Identification of Autoantibody-Negative Autoimmune Type 2 Diabetic Patients

OBJECTIVE

Islet autoimmunity has long been recognized in the pathogenesis of type 1 diabetes and is becoming increasingly acknowledged as a component in the pathogenesis of type 2 diabetes. Islet reactive T cells and autoantibodies have been demonstrated in type 1 diabetes, whereas islet autoimmunity in type 2 diabetes has been limited to islet autoantibodies. In this study, we investigated whether islet reactive T cells might also be present in type 2 diabetic patients and how islet reactive T cells correlate with β-cell function.

RESEARCH DESIGN AND METHODS

Adult phenotypic type 2 diabetic patients (n = 36) were screened for islet reactive T-cell responses using cellular immunoblotting and five islet autoantibodies (islet cell antibody, GADA, insulin autoantibody, insulinoma-associated protein-2 autoantibody, and zinc transporter autoantibody).

RESULTS

We identified four subgroups of adult phenotypic type 2 diabetic patients based on their immunological status (Ab⁻T⁻, Ab⁺T⁻, Ab⁻T⁺, and Ab⁺T⁺). The Ab⁻T⁺ type 2 diabetic patients demonstrated T-cell responses similar to those of the Ab⁺T⁺ type 2 diabetic patients. Data were adjusted for BMI, insulin resistance, and duration of diabetes. Significant differences (P < 0.02) were observed among groups for fasting and glucagon-stimulated C-peptide responses. T-cell responses to islet proteins were also demonstrated to fluctuate less than autoantibody responses.

CONCLUSIONS

We have identified a group of adult autoimmune phenotypic type 2 diabetic patients who are Ab⁻T⁺ and thus would not be detected using autoantibody testing alone. We conclude that islet autoimmunity may be more prevalent in adult phenotypic type 2 diabetic patients than previously estimated.Type 1 diabetes results from cell-mediated autoimmune β-cell dysfunction and destruction, whereas type 2 diabetes has been historically considered a metabolic disease (1). However, increasing evidence is pointing toward a relationship among inflammation, insulin resistance, and the subsequent development of type 2 diabetes. In fact, inflammation in the pancreatic islets of type 2 diabetes includes the presence of cytokines (2,3) and the infiltration of immune cells (3,4).Despite the fact that the pathological process in autoimmune diabetes involves T cells, immune markers of autoimmune diabetes have primarily centered on the presence of circulating serum autoantibodies to various islet antigens (5,6). However, ∼20% of patients with newly diagnosed autoimmune type 1 diabetes are autoantibody negative (7). It was also found that 9% of autoantibody-negative type 1 diabetic patients carry the highest risk HLA genotype (DR3-DQ2/DR4-DQ8), strongly suggesting that these patients had autoimmune diabetes that was undetected with autoantibody testing alone (7). Furthermore, patients with fulminant type 1 diabetes have been reported to be autoantibody negative but demonstrate islet-specific T-cell responses (8). Therefore, we hypothesized that there may exist a group of autoimmune phenotypic type 2 diabetic patients who are autoantibody negative, similar to the Ab⁻ type 1 diabetic patients, but who demonstrate autoimmunity with islet reactive T cells.Over the years, we have been investigating islet-specific T-cell responses using cellular immunoblotting in diabetic patients (9–13). Our assay has been validated to have excellent specificity and sensitivity for the detection of islet reactive T cells in type 1 diabetic patients (9,10). Moreover, we have previously observed that T-cell reactivity to islet proteins correlates more strongly with impaired β-cell function than with autoantibody positivity (12). In this study, we used our validated T-cell assay for the detection of islet reactive T cells to investigate whether autoantibody-negative T-cell reactive adult phenotypic type 2 diabetic patients could be identified. We provide evidence for the existence of this group of autoimmune phenotypic type 2 diabetic patients. We conclude that islet autoimmunity may be more prevalent in adult phenotypic type 2 diabetic patients than previously estimated and assessing autoimmunity through T cells is of importance.     

Zinc Transporter 8 Antibodies Complement GAD and IA-2 Antibodies in the Identification and Characterization of Adult-Onset Autoimmune Diabetes: Non Insulin Requiring Autoimmune Diabetes (NIRAD) 4

OBJECTIVE

Zinc transporter 8 (ZnT8) is an islet β-cell secretory granule membrane protein recently identified as an autoantibody antigen in type 1 diabetes. The aim of this study was to determine the prevalence and role of antibodies to ZnT8 (ZnT8As) in adult-onset diabetes.

RESEARCH DESIGN AND METHODS

ZnT8As were measured by a radioimmunoprecipitation assay using recombinant ZnT8 COOH-terminal or NH²-terminal proteins in 193 patients with adult-onset autoimmune diabetes having antibodies to either GAD (GADAs) or IA-2 (IA-2As) and in 1,056 antibody-negative patients with type 2 diabetes from the Non Insulin Requiring Autoimmune Diabetes (NIRAD) study.

RESULTS

ZnT8As-COOH were detected in 18.6% patients with autoimmune diabetes and 1.4% with type 2 diabetes. ZnT8As-NH² were rare. ZnT8As were associated with younger age and a high GADA titer. The use of GADAs, IA-2As, and ZnT8As in combination allowed a stratification of clinical phenotype, with younger age of onset of diabetes and characteristics of more severe insulin deficiency (higher fasting glucose and A1C, lower BMI, total cholesterol, and triglycerides) in patients with all three markers, with progressive attenuation in patients with two, one, and no antibodies (all P^trend < 0.001). Autoantibody titers, association with high-risk HLA genotypes, and prevalence of thyroid peroxidase antibodies followed the same trend (all P < 0.001).

CONCLUSIONS

ZnT8As are detectable in a proportion of patients with adult-onset autoimmune diabetes and seem to be a valuable marker to differentiate clinical phenotypes.Zinc transporter 8 (ZnT8) is a pancreatic β-cell secretory granule membrane protein that has been recently identified as a target of humoral immunity in type 1 diabetes (1). Autoantibodies to ZnT8 (ZnT8As) constitute an additional marker of autoimmune diabetes, which complement the established antibodies to insulin (IAAs) (2), GAD (GADAs) (3), and protein tyrosine IA-2 (IA-2As) (4). In the first report, ZnT8As were detected in 63% of young patients at onset of disease, overlapping with, but also independent of, GADAs, IAAs, and IA-2As, and the combined use of these four antibody markers raised the detection rate of autoimmunity to 94% in new-onset cases of type 1 diabetes. Moreover, ZnT8As could be detected also in the preclinical phase of type 1 diabetes, showing a trend to a later appearance relative to IAAs, GADAs, and IA-2As but with the ability to identify individuals with a more rapid progression to clinical disease. Although islet autoimmunity is responsible for the large majority of childhood- and adolescent-onset diabetes, it can be found also in 4–10% of adult-onset diabetes. This subgroup of patients test positive for humoral markers of islet autoreactivity, despite having clinical features indistinguishable from those of classic type 2 diabetes, and are characterized as having latent autoimmune diabetes of adult (LADA). Patients with LADA are identified solely by the detection of circulating islet autoantibodies, with islet cell antibodies (ICAs) and GADAs being the antibody markers with the highest prevalence (5,6), followed by IA-2As, which are detected in a minority of case subjects and are almost invariably associated with GADAs (7), whereas insulin autoantibodies, which constitute a specific marker of juvenile diabetes inversely related to age and rare in adults, are unlikely to be useful for LADA screening (8–10). The aim of this study was to evaluate the prevalence of ZnT8As in adult-onset diabetes and establish their potential use as an additional marker of autoimmunity and phenotype characterization in this patient population.     

