Doi:10.1016/s0140-6736(06)68341-4

Type 1 diabetes
Type 1 diabetes accounts for only about 5–10% of all cases of diabetes; however, its incidence continues to increase Lancet 2006; 367: 847–58
worldwide and it has serious short-term and long-term implications. The disorder has a strong genetic component,
See Comment page 795
inherited mainly through the HLA complex, but the factors that trigger onset of clinical disease remain largely
Division of Endocrinology,
unknown. Management of type 1 diabetes is best undertaken in the context of a multidisciplinary health team and
Department of Paediatrics,
Hospital for Sick Children and
requires continuing attention to many aspects, including insulin administration, blood glucose monitoring, meal
University of Toronto, Toronto,
planning, and screening for comorbid conditions and diabetes-related complications. These complications consist of ON, Canada M5G 1X8
microvascular and macrovascular disease, which account for the major morbidity and mortality associated with type
1 diabetes. Newer treatment approaches have facilitated improved outcomes in terms of both glycaemic control and [email protected]
reduced risks for development of complications. Nonetheless, major challenges remain in the development of
approaches to the prevention and management of type 1 diabetes and its complications.
In this age of increasing obesity, the epidemic of type 2 susceptibility, roughly 15% from two other genes— diabetes threatens both to overwhelm health care insulin-VNTR (IDDM2) and CTLA-4 (IDDM12)—with services and to obscure the health care implications and minor contributions from the other IDDM genes.4–6,9 challenges of type 1 diabetes.1,2 Although type 1 diabetes Both high risk (eg, DR3/4, DQA1*0301-DQB1*0302, accounts for only 5–10% of all those with diabetes, it and DQA1*0501-DQB1*0201) and protective HLA remains a serious chronic disorder, usually beginning haplotypes (eg, DQA1*0102-DQB1*0602, associated earlier in life than type 2 diabetes, but with important with diabetes resistance, and DR molecules such as DRB1*1401, associated with protection from diabetes) In this seminar on type 1 diabetes I emphasise: have been identified.4 These susceptibility genes are (i) current theories of pathogenesis; (ii) epidemiology thought to be important regulators of the immune and presentation; (iii) management; (iv) diabetes-related response. Other genes associated with either rare complications; (v) psychosocial concomitants; and syndromes including diabetes (eg, AIRE and Foxp3) or (vi) the challenges facing diabetes researchers and other autoimmune conditions (eg, PTPN22) might health-care professionals. Although not dealt with in this also provide important insights into the immune Seminar, issues such as diabetic ketoacidosis and its prevention and management, and the challenges of The next step requires exposure to one or more diabetes in pregnancy for both mother and fetus, should environmental triggers that alter immune function, not be overlooked in the comprehensive care of thereby initiating ␤-cell destruction. Putative triggers include viruses (eg, enteroviruses, coxsackie, congenital Pathogenesis
Chromosome Candidate genes/markers
Type 1 diabetes is a condition in which pancreatic ␤-celldestruction HLA DR/DQ regionMajor role in presentation of peptides to T cells deficiency.3–6 Two forms are identified: type 1A results Insulin-VNTR Protection associated with greater from a cell-mediated autoimmune attack on ␤ cells,4–6 whereas type 1B is far less frequent, has no known CTLA-4, CD28 Related to T-cell activation, cause, and occurs mostly in individuals of Asian or African descent, who have varying degrees of insulin For many of those not listed (IDDM 3-11, 13-17), either the responsible gene remains deficiency between sporadic episodes of ketoacidosis.7 unidentified or the gene function is uncertain in relation to type 1 diabetes.
In the 1980s Eisenbarth8 proposed the current model Table 1: Important susceptibility loci for type 1 diabetes
for the development of the immune form of type 1diabetes and although our understanding hasprogressed significantly since then, the basic aspects of Search strategy and selection criteria
this model remain pertinent.4–6 This model postulatesthat everyone is born with a degree of susceptibility to PubMed and the Cochrane Library database were searched with the terms: “type 1 develop type 1 diabetes: for some this susceptibility is diabetes”, “insulin-dependent diabetes mellitus”, “juvenile diabetes”, “insulin” and high, for others very low. Susceptibility is largely “insulin analogues”, “blood glucose monitoring”, “glycosylated haemoglobin” or inherited, residing predominantly in the HLA genotypes “haemoglobin A1c”, “glycaemic index”, “diabetes-related complications”, “diabetic DR and DQ, and to a lesser extent in a host of other nephropathy”, “retinopathy”, “neuropathy”; and “macrovascular complications of genetic loci termed IDDM (insulin-dependent diabetes diabetes”. Most recent papers, systematic review articles, meta-analyses and evidence- mellitus) susceptibility genes (table 1). The HLA locus based guidelines were preferentially selected.
