Type 1 diabetes: new perspectives on disease pathogenesis and

Mark A Atkinson, George S Eisenbarth
As our knowledge of type 1 (insulin-dependent) diabetes increases, so does our appreciation for the pathogenic
complexity of this disease and the challenges associated with its treatment. Many new concepts about the
pathogenesis of this disorder have arisen. The role of genetics versus environment in disease formation has been
questioned, and the basis on which type 1 diabetes is characterised and diagnosed is the subject of much debate.
Additionally, the care and treatment of patients with type 1 diabetes has seen a rapid evolution; with genetically
engineered insulins, glucose monitoring devices, and algorithms all contributing to a decrease in disease-related
complications. We focus this seminar on these changing views, and offer a new perspective on our understanding of
the pathogenesis of type 1 diabetes and on principles for therapeutic management of patients with this disorder.

In the early to mid 1990s, optimism was high that Epidemiology and genetics
knowledge about the pathogenesis of type 1 diabetes The incidence of type 1 disease is rapidly increasing in
(insulin-dependent) would result in a method for disease specific regions and shows a trend towards earlier onset.
prevention, perhaps by the end of the decade. The disease The incidence of type 1 diabetes is highly variable among
was known to result from an immunological destruction different ethnic populations.5 The overall age-adjusted
of the insulin-producing islet  cells. An interplay between incidence of type 1 diabetes varies from 0·1/100 000 per
genetic susceptibility (polygenic) and a triggering year in the Zunyi region within China to more than
environmental agent was thought to provide the 40/100 000 per year in Finland.6,7 This represents more
fundamental elements for disease formation and, than a 400-fold variation in the incidence among about
additionally, form potential targets for both improved 100 populations analysed. Furthermore, the incidence of
disease prediction and prevention.1,2 The moderate to type 1 diabetes seems to be increasing in almost all
long-term symptomless phase of the disorder could populations, with the increase particularly high in
readily be identified through serological markers of anti- nations with a low incidence of this disease. The
islet immunity (eg, autoantibodies to islet cell cytoplasm incidence of type 1 diabetes will be about 40% higher in
[ICA], insulin [IAA], glutamic acid decarboxylase 2010 than in 1997.7
[GADA], and ICA512/IA2A). The ability of such markers However, these data also suggest that the polar-
to serve as predictive tools provided the opportunity to equatorial gradient (ie, the north-south gradient) described
undertake clinical trials for testing potential preventive for disease incidence5,8 is not as strong as previously
therapies. Research in animals suggested a fixed natural thought.9 For example, whereas most populations with
history of disease that was subject to an undemanding very high incidence rates are of European origin, high
preventive intervention with an extensive number of incidence rates have also been noted in Kuwait and Puerto
therapy agents.3 Rico. The two areas with the highest incidence rates,
This knowledge fostered long-held opinions that it Finland and Sardinia, are 3000 km from each other,
would only be a matter of time before scientists found a whereas Estonia, bordering Finland, has an incidence rate
prevention or a cure for diabetes. Additionally, of about one-quarter of its neighbour.7 Such variations in
information about the benefits of intensive insulin therapy disease incidence are increasingly being seen to follow
generated substantial optimism for improved patient ethnic and racial distributions, which indicates that we
care.4 Today, however, the pathogenic and therapeutic should not rely on a model that accounts only for
complexity of this disorder is better appreciated. The geographic position. The explanation for these wide
optimism remains but there is a consensus that much disparities in risk within ethnic groups probably lies in
remains to be learned before radically improved treatment differences in genes or environment.
becomes a reality. The focus of this seminar is to highlight The EURODIAB collaborative study,6 a registry
new perspectives in the pathogenesis and treatment of consortium involving 44 centres representing most
type 1 diabetes. European countries and Israel, indicates an annual rate of
increase in type 1 diabetes incidence of 3–4%, but in
some central and eastern European countries (most
Lancet 2001; 358: 221–29 notably those of the former communist bloc), the
increase is far more rapid. Furthermore, examination of
Department of Pathology, Immunology, and Laboratory Medicine, the rates of type 1 diabetes as a function of the age at
College of Medicine, University of Florida, Gainesville, FL 32610 onset showed rates of increase of 6·3%, 3·1%, and 2·4%
0275, USA (M A Atkinson PhD); and Barbara Davis Center for in populations of children aged 0–4 years, 5–9 years, and
Childhood Diabetes, University of Colorado Health Sciences 10–14 years, respectively. These findings support the
Center, Denver, CO, USA (G S Eisenbarth MD) impressions of health-care professionals that they are
Correspondence to: Dr Mark A Atkinson seeing more and more cases of type 1 diabetes, especially
(e-mail: in younger children.