Pancreatic Islet Autoantibodies as Predictors of Type 1 Diabetes in the Diabetes Prevention Trial�CType 1

OBJECTIVE

There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes.

RESEARCH DESIGN AND METHODS

Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial–Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA⁺). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA⁺).

RESULTS

In both cohorts autoantibody number was highly predictive of type 1 diabetes (P < 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P < 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P < 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes.

CONCLUSIONS

The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.Autoantibodies to islet cell antigens are known predictors of type 1 diabetes and are commonly present at its diagnosis (1–12). Islet cell autoantibodies (ICAs), the first identified (1,2), actually represent autoimmunity to several different antigens. More recently, autoantibodies specific to single tissue antigens, termed biochemical autoantibodies, have been identified (4,7,8,11–13). These include antibodies to GAD 65 (GAD65), the antibody to an insulinoma-associated antigen-2 (ICA512), and antibodies to insulin (IAA).Type 1 diabetes prevention trials have used autoantibodies to screen for individuals at increased risk who might be candidates for participation (14–16). The Diabetes Prevention Trial–Type 1 (DPT-1) assessed parenteral and oral insulin as potential prevention modalities. First- and second-degree relatives of type 1 diabetic patients were screened for the presence of ICA, which was required for eligibility. Although not relevant to the trials, biochemical autoantibodies were subsequently measured from screening samples to learn more about their prediction of type 1 diabetes. The prevalence of autoantibodies according to various subgroups has been reported for DPT-1 (17).We used two DPT-1 cohorts to examine the prediction of type 1 diabetes by ICA and biochemical autoantibodies, as few large-scale studies have examined the prediction of type 1 diabetes by a variety of single autoantibodies in large numbers of individuals of whom many ultimately developed type 1 diabetes. One cohort includes DPT-1 participants who participated in the trials (the Trials cohort), and the other cohort includes participants who did not participate in either trial but responded to questionnaires (the Questionnaire cohort) used to ascertain information regarding the diagnosis of type 1 diabetes. The differing perspectives of these two cohorts and the large number of individuals studied, almost 30,000, provide a unique opportunity for studying the prediction of type 1 diabetes by autoantibodies.     

Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study

OBJECTIVE

To determine whether delaying the introduction of gluten in infants with a genetic risk of islet autoimmunity is feasible, safe, and may reduce the risk of type 1 diabetes–associated islet autoimmunity.

RESEARCH DESIGN AND METHODS

A total of 150 infants with a first-degree family history of type 1 diabetes and a risk HLA genotype were randomly assigned to a first gluten exposure at age 6 months (control group) or 12 months (late-exposure group) and were followed 3 monthly until the age of 3 years and yearly thereafter for safety (for growth and autoantibodies to transglutaminase C [TGCAs]), islet autoantibodies to insulin, GAD, insulinoma-associated protein 2, and type 1 diabetes.

RESULTS

Adherence to the dietary-intervention protocol was reported from 70% of families. During the first 3 years, weight and height were similar in children in the control and late-exposure groups, as was the probability of developing TGCAs (14 vs. 4%; P = 0.1). Eleven children in the control group and 13 children in the late-exposure group developed islet autoantibodies (3-year risk: 12 vs. 13%; P = 0.6). Seven children developed diabetes, including four in the late-exposure group. No significant differences were observed when children were analyzed as per protocol on the basis of the reported first gluten exposure of the children.

CONCLUSIONS

Delaying gluten exposure until the age of 12 months is safe but does not substantially reduce the risk for islet autoimmunity in genetically at-risk children.Type 1 diabetes is an autoimmune disease with a preclinical phase characterized by the presence of islet autoantibodies (1). Genetic susceptibility for islet autoimmunity is well documented (2), and environmental factors are assumed to modify the genetically defined risk of developing islet autoantibodies (1,3).Data from mouse models of autoimmune diabetes support a role for gluten in modifying autoimmune diabetes risk, with deprivation of gluten or even delayed introduction resulting in later and less frequent development of diabetes (4,5). In humans, prospective studies (6,7) show that the age at introduction of solid food, such as gluten-containing foods or cereals, affects the development of islet autoimmunity in children who are genetically susceptible to type 1 diabetes. Two studies report increased risk of islet autoimmunity in children who are exposed to gluten before the 4th month, and one of the studies also demonstrates increased risk when gluten exposure is delayed beyond age 6 months (6,7). Furthermore, intervention in islet autoantibody–positive children indicates that β-cell function may be improved by a deprivation of gluten for 6 months (8). Gluten is a driving antigen of celiac disease. There is no association between early gluten exposure and risk for autoantibodies to transglutaminase C (TGCAs), which is a marker of celiac disease (9,10), but one study reports an increased risk for TGCAs in children who were first exposed to cereals after the age of 7 months (10).We performed a dietary primary pilot intervention study to determine whether delaying the introduction of gluten to the diet may be beneficial in reducing the risk of type 1 diabetes–associated islet autoimmunity in children with a predetermined genetic risk of islet autoimmunity, which was ~15% of children (11). We specifically assessed the feasibility of such an intervention, the safety with respect to growth, the development of gluten-driven celiac disease, and, as a pilot efficacy measure, the cumulative frequency of islet autoimmunity by age 3 years.     

Contribution of antibodies against IA-2β and zinc transporter 8 to classification of diabetes diagnosed under 40 years of age

OBJECTIVE

We investigated whether measuring autoantibodies against zinc transporter 8 (ZnT8A) and IA-2β (IA-2βA) may improve classification of new-onset type 1 diabetic patients based on detection of autoantibodies against insulin (IAA), GAD (GADA), and IA-2 (IA-2A). In addition, we studied the correlation of IA-2βA and ZnT8A with other biological and demographic variables.

RESEARCH DESIGN AND METHODS

Circulating autoantibodies were determined by liquid-phase radiobinding assays from 761 healthy control subjects and 655 new-onset (<1 week insulin) diabetic patients (aged 0–39 years) with clinical type 1 diabetes phenotype consecutively recruited by the Belgian Diabetes Registry.

RESULTS

At diagnosis, IA-2βA and ZnT8A prevalences were 41 and 58%, respectively. In IAA-negative, GADA-negative, and IA-2A–negative patients, one IA-2βA–positive and eleven ZnT8A-positive individuals were identified at the expense of eight and seven additional positive control subjects (1%), respectively, for each test. ZnT8A or IA-2βA screening increased (P < 0.001; McNemar) the number of patients with ≥2 antibodies both under (from 78 to 87% for ZnT8A and 82% for IA-2βA) and above age 15 (from 51 to 63% for ZnT8A and 56% for IA-2βA) versus 0% in control subjects. IA-2βA and ZnT8A were preferentially associated with IA-2A, and with younger age at diagnosis. Unlike ZnT8A, IA-2βA levels were positively correlated with HLA-DQ8 and negatively with HLA-DQ2. ZnT8A could replace IAA for classification of patients above age 10 without loss of sensitivity or specificity.