is thought to confer about 50% of the genetic www.thelancet.com Vol 367 March 11, 2006
rubella),10,11 environmental toxins (eg, nitrosamines),12 or disorders are less frequent in children in large families or foods (eg, early exposure to cow’s milk proteins, cereals, those families receiving day care than in children in or gluten).13–17 A close relation has been identified only small families or those not in day care.29,31,32 Similarities with congenital rubella.10,11 The results of a 2004 study exist between these findings and reports of type 1 did not accord with a causal relation between childhood diabetes.33 These findings suggest that children in these vaccination and type 1 diabetes.18,19 Thus, the search for a circumstances are less exposed to infections or other so-called smoking gun trigger continues.
immune challenges early in life that act as protective The abnormal activation of the T-cell-mediated environmental influences. Gale29 has proposed that the immune system in susceptible individuals leads to an protective effect is mediated by regulatory T lymphocytes.
inflammatory response within the islets (insulitis) as Although plausible, this hypothesis lacks credible well as to a humoral (B cell) response with production of scientific support in the causation of type 1 diabetes.
antibodies to ␤-cell antigens. Islet cell antibodies were In the accelerator hypothesis, Wilkin30 postulates that the first described, but have been supplanted by more diabetes is a single disease, rather than two distinct specific autoantibodies to insulin (IAA), glutamic acid entities, type 1 and type 2 diabetes. He argues that the two decarboxylase (GADA/GAA), and the protein tyrosine types of diabetes are distinguished only by the rate of ␤-cell phosphatase IA2 (IA-2AA), all of which are easily loss, and the specific accelerators responsible. Wilkin detected by sensitive radioimmunoassay.6 The presence implicates three accelerators: the first is the intrinsic of one or more type of antibody can precede the clinical potential for a high rate of ␤-cell apoptosis, an essential but onset of type 1 diabetes by years or even decades. The insufficient step in the development of diabetes. The presence and persistence of positivity to multiple second accelerator is insulin resistance, resulting typically antibodies increases the likelihood of progression to from weight gain and physical inactivity, and is central to clinical disease.20–22 There is no evidence that any of these the proposed link between the two types of diabetes.
antibodies has an active role in the pathogenesis of this Insulin resistance puts pressure on a ␤-cell mass already at risk for accelerated apoptosis, contributing to the Continuing destruction of ␤ cells leads to progressive expression of clinical diabetes. The third accelerator is loss of insulin-secretory reserve with, in order, loss of present only in those individuals with genetically first phase insulin secretion in response to an determined predisposition to ␤-cell autoimmunity. The intravenous glucose tolerance test, then to clinical metabolically more active ␤ cell, in insulin-resistant diabetes when insulin secretion falls below a critical individuals who are genetically biased towards a high rate amount, and finally, in most but not all those with type 1 of apoptosis, is at greatest risk for rapid functional diabetes, to a state of absolute insulin deficiency.6,8 The deterioration and expression of typical type 1 diabetes. In honeymoon or remission period takes place soon after the absence of this immune accelerator, apoptosis is clinical diagnosis and initiation of insulin therapy when slower and progression is towards type 2 diabetes.
some endogenous insulin secretion is restored to Proponents of the accelerator hypothesis claim that the exhausted but not yet destroyed ␤ cells, and when rise in childhood obesity parallels the rise in both types insulin resistance associated with initial hyperglycaemia of diabetes in childhood, and that the decreasing age of is lessened.23,24 In general, these cells are destroyed more onset of type 1 diabetes in heavier children lends further rapidly when onset of clinical diabetes takes place at a support to their argument.34 Opponents argue that there young age, when there is also less likelihood of a long is sufficient evidence to support the Eisenbarth model remission period.23 Thus, older individuals are more for type 1 diabetes causation without having to implicate likely to respond soon after diagnosis to immune interventions aimed at preserving residual insulinsecretion.
Epidemiology and presentation
Supportive evidence for the autoimmune pathogenesis Past descriptions depict type 1 diabetes as a disease of of type 1 diabetes comes from the susceptibility of these childhood and early adulthood, with a sudden, severe individuals to other autoimmune conditions including presentation—ie, most people being younger than Hashimoto’s thyroiditis, Graves’ disease, Addison’s 20 years of age at diagnosis and presenting in diabetic disease, coeliac disease, myasthenia gravis, and ketoacidosis. More recent data suggest that only about vitiligo.25–28 Although recent knowledge has contributed 50–60% of those with type 1 diabetes are younger than to our understanding of the pathogenesis of type 1 16–18 years at presentation and that such disease diabetes, there remains no unifying theory of disease occurs at a low incidence level throughout adulthood.