THE LANCET • Vol 358 • July 21, 2001 221

For personal use. Only reproduce with permission from The Lancet Publishing Group.

immunology.14 Recent technological advances in gene beings and animal models) support an alternative and identification and the formation of cooperative study more complex model (figure 1) wherein the penetrance groups should enhance the speed at which true genes for and expression of heritable immune aberrations (ie. breast feeding versus early introduction of cow’s milk also on additional susceptibility associated with DQ.13 view is supported by the complexity of elucidating and This locus is a polymorphic region that maps to a identifying exposures (qualitatively and quantitatively) to variable number of tandem mini-satellite repeats environmental factors even in the first few years of life. 2001 For personal use. but (eg. 0405 0301 0302 intervention prediction 0301 0501 0201 Ability to predict type 1 diabetes Moderate risk 0801 0401 0402 0101 0101 0501 -cell mass 0901 0301 0303 Weak or moderate 0401 0301 0301 protection 0403 0301 0302 0701 0201 0201 1101 0501 0301 Strong protection 1501 0102 0602 1401 0101 0503 Ability to prevent 0701 0201 0303 Lower Less effective type 1 diabetes accuracy in methods for Type 1 diabetes risk associated with HLA-DR and HLA-DQ haplotypes disease preventative prediction intervention Onset of overt type 1 Genes diabetes Genes for type 1 diabetes provide both susceptibility towards. environmental risk determinants contribution to the pathogenesis of type 1 diabetes subject to the most widespread investigation can be remains unclear. (VNTR). the function of only two non-HLA obvious environmental candidates causes some loci are known. 0402. To date.19 from the USA 1% of children with type 1 diabetes are DR2 and BABYDIAB study20 from Germany have not (DQB1*0602) positive. early infant diet disease associated with HLA-DR3 and HLA-DR4. Another locus associated Environmental agents may serve as modifiers of disease with type 1 diabetes in some populations is IDDM12 on pathogenesis rather than as triggers. the disease. with short class I VNTR alleles predisposing to especially if environmental agents act asynchronously or type 1 diabetes. The importance of the class II classified into three groups: viral infections (eg. The traditional model provided represents common features cited within The genetics of type 1 diabetes cannot be classified numerous publications and presentations from 1986–98. with a number (about 20) of non.2.26 More recent observations (both in human responsiveness. and protection from. and over-ride other genetic or environmental factors which timing of vaccination.1. investigational programmes.10 contrast to Finnish reports suggesting the potential for Type 1 diabetes represents a heterogeneous and such associations. type 1 diabetes are uncovered. highlights the importance of documented any effects on disease of early cow’s milk genetics in disease development—ie. and climatic addition to forming susceptibility.11 The function of these genes in terms of an Despite much research. in combination with inherent 222 THE LANCET • Vol 358 • July 21. presentation of responsible for triggering type 1 diabetes have been antigenic peptides to T lymphocytes). The improve and refine our understanding of potential observation that 20% of people from Europe or the USA environmental-like triggering factors in infancy. immune dysregulation). the DAISY study18. on chromosome 6p21. Only reproduce with permission from The Lancet Publishing Group. accounting for about 45% of genetic susceptibility for Environment the disease. which has an apparent action on the of type 1 diabetes postulates that an environmental agent cytotoxic T-lymphocyte-associated protein 4 (CTLA–4) triggers the onset of disease in genetically susceptible that is responsible for modulating immune individuals. IDDM2 on chromosome 11p5·5 pessimism that such agents will soon be identified. Although Figure 1: Traditional and modern models of the pathogenesis many chromosomal loci associated with such activities and natural history of type 1 diabetes have been located. no environmental agent or agents immune response is well known (ie.SEMINAR Risk HLA More effective Higher methods for accuracy in HLA DRB1 HLA DQA1 HLA DQB1 preventative disease High risk 0401.12 However. and environment in histocompatibility complex (MHC) HLA class II region the natural history of type 1 diabetes. Prospective studies of infants developing anti- haplotypes provide significant protection. Type 1 diabetes seems Other non-genetic disease-modifying factors include somewhat unique among autoimmune diseases in that in vaccine administration. and toxins (eg.26 The modern model expands and updates the traditional intermediate inheritance of a specific set of genes. yet their specific uncovered. certain MHC influences. with islet autoantibodies and eventually diabetes could protection dominant over susceptibility (table). components). These studies stand in modest predispose to disease.25 a dominant protective effect. N-nitroso derivatives). or diabetes. breast feeding.24 This contributes about 10% towards disease susceptibility. recessive. .10 The model by inclusion of information gained through an improved most important genes are located within the major understanding of the roles for genetics. enteroviral infection. few true genes have been identified. psychological stress. The traditional view chromosome 2q33. while the longer class III alleles provide multifactorially. to date. carry the protective HLA-DR2 haplotype. many of which were derived from one schematic of the so-called stages of type 1 according to a specific model of dominant. formally termed (IDDMl). one HLA allele can exposure. the failure of most of these HLA loci contributing to disease susceptibility already studies and others to find disease associations with identified.21-23 Although still early in their polygenic disorder.15–17 chains and DQ-chains. haplotype not only depends on the well-known risk for coxsackievirus and cytomegalovirus). yet fewer than However.

