Latent autoimmune diabetes of the adult: current knowledge and uncertainty.

Patients with adult-onset autoimmune diabetes have less Human Leucocyte Antigen (HLA)-associated genetic risk and fewer diabetes-associated autoantibodies compared with patients with childhood-onset Type 1 diabetes. Metabolic changes at diagnosis reflect a broad clinical phenotype ranging from diabetic ketoacidosis to mild non-insulin-requiring diabetes, also known as latent autoimmune diabetes of the adult (LADA). This latter phenotype is the most prevalent form of adult-onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. Although LADA is associated with the same genetic and immunological features as childhood-onset Type 1 diabetes, it also shares some genetic features with Type 2 diabetes, which raises the question of genetic heterogeneity predisposing to this form of the disease. The potential value of screening patients with adult-onset diabetes for diabetes-associated autoantibodies to identify those with LADA is emphasized by their lack of clinically distinct features, their different natural history compared with Type 2 diabetes and their potential need for a dedicated management strategy. The fact that, in some studies, patients with LADA show worse glucose control than patients with Type 2 diabetes, highlights the need for further therapeutic studies. Challenges regarding classification, epidemiology, genetics, metabolism, immunology, clinical presentation and treatment of LADA were discussed at a 2014 workshop arranged by the Danish Diabetes Academy. The presentations and discussions are summarized in this review, which sets out the current ideas and controversies surrounding this form of diabetes.

Similar weight-adjusted insulin secretion and insulin sensitivity in short-duration late autoimmune diabetes of adulthood (LADA) and type 2 diabetes: Action LADA 9 [corrected].

AIMS: To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with type 2 diabetes. METHODS: A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year of insulin independency (group A) were age-matched pairwise to people with type 2 diabetes (group B) and to six people with type 2 diabetes of similar age and BMI (group C). ß-Cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic-euglycemic clamp) and metabolic response during a mixed meal were studied. RESULTS: Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C) and could be explained by BMI alone in a multivariate analysis. Neither insulin pulsatility, incretin secretion nor insulin sensitivity differed among the groups. CONCLUSIONS: We found no evidence that LADA and type 2 diabetes were distinct disease entities beyond the differences explained by BMI.

Age-dependent decline of ß-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study.

AIMS: C-peptide secretion is currently the only available clinical biomarker to measure residual ß-cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. METHODS: We analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on ß-cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. RESULTS: Fasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (<5 years, n = 344; >5 years < 10 years, n = 668; >10 years < 18 years, n = 991; >18 years, n = 1655). FCP levels were positively correlated with age (p < 0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (p < 0.0001). CONCLUSIONS: This study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of ß-cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.

The broad clinical phenotype of Type 1 diabetes at presentation.

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

Increased serum concentrations of adhesion molecules but not of chemokines in patients with Type 2 diabetes compared with patients with Type 1 diabetes and latent autoimmune diabetes in adult age: action LADA 5.

AIMS: Systemic concentrations of adhesion molecules and chemokines are associated with increased risk of cardiovascular complications. We compared these factors between patients with Type 2 diabetes vs. Type 1 diabetes or latent autoimmune diabetes in adults. METHODS: Serum concentrations of adhesion molecules sE-selectin, sICAM-1 and sVCAM-1, and chemokines CCL2, CCL3 and CCL4 were measured in 61 patients with latent autoimmune diabetes in adults, 90 with Type 1 diabetes, 465 with Type 2 diabetes and in 41 control subjects, using multiple regression models to adjust for possible confounders. RESULTS: Patients with Type 2 diabetes exhibited greater concentrations of adhesion molecules (P < 0.02) than those with Type 1 diabetes, latent autoimmune diabetes in adults and control subjects. These differences persisted upon adjustments for age, sex, BMI, blood pressure and diabetes duration (P < 0.04). Higher BMI positively correlated with concentrations of adhesion molecules in all subjects (P < 0.0001). Concentrations of sE-selectin positively related to diastolic (ß = 0.31) and systolic (ß = 0.28) blood pressure in the adjusted model (P < 0.04). Concentrations of the chemokines, CCL2 and CCL4, did not differ between groups, while CCL3 was higher in patients with latent autoimmune diabetes in adults and Type 1 diabetes than in those with Type 2 diabetes and control subjects (P < 0.05). CONCLUSIONS: Systemic concentrations of adhesion molecules, but not chemokines, relate to cardiovascular risk factors, but remain higher after adjustments in Type 2 diabetes, suggesting a diabetes-type specific effect without difference between latent autoimmune diabetes in adults and Type 1 diabetes, despite their dissimilar phenotype.

