress over the past decades shows that neutrophils might have essential effects on the onset and perpetuation of type 1 diabetes. Neutrophil‐derived cytotoxic substances, including degranulation products, cytokines, reactive oxygen species and extracellular traps that are released during the process of neutrophil maturation or activation, could cause destruction to islet cells. In addition, these cells can initiate diabetogenic T cell response and promote type 1 diabetes development through cell–cell interactions with other immune and non‐immune cells. Furthermore, relevant antineutrophil therapies have been shown to delay and dampen the progression of insulitis and autoimmune diabetes. Here, we discuss the relationship between neutrophils and autoimmune type 1 diabetes from the aforementioned aspects to better understand the roles of these cells in the initiation and development of type 1 diabetes.     

DPP‐4 inhibition and islet function

During recent years, dipeptidyl peptidase‐4 (DPP‐4) inhibition has been included in the clinical management of type 2 diabetes, both as monotherapy and as add‐on to several other therapies. DPP‐4 inhibition prevents the inactivation of the incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1). This results in stimulation of insulin secretion and inhibition of glucagon secretion, and there is also a potential β‐cell preservation effect, as judged from rodent studies; that is, it might target the key islet dysfunction in the disease. In type 2 diabetes. This reduces 24‐h glucose levels and reduces HbA_1c by ≈ 0.8–1.1% from baseline levels of 7.7–8.5%. DPP‐4 inhibition is safe, with a very low risk for adverse events including hypoglycemia, and it prevents weight gain. The present review summarizes the studies on the influence of DPP‐4 inhibition on islet function. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00184.x, 2012)     

β‐Cell failure in type 2 diabetes

Type 2 diabetic patients are insulin resistant as a result of obesity and a sedentary lifestyle. Nevertheless, it has been known for the past five decades that insulin response to nutrients is markedly diminished in type 2 diabetes. There is now a consensus that impaired glucose regulation cannot develop without insulin deficiency. First‐phase insulin response to glucose is lost very early in the development of type 2 diabetes. Several prospective studies have shown that impaired insulin response to glucose is a predictor of future impaired glucose tolerance (IGT) and type 2 diabetes. Recently discovered type 2 diabetes‐risk gene variants influence β‐cell function, and might represent the molecular basis for the low insulin secretion that predicts future type 2 diabetes. We believe type 2 diabetes develops on the basis of normal but ‘weak’β‐cells unable to cope with excessive functional demands imposed by overnutrition and insulin resistance. Several laboratories have shown a reduction in β‐cell mass in type 2 diabetes and IGT, whereas others have found modest reductions and most importantly, a large overlap between β‐cell masses of diabetic and normoglycemic subjects. Therefore, at least initially, the β‐cell dysfunction of type 2 diabetes seems more functional than structural. However, type 2 diabetes is a progressive disorder, and animal models of diabetes show β‐cell apoptosis with prolonged hyperglycemia/hyperlipemia (glucolipotoxicity). β‐Cells exposed in vitro to glucolipotoxic conditions show endoplasmic reticulum (ER) and oxidative stress. ER stress mechanisms might participate in the adaptation of β‐cells to hyperglycemia, unless excessive. β‐Cells are not deficient in anti‐oxidant defense, thioredoxin playing a major role. Its inhibitor, thioredoxin‐interacting protein (TXNIP), might be important in leading to β‐cell apoptosis and type 2 diabetes. These topics are intensively investigated and might lead to novel therapeutic approaches. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00094.x, 2011)     

Islet cell transplantation for Type 1 diabetes

Islet transplantation is an attractive concept for the treatment of Type 1 diabetes because of its potential high efficacy and minimal invasion to patients. The treatment may effectively control blood glucose for brittle Type 1 diabetes, resulting in a marked reduction in hypoglycemic episodes and improvements in HbA 1 c. In addition, approximately 70% of transplanted Type 1 diabetic patients have achieved insulin independence. However, there are still important issues to be addressed before this treatment is widely applicable, including difficulty in maintaining insulin independence, low islet isolation success rate, multiple donor requirements, and side effects associated with the use of immunosuppressants. Donor shortage is another dilemma. To address the issue of donor shortage, living donor islet transplantation and bioartificial islet transplantation using pig islets are being evaluated. Bioartificial islet transplantation could be the ultimate solution of the donor shortage. Currently, overcoming immunological hurdles, establishing reliable islet isolation methods, and controlling porcine endogenous retrovirus are the primary obstacles to the implementation of this treatment. If bioartificial islet transplant becomes a clinical reality, it may even be applicable in the treatment of select Type 2 diabetic patients. β‐Cell regeneration from naïve pancreas and β‐cell generation from embryonic stem cells or induced pluripotent stem cells are the next‐generation treatments for Type 1 diabetes.     