Between to type 1 diabetes.41 Pancreatic islets obtained in this way have and standards of sanitation have improved. and considered a disorder predominately of children and ICA512/IA2A. SEMINAR target organ defects. Most individuals progressing to overt diabetes During the past 10 years. much progress has occurred in express multiple anti-islet autoantibodies by the time of determining the biochemical nature of the autoantigens diabetes onset. Germany. different model in which the disease can occur at any age. ten times greater than type 1 diabetes). with a type 1 diabetes and individuals from the general predominance of CD8 T cells.46 type 2 diabetes actually have type 1 diabetes. recognised by anti-islet autoantibodies. quantitative assays with high specificity Type 1 diabetes is not a disorder limited to young and sensitivity for type 1 diabetes are now available for people. with effect and technical reasons. despite best efforts. studies at the level of cellular immune function also report early of this test have greatly aided our knowledge of the immune dysregulation.38 diabetes. The slow onset and There is as yet no identified agent capable of preventing protracted disease course has led to the disease diabetes. Finally. and macrophages.36 Given the large numbers of dietary factors. patients with care access. most notably that of aberrant pathophysiology of type 1 diabetes and facilitated a production of prostaglandins. B lymphocytes. but commonly develop by age 9 months. sanitation. only recently have we been able to dependent upon both timing and quantity of exposures extend our knowledge of the insulitis lesion. in some countries such as observation that multiple infections during the first few Japan. in particular. The first autoantibody for infants is usually.39 For ethical during different stages of development. these with a very low risk of progression to diabetes (panel 1). despite wide geographical of MHC class I moleculars correlated with deteriorating differences in the populations studied (eg. in part.27-29 Similarly. whereas islet- autoantibodies disappear slowly (ie. with GADA being the second most prevention frequent. shown various degrees of reduction in  cell volume in all patients. the degree of insulitis and hyperexpression diabetes. who were followed from birth to measure showed hyperexpression of MHC class I molecules. and are unable to is hard to standardise and reproduce. Transplacental detected on  cells within inflamed islets. activation. with a small percentage of infants who have These results suggest that an interaction between Fas on antibodies persisting until 1 year of age.36. yet there are cytoplasmic islet-cell Specifically.35 However. through (figure 1). 2001 223 For personal use. Interestingly. Historically. the infiltrate was composed of CD8 and CD4 of young children (first-degree relatives of patients with T cells. are part of the life-long influence of designation of such individuals as latent autoimmune multiple environmental factors such as infectious agents.40 In terms of uncovering Finland. the assay can ages 10–14 years). a marker of monocyte means for predicting future cases of the disease. Interestingly. very few the cytoplasmic islet-cell-antibody test. However. Clinically. most cases of type 1 diabetes develop during years of life are associated with a reduced risk of type 1 adulthood. and gangliosides. increased risk has been Examination of islet inflammatory infiltrate suggests associated with perinatal infections coupled with a Fas-mediated apoptosis may provide one mechanism of protective effect of preschool day care. the islet-cell-antibody assay respond to oral hypoglycaemic therapy. . In the samples in which insulitis was Researchers31–34 have reported results from investigations detected.42 Without question. 5–30% of patients initially diagnosed with autoantibodies that are not reactive to these molecules. do not Finally. yet insulitis could only be identified in about Pathogenesis half patients tested. the results of the different potential mechanisms of  cell destruction. at 6–9 months of infiltrating mononuclear cells expressed Fas ligand. This assay children expressing autoantibodies react with more than measures the degree of binding of immunoglobulin with one islet antigen and have only transient expression of islets compared with acinar pancreas. Mononuclear cell infiltration into the the age-dependent modifying influence of infections on pancreatic islets (insulitis) and a reduction of insulin- the developing immune system. Inflamed islet cells population). glutamic acid in adults. environmental pathological features of the pancreas when obtained at encounters could act to promote and attenuate disease necropsy from patients with type 1 diabetes.37 Such Nevertheless. LADA are likely to comprise about half all patients with A specific example supporting this model includes the type 1 diabetes. Colorado. children develop autoantibodies than at any other time. recent studies support a detect autoantibodies reacting with GAD. and uses frozen autoantibodies. detection of islet-cell antibody in the patients are best identified by the expression of anti-islet absence of the above three autoantibodies is associated autoantibodies.48. and vaccinations). ICA512/IA2A.43–45 Determination of autoantibodies young adults (the disease is commonly referred to as reacting with these three molecules has improved the juvenile diabetes because