causation. The hygiene and accelerator hypotheses, Furthermore, studies of the natural history of type 1 diabetes in first-degree relatives with positive islet- The hygiene hypothesis stems from observations that related antibodies indicate that there is often a long atopic disorders such as asthma are more common in prodrome preceding clinical onset, in which glucose affluent than in traditional societies, their prevalence homoeostasis is either normal or only mildly disturbed.6,22 rising with increasing modernisation, and that such Finally, diabetic ketoacidosis is not universal at disease www.thelancet.com Vol 367 March 11, 2006
lends support to a strong contribution of environmental Children
factors in causation. This conclusion is further supported by reports that the rising incidence of childhood disease is associated with reduced contributions from high-risk HLA haplotypes.41 Management
Intensive approaches to management are based on three sentinel observations highlighted by the extensively documented cohort of type 1 diabetes subjects enrolled in the Diabetes Control and Complications Trial *Polyuria, nocturia, enuresis, polydipsia, polyphagia, weight loss, lethargy, fatigue, (DCCT) and followed in the Epidemiology of Diabetes abdominal pain. Data modified with permission from Booth38 and Curtis and Interventions and Complications (DCCT/EDIC) study.57–62 First, the DCCT provided unquestionable evidence of a Table 2: Presentation of type 1 diabetes by age
very close, curvilinear relation between the degree ofglycaemic control (measured by haemoglobin A1c(HbA ) concentrations), maintained over the long term, onset: in children, rates of 15–67% have been reported, and the onset or progression of microvascular inversely correlated with the incidence of type 1 diabetes (retinopathy, nephropathy, and neuropathy) and likely in the particular geographic location.36,37 Table 2 also macrovascular (cardiovascular, cerebrovascular, summarises the presentation of type 1 diabetes and peripheral vascular disease) complications.57,58 Furthermore, there is no threshold effect: any decrease The epidemiology of type 1 diabetes has been reported in HbA concentrations is associated with a similar in many countries, predominantly in children younger decline in relative risk of complications. There is also no than 15–18 years of age. Many important observations HbA level below which complications are completely derive from registries: first, incidence has been prevented, nor one above which complications are increasing at roughly 2–5% per year worldwide. The certain to develop. These data underscore not only the increase is steeper in the populations with a lower pivotal role of glycaemic control, but also the presence of incidence; however, even in countries with the highest other factors, such as genes, smoking, obesity, rates such as Finland, there has been no levelling off hypertension, and hyperlipidaemia, in the development since statistics started being recorded in the 1950s.40–42 Second, there is huge geographical variation, with Second, the DCCT/EDIC cohort has convincingly countries such as China reporting the lowest incidence shown that those initially treated intensively, and rates (about 0·57 cases per 100 000 population younger achieving reduced HbA concentrations, continue to have than 18 years of age per year) to rates roughly 30 times greater protection against development or progression of higher in the UK (18–20 per 100 000 per year) to almost complications than those initially receiving conventional 100-fold higher (about 48–49 per 100 000 per year) in therapy.59–61 This protection arises despite similar levels of glycaemic control in the 6–10 years after completion of Third, there is a significant trend towards decreasing the intervention part of the study. This metabolic or age at presentation, particularly in children younger hyperglycaemic memory demands that intensive than 5 years. The Swedish and Belgian data are notable management be instituted as soon as diabetes is here.52,53 In Sweden from 1983 to 1998, the overall incidence of type 1 diabetes did not go up in the Finally, there is an inverse relation between glycaemic 0–34 year age group, but median age at diagnosis fell.52 control and the risk of severe hypoglycaemic episodes) in Similar findings were reported from 1989 to 2000 in people with type 1 diabetes (panel 1).62 In the DCCT, Belgium in those younger than 40 years.53 This shift to a severe hypoglycaemia occurred about 2·5–3 times more younger age at diagnosis could indicate either exposure often in those in the intensive therapy groups compared to heavier doses of environmental triggers or perhaps with those in conventional therapy groups; adolescents the increasing weight of the population.54,55 were about 1·5 times more likely to have hypoglycaemia Finally, migrating populations take on the incidence than adults in both groups. In the youngest children with rates of their new countries within a short time. For the disease, as well as in the older age group with example, incidence rates for type 1 diabetes in south enduring disease, repeated episodes of severe Asian children in the UK are similar to those of white or hypoglycaemia could lead to cognitive impairment.64–66 other ethnic backgrounds in the same area, which is in Thus, hypoglycaemia is a major limiting step to striking contrast to the very low rates reported from achieving control with present treatment approaches.