CONCLUSIONS

ZnT8A, and to a lesser degree IA-2βA, may usefully complement GADA, IA-2A, and IAA for classifying insulin-treated diabetes under age 40 years.It is sometimes difficult to distinguish type 1 diabetes from other forms of the disease solely on clinical grounds—especially in adults—because of the large age-dependent heterogeneity in terms of severity of the initial clinical phenotype and the underlying insulitis and β-cell loss (1–3). The final classification of an individual as a type 1 diabetic patient relies heavily on the detection of antibodies against islet cell autoantigens (1). To this end, antibodies against insulin (IAA), the 65 kDa isoform of glutamate decarboxylase (GADA), insulinoma-associated antigen 2 (IA-2A), and as yet incompletely identified cytoplasmic antigens (ICA) have been widely used (4–8). About 10% of patients presenting with clinical features of type 1 diabetes are scored negative for these four types of antibodies, but the overrepresentation of the HLA-DQ2/DQ8 high-risk genotype in these individuals with idiopathic type 1 diabetes suggests that at least some of them have an immune-mediated disease process (1,9). Recently, antibodies against IA-2β/phogrin (IA-2βA; a protein with 79% homology to IA-2 in the protein tyrosine phosphatase domain [10–12]) and against zinc transporter 8 (ZnT8A; an isoform largely confined to pancreatic β-cells [8,13]) have been proposed as independent immune markers of type 1 diabetes (13–15).The aim of the current study was to measure IA-2βA and ZnT8A in a registry-based representative group of type 1 diabetic patients diagnosed under age 40 years and in healthy control subjects, with the following aims: 1) to improve the diagnosis of immune-mediated type 1 diabetes by increasing the number of autoantibody-positive patients (higher diagnostic sensitivity) and/or the number of patients with at least two different autoantibody specificities, a condition that is extremely rare in absence of diabetes (3) (higher diagnostic specificity); 2) to investigate associations of these additional autoantibodies with established antibody markers and with demographic (age and sex) and genetic (HLA-DQ) characteristics that have previously been correlated to some extent with differences in prevalence or levels of autoantibodies, diabetes incidence, or clinical severity of diabetes (1–4,9,16–19) to further document disease heterogeneity and patient subcategories; and 3) to search for markers that may advantageously replace IAA, an autoantibody test influenced by insulin treatment, with low sensitivity for onset after age 15 years and with generally only modestly elevated levels in case of positivity (3,7,19). These investigations are also relevant for the identification of preclinical subjects who may be enrolled in prevention studies in the future (13–15).     

Maternal BMI Before Pregnancy, Maternal Weight Gain During Pregnancy, and Risk of Persistent Positivity for Multiple Diabetes-Associated Autoantibodies in Children With the High-Risk HLA Genotype: The MIDIA study

OBJECTIVE

To assess whether maternal BMI before pregnancy and weight gain during pregnancy predicted the risk of islet autoimmunity in genetically susceptible children.

RESEARCH DESIGN AND METHODS

Of 46,939 newborns screened for the high-risk HLA genotype DR4-DQ8/DR3-DQ2, 1,003 were positive and 885 were followed with serial blood samples tested for autoantibodies to insulin, GAD, and insulinoma-associated protein 2 (IA2). The end point was defined as repeated positivity for two or three autoantibodies or the onset of type 1 diabetes (islet autoimmunity).

RESULTS

Thirty-six children developed islet autoimmunity, of whom 10 developed type 1 diabetes. Both maternal BMI ≥30 kg/m² before pregnancy and maternal weight gain ≥15 kg predicted the increased risk of islet autoimmunity (hazard ratio [HR] 2.5, P = 0.023, and HR 2.5, P = 0.015, respectively), independent of maternal diabetes.

CONCLUSIONS

Maternal weight may predict risk of islet autoimmunity in offspring with a high genetic susceptibility for type 1 diabetes.Type 1 diabetes is caused by specific autoimmunity against pancreatic β-cells. The incidence of type 1 diabetes is increasing worldwide, and Norway currently has one of the world''s highest incidence rates (1,2). The etiology is multifactorial, determined by a combination of genetic and nongenetic factors. In Norway, 2.1% of newborns carry the HLA genotype DR4-DQ8/DR3-DQ2, which confers a relative risk for type 1 diabetes in excess of 20 and an estimated absolute risk of 7% by age 15 years (3,4). Nongenetic factors have been difficult to identify. Islet autoimmunity may start as early as in the 1st year of life before clinical type 1 diabetes with variable duration or even in utero (5). Studies have suggested that growth and obesity in childhood are associated with risk of type 1 diabetes and islet autoimmunity (6,7), but we are not aware of previous studies investigating the role of maternal BMI or weight gain in pregnancy.     

Extended Family History of Type 1 Diabetes and Phenotype and Genotype of Newly Diagnosed Children

OBJECTIVE

To determine the frequency of newly diagnosed diabetic children with first- and second-degree relatives affected by type 1 diabetes and to characterize the effects of this positive family history on clinical markers, signs of β-cell autoimmunity, and HLA genotype in the index case.

RESEARCH DESIGN AND METHODS

Children (n = 1,488) with type 1 diabetes diagnosed under 15 years of age were included in a cross-sectional study from the Finnish Pediatric Diabetes Register. Data on family history of diabetes and metabolic decompensation at diagnosis were collected using a questionnaire. Antibodies to β-cell autoantigens (islet cell antibodies, insulin autoantibodies, GAD antibodies, and antibodies to the islet antigen 2 molecule) and HLA genotypes were analyzed.

RESULTS

A total of 12.2% of the subjects had a first-degree relative with type 1 diabetes (father 6.2%, mother 3.2%, and sibling 4.8%) and 11.9% had an affected second-degree relative. Children without affected relatives had lower pH (P < 0.001), higher plasma glucose (P < 0.001) and β-hydroxybutyrate concentrations (P < 0.001), a higher rate of impaired consciousness (P = 0.02), and greater weight loss (P < 0.001). There were no differences in signs of β-cell autoimmunity. The familial cases carried the HLA DR4-DQ8 haplotype more frequently than sporadic cases (74.0 vs. 67.0%, P = 0.02).

CONCLUSIONS

When the extended family history of type 1 diabetes is considered, the proportion of sporadic diabetes cases may be reduced to <80%. A positive family history for type 1 diabetes associates with a less severe metabolic decompensation at diagnosis, even when only second-degree relatives are affected. Autoantibody profiles are similar in familial and sporadic type 1 diabetes, suggesting similar pathogenetic mechanisms.Familial clustering of type 1 diabetes is a conspicuous feature; the risk of developing type 1 diabetes is 8–15-fold higher in first-degree relatives (1–6) and twofold in second-degree relatives (1,7). Despite this, the vast majority of children are diagnosed with the sporadic form of diabetes. The proportion of children with an affected first-degree relative at the time of diagnosis is ∼10–12% (7–13), and after decades of follow-up, this frequency increases to >20% (8,14,15). Fathers transmit the disease to their offspring more often than mothers (3,16). Accordingly, at diagnosis, 4–7% of children have a father with type 1 diabetes whereas only 1.5–3% have an affected mother (7–12,17). Fewer reports exist on type 1 diabetes in the extended family. Depending on the definition of second-degree relatives and length of time from the diagnosis of the index case, 5–16% of children with type 1 diabetes have an affected second-degree relative (1,5,11,17–19).Familial and sporadic type 1 diabetes have been suggested to differ in terms of pathogenetic mechanisms (20,21). The risk-associated HLA genotypes have been observed more often in familial type 1 diabetes (8,20,22,23), although not all studies have found significant differences (24). Two studies have noticed no differences in diabetes-associated autoantibodies, e.g., insulin autoantibodies (IAAs) (8), GAD antibodies (GADAs) (8), or islet cell antibodies (ICAs) (8,20). A recent study from Israel reported, however, higher frequencies of IAAs and a higher number of positive antibody responses among familial cases (13). In families with prior experience of type 1 diabetes in a first-degree relative, the clinical status of the child at diagnosis is less severe (8,13,21).Data on the possible pathogenetic differences between familial and sporadic type 1 diabetes are still inconsistent and based on a positive family history in first-degree relatives only. To further our understanding of familial clustering of type 1 diabetes, we used data from the large, nationwide Finnish Pediatric Diabetes Register for a cross-sectional observational study. Since the knowledge of the effects of an extended family history on the diabetes of the index case is lacking, we included information on second-degree relatives (grandparents and siblings of parents). β-Cell autoimmunity, metabolic decompensation at diagnosis, and HLA genetics were compared in children with familial or sporadic type 1 diabetes. We postulated to see a stronger genetic susceptibility to type 1 diabetes and a milder metabolic decompensation in children with a positive family history for type 1 diabetes, whereas no differences were expected in the autoantibody profile.     