Guts, germs, and meals: the origin of type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is due, in part, to non-genetically determined factors including environmental factors. The nature of these environmental effects remains unclear but they are important to identify since they may be amenable to therapy. Recently, the gut microbiota, the trillions of microorganisms inhabiting the gut, as well as diet, have been implicated in T1DM pathogenesis. Since dietary changes can reshape this complex gut community, its co-evolution could have been altered by changes to our diet, agriculture, personal hygiene, and antibiotic usage, which coincide with the increased incidence of T1DM. Recent studies demonstrate an association between altered gut microbiota and T1DM in both T1DM patients and animal models of the disease. Further studies should provide new insight into those critical host-microbial interactions, potentially suggesting new diagnostic or therapeutic strategies for disease prevention.

Adult-onset type 1 diabetes: A changing perspective.

Type 1 diabetes most commonly presents in adulthood, contrary to the widely held view that it is a disease of childhood. Furthermore, a substantial proportion of cases of adult-onset type 1 diabetes does not require insulin therapy at clinical onset. Recent studies have emphasised the evidence that adult-onset type 1 diabetes is prevalent but often misclassified initially as type 2 diabetes (1, 2). In this review, we discuss that recent literature, highlighting the similarities and differences between adult-onset and childhood-onset type 1 diabetes, exploring recent debates surrounding its epidemiology and genetics, as well as expanding on important issues of diagnostic criteria for individuals presenting with adult-onset diabetes and the subsequent management once identified as having an autoimmune basis. In addition, this review looks at the psychosocial challenges faced by T1D patients and their possible management.

Pro- and anti-inflammatory cytokines in latent autoimmune diabetes in adults, type 1 and type 2 diabetes patients: Action LADA 4.

AIMS/HYPOTHESIS: Systemic pro- and anti-inflammatory cytokines are associated with both type 1 and type 2 diabetes, while their role in latent autoimmune diabetes in adults (LADA) is unclear. Therefore, we compared cytokine concentrations in patients with LADA, type 1 or type 2 diabetes and healthy individuals to test the hypothesis that differences of cytokine concentrations between all groups are attributable to diabetes type and BMI. METHODS: The pro-inflammatory cytokines IL-6 and TNF-α, and the anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10 were measured in 90 participants with type 1 diabetes, 61 with LADA, 465 with type 2 diabetes and 41 control participants using multiple regression models adjusted for BMI, sex, age, blood pressure and diabetes duration. RESULTS: Patients with type 2 diabetes had higher concentrations of systemic IL-1RA, IL-6 and TNF-α cytokines than patients with either LADA or type 1 diabetes (p < 0.0001 for all differences). Cytokine concentrations in controls were lower than those in all diabetes types (p < 0.04). Increased BMI was positively associated with higher systemic cytokine concentrations in all diabetes types (p < 0.0001). Despite the association of cytokines with anthropometric data, differences between diabetes forms persisted also after adjusting analysis for the confounders BMI, age, sex, disease duration and blood pressure (p < 0.04). CONCLUSIONS/INTERPRETATION: Although body mass associates positively with pro- and anti-inflammatory cytokine levels, patients with type 2 diabetes have higher cytokine levels independent of the prevailing BMI. LADA and type 1 diabetes could not be distinguished by systemic cytokines.

Altered monocyte cyclo-oxygenase response in non-obese diabetic mice.

Monocytes infiltrate islets in non-obese diabetic (NOD) mice. Activated monocyte/macrophages express cyclo-oxygenase-2 (COX-2) promoting prostaglandin-E(2) (PGE(2)) secretion, while COX-1 expression is constitutive. We investigated in female NOD mice: (i) natural history of monocyte COX expression basally and following lipopolysaccharide (LPS) stimulation; (ii) impact of COX-2 specific inhibitor (Vioxx) on PGE(2), insulitis and diabetes. CD11b(+) monocytes were analysed for COX mRNA expression from NOD (n = 48) and C57BL/6 control (n = 18) mice. NOD mice were treated with either Vioxx (total dose 80 mg/kg) (n = 29) or methylcellulose as control (n = 29) administered by gavage at 4 weeks until diabetes developed or age 30 weeks. In all groups, basal monocyte COX mRNA and PGE(2) secretion were normal, while following LPS, after 5 weeks of age monocyte/macrophage COX-1 mRNA decreased (P < 0.01) and COX-2 mRNA increased (P < 0.01). However, diabetic NOD mice had reduced COX mRNA response (P = 0.03). Vioxx administration influenced neither PGE(2), insulitis nor diabetes. We demonstrate an isoform switch in monocyte/macrophage COX mRNA expression following LPS, which is altered in diabetic NOD mice as in human diabetes. However, Vioxx failed to affect insulitis or diabetes. We conclude that monocyte responses are altered in diabetic NOD mice but COX-2 expression is unlikely to be critical to disease risk.

Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes.

Type I diabetes (T1D) is a T cell-mediated autoimmune disease characterized by loss of tolerance to islet autoantigens, leading to the destruction of insulin-producing beta cells. Peripheral tolerance to self is maintained in health through several regulatory mechanisms, including a population of CD4+CD25hi naturally occurring regulatory T cells (T(regs)), defects in which could contribute to loss of self-tolerance in patients with T1D. We have reported previously that near to T1D onset, patients demonstrate a reduced level of suppression by CD4+CD25hi T(regs) of autologous CD4+CD25- responder cells. Here we demonstrate that this defective regulation is also present in subjects with long-standing T1D (> 3 years duration; P = 0.009). No difference was observed in forkhead box P3 or CD127 expression on CD4+CD25hi T cells in patients with T1D that could account for this loss of suppression. Cross-over co-culture assays demonstrate a relative resistance to CD4+CD25hi T(reg)-mediated suppression within the CD4+CD25- T cells in all patients tested (P = 0.002), while there appears to be heterogeneity in the functional ability of CD4+CD25hi T(regs) from patients. In conclusion, this work demonstrates that defective regulation is a feature of T1D regardless of disease duration and that an impaired ability of responder T cells to be suppressed contributes to this defect.

Early environmental events as a cause of IDDM. Evidence and implications.

Insulin-dependent diabetes mellitus (IDDM) is caused by destruction of the insulin-secreting beta-cells of the islets of Langerhans. It is proposed that the disease is caused by nongenetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These environmental factors may operate over a limited period in early childhood to induce the immune process that destroys the islet beta-cell. Thereafter, there is a long prodrome before the onset of clinical diabetes, during which clinical, immune, and metabolic changes can be detected. If these proposals are correct, epidemiological studies should focus on environmental events in early childhood that might induce, or accelerate, the disease process. Moreover, it should be possible to identify, from an early age, changes in the prediabetic period that persist to diagnosis and have predictive value. The variable age of presentation of IDDM may, therefore, reflect different rates of disease progression rather than different ages of exposure to the critical environmental events. Those patients in whom the disease process is slow could present with IDDM as adults, develop diabetes that does not require insulin treatment, or even fail to develop diabetes altogether. These proposed features, if confirmed, would have important implications for the prediction of IDDM and raise the possibility that modulation of the destructive immune process could prevent progression to clinical diabetes.

Diabetic retinopathy in identical twins.

The prevalence and features of diabetic retinopathy have been examined in 95 pairs of identical twins, 31 concordant for insulin-dependent diabetes (IDD), 27 discordant for IDD, and 37 concordant for non-insulin-dependent diabetes (NIDD). Optic fundi were examined after pupillary dilatation and retinopathy was classified as nil, background, or severe. In the NIDD twins, 35 of the 37 pairs were in the same category including all but one of the 15 pairs with the same duration of diabetes. However, in insulin-dependent diabetic pairs the situation was quite different; only 21 of 31 pairs were in the same retinopathy category, and of the 10 pairs of co-twins with the same duration of diabetes 5 pairs showed a striking difference for retinopathy. There was no significant difference in the prevalence of retinopathy in the concordant and discordant IDD twin pairs. Diabetic retinopathy was not observed in 32 unaffected co-twins of diabetics. We conclude that genetic factors may be important in the etiology of retinopathy in non-insulin-dependent diabetes but that nongenetic factors must be important in the pathogenesis of retinopathy in insulin-dependent diabetes.

Alterations in T-lymphocyte subpopulations in type I diabetes. Exploration of genetic influence in identical twins.