Asia.56 This convergence of incidence rates for immigrant There are two caveats here: first, both in the DCCT62 as populations with those of the background population well as in a study of almost 3000 children and adolescents www.thelancet.com Vol 367 March 11, 2006
Panel 1: Severity and treatment of hypoglycaemia
Panel 2: Components of management of individuals with
type 1 diabetes
● Mild: Autonomic symptoms (trembling, palpitations, sweating, anxiety, hunger, nausea, tingling) are present; can be self-treated with ingestion of simple sugars ● Appropriate insulin delivery: most regimens include either multiple daily injections or continuous subcutaneous ● Moderate: Autonomic and neuroglycopenic symptoms (difficulty concentrating, insulin infusions with basal-bolus approach to insulin confusion, weakness, drowsiness, blurred vision, dizziness, difficulty speaking) symptoms are present, but the individual can still self-treat.
● Self-monitoring of blood glucose concentration: ● Severe: Assistance of another individual is required to reverse hypoglycaemia, usually frequency of testing correlates with glycaemic outcomes associated with confusion, convulsion or unconsciousness. Requires intravenous ● Nutritional planning: more flexible programmes, including glucose (10–25 g) or subcutaneous glucagon (0·5–1·0 mg) injection.
carbohydrate counting, replacing more rigid approaches ● Avoidance or treatment of severe hypoglycaemia and diabetic ketoacidosis: careful attention to other with type 1 diabetes from 18 countries,67,68 the risk of components of management greatly decreases risk of hypoglycaemia was not evenly spread across all centres compared with controls. Thus, some therapeutic ● Screening for and treatment of associated disorders: approaches might foster glycaemic control without the specifically thyroid dysfunction (regular measurement of same risk of severe hypoglycaemia. Second, treatments thyroid-stimulating hormone) and coeliac disease (specific using insulin analogues or continuous subcutaneous antibodies—eg, tissue transglutaminase) insulin infusion pumps have a lower incidence of ● Compensation for non-basal conditions—eg, physical hypoglycaemia than seen with traditional insulins and ● Screening for and treatment of diabetes-related Individuals should be fully informed about these rationales for management and provided with realistic targets for glyceamic control. Tables 3 and 4 provide glucose and HbA targets established in the evidence- based 2003 clinical practice guidelines of the Canadian Macrovascular: detection of hyperlipidaemia and adolescents. Diabetes self-care requires a high standard of both initial and continuing education and care, best ● Attention to psychological and psychosocial wellbeing— provided by a multidisciplinary health care team eg, awareness of psychosocial stresses of chronic disorder; consisting of physicians, nurses, dietitians, and eating disorders; adolescent non-compliance; depression FPG/preprandial PG
2 h postprandial PG
(mmol/L)
(mmol/L)
behavioural specialists experienced in the management of type 1 diabetes.75–79 Panel 2 shows the components of Treatment targets must be tailored to the patient, with consideration given to Different centres use various approaches to insulin individual risk factors. Normal range should be considered for patients in whom it canbe achieved safely. HbA =haemoglobin A1c; FPG=fasting plasma glucose; PG=plasma management, with increasing numbers of individuals glucose. Data used with permission from Canadian Diabetes Association.75 using basal-bolus approaches with either multiple dailyinsulin injections or insulin pumps.80 Table 5 details the Table 3: Glycaemia and HbA targets for adults with diabetes
characteristics of commonly used insulin preparations.
Multiple daily injection routines have traditionallyconsisted of isophane (NPH) or ultralente given once or Plasma glucose HbA
Considerations
(mmol/L)
twice daily as the basal insulin, with regular humaninsulin boluses before meals. With the availability of Careful avoidance of hypoglycaemia in this age group due to risk of both fast-acting and very long-acting insulin analogues, multiple daily injection routines increasingly use insulin glargine or detemir as the basal insulin and insulin lispro or aspart as the boluses before meals.69–74,81–83 Insulin pumps use fast-acting insulin in a continuousbasal rate with boluses before meals.84–87 When basal- HbA =haemoglobin A . Source: 2003 clinical practice guidelines of the Canadian bolus routines are fastidiously applied in conjunction with the other aspects of management, many individuals Table 4: Glycaemic and HbA targets by age for children and
with type 1 diabetes are able to maintain near-normal adolescents with type 1 diabetes
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Self-monitoring of blood glucose is fundamental to Appearance
Action characteristics*
diabetes care.75,88,89 Frequent monitoring facilitates improved glycaemic control, avoidance of hypoglycaemia, Rapid-acting analogues
and lifestyle flexibility when the results are used to assist the individual in their dietary choices, physical activity, Fast-acting
Glucose monitors are now much smaller than previously, require very small amounts of blood Intermediate-acting
Isophane
(2–10 ␮L), are faster at providing a result (5–15 s), and can be used at sites other than fingertips.89 Verification Long-acting
of accuracy of self-monitoring is achieved by comparing results obtained from the patient’s meter with a Very long-acting analogues
Detemir
simultaneous specimen sent to the laboratory. A difference of less than 20% between meter andlaboratory measurements is thought acceptable, which This list represents the most commonly used insulin preparations and provides averagesfor the action characteristics, but these preparations also show variability within and might be difficult in concentrations less than 4 mmol/L.