New prospects for immunotherapy at diagnosis of type 1 diabetes

Immune intervention at diagnosis of type 1 diabetes (T1D) aims to prevent or reverse the disease by blocking autoimmunity, thereby preserving/restoring β‐cell mass and function. Recent clinical trials of non‐specific and of antigen‐specific immune therapies have demonstrated the feasibility of modulation of islet‐specific autoimmunity in patients with partial prevention of loss of insulin secretion. In a series of review articles published in this issue of the journal, some of the most promising approaches of immune intervention in T1D are presented. Here we outline the rationale of such interventions and future prospects in this area. Copyright © 2009 John Wiley & Sons, Ltd. Insulin therapy in type 1 diabetes (T1D) rescues the patient from a certain death but not cure the disease. The goal of any therapeutic intervention in T1D is the preservation of insulin‐secreting cells; this is achieved by the abrogation of pathogenic reactivity to beta cell autoantigens while preserving full capacity to generate a normal immune response against foreign antigens. Although several therapeutic candidates have been investigated in experimental models of T1D many of which showed promising results, a successful extrapolation of these findings to human T1D has proved to be difficult. In part, this failure results from the considerable disease heterogeneity associated with diverse genetic and non‐genetic disease determinants and the spectrum of clinical phenotype at diagnosis. Thus, a younger age at onset is associated with stronger genetic susceptibility, more intense immune response to β‐cell antigens, shorter duration of symptoms, more severe metabolic derangement at diagnosis and a more rapid rate of β‐cell‐destruction 1 - 3 . Therefore, designing therapies that would be effective in all clinical settings is definitely challenging. In this issue five different approaches are discussed ranging from antigen‐specific therapies [DiaPep277 and glutamic acid decarboxylase(GAD)], to non‐antigen‐specific immunoregulation (anti‐CD3) and to anti‐inflammatory (anti‐IL1 receptor antagonist). These approaches are currently being tested in large international multicenter trials, and all of them use very similar outcome in terms of a beneficial effect (C‐peptide secretion as evidence of a therapeutic effect on restoration of β‐cell function). The authors have been asked to follow a similar format in presenting their approaches so that the reader can easily compare them in terms of rationale and therapeutic goals.     

Augmented reduction of islet β‐cell mass in Goto‐Kakizaki rats fed high‐fat diet and its suppression by pitavastatin treatment

Aims/Introduction: High fat diet (HFD) is known to be a risk for development of type 2 diabetes. It is unclear, however, how it affects the glucose tolerance or the islet structure in type 2 diabetes. The aim of this study is: (i) to examine the effects of HFD on the islet in GK rats, non‐obese type 2 diabetic model; and (ii) to explore if pitavastatin treatment influences the change. Materials and Methods: To see the effects of HFD on islet changes in type 2 diabetes, 4‐week old male GK and Wistar rats were fed HFD for 16 weeks and subjected to glucose tolerance tests and pathological studies of the islet. The effects of pitavastatin (3 mg/kg/day for 16 weeks, oral), one of the lipophilc statins, were also examined in both GK and Wistrar rats fed with or without HFD. Results: The HFD induced hyperlipidemia and aggravated glucose intolerance in both GK and Wistar rats. Pitavastatin treatment did not influence the glucose tolerance in HFD‐fed animals. HFD caused an increase in hepatic lipid contents in all the animals, which was partially suppressed by pitavastatin treatment. GK rats showed reduced β‐cell mass, and fibrosis and macrophage migration in the islets. HFD feeding in GK rats augmented these changes which were associated with enhanced expression of 8‐hydroxydeoxyguanosine and an increase in apoptotic cells. Pitavastatin treatment improved the HFD‐induced islet pathology, and pancreatic insulin contents paralleled the structural changes. Conclusions: HFD feeding worsened the islet pathology in GK rats which was suppressed by pitavastatin treatment. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00173.x, 2011)     

Beta‐cell replacement strategies for diabetes

Diabetes is characterized by elevated levels of blood glucose as a result of insufficient production of insulin from loss or dysfunction of pancreatic islet β‐cells. Here, we review several approaches to replacing β‐cells that were recently discussed at a symposium held in Kyoto, Japan. Transplant of donor human islets can effectively treat diabetes and eliminate the need for insulin injections, supporting research aimed at identifying abundant supplies of cells. Studies showing the feasibility of producing mouse islets in rats support the concept of generating pigs with human pancreas that can serve as donors of human islets, although scientific and ethical challenges remain. Alternatively, in vitro differentiation of both human embryonic stem cells and induced pluripotent stem cells is being actively pursued as an islet cell source, and embryonic stem cell‐derived pancreatic progenitor cells are now in clinical trials in North America in patients with diabetes. Macro‐encapsulation devices are being used to contain and protect the cells from immune attack, and alternate strategies of immune‐isolation are being pursued, such as islets contained within long microfibers. Recent advancements in genetic engineering tools offer exciting opportunities to broaden therapeutic strategies and to probe the genetic involvement in β‐cell failure that contributes to diabetes. Personalized medicine might eventually become a possibility with genetically edited patient‐induced pluripotent stem cells, and the development of simplified robust differentiation protocols that ideally become standardized and automated. Additional efforts to develop a safe and effective β‐cell replacement strategy to treat diabetes are warranted.     

The multiple origins of Type 1 diabetes

It is widely accepted that Type 1 diabetes is a complex disease. Genetic predisposition and environmental factors favour the triggering of autoimmune responses against pancreatic β‐cells, eventually leading to β‐cell destruction. Over 40 susceptibility loci have been identified, many now mapped to known genes, largely supporting a dominant role for an immune‐mediated pathogenesis. This role is also supported by the identification of several islet autoantigens and antigen‐specific responses in patients with recent onset diabetes and subjects with pre‐diabetes. Increasing evidence suggests certain viruses as a common environmental factor, together with diet and the gut microbiome. Inflammation and insulin resistance are emerging as additional cofactors, which might be interrelated with environmental factors. The heterogeneity of disease progression and clinical manifestations is likely a reflection of this multifactorial pathogenesis. So far, clinical trials have been mostly ineffective in delaying progression to overt diabetes in relatives at increased risk, or in reducing further loss of insulin secretion in patients with new‐onset diabetes. This limited success may reflect, in part, our incomplete understanding of key pathogenic mechanisms, the lack of truly robust biomarkers of both disease activity and β‐cell destruction, and the inability to assess the relative contributions of various pathogenic mechanisms at various time points during the course of the natural history of Type 1 diabetes. Emerging data and a re‐evaluation of histopathological, immunological and metabolic findings suggest the hypothesis that unknown mechanisms of β‐cell dysfunction may be present at diagnosis, and may contribute to the development of hyperglycaemia and clinical symptoms.