Zinc transporter-8 autoantibodies improve prediction of type 1 diabetes in relatives positive for the standard biochemical autoantibodies

OBJECTIVE

We assessed diabetes risk associated with zinc transporter-8 antibodies (ZnT8A), islet cell antibodies (ICA), and HLA type and age in relatives of people with type 1 diabetes with the standard biochemical autoantibodies (BAA) to insulin (IAA), GAD65 (GAD65A), and/or insulinoma-associated protein 2 antigen (IA-2A).

RESEARCH DESIGN AND METHODS

For this analysis, 2,256 relatives positive for at least one BAA, of whom 142 developed diabetes, were tested for ZnT8A, ICA, and HLA genotype followed by biannual oral glucose tolerance tests. ZnT8A were also tested in 911 randomly chosen antibody-negative relatives.

RESULTS

ZnT8A were associated with the other BAA (548 of 2,256 [24.3%] BAA⁺ vs. 8 of 911 [0.8%] BAA⁻, P < 0.001) and BAA number (177 of 1,683 [10.5%] single-, 221 of 384 [57.6%] double-, and 150 of 189 [79.4%] triple-BAA positivity, P < 0.001). The 4-year diabetes risk was higher in single BAA⁺ relatives with ZnT8A than ZnT8A⁻ relatives (31 vs. 7%, P < 0.001). In multivariable analysis, age ≤20 years (hazard ratio 2.13, P = 0.03), IA-2A (2.15, P = 0.005), IAA (1.73, P = 0.01), ICA (2.37, P = 0.002), and ZnT8A (1.87, P = 0.03) independently predicted diabetes, whereas HLA type (high and moderate vs. low risk) and GAD65A did not (P = 0.81 and 0.86, respectively).

CONCLUSIONS

In relatives with one standard BAA, ZnT8A identified a subset at higher diabetes risk. ZnT8A predicted diabetes independently of ICA, the standard BAA, age, and HLA type. ZnT8A should be included in type 1 diabetes prediction and prevention studies.Type 1 diabetes is usually preceded by a subclinical prodrome marked by islet cell antibodies (ICA) and biochemical autoantibodies (BAA) to insulin (IAA), GAD65 (GAD65A), and the insulinoma-associated protein 2 antigen (IA-2A/ICA512A) (1). The predictive validity of the autoantibodies for diabetes in relatives of people with type 1 diabetes has made autoantibody positivity an entry criterion for type 1 diabetes secondary prevention trials (2–5) and a surrogate outcome in primary prevention trials (6). Autoantibodies to the islet antigen zinc transporter-8 (ZnT8A) recently were found to predict type 1 diabetes (7–9). However, the relationship between diabetes risk and ZnT8A in combination with other risk markers, including ICA, the standard BAA, HLA genotype, and age, remains unclear.We therefore measured ZnT8A in a large cohort of relatives being followed in the TrialNet Natural History Study of Type 1 Diabetes (NHS). We hypothesized that ZnT8A positivity would increase diabetes risk in relatives positive for a single BAA—a group that accounts for most autoantibody-positive relatives but whose members are at much lower risk compared with relatives with two or more autoantibodies (10). We also assessed whether ZnT8A increased diabetes risk independently of ICA, the BAA, HLA class II genotype, and age.     

Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: diabetes autoimmunity study in the young

OBJECTIVE

We evaluated predictors of progression to diabetes in children with high-risk HLA genotypes and persistent islet autoantibodies.

RESEARCH DESIGN AND METHODS

The Diabetes Autoimmunity Study in the Young (DAISY) followed 2,542 children with autoantibodies measured to GAD, IA-2, and insulin.

RESULTS

Persistent islet autoantibodies developed in 169 subjects, and 55 of those progressed to diabetes. Children expressing three autoantibodies showed a linear progression to diabetes with 74% cumulative incidence by the 10-year follow-up compared with 70% with two antibodies and 15% with one antibody (P < 0.0001). Both age of appearance of first autoantibody and insulin autoantibody (IAA) levels, but not GAD or IA-2 autoantibodies, were major determinants of the age of diabetes diagnosis (r = 0.79, P < 0.0001).

CONCLUSIONS

In the DAISY cohort, 89% of children who progressed to diabetes expressed two or more autoantibodies. Age of diagnosis of diabetes is strongly correlated with age of appearance of first autoantibody and IAA levels.Most of the trials to prevent type 1A diabetes target individuals in the preclinical phase of the disease, marked by the presence of persistent islet autoantibodies (1). Screening for autoantibodies to insulin (IAA) (2), GAD (3), and protein tyrosine IA-2 (ICA512) (4) is the mainstay of risk prediction (5). Factors correlating and potentially predictive of age of diagnosis of children followed from birth are less well characterized.     

The Presence of GAD and IA-2 Antibodies in Youth With a Type 2 Diabetes Phenotype: Results from the TODAY study

OBJECTIVE

To determine the frequency of islet cell autoimmunity in youth clinically diagnosed with type 2 diabetes and describe associated clinical and laboratory findings.

RESEARCH DESIGN AND METHODS

Children (10–17 years) diagnosed with type 2 diabetes were screened for participation in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Measurements included GAD-65 and insulinoma-associated protein 2 autoantibodies using the new National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) standardized assays, a physical examination, and fasting lipid, C-peptide, and A1C determinations.

RESULTS

Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive; of these, 71 (5.9%) were positive for a single antibody, and 47 were positive (3.9%) for both antibodies. Diabetes autoantibody (DAA) positivity was significantly associated with race (P < 0.0001), with positive subjects more likely to be white (40.7 vs. 19%) (P < 0.0001) and male (51.7 vs. 35.7%) (P = 0.0007). BMI, BMI z score, C-peptide, A1C, triglycerides, HDL cholesterol, and blood pressure were significantly different by antibody status. The antibody-positive subjects were less likely to display characteristics clinically associated with type 2 diabetes and a metabolic syndrome phenotype, although the range for BMI z score, blood pressure, fasting C-peptide, and serum lipids overlapped between antibody-positive and antibody-negative subjects.