between individuals. In general, there is less variability with insulin analogues than with Most meters incorporate data management systems; either animal derived or biosynthetic human insulin preparations. *Shown in hours, however, keeping a blood glucose logbook is needed to unless otherwise indicated. †Intermediate-acting and long-acting insulin preparationsneed agitation before use to allow resuspension, whereas very long-acting analogues detect patterns of glucose control and make appropriate dose adjustments. Continuous glucose monitoringtechnologies using subcutaneous sensors have become Table 5: Time course of action of currently available subcutaneously
injected insulin preparations
increasingly used in clinical care as a means of accessingmore complete glycaemic data than is available withtraditional self-monitoring.89,93 Both a meta-analysis and the Cochrane Metabolic and Whereas self-monitoring records daily variations in Endocrine Disorders Group reviewed randomised blood glucose concentrations, long-term control is best controlled trials comparing intensive therapy regimens measured by HbA concentrations, indicating average using fast-acting insulin analogues with regimens using regular insulin.74,81 A small (Ϫ0·1 to Ϫ0·15%) but 90–120 days.94 Each laboratory needs to standardise its significant reduction in HbA was reported with the analogues, with comparable results between the internationally recognised reference laboratory since analogues and regular insulin in terms of overall there are no universal standards against which individual hypoglycaemia. Although fast-acting analogues did not There are few data that lend support to rigid adherence macrovascular risk by reducing post-prandial glycaemia.
to one particular approach to nutritional therapy in Quality of life was improved with analogue use, largely individuals with type 1 diabetes.97 Thus, nutritional because of the shorter interval between injection and food planning should be tailored to the individual’s dietary preferences, age and stage of development, weight, Several open-label randomised controlled trials as well culture, and lifestyle.97,98 In general, patients are as observational studies have assessed insulin glargine or encouraged to follow guidelines for healthy eating similar detemir in adults with type 1 diabetes70–73,83 All participants to the general population—ie, varied consumption from in these trials used basal–bolus insulin regimens. The all food groups, maintaining a healthy weight, limiting results of most trials showed no differences in HbA total fat to less than about 30% of daily caloric intake, and concentrations between groups receiving insulin glargine ensuring adequate intake of carbohydrate, protein, or detemir, and those receiving isophane insulin. A few minerals, vitamins, and essential fatty acids. Consistency in meal planning can assist in reaching glycaemic targets, glargine was compared with isophane or ultralente. Some and modifications in the diet could also be helpful in studies reported less night time or day time achieving lipid and lipoprotein profiles aimed at reducing hypoglycaemia or less severe hypoglycaemic events in macrovascular risk. Nutritional planning in children and those receiving insulin glargine than in those receiving adolescents aims to provide adequate energy to promote Studies in children and adolescents with type 1 diabetes Although most agree that the quantity of carbohydrate with insulin analogues show similar findings to those in ingested substantially affects glycaemia, disagreement adults.69,70 Nonetheless, despite advances in insulin has focused on the importance of the quality of the therapeutics during the past 25 years, only a few ingested carbohydrate,98–100 despite the demonstration of individuals with type 1 diabetes are able to reach the a five-fold difference in the effect on glycaemia when equivalent amounts of carbohydrate from different www.thelancet.com Vol 367 March 11, 2006
sources are compared by glycaemic index. A meta-analysis of 14 randomised controlled trials (six in type 1 Panel 3: Risk factors for diabetes-related complications
diabetes) shows a small but clinically significant improvement in HbA levels in those receiving low ● Early onset and long duration of type 1 diabetes versus high glycaemic index diets.99 Thus, individuals ● Genetic predisposition—eg, family history of diabetes- should be informed about the notion of glycaemic index and encouraged to incorporate foods that score lower on the index, such as wholegrain cereals, breads and pastas, Approaches with carbohydrate counting to the nutritional management of type 1 diabetes have developed in parallel with basal-bolus insulin regimens.98Carbohydrate counting allows adjustment of premeal *No single gene or cluster of genes has been identified that explains a majorportion of the risk of microvascular or macrovascular complications. Candidate insulin boluses of fast-acting insulin analogues genes include those involved in the renin-angiotensin-system in nephropathy according to both the premeal glucose concentration as (eg, angiotensin-converting enzyme gene or angiotensin 2 receptor genes); well as the carbohydrate content of the meal. Calculation genes related to disruptions in growth factors and cytokines (eg, vascularendothelial growth factor), the polyol pathway (eg, aldose reductase), protein of insulin to carbohydrate ratios (ie, the amount of kinase C activation, vascular or platelet function, or the nitric oxide pathway. So insulin needed to limit glycaemic excursions after far, the demonstrated interactions between gene polymorphisms and diabetes-related complications have been quite weak.
meals) allows for increased flexibility in meal planningwithout sacrificing glycaemic control.