it has peak expression between islet-cell-antibody assay.49 There are many reasons why this is the case.34 Other studies of immune dysregulation sections of human pancreas.40. and USA). and environmental toxins as well as new patients diagnosed with type 2 diabetes (estimated to be classes of influencing variables (eg. Anti-islet  cells and Fas ligand on infiltrating cells might trigger autoantibodies can be present in the first few months of selective apoptotic -cell death in inflamed islets. the though a few individuals lose antibody expression gold-standard assay for anti-islet autoantibodies has been without progressing to diabetes. expression of autoantibodies and development of type 1 Furthermore. Only reproduce with permission from The Lancet Publishing Group. THE LANCET • Vol 358 • July 21. diabetes of adults (LADA). Furthermore. The autoantibodies are usually persistent. a theory linked to -cell destruction.41 age). Fas was populations are highly concordant. IAA. glycaemic control and GADA. but not Prediction and prospects for disease exclusively. More studies need to be done to ages 9 months and 3 years a greater percentage of confirm these findings.30 This newer model may explain. why examination of samples obtained from pancreatic biopsy the frequency of type 1 diabetes has increased of prediabetic patients and those with recent-onset type 1 dramatically during the past three decades as healthcare diabetes.25. GADA. Type 1 diabetes has historically been decarboxylase (in particular GADA65). Rather than mere producing  cells have long been recognised as key exposure to one particular agent. and the rate of disease may be equally prevalent three major islet autoantigens: insulin.47 maintain adequate glucose control. individuals are commonly treated with oral agents. health. leading life.

the onset of this disease should be undertaken. and clinical history (eg. and metabolic markers of the disease to identify be clinically effective. a population groups at different stages of the disease process situation that has positioned the need for a safe and can be implemented. islet-autoantibody-positive relatives of a vention Trial (ENDIT)50 has enrolled more than 550 person with type 1 diabetes). Both models have randomly assigned nicotinamide or placebo. participation among some health. the With this model. serum-sample handling mistakes occasion may approach true positive rate only a few of which will be addressed here. No major strengths and weaknesses in terms of therapeutic side-effects have been reported with this agent. although major obstacles for design of trials that provide answers in a major benefit to knowledge about the natural history of short time frames.50. the delaying. and. The first would involve therapy of high-risk risk. participants are a general population approach. we propose a new generation of process of disease prediction (ie. but also should lead to never develop type 1 diabetes. using immunological. although would ideally be implemented. in an agent capable of preventing type 1 diabetes could soon combination. the Diabetes and benign therapy capable of interrupting adverse Prevention Trial (DPT-1)51 was started in 1994 with the immune events and environmental agents (such as a goal of finding out whether antigen-based therapies with vaccine) or alterations in lifestyle providing avoidance of insulin (ie. A wide body of evidence. yet in terms of stress. both in animal field is currently being directed at taking a step back models of type 1 diabetes and in individuals with towards trials as they were done in the 1980s and early increased risk of the disease. As a field has been referred to as the treatment dilemma result. Another issue is the lack of an obvious therapeutic A second major obstacle facing the diabetes prevention agent for the next round of large prevention trials. and prevention strategies in different period in which disease prediction is less accurate. the general population approach insurability. First. autoimmunity) no known autoantibody may aid in diagnosis Autoantibodies can appear at any age. Doing clinical trials in those type 1 diabetes—in the absence of a preventative agent— populations who are at higher risk might prove more has raised ethical considerations related to the induction costeffective (in terms of a trial) and efficient. including two large trials aimed at diabetes will most probably address two distinct preventing disease in individuals considered at increased populations. and results intervention. lifestyle changes. been limited. reserve for confirmation if needed Specific autoantibodies expressed vary. and Measurement over time is important often develop sequentially Antibodies reacting with a single islet autoantigen Antibodies reacting with multiple epitopes of a single molecule or do not always indicate impending progression multiple islet autoantigens are more likely to be disease associated to type 1 disease Autoantibodies can disappear. although there would be few would argue that such a discovery would represent a substantial costs associated with screening general milestone for type 1 diabetes. By contrast. or at least preventive measures within the general population. and. disease frequency and unpredictable time of onset form The ability to predict future cases of the disease. supports the notion that the 1990s: studies to identify new and perhaps more most effective interventions will be those that are begun promising agents capable of preserving -cell function. in low-risk Rely on a serum determination of autoantibodies on more than one populations. The identification of such greater insight into disease pathogenesis. there is still a possibility that Another challenge relates to properly addressing. insulin secretion. 