Johnny Ludvigsson

GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes

BACKGROUND The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age. METHODS We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 microg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. RESULTS Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (-0.21 vs. -0.27 nmol per liter [-0.62 vs. -0.81 ng per milliliter], P=0.045), as did stimulated secretion measured as the area under the curve (-0.72 vs. -1.02 nmol per liter per 2 hours [-2.20 vs. -3.08 ng per milliliter per 2 hours], P=0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response. CONCLUSIONS GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.)

Declining incidence of nephropathy in insulin-dependent diabetes mellitus.

BACKGROUND The high relative mortality among patients with insulin-dependent diabetes mellitus results mainly from diabetic nephropathy. The cumulative incidence of nephropathy of 25 to 30 percent among patients who had had diabetes for 25 years remained stable from 1950 to the early 1980s. In a population study, we assessed recent trends in the incidence of diabetic nephropathy. METHODS We studied all 213 patients in whom insulin-dependent diabetes mellitus was diagnosed before the age of 15 years between 1961 and 1980 in a district in southeastern Sweden. Ninety-two percent of the patients were followed from the onset of diabetes to 1991 or to death. Patients with persistent albuminuria (positive Albustix test) were considered to have diabetic nephropathy. Glycosylated hemoglobin was measured periodically in all patients, beginning in 1980. RESULTS The cumulative incidence of persistent albuminuria after 25 years of diabetes decreased from 30.0 percent among the patients in whom diabetes developed in the period 1961 to 1965 to 8.9 percent among those in whom it developed from 1966 to 1970 (P = 0.01). After 20 years of diabetes, the cumulative incidence decreased from 28.0 percent among the patients in whom diabetes developed from 1961 to 1965 to 5.8 percent among those in whom it developed from 1971 to 1975 (P = 0.01). Persistent albuminuria has not yet developed in any patient in whom diabetes was diagnosed in the period 1976 to 1980. The average glycosylated hemoglobin value decreased from 7.4 percent in the period 1980 to 1985 to 7.0 percent from 1986 to 1991 (P < 0.001). The mean glycosylated hemoglobin value was higher in the patients with persistent albuminuria than the patients with no albuminuria (8.1 percent vs. 7.1 percent, P < 0.001). CONCLUSIONS During the past decade the cumulative incidence of diabetic nephropathy, as manifested by persistent albuminuria, among patients who have had diabetes for 25 years has decreased substantially, probably as a result of improved glycemic control.

Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial

BACKGROUND Findings of small studies have suggested that short treatments with anti-CD3 monoclonal antibodies that are mutated to reduce Fc receptor binding preserve β-cell function and decrease insulin needs in patients with recent-onset type 1 diabetes. In this phase 3 trial, we assessed the safety and efficacy of one such antibody, teplizumab. METHODS In this 2-year trial, patients aged 8-35 years who had been diagnosed with type 1 diabetes for 12 weeks or fewer were enrolled and treated at 83 clinical centres in North America, Europe, Israel, and India. Participants were allocated (2:1:1:1 ratio) by an interactive telephone system, according to computer-generated block randomisation, to receive one of three regimens of teplizumab infusions (14-day full dose, 14-day low dose, or 6-day full dose) or placebo at baseline and at 26 weeks. The Protégé study is still underway, and patients and study staff remain masked through to study closure. The primary composite outcome was the percentage of patients with insulin use of less than 0·5 U/kg per day and glycated haemoglobin A(1c) (HbA(1C)) of less than 6·5% at 1 year. Analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00385697. FINDINGS 763 patients were screened, of whom 516 were randomised to receive 14-day full-dose teplizumab (n=209), 14-day low-dose teplizumab (n=102), 6-day full-dose teplizumab (n=106), or placebo (n=99). Two patients in the 14-day full-dose group and one patient in the placebo group did not start treatment, so 513 patients were eligible for efficacy analyses. The primary outcome did not differ between groups at 1 year: 19·8% (41/207) in the 14-day full-dose group; 13·7% (14/102) in the 14-day low-dose group; 20·8% (22/106) in the 6-day full-dose group; and 20·4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p=0·03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group). INTERPRETATION Findings of exploratory analyses suggest that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children. FUNDING MacroGenics, the Juvenile Diabetes Research Foundation, and Eli Lilly.