CONCLUSIONS

Obese youth with a clinical diagnosis of type 2 diabetes may have evidence of islet autoimmunity contributing to insulin deficiency. As a group, patients with DAA have clinical characteristics significantly different from those without DAA. However, without islet autoantibody analysis, these characteristics cannot reliably distinguish between obese young individuals with type 2 diabetes and those with autoimmune diabetes.Type 2 diabetes in youth was rarely reported before the 1990s, but increased in the late 1990s, associated with the burgeoning of childhood obesity (1–3). Type 2 diabetes now accounts for 15–87% of new-onset diabetes in U.S. youth aged 10–20 years, varying with race/ethnicity (4). In addition, there have been significant increases in the occurrence of type 1 diabetes in the last 25 years (5–7). Given the obesity epidemic, many youth with type 1 diabetes are either overweight or obese at diagnosis (8,9), making it difficult for clinicians to distinguish between type 1 and type 2 diabetes based on weight alone. As the classic criteria for distinguishing between these two major types of diabetes (i.e., age at onset and weight) are increasingly blurred, there has been a need to develop better methods of diabetes classification in youth.This dilemma was highlighted by the SEARCH for Diabetes in Youth study, which reported that 21.2% of children aged 10–19 years of age with physician-identified type 2 diabetes were found to be positive for GAD-65 antibodies (4). Although the significance of these antibodies in children with phenotypic type 2 diabetes is not currently understood, in adults in the UK Prospective Diabetes Study (UKPDS) who had positive GAD-65 antibodies and physician-diagnosed type 2 diabetes, oral treatment failed significantly more rapidly than in those without autoimmunity (94 vs. 14% at 6 years) (10). These and other studies suggest that there are clinically significant differences between individuals with clinical signs of type 2 diabetes and islet autoimmunity compared with those without evidence of autoimmunity.With the dramatic increase in type 2 diabetes in youth of all ethnic origins, the importance of determining the effectiveness of treatment options became a child health priority. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is a National Institutes of Health (NIH)-sponsored multicenter clinical trial designed to compare treatment with metformin alone, metformin with rosiglitazone, and metformin with an intensive lifestyle intervention program in children 10–17 years of age (11). In designing the TODAY study, the UKPDS experience led to a decision to exclude islet antibody-positive individuals from the trial. This report examines islet autoimmunity in youth who were considered by pediatric endocrinologists to have type 2 diabetes based on their phenotypic presentation. Subjects were assessed for islet autoimmunity at the screening visit for the TODAY study; those with islet autoimmunity were excluded from participation. Clinical and laboratory differences between islet antibody-positive and antibody-negative participants at screening are described.     

Age at Development of Type 1 Diabetes�C and Celiac Disease�CAssociated Antibodies and Clinical Disease in Genetically Susceptible Children Observed From Birth

OBJECTIVE

To compare the ages and sequence in which antibodies associated with type 1 diabetes and celiac disease appear and overt diseases develop in children with an HLA-conferred susceptibility to both diseases.

RESEARCH DESIGN AND METHODS

We observed 2,052 children carrying genetic risks for both type 1 diabetes and celiac disease from birth until the median age of 5.7 years and analyzed diabetes- and celiac disease–associated antibodies in serum samples collected at 3- to 12-month intervals. Diabetes was confirmed by World Health Organization criteria and celiac disease by duodenal biopsies.

RESULTS

Altogether 342 children seroconverted to positivity for at least one diabetes-associated autoantibody and 88 to positivity for at least one celiac disease–associated antibody at the median ages of 3.0 and 1.5 years, respectively (P < 0.001). If only children with biochemically defined diabetes-associated autoantibodies against insulin, GAD, or IA-2A protein (n = 146) and children with tissue transglutaminase autoantibodies were compared (n = 86), the median seroconversion ages were 2.5 and 3.0 years (P = 0.011). Fifty-one children progressed to overt diabetes at 4.5 years and 44 children to celiac disease at 4.3 years (P = 0.257). Of the 19 children who developed both diabetes- and celiac disease–associated antibodies, 3 progressed to both diabetes and celiac disease.

CONCLUSIONS

Children with HLA-conferred susceptibility to type 1 diabetes and celiac disease develop celiac disease–associated antibodies mostly at a younger age or the same age at which they develop diabetes-associated autoantibodies. Clinical diabetes and celiac disease are commonly diagnosed at the same median age.The incidences of type 1 diabetes and celiac disease are increasing rapidly (1). These autoimmune diseases often occur together, as ∼4.5% of subjects with recent-onset type 1 diabetes also have celiac disease, and the coexistence is even more common in subjects with long-standing type 1 diabetes (2,3). Shared susceptibility alleles in the HLA region probably contribute to this coexistence (4). Although appearance of diabetes- and celiac disease–specific antibodies strongly indicates commencement of autoimmunity (5), antibodies also predict progression to the respective clinical diseases. However, in the case of diabetes, in particular, the time from autoimmunity to overt disease may vary from months to years. Interestingly, clinical type 1 diabetes is usually diagnosed first and celiac disease within the following few years (6,7). The order is rarely reversed (8).Although coexistence of type 1 diabetes and celiac disease has been studied mainly in clinical patients, Williams et al. (9) showed in a cross-sectional study that 5.4% of nondiabetic first-degree relatives of type 1 diabetic patients who were positive for diabetes-associated autoantibodies were positive also for tissue transglutaminase autoantibody (TGA). However, the findings of the Diabetes Autoimmunity Study in the Young (DAISY) indicated that the two types of antibodies rarely appeared simultaneously (10), whereas the German BabyDiab study suggested that celiac disease–associated antibodies invariably develop later than diabetes-associated autoantibodies (11,12).Here we report the age and order in which the diabetes- and celiac disease–associated antibodies and the two clinical diseases developed in children who carried genetic type 1 diabetes and celiac disease susceptibility and participated in the type 1 Diabetes Prediction and Prevention (DIPP) study.     

The Prediction of Type 1 Diabetes by Multiple Autoantibody Levels and Their Incorporation Into an Autoantibody Risk Score in Relatives of Type 1 Diabetic Patients

OBJECTIVE

We assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D).

RESEARCH DESIGN AND METHODS

TrialNet Natural History Study participants (n = 784) were tested for three autoantibodies (GADA, IA-2A, and mIAA) at their initial screening. Samples from those positive for at least one autoantibody were subsequently tested for ICA and ZnT8A. An autoantibody risk score (ABRS) was developed from a proportional hazards model that combined autoantibody levels from each autoantibody along with their designations of positivity and negativity.

RESULTS

The ABRS was strongly predictive of T1D (hazard ratio [with 95% CI] 2.72 [2.23–3.31], P < 0.001). Receiver operating characteristic curve areas (with 95% CI) for the ABRS revealed good predictability (0.84 [0.78–0.90] at 2 years, 0.81 [0.74–0.89] at 3 years, P < 0.001 for both). The composite of levels from the five autoantibodies was predictive of T1D before and after an adjustment for the positivity or negativity of autoantibodies (P < 0.001). The findings were almost identical when ICA was excluded from the risk score model. The combination of the ABRS and the previously validated Diabetes Prevention Trial–Type 1 Risk Score (DPTRS) predicted T1D more accurately (0.93 [0.88–0.98] at 2 years, 0.91 [0.83–0.99] at 3 years) than either the DPTRS or the ABRS alone (P ≤ 0.01 for all comparisons).

CONCLUSIONS

These findings show the importance of considering autoantibody levels in assessing the risk of T1D. Moreover, levels of multiple autoantibodies can be incorporated into an ABRS that accurately predicts T1D.Several autoantibodies have now been shown to be predictive of type 1 diabetes (T1D) (1–8). For the most part, prediction has been based on the positivity of those autoantibodies. Although the dichotomy of positivity and negativity has provided prediction accuracy, the consideration of autoantibody levels could further enhance prediction. Data from some studies already suggest this (3–7).In addition to autoantibodies, other measures have been shown to be predictive of T1D (9–14). With the growing number of T1D predictors, it has become cumbersome and somewhat arbitrary to use prediction algorithms that rely on various combinations and cutoffs of those predictors. Thus, there is a rationale for developing risk scores based on multivariate models that can more efficiently optimize the accuracy of combined predictors. The Diabetes Prevention Trial–Type 1 Risk Score (DPTRS), which includes several metabolic measures along with age and BMI, is an example (15,16).We assessed whether levels from multiple autoantibodies can be incorporated into an autoantibody risk score (ABRS) that accurately predicts T1D in participants of the TrialNet Natural History Study (TNNHS). In addition, we assessed whether the prediction of T1D can be further enhanced when autoantibody information is combined with information from the DPTRS.     