Hypoglycaemia
Despite these efforts, severe hypoglycaemia occurs with Hypoglycaemia is a major obstacle to glycaemic control a frequency of about five to 50 episodes per 100 patient- for many patients (panel 1). Causes include inadequate years, dependent both on treatment approach and level caloric intake, excessive insulin dosage, and inadequate preparation for physical activity. Often the cause cannotbe determined.
Complications and comorbid conditions
Long-term diabetes-related complications are divided hypoglycaemia often interferes with an individual’s into microvascular and macrovascular disorders, which ability to achieve near-normal glycaemic concentrations.101 account for most of the increased morbidity and This fear might be based on previous experiences with mortality associated with the disease (panel 3). hypoglycaemia, or it may be part of wider anxiety aboutdiabetes. Second, hypoglycaemia unawareness—ie, the Microvascular complications
occurrence of neuroglycopenia without early warning Diabetic nephropathy is the most common cause of renal adrenergic symptoms, can occur in individuals with failure in the developed world. The proportion of longstanding disease.102 Finally, an episode of severe individuals who progress to end-stage renal disease used hypoglycaemia predisposes that individual to further to be estimated as 30–40%; however, more recent data episodes, as a result of downgraded regulatory responses suggest that this proportion is decreasing, probably as a to repeated hypoglycaemic events.103 In these situations, result of intensive efforts to control both glycaemia and reassessment of glycaemic targets is needed and the hypertension.108–112 In a cohort of 20 005 individuals from regimen adjusted to carefully avoid further episodes of Finland diagnosed younger than 30 years of age between 1965 and 1999, Finne and colleagues111 reported a Short-term risks of hypoglycaemia include potentially cumulative prevalence of end-stage renal disease of 2·2% dangerous circumstances that may arise when someone at 20 years and 7·7% at 30 years, which are much lower is hypoglycaemic while, for example, driving a car.104,105 than previously estimated. Diabetic nephropathy Long-term consequences of severe, longlasting or progresses through a series of recognisable steps: from repetitive hypoglycaemia include mild cognitive subclinical disease, to the earliest detectable phase of impairments in teenagers with early onset type 1 microalbuminuria (defined as a urinary albumin diabetes or older adults with longstanding disease.64–66 excretion rate Ͼ20Ͻ200 ␮g per day) to overt nephropathy Controversy remains about whether cognitive effects in or macroalbuminuria (Ͼ200 ␮g per day) with renal young children are a result of severe hypoglycaemia or dysfunction and eventual end-stage renal disease. rather due to effect of chronic hyperglycaemia.106 The presence of microalbuminuria has been shown to Prevention of hyopoglycaemia needs frequent blood be highly predictive of progression to advanced stages of glucose monitoring and careful balance between insulin diabetic nephropathy: a 75–80% probability of dose, food ingestion, and physical activity. With respect progression had been reported,108,109 but more recently to physical activity, the focus should be on adjustment of Perkins and colleagues110 have suggested that the therapy to allow safe participation in these activities.107 probability is only 50–66% and that, in a substantial www.thelancet.com Vol 367 March 11, 2006
proportion, microalbuminuria can regress. These Diabetic neuropathy refers to a complex group of investigators showed that the factors predictive of conditions falling into two major categories: focal and greater likelihood of regression included younger age, improvement in metabolic control, reduced cholesterol example, carpal tunnel syndrome, peroneal nerve and and triglyceride concentrations, and lowered systolic third cranial nerve palsies, and diabetic amyotrophy blood pressure. In adolescents with microalbuminuria, (proximal nerve conditions). The most common progression is seen in about 50%, with regression in generalised neuropathy is sensorimotor polyneuropathy, many of the others during 3–10 years’ follow-up.63 which often first presents as a peripheral neuropathy Screening of individuals with type 1 diabetes for alone, but often also affects the autonomic system with microalbuminuria should be instituted early in the course of their disorder: the Canadian Diabetes dysfunction. Peripheral neuropathy, in conjunction with Association75 suggests annual screening every year, with peripheral vascular disease, can lead to skin ulceration of a random urine albumin-creatinine ratio in postpubertal the lower limbs, poor healing and gangrene, and individuals with diabetes of duration 5 years or greater.
