Tadej Battelino

Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A–producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.

Nocturnal Glucose Control with an Artificial Pancreas at a Diabetes Camp

BACKGROUND Recent studies have shown that an artificial-pancreas system can improve glucose control and reduce nocturnal hypoglycemia. However, it is not known whether such results can be replicated in settings outside the hospital. METHODS In this multicenter, multinational, randomized, crossover trial, we assessed the short-term safety and efficacy of an artificial pancreas system for control of nocturnal glucose levels in patients (10 to 18 years of age) with type 1 diabetes at a diabetes camp. In two consecutive overnight sessions, we randomly assigned 56 patients to receive treatment with an artificial pancreas on the first night and a sensor-augmented insulin pump (control) on the second night or to the reverse order of therapies on the first and second nights. Thus, all the patients received each treatment in a randomly assigned order. The primary end points were the number of hypoglycemic events (defined as a sensor glucose value of <63 mg per deciliter [3.5 mmol per liter] for at least 10 consecutive minutes), the time spent with glucose levels below 60 mg per deciliter (3.3 mmol per liter), and the mean overnight glucose level for individual patients. RESULTS On nights when the artificial pancreas was used, versus nights when the sensor-augmented insulin pump was used, there were significantly fewer episodes of nighttime glucose levels below 63 mg per deciliter (7 vs. 22) and significantly shorter periods when glucose levels were below 60 mg per deciliter (P=0.003 and P=0.02, respectively, after adjustment for multiplicity). Median values for the individual mean overnight glucose levels were 126.4 mg per deciliter (interquartile range, 115.7 to 139.1 [7.0 mmol per liter; interquartile range, 6.4 to 7.7]) with the artificial pancreas and 140.4 mg per deciliter (interquartile range, 105.7 to 167.4 [7.8 mmol per liter; interquartile range, 5.9 to 9.3]) with the sensor-augmented pump. No serious adverse events were reported. CONCLUSIONS Patients at a diabetes camp who were treated with an artificial-pancreas system had less nocturnal hypoglycemia and tighter glucose control than when they were treated with a sensor-augmented insulin pump. (Funded by Sanofi and others; ClinicalTrials.gov number, NCT01238406.).

Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes

OBJECTIVE To assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes. RESEARCH DESIGN AND METHODS In this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A1c (HbA1c) <7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration <63 mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients. RESULTS The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26–0.76; P = 0.03). HbA1c at 26 weeks was lower in the continuous monitoring group than in the control group (difference −0.27%; 95% CI −0.47 to −0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009). CONCLUSIONS Continuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA1c in children and adults with type 1 diabetes.

Use of insulin pump therapy in the pediatric age-group: consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes

Young patients with diabetes, their families, and their diabetes care providers continue to be faced with the challenge of striving to maintain blood glucose levels in the near-normal range. High blood glucose levels with elevated A1C levels are associated with long-term microvascular and macrovascular complications. Recurrent episodes of hypoglycemia, especially at young ages, may cause short- and long-term adverse effects on cognitive function and lead to hypoglycemia unawareness and may be associated with significant emotional morbidity for the child and parents. Fear of hypoglycemia, especially during the night, may compromise quality of life (QOL) for the family and jeopardize efforts to achieve optimal metabolic control. Over the past decade, continuous subcutaneous insulin infusion (CSII) has gained increasing popularity among patients with diabetes. CSII is the most physiologic method of insulin delivery currently available. It is able to closely simulate the normal pattern of insulin secretion, namely continuous 24-h adjustable “basal” delivery of insulin upon which are superimposed prandial “boluses.” In addition, CSII offers the possibility of more flexibility and more precise insulin delivery than multiple daily injection (MDI). However, there is still debate among diabetes care practitioners around the world as to whether CSII has advantages over MDI in terms of reduction in A1C levels, occurrence of severe hypoglycemic events, episodes of diabetic ketoacidosis (DKA), and frequency of hospitalizations in young patients. Furthermore, no clear criteria have been established to help the physician choose the “appropriate” patient for CSII therapy. To address these issues, the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), and the International Society for Pediatric and Adolescent Diabetes (ISPAD) convened a panel of expert physicians for a consensus conference endorsed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). For each major topic area, …

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.).

Consensus Statement on the Use of Insulin Pump Therapy in the Pediatric Age-Group

Young patients with diabetes, their families, and their diabetes care providers continue to be faced with the challenge of striving to maintain blood glucose levels in the near-normal range. High blood glucose levels with elevated A1C levels are associated with long-term microvascular and macrovascular complications. Recurrent episodes of hypoglycemia, especially at young ages, may cause short- and long-term adverse effects on cognitive function and lead to hypoglycemia unawareness and may be associated with significant emotional morbidity for the child and parents. Fear of hypoglycemia, especially during the night, may compromise quality of life (QOL) for the family and jeopardize efforts to achieve optimal metabolic control. Over the past decade, continuous subcutaneous insulin infusion (CSII) has gained increasing popularity among patients with diabetes. CSII is the most physiologic method of insulin delivery currently available. It is able to closely simulate the normal pattern of insulin secretion, namely continuous 24-h adjustable “basal” delivery of insulin upon which are superimposed prandial “boluses.” In addition, CSII offers the possibility of more flexibility and more precise insulin delivery than multiple daily injection (MDI). However, there is still debate among diabetes care practitioners around the world as to whether CSII has advantages over MDI in terms of reduction in A1C levels, occurrence of severe hypoglycemic events, episodes of diabetic ketoacidosis (DKA), and frequency of hospitalizations in young patients. Furthermore, no clear criteria have been established to help the physician choose the “appropriate” patient for CSII therapy. To address these issues, the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), and the International Society for Pediatric and Adolescent Diabetes (ISPAD) convened a panel of expert physicians for a consensus conference endorsed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). For each major topic area, …

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.

Night glucose control with MD‐Logic artificial pancreas in home setting: a single blind, randomized crossover trial—interim analysis

Artificial pancreas (AP) systems have shown an improvement in glucose control and a reduced risk of nocturnal hypoglycemia under controlled conditions but remain to be evaluated under daily‐life conditions.

A cross‐sectional international survey of continuous subcutaneous insulin infusion in 377 children and adolescents with type 1 diabetes mellitus from 10 countries

Objective:  To document current practices using continuous subcutaneous insulin infusion (CSII) by downloading electronically the 90‐d pump data held within the pump memory and relating that to clinical data from children and adolescents in different pediatric diabetes centers from Europe and Israel.

Use of continuous glucose monitoring in children and adolescents

Moshe Phillipa,b,c, Thomas Danned, Shlomit Shalitina,b,c, Bruce Buckinghame, Lori Laffelf, William Tamborlaneg, Tadej Battelinoh and for the Consensus Forum Participantsi aThe Jesse Z and Sara Lea Shafer Institute of Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel; bMolecular Endocrinology and Diabetes Laboratory, Felsenstein Medical Research Center, Petah Tikva, Israel; cSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; dDiabetes Zentrum fur Kinder und Jugendliche, Kinderkrankenhaus auf der Bult, Hannover, Germany; ePediatric Endocrinology, Stanford University, Stanford, CA, USA; fPediatric, Adolescent and Young Adult Section, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; gPediatric Endocrinology, Yale University School of Medicine, New Haven, CT, USA; hDepartment of Pediatric Endocrinology, Diabetes Metabolism, University Children’s Hospital, Ljubljana, Slovenia and iA complete list of participants in the forum can be found in the acknowledgments.