To evaluate factors influencing the alteration in subsets of T-lymphocytes, we studied 24 pairs of identical twins discordant for insulin-dependent (type I) diabetes mellitus. Subsets were assessed by monoclonal antibodies and a pure preparation of peripheral blood mononuclear cells obtained by centrifugation of heparinized whole blood with a Ficoll/Triosil gradient. In 12 pairs studied within 5 yr of diagnosis, we observed a reduction in the percentage of cells reacting with OKT8 (recognizing the CD8 antigen present on the suppressor/cytotoxic subset) (P less than .05), but a similar level was detected in their nondiabetic cotwins. In 12 pairs studied greater than 5 yr after the diagnosis and in whom the nondiabetic twin is less likely to develop diabetes, the percentage of cells reacting with OKT8 was reduced in both the diabetic (P less than .05) and the nondiabetic (P less than .01) twins. Reductions were also seen with OKT3 (recognizing the CD3 antigen present on the total T-lymphocyte population) and OKT4 (recognizing the CD4 antigen present on the helper/inducer subset), but only in the diabetic twins from the group with longer discordance. We conclude that a reduced percentage of suppressor/cytotoxic cells is associated with type I diabetes, but the reduction appears to be genetically determined. Total T-lymphocytes are also reduced but mainly in the helper/inducer subset and only in diabetic patients of long duration. Such a reduction cannot therefore be primarily genetically determined.

Decreased growth velocity before IDDM onset.

Diabetes can retard growth. Growth was studied prospectively in 12 nondiabetic identical twins aged less than 14 yr and in their co-twins with insulin-dependent diabetes mellitus (IDDM) to determine whether changes in growth occur before the onset of IDDM. Seven of the 12 nondiabetic twins subsequently developed IDDM; the remainder are now unlikely to become diabetic. A significantly reduced growth velocity was observed more frequently in the nondiabetic twins (7 of 12) than in their diabetic co-twins (1 of 12; P = 0.03). Of the 7 nondiabetic twins who were prediabetic, 6 had a reduction in growth velocity to below the 3rd percentile before the onset of diabetes compared with 1 of their diabetic co-twins (P = 0.03). However, only 1 of the 5 nondiabetic twins who did not develop diabetes showed a reduction in growth velocity. The nadir of growth in the twins who developed diabetes occurred a mean of 1.2 yr before diagnosis (range 0.3-2.3 yr). All 7 of the prediabetic twins had islet cell antibodies when first seen, and 3 had them before they showed either decreased growth velocity or impaired glucose tolerance. In 4 prediabetic twins, the decreased growth preceded impaired glucose tolerance. The prediabetic twins tested had lower testosterone or estradiol levels at the time they showed decreased growth than their diabetic twins. We conclude that decreased growth velocity is an early sensitive marker of IDDM.

Increased expression of T-cell markers of immunological memory associated with protection from type I diabetes. A study of identical twins.

Disturbances in the balance of CD4+ helper T-lymphocytes expressing the surface molecules CD45RA and CD45R0, which define naive and memory populations, respectively, are present at diagnosis of type I diabetes. In a prospective study over 10 years, these subsets were analyzed in samples obtained from 18 identical twins of patients with type I diabetes, 8 of whom became diabetic (prediabetic twins), whereas the rest remained nondiabetic after at least 8 years follow-up and are now unlikely to develop the disease (diabetes-protected twins). At the beginning of the study, percentage levels of naive (CD45RA+) CD4+ lymphocytes were significantly elevated in prediabetic twins compared with diabetes-protected twins (P < 0.05) and remained so throughout the study (P < 0.01). Percentage levels of naive cells in diabetes-protected twins were significantly reduced compared with control subjects both at the beginning and throughout the study (P < 0.05, P < 0.01, respectively). In contrast, diabetes-protected twins at the beginning of the study had elevated percentage levels of memory (CD45R0+) CD4+ lymphocytes that persisted throughout the study compared with prediabetic twins (P < 0.05 for both). Percentage levels of memory cells in prediabetic twins were significantly reduced compared with control subjects both at the beginning and throughout the study (P < 0.01, P < 0.05, respectively). Increased percentage levels of a population of CD4+ lymphocytes coexpressing CD45RA and CD45R0 were seen in both twin groups compared with control subjects at entry into and during the study (P < 0.05 for all), but persisted only in the prediabetic twins.(ABSTRACT TRUNCATED AT 250 WORDS)