amputation (the diabetic foot). Good foot care may Positive screening tests should be confirmed with greatly lower the risk of these outcomes.75 further random albumin-creatinine ratios or timed urine Screening for neuropathy should also begin about collections for 2–3 months. Persistent positive results 5 years after type 1 diabetes diagnosis, with appropriate require introduction of renoprotective measures, methods: testing at the great toe with a 10 gauge including further intensification of glycaemic control monofilament to detect loss of sensitivity, and clinical and control of hypertension or hyperlipidaemia, or both, assessment for the other manifestations75 Again, if present.112,113 First-line drugs of choice include attention to glycaemic control represents the first step in management; if unsuccessful in controlling symptoms, angiotensin receptor-blocking agents, both of which are referral to a specialist is indicated. Attention to preventive highly effective in slowing progression of renal disease foot care is an essential component of diabetes Individuals who reach end-stage renal disease tend to do less well in dialysis and transplantation programmes Macrovascular complications
than others with such disease that is unrelated to Although cardiovascular disease accounts for about 70% diabetes. The major part of the excessive cardiovascular of all deaths in people with type 2 diabetes, considerably morbidity and mortality resides in this group that less is known about its associations in type 1 diabetes.
develops advanced diabetic nephropathy.
The relative risk of cardiovascular disease in type 1 Diabetic retinopathy is the most common cause of diabetes can be as much as 10-fold greater than that in acquired blindness in the western world, with a non-diabetic individuals. Risk factors for cardiovascular prevalence rate of proliferative retinopathy of about disease in type 1 diabetes include the presence of 20–25% in type 1 diabetes.115 It also progresses through diabetic nephropathy, but also autonomic neuropathy, recognisable stages: from early non-proliferative dyslipidaemia, hypertension, and perhaps also specific changes, previously called background retinopathy microvascular cardiac disease. The role of glycaemic (microaneurysms, exudates, and haemorrhages), which control has not been easy to define, although two reports appear in almost all individuals with type 1 diabetes by are important: a meta-analysis of randomised controlled about 20 years’ duration, to preproliferative retinopathy, trials in type 1 diabetes found that intensive insulin and then predictably on to proliferative retinopathy (with therapy may stabilise macrovascular disease or prevent risk of retinal detachment and vitreous haemorrhage) progression in those at risk,119 whereas the follow-up and macular oedema. Unlike early retinopathy, the later phase of the DCCT/EDIC showed that intensive stages can be sight-threatening. There is a close treatment during the active intervention phase of the association between diabetic retinopathy and diabetic DCCT led to reduced progression of carotid intima- media thickness during 6 years’ follow-up.120 Screening for diabetic retinopathy should begin Reduction of risk of vascular disease includes attention 5 years after diagnosis in individuals of 15 years of age or to healthy lifestyle (weight control and physical activity), older and be done yearly by one of the following smoking avoidance, with optimum glycaemic, blood methods: seven-field stereoscopic fundus photography pressure (Ͻ130/80 mmHg in adults), and lipid control interpreted by trained readers (gold standard); direct (LDL-cholesterol Ͻ2·5 mmol/L and total:HDL- ophthalmoscopy or indirect slit lamp fundoscopy cholesterol ratios Ͻ4·0 mmol/L for those at high risk of through a dilated pupil; or digital fundus photography.75 an event, and Ͻ3·5 mmol/L and Ͻ5·0 mmol/L, The presence of diabetic retinopathy requires enhanced respectively, for those at moderate risk75). There has been attention to glycaemic, blood pressure, and lipid a steady decline in the recommended targets for lipid control, with laser therapy in sight-threatening diabetic control with particular emphasis on control of LDL- www.thelancet.com Vol 367 March 11, 2006
Comorbid conditions
have shown the usefulness of current prediction models Clinical automimmune thyroid disease occurs in about and the feasibility of large-scale multinational studies.127,128 5% and coeliac disease in 3–10% of children with type 1 Second, techniques for islet cell replacement need to diabetes.25–28 The number of children with positive be improved, through either islet cell transplantation or thyroid antibodies is higher than 5% (manifest disease) islet differentiation from stem cell sources. Initial and increases with age. Annual screening of individuals enthusiasm about improved outcomes of islet cell with thyroid-stimulating hormone measurements will transplantation, raised by use of the Edmonton enable early initiation of thyroxine replacement protocol129,130 for islet harvesting and rejection prevention therapy.26 The need to screen for coeliac disease has been has been tempered by the lack of availability of islets, the debated75 but is now a recommended part of routine side-effects of the procedure (such as bleeding, mouth management.27,28 The timing and frequency of screening ulcers, diarrhoea, anaemia, and ovarian cysts), and the for coeliac disease have not been defined; however, increasing reversal of insulin independence in as many initial screening soon after diagnosis and then every as 80% of the recipients 5 years after the transplantation, 5 years is a reasonable recommendation. Although more although some ␤-cell function and hypoglycaemia common than in the general public, the presence of awareness seems to persist for longer than 5 years.129,130.