2001 For personal use. Once a promising agent is identified. In the general population approach. an agent has thus far proven extremely difficult to find. and potential effects on of humanitarian benefit. with IAA Measure multiple biochemical autoantibodies most common in young children and GADA more frequent in adults Subset of apparent type 1 patients express HLA typing. As a result. Despite these challenges. diabetogenic dietary components) risk relatives. The second would be that of relatives of patients with type 1 diabetes. in some cases. attempts to prevent type 1 address this question. exploratory pilot studies. the questions of whom to treat and what be found. In theory. or oral insulin vs placebo to intermediate- 224 THE LANCET • Vol 358 • July 21. Only reproduce with permission from The Lancet Publishing Group. Yet in terms of doing clinical trials to test whether or not studies aimed at preventing. overt diabetes. In the USA. controversy has existed as to populations. a conflict (both ethical and prospective randomised controlled studies with clinical) exists wherein the most effective forms of therapy appropriate statistical power and objective endpoints can might involve the early treatment of individuals in a be designed. if a new therapy is shown to genetic. screening programmes has. Use biochemical autoantibody assays with documented proficiency specificity. low-dose parenteral insulin therapy to high- disease risk factors (eg.51 The European Nicotinamide Diabetes Inter- individuals (eg. . a major effort in the type 1 diabetes prevention (figure 2). may be more important because about 85% of newly- care professionals and acceptance by family members in diagnosed patients have no family history of the disease. As a result. then a larger preventive trial should risk) is most accurate in the period close to the onset of be initiated.SEMINAR Panel 1: Caveats of autoantibody determination Caveat Suggestion Assays vary dramatically in sensitivity. early in the autoimmune disease process. a safe are expected within 2 years. Not only will these studies ascertain benign form of therapy against treating those who might potential efficacy and safety. and ability to standardise testing and specificity >99% for screening Do not use cytoplasmic islet-cell antibody assay for screening. Several studies are currently being done to agent to use.

36. IAA. are the findings that among patients with diagnosis and therapy of these under-diagnosed and type 1 diabetes. intestinal other ethnic groups with diabetes do not have type 1A cancer. As disease on subsequent intestinal biopsy. Anti-islet autoantibody deter- mination with specific assays (eg. An expert committee of the American Time Diabetes Association (ADA) has published aetiological diagnostic criteria.65 Hence. Thus. on the basis of hyperglycaemia.56. 2001 225 For personal use. routinely screen (including overweight non-insulin-treated adults) have for coeliac disease and recommend a gluten-free diet upon anti-islet autoantibodies and in fact have a variant of type diagnosis. . no symptoms.63.62 Whether such previously indicated.60 Screening for autoantibodies to tissue ICA512A/IA2A). Only reproduce with permission from The Lancet Publishing Group.52 These criteria recognise that most patients with type 1 Immune Environmental diabetes are not children at onset. mass must be considered when assigning individuals to various therapeutic protocols.61 A high diabetes. about one in 20 have coeliac disease with commonly overlooked diseases.64 Many other their relatives are at increased risk for other organ-specific autoimmune diseases are associated with type 1 diabetes. -cell mass GADA IAA Genetic Progressive loss of Diagnosis predisposition insulin release The diagnostic criteria for different Early forms of diabetes are being revised. and osteoporosis—as are patients with diabetes. autoimmune diseases. The ADA committee insulin response genes (IVGTT) recommended using the term imparting Variable insulitis type 1A diabetes for immune. a high that routine testing of thyroid-stimulating hormone index of suspicion for other forms of autoimmunity (TSH) is commonplace. In contrast. Type 2 diabetes is a term to be used for idiopathic Overt diabetes forms of diabetes with insulin Pre-diabetes resistance and without severe insulin deficiency or dramatic loss of Time  cells. IVGTT=intravenous glucose tolerance test. occurring in about 1A diabetes. Many studies from animal models of type 1 diabetes in combination with a much more limited series of mutations of the hepatocyte nuclear investigations in human beings suggest that early intervention not only is more effective in terms of disease prevention.57 About 90% of white children will have at least concentration of transglutaminase is predictive of coeliac one of these autoantibodies at disease diagnosis. particularly in Europe.53 dysregulation triggers and and that not all individuals at onset regulators Modern model are insulin dependent54 or have an IAA immune-mediated form of dia- 55 betes. Gestational diabetes was classified in a separate category. pre-diabetes Overt diabetes periodic updates of diagnostic criteria are likely to follow. GADA. but also often requires more benign forms of therapy.59. but in as many as one in We know that both the patient with type 1 diabetes and 200–500 patients with type 1 diabetes. such as thyroid autoimmunity in including characteristic autoimmune syndromes such as type 1 diabetes and Addison’s disease. or insulin-dependent diabetes Interactions Loss of first phase mellitus (IDDM) are no longer between -cell mass used. can be used to diagnose type 1A transglutaminase can identify such individuals.58 Less known. the degree of residual -cell of diabetes. 