Overweight and obesity in infants and pre-school children in the European Union: a review of existing data

The objective of this study was to synthesize available information on prevalence and time trends of overweight and obesity in pre‐school children in the European Union. Retrieval and analysis or re‐analysis of existing data were carried out. Data sources include WHO databases, Medline and Google, contact with authors of published and unpublished documents. Data were analysed using the International Obesity Task Force reference and cut‐offs, and the WHO standard. Data were available from 18/27 countries. Comparisons were problematic because of different definitions and methods of data collection and analysis. The reported prevalence of overweight plus obesity at 4 years ranges from 11.8% in Romania (2004) to 32.3% in Spain (1998–2000). Countries in the Mediterranean region and the British islands report higher rates than those in middle, northern and eastern Europe. Rates are generally higher in girls than in boys. With the possible exception of England, there was no obvious trend towards increasing prevalence in the past 20–30 years in the five countries with data. The use of the WHO standard with cut‐offs at 1, 2 and 3 standard deviations yields lower rates and removes gender differences. Data on overweight and obesity in pre‐school children are scarce; their interpretation is difficult. Standard methods of surveillance, and research and policies on prevention and treatment, are urgently needed.

GAD65 Antigen Therapy in Recently Diagnosed Type 1 Diabetes Mellitus

BACKGROUND The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes. METHODS We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels. RESULTS The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences. CONCLUSIONS Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.).

Declining incidence of severe retinopathy and persisting decrease of nephropathy in an unselected population of Type 1 diabetes— the Linköping Diabetes Complications Study

Aims/hypothesisIn a previous study conducted over the last decades we found a decreased incidence of nephropathy but unchanged incidence of severe retinopathy among patients with Type 1 diabetes diagnosed in childhood and with 20 years duration of diabetes. The aim of our current study was to investigate the incidence 5 to10 years later in the same population.MethodsWe studied all 269 patients in whom Type 1 diabetes was diagnosed in childhood between 1961 and 1985 in a district in southeastern Sweden. Ninety-one percent were monitored for retinopathy until at least 1997 and 95% were monitored for nephropathy. Severe retinopathy was defined as laser-treated retinopathy and nephropathy as persistent proteinuria. Survival analysis was used and the patients divided into five cohorts according to the time of onset of diabetes.ResultsThe cumulative proportion of severe retinopathy had declined (p=0.006). After 25 years it was 47% (95% CI 34–61), 28% (15–40) and 24% (12–36) in the cohorts 1961 to 1965, 1966 to 1970 and 1971 to 1975 respectively. After 30 years it was 53% (40–66) and 44% (28–59) in the oldest cohorts. The cumulative proportion of nephropathy after 25 years duration was 30% (18–42), 8% (1–16) and 13% (4–23) in the cohorts 1961 to 1965, 1966 to 1970 and 1971 to 1975 respectively. After 30 years, it was 32% (20–44) and 11% (2–20) for the oldest cohorts (p<0.0001).Conclusions/interpretationIn an unselected population with Type 1 diabetes diagnosed in childhood, modern diabetes care markedly reduced the incidence of severe retinopathy and nephropathy.

Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes

OBJECTIVE—β-Cell function in type 1 diabetes clinical trials is commonly measured by C-peptide response to a secretagogue in either a mixed-meal tolerance test (MMTT) or a glucagon stimulation test (GST). The Type 1 Diabetes TrialNet Research Group and the European C-peptide Trial (ECPT) Study Group conducted parallel randomized studies to compare the sensitivity, reproducibility, and tolerability of these procedures. RESEARCH DESIGN AND METHODS—In randomized sequences, 148 TrialNet subjects completed 549 tests with up to 2 MMTT and 2 GST tests on separate days, and 118 ECPT subjects completed 348 tests (up to 3 each) with either two MMTTs or two GSTs. RESULTS—Among individuals with up to 4 years’ duration of type 1 diabetes, >85% had measurable stimulated C-peptide values. The MMTT stimulus produced significantly higher concentrations of C-peptide than the GST. Whereas both tests were highly reproducible, the MMTT was significantly more so (R2 = 0.96 for peak C-peptide response). Overall, the majority of subjects preferred the MMTT, and there were few adverse events. Some older subjects preferred the shorter duration of the GST. Nausea was reported in the majority of GST studies, particularly in the young age-group. CONCLUSIONS—The MMTT is preferred for the assessment of β-cell function in therapeutic trials in type 1 diabetes.

Longer breastfeeding is an independent protective factor against development of type 1 diabetes mellitus in childhood

Early weaning diet, early introduction of breast milk substitution and cows milk have been shown to increase the risk of type 1 diabetes later in life. It is also shown that older maternal age, maternal education, preeclampsia, prematurity, neonatal illness and neonatal icterus caused by blood group incompatibility, infections and stress might be risk factors for type 1 diabetes. We aimed to determine whether early nutrition is an independent risk factor for diabetes despite other life events.

A high weight gain early in life is associated with an increased risk of Type 1 (insulin-dependent) diabetes mellitus

SummaryGrowth during the first years of life in relation to type of feeding in infancy was retrospectively studied in an unselected population-based group of 297 children who had been diagnosed with Type 1 (insulin-dependent) diabetes mellitus before the age of 15 years (probands) and 792 individually-matched referent subjects. Reliable data were collected from child welfare clinics. Probands weighed slightly less at birth but their weight gain at 6, 9, 18 and 30 months of age was significantly greater (p<0.02) than that of referent children. The weight gain of children who had never been breast-fed was more marked than that of breast-fed children; this was found for both probands and referent children. But also among exclusively breast-fed children (> 2 months), probands gained significantly more in weight from birth up to 18 and 30 months of age than exclusively breast-fed referent children. Early weight gain appears to be a risk factor for development of Type 1 diabetes. The lower weight gain in breast-fed compared to non-breast-fed children may explain the protective effect of breast feeding against Type 1 diabetes observed in several studies.

Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study

Aims/hypothesisWe aimed to assess the feasibility of a dietary intervention trial with weaning to hydrolysed formula in infants at increased risk of type 1 diabetes and to study the effect of the intervention on the emergence of diabetes-associated autoantibodies in early childhood.MethodsWe studied 242 newborn infants who had a first-degree relative with type 1 diabetes and carried risk-associated HLA-DQB1 alleles. After exclusive breastfeeding, the infants underwent a double-blind, randomised pilot trial of either casein hydrolysate (Nutramigen; Mead Johnson) or conventional cow’s milk-based formula until the age of 6–8 months. During a mean observation period of 4.7 years, autoantibodies to insulin, anti-glutamic acid decarboxylase and insulinoma-associated antigen-2 were measured by radiobinding assays, and islet cell antibodies (ICA) by immunofluorescence.ResultsThe feasibility of screening and identifying a cohort of first-degree relatives with HLA-conferred disease susceptibility, enrolling them in a dietary intervention trial and following them for seroconversion to autoantibody positivity is established. The cumulative incidence of autoantibodies was somewhat smaller in the casein hydrolysate vs control formula group, suggesting the need for a larger well-powered study. After adjustment for duration of study formula feeding, life-table analysis showed a significant protection by the intervention from positivity for ICA (p=0.02) and at least one autoantibody (p=0.03).Conclusions/interpretationThe present study provides the first evidence ever in man, despite its limited power, that it may be possible to manipulate spontaneous beta cell autoimmunity by dietary intervention in infancy.