Diabetic Subjects Diagnosed Through the Diabetes Prevention Trial�CType 1 (DPT-1) Are Often Asymptomatic With Normal A1C at Diabetes Onset

OBJECTIVE

Upon diagnosis of type 1 diabetes, patients are usually symptomatic, and many have ketoacidosis. Screening for islet autoantibodies (IAs) has been shown to decrease A1C level and rate of hospitalization at diabetes onset. Metabolic tests and the presence of symptoms were described at diabetes onset during the Diabetes Prevention Trial–Type 1 (DPT-1).

RESEARCH DESIGN AND METHODS

The DPT-1 screened relatives of patients with type 1 diabetes for islet cell autoantiobodies (ICAs). Those with positive ICAs had intravenous and oral glucose tolerance tests (IVGTTs and OGTTs) and were randomized into one of two prevention trials. Throughout the DPT-1 parenteral and oral insulin study, 246 people were diagnosed with type 1 diabetes.

RESULTS

Of the 246 subjects diagnosed with diabetes, 218 had data regarding the presence of symptoms, and 138 (63.3%) reported no symptoms suggestive of diabetes. Eight subjects (3.67%) presented with ketosis. Subjects presented with a mean ± SD A1C of 6.41 ± 1.15%. At diagnosis, 90 subjects (50.8%) had A1C in the normal range (<6.2%). OGTT data at the time of diagnosis indicate that 35.4% had a glucose result of <100 mg/dl at 0 min.

CONCLUSIONS

The majority of subjects diagnosed with type 1 diabetes through the DPT-1 were asymptomatic at onset and had normal fasting glucose and A1C levels. This suggests that intermittent screening (IA followed by OGTT) may allow diagnosis of diabetes before severe metabolic decompensation. Screening with A1C will miss identifying many of the subjects with newly diagnosed type 1 diabetes in this cohort.Type 1 diabetes affects ∼15–30 million people worldwide and 1.4 million people in the U.S. (1) and is responsible for significant morbidity, premature mortality, and financial burden (2). Onset of disease is usually preceded by a preclinical period that can last for months or years. Pre-diabetes can often be detected by the presence of autoantibodies to islet antigens such as GAD65, insulin, insulinoma-associated protein 2 (IA-2), and the recently identified ZnT8 (3). These antibodies can be highly predictive of diabetes risk in children with (4) and without (5) a first-degree relative with type 1 diabetes. First-degree relatives of patients with type 1 diabetes carry a 10- to 20-fold higher risk for diabetes than the general population (6).The onset of type 1 diabetes is often marked by the presence of symptoms including polyuria, polydipsia, polyphagia, weight loss, and diabetic ketoacidosis (DKA). DKA is the leading cause of morbidity and mortality in children with type 1 diabetes. Approximately 25% of newly diagnosed cases present with DKA in the U.S. (7). Cerebral edema complicates 0.5–1% of cases of DKA in children, and there is a 50% risk for significant morbidity and mortality in patients with cerebral edema. New-onset diabetes is a risk factor for DKA (8). Therefore, preventing DKA at onset may have a significant impact on diabetes-related mortality in childhood. A prospective follow-up of children through the Diabetes Autoimmunity Study in the Young (DAISY) for islet autoantibodies (IAs) and diabetes showed that children followed in DAISY were hospitalized less often and had milder metabolic abnormalities at diagnosis compared with a control population of children diagnosed in the community (9).The Diabetes Prevention Trial–Type 1 (DPT-1) parenteral and oral insulin trials (10,11) screened relatives of people with type 1 diabetes with islet cell autoantibodies (ICAs). Subjects positive for these antibodies were invited for further testing including oral and intravenous glucose tolerance testing (OGTT and IVGTT). If eligible, subjects were enrolled in one of the two prevention trials and were followed with serial OGTTs for the diagnosis of type 1 diabetes. By studying those diagnosed with diabetes during the DPT-1, metabolic characteristics and the presence of symptoms were evaluated in those enrolled in prevention and screening trials. Previous reports have focused on a subset of asymptomatic individuals who were diagnosed solely by 2-h OGTT (12). Metabolic tests and the presence of symptoms were described in the individuals diagnosed through DPT-1 during the two clinical trials.     

Prediction of Type 1 Diabetes in the General Population

OBJECTIVE

To evaluate the utility of GAD antibodies (GADAs) and islet antigen-2 antibodies (IA-2As) in prediction of type 1 diabetes over 27 years in the general population and to assess the 6-year rates of seroconversion.

RESEARCH DESIGN AND METHODS

A total of 3,475 nondiabetic subjects aged 3–18 years were sampled in 1980, and 2,375 subjects (68.3%) were resampled in 1986. All subjects were observed for development of diabetes to the end of 2007. GADAs and IA-2As were analyzed in all samples obtained in 1980 and 1986.

RESULTS

A total of 34 individuals (1.0%; 9 developed diabetes) initially had GADAs and 22 (0.6%; 9 developed diabetes) IA-2As. Seven subjects (0.2%) tested positive for both autoantibodies. The positive seroconversion rate over 6 years was 0.4% for GADAs and 0.2% for IA-2As, while the inverse seroconversion rates were 33 and 57%, respectively. Eighteen subjects (0.5%) developed type 1 diabetes after a median pre-diabetic period of 8.6 years (range 0.9–20.3). Initial positivity for GADAs and/or IA-2As had a sensitivity of 61% (95% CI 36–83) for type 1 diabetes. Combined positivity for GADAs and IA-2As had both a specificity and a positive predictive value of 100% (95% CI 59–100).

CONCLUSIONS

One-time screening for GADAs and IA-2As in the general childhood population in Finland would identify ∼60% of those individuals who will develop type 1 diabetes over the next 27 years, and those subjects who have both autoantibodies carry an extremely high risk for diabetes. Both positive and inverse seroconversions do occur over time reflecting a dynamic process of β-cell autoimmunity.Type 1 diabetes is an immune-mediated disease leading to chronic insulin deficiency due to extensive and selective β-cell destruction in subjects with increased genetic disease susceptibility (1). The clinical disease manifestation represents end-stage insulitis, since only 10–20% of the insulin-producing β-cells have been estimated to still be functioning at the time of diagnosis (2). The clinical disease presentation is preceded by an asymptomatic period of variable duration. β-cell autoimmunity is characterized by the presence of autoantibodies, such as islet cell autoantibodies (ICAs), insulin autoantibodies (IAAs), autoantibodies to the 65-kDa isoform of GAD (GADAs), and autoantibodies to the intracellular portion of the protein tyrosine phosphatase–related islet antigen-2 molecule (IA-2As), in the peripheral circulation (3). Many studies (3–5) have shown that these antibodies can be used efficiently for the prediction of type 1 diabetes in first-degree relatives of affected patients. The combination of GADAs and IA-2As has a high sensitivity and specificity for type 1 diabetes in family members, although prospective studies from birth have shown that IAAs are usually the first or among the first antibodies to appear in young children (6–8). In a previous survey, we showed that the predictive characteristics of combined positivity for GADAs and IA-2As were of the same magnitude in the general population as those seen among first-degree relatives over an observation period of 15 years (9). In this study, we set out to assess the predictive characteristics of GADAs and IA-2As over a period of 27 years in a population-based series of 3,475 Finnish subjects initially aged 3–18 years. We also had the opportunity to define in this population the rates of positive and inverse seroconversions over the initial 6 years of follow-up.     

Adverse Outcomes After Noncardiac Surgery in Patients With Diabetes: A nationwide population-based retrospective cohort study

OBJECTIVE

To investigate whether diabetes affects perioperative complications or mortality and to gauge its impact on medical expenditures for noncardiac surgeries.