5–30% of symptomatic disease—is not yet clearly defined. susceptibility -cell sensitivity Glucose intolerance mediated diabetes and type 1B for and resistance to injury Absence of C-peptide non-immune diabetes with severe 52 insulin deficiency. Although this model does not restrict the ability to provide classification of other specific forms preventative intervention therapy for individuals at or near onset of disease. the terms juvenile GADA ICA512A ICA onset. GADA=glutamic acid The diagnosis of diabetes is made decarboxylase. a practice that will allow for early significance. environmental Therapy did not provide evidence event for disease prevention and we Overt immunological expect the results of the oral insulin abnormalities therapy to be released with 2 years outcome data for the low dose Islet-cell antibody parenteral insulin. Figure 2: The “treatment dilemma” for type 1 diabetes Specific genetic syndromes (eg. Addison’s disease is rare. SEMINAR risk relatives) would prevent or Precipitating Traditional model delay the onset of diabetes. but of increasing should be considered. Graves’ disease APS-I (autoimmune polyendocrine syndrome) and and hypothyroidism are so prevalent in type 1 diabetes APS-II. the ability to factor and glucokinase genes) identify an individual who will truly develop type 1 diabetes (among an at-risk population) increases as the contribute to the final category for individual approaches onset of overt disease. THE LANCET • Vol 358 • July 21. for patients with type 1 diabetes. as many as 50% of children from individuals are at increased risk for anaemia.37 one in 20 000 individuals. IAA=insulin autoantibodies. pre-diabetes Glucose intolerance As our knowledge of the Late C-peptide absence pathogenesis of a disease increases. indeed most have type 2 diabetes.62 Several adults with what initially seems to be type 2 diabetes diabetes centres.

In many diabetes chronic complications.75 Regular insulin the skin surface by iontophoreses. a concept that remains common among those unfamiliar with the disorder. The availability of therapy. either with insulin pens or family. These devices after subcutaneous injection due to alterations in the use a number of strategies for sampling interstitial molecule that interfere with formation of insulin glucose. 30 min to 1 h before). However. Only reproduce with permission from The Lancet Publishing Group. Although even with glucose monitoring and routine determination of HbA1c. Unfortunately. a factor perhaps related to public awareness of Reproducible absorption diabetes within populations. postmarketing experience will be important to Most individuals in more-developed countries are now document whether the altered insulins have any treated with recombinant human insulin. this is not the case.66. although during the next decade.67 The Diabetes Control and Complications Trial administration. introduction ultralente) this has been difficult to achieve.70 showed the importance of possible to administer rapid-acting insulin after the meal. there have been improvements in rapid-acting insulins has also contributed to the greater type 1 diabetes therapy that may bring about advances use of insulin pumps. Acute morbidity and needs to be given before meals (ie.76. including the placement of a subcutaneous multimers. Pre-packaged insulin mixtures USA (with a population of 4 million) about one child dies Improved laboratory services at the onset of type 1 diabetes every 2 years. it is now (DCCT) research group4. the long-acting insulin should and devices that might be keys to this evolutionary provide a peakless basal insulin level and thus not progress include improved devices for home blood.SEMINAR Contrary to popular beliefs. and classic Islet transplantation symptoms of diabetes (ie. although ACE inhibitors for nephropathy permanent neurological deficits could remain. the increasing availability of standard human insulins (eg. Humalogue and devices that continuously monitor cutaneous interstitial Aspart insulin). However. These deaths are characteristically associated VEGF measurements for retinopathy with ketoacidosis and development of cerebral oedema. introduction of human insulin has come the ability to alter What is likely to represent a major milestone in the the insulin molecule for improved pharmacokinetics. new long- of the first sensors for continuous glucose monitoring. Similar effects can be obtained with multiple daily hypoglycaemia.72 therapy of type 1 diabetes is the discovery that interstitial Thus.80 The first generation of practical variability of insulin absorption (eg. a factor that seems to greatly increase the risk of subsequent death at presentation. development of a series of insulin analogues. strict metabolic control for the delay and prevention of thereby alleviating parental stress.79 Although these new insulins