Addison’s disease in individuals with type 1 diabetes is Stem cell research as a means of developing a potentially rare and screening cannot be justified. infinite source of functional islets is still at a veryfundamental stage.131,132 Psychosocial concomitants
Research has focused attention on the psychosocial normoglycaemia are called for. Although insulin concomitants of type 1 diabetes particularly in children analogues and insulin pumps help more physiological and teenagers, but also in adults. For example, children insulin replacement approaches to be developed, they from single parent families and low socioeconomic remain imperfect because of factors other than insulin status are more likely to present in diabetic ketoacidosis that affect glycaemia (food intake, activity, stress, etc), the at disease onset, have more episodes of diabetic absence of closed loop systems linking insulin infusion to ketoacidosis during the course of their diabetes, attend ambient glycaemia, and peripheral rather than portal clinic less frequently, and are less likely to maintain insulin delivery. These shortcomings might be partly good glycaemic control than those from two-parent and overcome by progress in development of continuous glucose monitoring systems. Linking of these systems to colleagues122 showed that over 40% of teenagers had a sophisticated pump technologies offers the promise of an period of pervasive non-compliance with major aspects artificial endocrine pancreas. Additionally, increasing of their diabetes routines, and that these individuals rates of obesity have focused attention on the were more likely to show serious psychopathology— development of characteristics of type 2 diabetes in those most commonly depression—in early adulthood.122 with diagnosed type 1, so-called double diabetes (ie, Other researchers have also reported an increased increasing insulin resistance and cardiovascular risk).133 prevalence of depression in adults with type 1 diabetes.123 This double diabetes has prompted the search for Our research group has reported that nearly a quarter adjunctive drugs (eg, metformin) that might lessen the of teenage and young adult women with type 1 diabetes insulin resistance and improve glycaemic control.134,135 have either a full-blown (about 10%) or sub-threshold Furthermore, drugs that either suppress glucagon (eg, (about 14%) eating disorder, and that such disorders are amylin), or have multiple effects on pathways such as associated with insulin omission to control weight appetite regulation, stomach emptying, and continuing through induced glycosuria, poor glycaemic control, and ␤-cell apoptosis, such as those with activity associated with early onset of diabetes-related complications.124,125 glucagon-like peptide 1 (eg, exenatide and liraglutide), Interventions intended to improve the psychological have potential to benefit individuals not only with type 2 concomitants of diabetes in an effort to enhance diabetes, but also those with type 1 disease.136–138 glycaemic control have not been very successful.126 Finally, we should define strategies for complication prevention or risk factors for development of compli- Challenges
cations. Better understanding of pathophysiological Some of the challenges facing researchers and health-care mechanisms and susceptibility genes is already leading professionals are as follows. First, we need to perfect the to new targets for treatment.139 In the meantime, attention prediction model for type 1 diabetes in both high risk and should be focused on how to prevent complications general populations, and to develop effective and safe with drugs such as angiotensin-converting enzyme interventions that reverse the condition either in its inbibitors or angiotensin receptor blockers, beta- preclinical or early clinical phase. The multicentre hydroxy-beta-methylglutaryl-coenzyme A (HMG-CoA) prevention trials (eg, European Nicotinamide Diabetes reductase inhibitors (statins), or even aspirin, deserves Intervention Trial of nicotinamide, and Diabetes attention.140–142 Evidence-based recommendations about Prevention Trial Type 1 of insulin), although ineffective, the prophylactic use of these agents are not available.
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Conclusions
Virtanen SM, Laara E, Hypponen E, et al. Cow’s milk Type 1 diabetes has transformed from a disease with consumption, HLA-DQB1 genotype, and type 1 diabetes: a nestedcase-control study of siblings of children with diabetes. Childhood certain death in the era before the discovery of insulin to diabetes in Finland study group. Diabetes 2000; 49: 912–17.
one with substantial risk of long-term morbidity and Vaarala O, Knip M, Paronen J, et al. Cow’s milk formula feeding mortality.143 For example, a report from the US Centers induces primary immunization to insulin in infants at genetic riskfor type 1 diabetes. for Disease Control recently estimated that a 10-year-old Diabetes 1999; 48: 1389–94.
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Conflict of interest statement
Barker JM, Yu J, Yu L, et al. Autoantibody “subspecificity” in type 1 D Daneman has received research funding from Novo Nordisk, has co- diabetes: risk for organ-specific autoimmunity clusters in distinct organised a continuing education programme sponsored by Lifescan groups. Diabetes Care 2005; 28: 850–55.
Canada, and has spoken at other continuing education programmes.
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