RESEARCH DESIGN AND METHODS

With the use of reimbursement claims from the Taiwan National Health Insurance system, we performed a population-based cohort study of patients with and without diabetes undergoing noncardiac surgeries. Outcomes of postoperative complications, mortality, hospital stay, and medical expenditures were compared between patients with and without diabetes.

RESULTS

Diabetes increased 30-day postoperative mortality (odds ratio 1.84 [95% CI 1.46–2.32]), particularly among patients with type 1 diabetes or uncontrolled diabetes and patients with preoperative diabetes-related comorbidities, such as eye involvement, peripheral circulatory disorders, ketoacidosis, renal manifestations, and coma. Compared with nondiabetic control patients, coexisting medical conditions, such as renal dialysis (5.17 [3.68–7.28]), liver cirrhosis (3.59 [2.19–5.88]), stroke (2.87 [1.95–4.22]), mental disorders (2.35 [1.71–3.24]), ischemic heart disease (2.08 [1.45–2.99]), chronic obstructive pulmonary disease (1.96 [1.29–2.97]), and hyperlipidemia (1.94 [1.01–3.76]) were associated with mortality for patients with diabetes undergoing noncardiac surgery. Patients with diabetes faced a higher risk of postoperative acute renal failure (3.59 [2.88–4.48]) and acute myocardial infarction (3.65 [2.43–5.49]). Furthermore, diabetes was associated with prolonged hospital stay (2.30 [2.16–2.44]) and increased medical expenditures (1.32 [1.25–1.40]).

CONCLUSIONS

Diabetes increases postoperative 30-day mortality, complications, and medical expenditures in patients undergoing in-hospital noncardiac surgeries.Diabetes is a common chronic disease that causes widespread disability and death, with a global prevalence of 2.8% in 2000 and an estimated prevalence of 4.4% in 2030 (1). In the U.S., the national burden of diabetes was estimated to be $245 billion in 2012 (2). The epidemiology, pathogenesis, prevention, and treatment of diabetes have been well established over the past 2 centuries (3).Diabetes is an independent determinant of increased risk of perioperative complications and mortality in cardiovascular surgeries (4,5), yet how extensively diabetes affects postoperative mortality and complications in noncardiac surgeries has not been determined. Some studies indicated that survival outcomes and perioperative complications in noncardiac surgeries do not differ between patients with and without diabetes (6,7), whereas other research showed conflicting data about whether diabetes increased perioperative complications, mortality, hospital stay, and health care expenditures (8–16).Previous studies were limited by several factors, including a focus on a single type of noncardiac surgery (6,8,10,12,14), small sample size (6,7,9,13), inappropriate selection of nondiabetes control subjects (6–16), inadequate adjustment for potential confounders (7,9–12,15), and reporting of a single outcome after surgery (10,16). It remains unclear whether coexisting medical conditions, types of diabetes, glycemic control, and diabetes-related comorbidities affect postoperative outcomes in patients with diabetes.This study used Taiwan National Health Insurance Program reimbursement claims to investigate postoperative complications, 30-day mortality, length of hospital stay, and medical expenditures after adjustment by propensity score-matched pair method in patients with diabetes undergoing noncardiac surgeries. We also investigated the impact of coexisting medical conditions and diabetes-related comorbidities on postoperative 30-day mortality among patients with diabetes.     

Long-Term Cardiovascular Risk in Type 2 Diabetic Compared With Nondiabetic First Acute Myocardial Infarction Patients: A population-based cohort study in southern Europe

OBJECTIVE

The aim of this study was to determine whether long-term cardiovascular risk differs in type 2 diabetic patients compared with first acute myocardial infarction patients in a Mediterranean region, considering therapy, diabetes duration, and glycemic control.

RESEARCH DESIGN AND METHODS

A prospective population-based cohort study with 10-year follow-up was performed in 4,410 patients aged 30–74 years: 2,260 with type 2 diabetes without coronary heart disease recruited in 53 primary health care centers and 2,150 with first acute myocardial infarction without diabetes recruited in 10 hospitals. We compared coronary heart disease incidence and cardiovascular mortality rates in myocardial infarction patients and diabetic patients, including subgroups by diabetes treatment, duration, and A1C.

RESULTS

The adjusted hazard ratios (HRs) for 10-year coronary heart disease incidence and for cardiovascular mortality were significantly lower in men and women with diabetes than in myocardial infarction patients: HR 0.54 (95% CI 0.45–0.66) and 0.28 (0.21–0.37) and 0.26 (0.19–0.36) and 0.16 (0.10–0.26), respectively. All diabetic patient subgroups had significantly fewer events than myocardial infarction patients: the HR of cardiovascular mortality ranged from 0.15 (0.09–0.26) to 0.36 (0.24–0.54) and that of coronary heart disease incidence ranged from 0.34 (0.26–0.46) to 0.56 (0.43–0.72).

CONCLUSIONS

Lower long-term cardiovascular risk was found in type 2 diabetic and all subgroups analyzed compared with myocardial infarction patients. These results do not support equivalence in coronary disease risk for diabetic and myocardial infarction patients.The prevalence of diabetes is reaching epidemic proportions in developed countries (1). For example, the U.S. has 18 million diabetic patients, Spain has >2 million diabetic patients, and management of the disease costs >$132 and >$3.3 billion per year, respectively (2).Some studies (3–5), several of them with great influence on important guidelines for cardiovascular prevention (3), suggest that the cardiovascular risk of diabetic patients is similar to that of coronary heart disease secondary prevention patients. Other reports, however, do not confirm these observations (6–10).Part of the discrepancy may stem from differences in the duration of diabetes, type of treatment, and baseline glucose control of diabetic patients included in the studies (3–5). These limit comparability, given the fact that time of evolution and treatment required to attain appropriate glycemic control are key determinants of prognosis (10–16).Among population-based cohort studies that compared the prognosis of diabetic patients with that of myocardial infarction patients without diabetes (3–10), only two analyzed the role of diabetes duration (11,12). Even these studies did not include unstable angina among the end points and risk was not stratified by type of treatment. To our knowledge, the effect of type 2 diabetes on coronary heart disease incidence has barely been studied in southern Europe, a region known for low cardiovascular mortality (17). The aim of this study was to determine whether long-term cardiovascular risk differed between type 2 diabetic patients and first acute myocardial infarction patients and to assess the influence of diabetes duration, type of treatment, and glycemic control at baseline.     

Associations between media consumption habits, physical activity, socioeconomic status, and glycemic control in children, adolescents, and young adults with type 1 diabetes

OBJECTIVE

To evaluate the relationship between media consumption habits, physical activity, socioeconomic status, and glycemic control in youths with type 1 diabetes.

RESEARCH DESIGN AND METHODS

In the cross-sectional study, self-report questionnaires were used to assess media consumption habits, physical activity, and socioeconomic status in 296 children, adolescents, and young adults with type 1 diabetes. Clinical data and HbA_1c levels were collected. Risk factors were analyzed by multiple regression.

RESULTS

Youths with type 1 diabetes (aged 13.7 ± 4.1 years, HbA_1c 8.7 ± 1.6%, diabetes duration 6.1 ± 3.3 years) spent 2.9 ± 1.8 h per day watching television and using computers. Weekly physical activity was 5.1 ± 4.5 h. Multiple regression analysis identified diabetes duration, socioeconomic status, and daily media consumption time as significant risk factors for glycemic control.