appear chronic complications (panel 2). it is recommended that rapid-acting insulins be represents a major undertaking for the patient and their administered with each meal. in Fructosamine many instances.77 These pumps. Although type 1 diabetes usually established type 1 diabetes develops slowly.69 Bedside Rigorous control of lipids with new generation statins tests for hyperglycaemia are readily available and a high Protein kinase C inhibitors index for suspicion of diabetes is important.82 One device uses a sub- 226 THE LANCET • Vol 358 • July 21. microalbuminuria clinical history is almost always associated with delayed Assessment of endproducts of advanced glycosylation diagnosis. and acting insulin (eg. especially for Improved digital retinal-imaging systems children with nausea. mortality as well as a series of chronic complications still yet it is common for a toddler to refuse food after insulin occurs. The examples of concepts acting insulin. promising.74 These insulins are rapidly absorbed glucose are being introduced into practice. 2001 For personal use.66. The rate of death at Insulin analogues with improved pharmacokinetics onset of type 1 diabetes apparently varies between Faster absorption countries. . Continuous glucose-monitoring devices Severe metabolic decompensation as well as rapid Measurement of real time bicarbonate administration are risk factors for the Non-invasive or minimally invasive development of cerebral oedema. achieving such control centres. pulmonary) are also being studied. insulin Glargine) should be an development of therapies aimed at delaying or preventing improvement. Xenoislets Encapsulation Treatment Improved immunosuppressants Insulin Gene therapy The 1921 discovery of insulin was initially thought to Tolerance represent a cure for the disease. polydipsia. With these new analogues. With the deleterious effects. polyuria. Ideally. contribute to erratic insulin therapy. expensive. acute illness.71 Nevertheless. allow for the setting of multiple basal rates of A substantial advance in diabetes care would allow insulin administration and bolus administration with each individuals to have euglycaemia without risk of severe meal. insulin analogues are now available that can be glucose reflects blood glucose with a sufficiently short lag absorbed more rapidly and that can decrease the time to be of clinical use. The risk of severe hypoglycaemia limits the chance with pumps. and the Point-of-care testing for HbA1c. death at the onset of type 1 Panel 2: Therapeutic innovations for patients with diabetes still occurs. and early therapy of cerebral Drugs for prevention of specific complications oedema with mannitol might prevent death. vomiting. the onset of Glucose hyperglycaemia can often be abrupt.68 Careful monitoring of mental status is essential. A simple example of their use relates to the sensor81 or use of an electric current to bring glucose to care of toddlers with type 1 diabetes.78. Alternative routes of insulin administration of the patient achieving euglycaemia with insulin (eg. and with much less effort than is currently injections of rapid-acting insulin combined with long- devoted to intensive therapy. as shown in studies which have Improved home devices and monitors prospectively followed up children.67 In the state of Colorado. and weight Stem cells loss). the first health-care provider to see a HbA1c child with type 1 diabetes does not properly diagnose the Data download to physician via web disorder.73.

N Engl J Med 1994. many of the chronic complications of their promise of providing accurate real-time glucose type 1 diabetes can be delayed or prevented. 1 Castano L.94 Finally.89. The basic biological barriers Furthermore. group has introduced a modified immunosuppressive 2 Atkinson MA. but it may development of dramatically improved therapy and trials be at the cost of surgical complications and immuno. because such values are used to calibrate tolerance-inducing therapies such that life-long the monitors. but procedures as simple as yearly morbidity.84 Despite these maintained at less than 100 mg/dL (2·6 mmol/L). From a surgical standpoint. For these device can be useful in discovering severe nocturnal procedures to have a major clinical impact. and the the transplant. Eisenbarth GS. patients and their families is a standard of care. finger-stick testing (or forearm testing with new meters) of Additional hopes are high for the development of blood glucose. but also to block recurrent autoimmune islet diabetes should have routine foot examinations and destruction. as well as 1-year graft survival of more within the European and North American continents and than 90%. Immunol Today 1994. and many islet isolations do not yield usable monitoring. The promising for promotion of euglycaemia. We predict that these insulins or insulin pumps) in real-time on the basis of therapies will certainly evolve over the next decade and glucose values. we believe they will revolutionise the therapy individuals this does not happen.85 The immunosuppressive regimens for aggressive therapy of early lesions.81 The device that uses an electric current does islets.90 one using gut K cells and the other involving require extensive study. more than one donor pancreas is needed for 4 Diabetes Control and Complications Trial Research Group. few patients will have their have to be downloaded at a physician’s office. much to their ability to procure and isolate