CONCLUSIONS

Diabetes duration, socioeconomic status, and daily media consumption time, but not physical activity, were significant risk factors for glycemic control in youths with type 1 diabetes.The pivotal Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) study demonstrate that poor glycemic control is associated with an increased risk of developing complications in type 1 diabetes (1). Various factors contributing to glycemic control have been identified (2). Immutable parameters such as age, sex, diabetes duration, and socioeconomic status have a major effect on metabolic control (2–6). Lower socioeconomic status is an important determinant for poor glycemic control (4,5). Modifiable factors influencing metabolic control are diabetes-related knowledge, frequency of blood glucose monitoring, and daily insulin dose (3,4,6,7). Lastly, psychosocial parameters are important in achieving good glycemic control (3–5,8–10). The influence of physical activity on metabolic control is unclear (9,11,12).Recent research addresses the influence of modern life habits on general health. Youths spend more and more time watching television and using computers. Many studies suggest that sedentary behaviors such as watching television lead to obesity in children (13,14). In one study in youths with type 1 diabetes, Margeirsdottir et al. (15) showed that poor metabolic control was associated with extensive television watching. However, the authors did not examine other covariables, such as socioeconomic status, which is associated with both glycemic control and media consumption (4,5,16,17). Hence, the aim of this study was to examine the impact of media consumption habits, physical activity, and socioeconomic status on glycemic control in youths with type 1 diabetes.     

Minimal Contribution of Fasting Hyperglycemia to the Incidence of Type 2 Diabetes in Subjects With Normal 2-h Plasma Glucose

OBJECTIVE

To assess the relative contribution of increased fasting and postload plasma glucose concentrations to the incidence of type 2 diabetes in subjects with a normal 2-h plasma glucose concentration.

RESEARCH DESIGN AND METHODS

A total of 3,450 subjects with 2-h plasma glucose concentration <140 mg/dl at baseline were followed up in the San Antonio Heart Study (SAHS) and the Botnia Study for 7–8 years. The incidence of type 2 diabetes at follow-up was related to the fasting, 1-h, and 2-h plasma glucose concentrations.

RESULTS

In subjects with 2-h plasma glucose <140 mg/dl, the incidence of type 2 diabetes increased with increasing fasting plasma glucose (FPG) and 1-h and 2-h plasma glucose concentrations. In a multivariate logistic analysis, after adjustment for all diabetes risk factors, the FPG concentration was a strong predictor of type 2 diabetes in both the SAHS and the Botnia Study (P < 0.0001). However, when the 1-h plasma glucose, but not 2-h plasma glucose, concentration was added to the model, FPG concentration was no longer a significant predictor of type 2 diabetes in both studies (NS). When subjects were matched for the level of 1-h plasma glucose concentration, the incidence of type 2 diabetes markedly increased with the increase in 1-h plasma glucose, but the increase in FPG was not associated with a significant increase in the incidence of type 2 diabetes.

CONCLUSIONS

An increase in postload glycemia in the normal range is associated with an increase in the incidence of type 2 diabetes. After controlling for 1-h plasma glucose concentration, the increase in FPG concentration is not associated with an increase in the incidence of type 2 diabetes.Impaired fasting glucose (IFG) was introduced in 1997 by the American Diabetes Association (ADA) (1), and, analogous with impaired glucose tolerance (IGT), it was meant to represent an intermediate stage in the transition from normal glucose tolerance (NGT) to overt type 2 diabetes. Both IFG and IGT indicate an increased risk for future type 2 diabetes (2–4). Previously (5–7), we have shown that the 1-h plasma glucose concentration has better predictive power than either fasting plasma glucose (FPG) or 2-h plasma glucose, suggesting that the 1-h plasma glucose concentration may have greater utility in identifying subjects at increased risk for type 2 diabetes in routine clinical practice.Previous studies have reported that IFG and IGT represent separate clinical entities, which are characterized by distinct metabolic abnormalities (8–13). Subjects with IGT manifest insulin resistance in skeletal muscle (9–12) and impaired β-cell function (both early and late phases of insulin secretion) (10,14–16), whereas subjects with IFG are characterized by increased hepatic insulin resistance (9,16), impaired early insulin response (12), and decreased non–insulin-dependent glucose clearance (15). Because of the prominent role of progressive β-cell failure in the development of hyperglycemia (17), the impairment in β-cell function in subjects with IGT represents a major pathogenic factor for their increased risk for future type 2 diabetes. Although the increase in fasting plasma glucose is associated with a decrease in first-phase insulin secretion (11–13,18), subjects with IFG have robust second-phase insulin secretion, and, when related to their prevailing level of insulin resistance, they have second-phase insulin secretion comparable with that of subjects with NGT (12,13). Thus, impaired β-cell function cannot fully explain the increased incidence of type 2 diabetes associated with the increase in FPG concentration, e.g., in subjects with isolated IFG.Previously we have shown a strong correlation between insulin resistance in skeletal muscle and liver (16). Thus, a strong correlation between FPG and postload plasma glucose concentrations is anticipated. Therefore, we hypothesized that the increased type 2 diabetes risk associated with the increase in FPG, at least in part, is due to the increased postprandial plasma glucose concentration associated with the increase in FPG and is not due to the increase in FPG per se. The aim of this study was to test this hypothesis.     

Prevalence of Type 1 Diabetes Autoantibodies (GADA, IA2, and IAA) in Overweight and Obese Children

OBJECTIVE

Little is known about the prevalence of β-cell autoantibodies in children with excess body weight. The prevalence of type 1 diabetes autoantibodies and its relation with hyperglycemia was analyzed in 686 overweight/obese children and adolescents.

RESEARCH DESIGN AND METHODS

All children underwent an oral glucose tolerance test, and anti-GAD, anti-IA2, and anti-IAA autoantibodies were measured. Autoantibody prevalence was evaluated in 107 normal-weight children for comparison.

RESULTS

A single autoantibody was present in 2.18% of overweight/obese subjects and 1.86% normal-weight subjects (P = NS). Postload glycemia was significantly higher in antibody-positive children (133 ± 69.9 vs. 105.4 ± 17.7 mg/dl, P < 0.0001) compared with autoantibody-negative subjects. No difference in autoantibody distribution was seen when our cohort was stratified by age, sex, SDS-BMI, pubertal stage, and homeostasis model assessment–insulin resistance (HOMA-IR).

CONCLUSIONS

The 2.18% prevalence of type 1 diabetes autoantibodies is similar to that reported in nonobese children. This study provided evidence that excess body weight and insulin resistance do not influence autoantibody frequency.Over the last 60 years, a striking increase in the incidence of childhood type 1 diabetes has been observed consistently in almost all populations. EURODIAB (1) reported an overall increase of 3.2% per annum in Europe between 1989 and 1998. There have also been considerable changes in childhood nutrition, which have resulted in changes in growth. Increased weight, height, and BMI in children have all been associated with a higher risk of type 1 diabetes (2). The so-called “accelerator hypothesis” argues that obesity causing overworked β-cells underlies both type 1 and type 2 diabetes and that these “types” are only distinguished by how the body responds to this growth-induced β-cell stress. This hypothesis therefore attributes the rise in type 1 diabetes to an increase in child obesity (3). A variation of the hypothesis suggests that, once initiated, islet autoimmunity progresses more rapidly in the context of “overload” of the β-cells due to increased insulin resistance (4).Sardinia has one of the highest incidences of type 1 diabetes worldwide, second only to Finland (5). Moreover, Sardinian children and adolescents are experiencing the same increase in obesity as other European populations (6). To date, little is known on the prevalence of autoantibodies against β-cells in children with excess body weight.The aim of our study was to analyze the prevalence of type 1 diabetes autoantibodies in a cohort of Sardinian overweight/obese children and adolescents and to evaluate their distribution in relation to the presence of glucose abnormalities.