islets. showed that the insulin gene delivery could be in national health systems and insurance companies both glucose responsive and establish euglycaemia. Only reproduce with permission from The Lancet Publishing Group. sirolimus.91 Ophthalmological Other treatments screening needs to be made more accessible. and should provide the added information therapy of type 1 diabetes.87 Immediately after Providing the basics of appropriate care. Cures have been progressive course of diabetic renal disease. islet transplantation represents an attractive alternative in that islets can simply References be infused into the liver through a catheter. the group’s success owes as mice: a genetic program interruptible by environmental manipulation. significant obstacles remain. The Edmonton 8: 647–79. Leiter E. Many centres now connect the pancreas directly to the bowel by anastomosis rather than Present and future using bladder drainage of exocrine secretions. regimen that involves the use of daclizumab. 331: 1428–36. devastating disease. SEMINAR cutaneous sensor and provides up to 3 days of glucose each patient. the consideration for patients with diabetes who require renal development of the disorder is a life sentence to an transplantation. and the glucose toxicity. Such a diabetes cured with islet transplantation. and the rat. should be our response to this suppression. and when coupled with early would obviously prefer the disorder to be cured without angiotensin-converting-enzyme therapy can change the the need for insulin injections. . &c). because data yet. however. The pathogenesis of insulin dependent diabetes. these devices do not eliminate the need for to using such cells are in the early stages of research. or for rare instances where patients have extremely tedious and only partly effective therapy.90 funding such new treatments. However. for diabetes prevention. mouse. mortality. Gene therapy might be needed to implement intensive insulin therapy. control is essential. Type 1 diabetes: a chronic autoimmune until the study from the Edmonton group. of islets from stem cells. Annu Rev Immunol 1990. of glucocorticoid therapy. intractable diabetes-related problems. and may offer a major contribution to the need for continuous immunosuppression. The ideal is for continuous monitoring with immunosuppression will not be needed.92 so that all patients are excited about the promise of improved glucose appropriately screened. but there of islets will be required (xenogeneic transplants. hyperglycaemia can be cured. make pancreas transplantation a realistic this number will dramatically increase. given the constraints. treatment of proliferative retinopathy could prevent the bulk of diabetes-related blindness. 15: 115–20.93 LDL accomplished with both pancreas transplantation83 and cholesterol for patients with diabetes should be more recently with islet transplantation. growth is a need for devices with real-time information. with non- Although physicians treating patients with diabetes are mydriatic digital retinal imaging.86 These More than 2 million individuals have type 1 diabetes improvements. all patients with rejection. Such a therapeutic strategy will come should compete with mechanical insulin delivery systems much closer to the manner in which healthy individuals coupled to real-time glucose monitoring to revolutionise secrete insulin. and allowing for much lower doses delay of complications in many patients. and quality-of-life issues) caused by ophthalmologic eye examinations coupled with early wide swings in blood glucose concentrations. Two recent development of clinical algorithms for such therapies will studies. Atkinson M. 2001 227 For personal use. Autoimmune diabetes in NOD and tacrolimus. Periodic microalbuminuria testing monitoring and insulin therapy. glucose concentrations on a real time basis. Meticulous glucose of type 1 diabetes. islet transplantation was sporadic at best. 3 Bowman M. a strong pancreas transplantation have improved greatly during the commitment to routine procedures by both the patient as past decade. Indeed.89. Several centres will be implementing the Edmonton not have an alarm nor does it allow the patient to know protocol during the next year with great hope for success. Limitations Selective protein kinase C inhibitors may provide a so- for both forms of transplantation include the relative lack called golden bullet for microvascular disease caused by of organ donors for allogeneic transplantation. with drugs such as mycophenolate mofetil well as the health-care team should lead to prevention or replacing azathioprine. ameliorating the problems (ie. and there is likely to be a lag time liver cells. Furthermore. Experiences with alarms for high-glucose and low glucose concentrations. the medical management of diabetic retinopathy and diabetic immunosuppression is needed not only to prevent neuropathy and nephropathy. The THE LANCET • Vol 358 • July 21. but for many information. improvements. a new source hypoglycaemia or to modify insulin therapy. At present. and administration (with multiple injections of rapid-acting that isolated islets can cure diabetes. If the devices live up to Even today.95 In short.88 successful disease of human. Maclaren NK. transplantation have taught researchers that autoimmune as well as allowing patients to modify their insulin and alloimmune islet destruction can be overcome.

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