INnoVative trial design for testing the Efficacy, Safety and Tolerability of 6-month treatment with incretin-based therapy to prevent type 1 DIAbetes in autoantibody positive participants: A protocol for three parallel double-blind, randomised controlled trials (INVESTDIA)

Aims beta-cell stress and dysfunction may contribute to islet autoimmunity and progression to clinical type 1 diabetes. We present a protocol of three randomised controlled trials assessing the effects of glucagon-like peptide 1 (GLP - 1) analogue liraglutide in three early stages of type 1 diabetes.Methods We will test 10- to 30-year-old people with multiple islet autoantibodies for their glucose metabolism and randomise participants with stage 1 (multiple islet autoantibodies and normoglycaemia), stage 2 (multiple islet autoantibodies and dysglycaemia) and early stage 3 (clinical diagnosis) type 1 diabetes, 10-14 persons in each, to a 6-month intervention with liraglutide or placebo with 6-month follow-up in the stage 2 and stage 3 trials and 18-month follow-up in the stage 1 trial. Primary efficacy outcome in the stage 1 and stage 2 trials is a first-phase insulin response in an intravenous glucose tolerance test and C-peptide area under the curve in a 2-h mixed-meal tolerance test in the stage 3 trial. In addition, safety and tolerability of liraglutide treatment will be assessed.Conclusions Most prevention trials of type 1 diabetes have targeted the immune system. Treatment with GLP-1 analogue liraglutide supports the pancreatic beta-cells, which should likewise attenuate islet autoimmunity. Our innovative study design allows simultaneous investigation of an intervention in three groups of people who represent various early stages of type 1 diabetes and maximises the eligibility to participate.Trial registration NCT02611232 (stage 1 trial), NCT02898506 (stage 2 trial), NCT02908087 (stage 3 trial).</p

Beta cell function in participants with single or multiple islet autoantibodies at baseline in the TEDDY Family Prevention Study: TEFA

AimThe aim of the present study was to assess beta cell function based on an oral glucose tolerance test (OGTT) in participants with single islet autoantibody or an intravenous glucose tolerance test (IvGTT) in participants with multiple islet autoantibodies.Materials and methodsHealthy participants in Sweden and Finland, between 2 and 49.99 years of age previously identified as positive for a single (n = 30) autoantibody to either insulin, glutamic acid decarboxylase, islet antigen-2, zinc transporter 8 or islet cell antibodies or multiple autoantibodies (n = 46), were included. Participants positive for a single autoantibody underwent a 6-point OGTT while participants positive for multiple autoantibodies underwent an IvGTT. Glucose, insulin and C-peptide were measured from OGTT and IvGTT samples.ResultsAll participants positive for a single autoantibody had a normal glucose tolerance test with 120 minutes glucose below 7.70 mmol/L and HbA1c values within the normal range (ConclusionParticipants positive for a single autoantibody appeared to have a normal beta cell function. Participants positive for three or more autoantibodies had a lower FPIR as compared to participants with two autoantibodies, supporting the view that their beta cell function had deteriorated.</p

INnoVative trial design for testing the Efficacy, Safety and Tolerability of 6-month treatment with incretin-based therapy to prevent type 1 DIAbetes in autoantibody positive participants:a protocol for three parallel double-blind, randomised controlled trials (INVESTDIA)

Abstract Aims: β-cell stress and dysfunction may contribute to islet autoimmunity and progression to clinical type 1 diabetes. We present a protocol of three randomised controlled trials assessing the effects of glucagon-like peptide 1 (GLP − 1) analogue liraglutide in three early stages of type 1 diabetes. Methods: We will test 10- to 30-year-old people with multiple islet autoantibodies for their glucose metabolism and randomise participants with stage 1 (multiple islet autoantibodies and normoglycaemia), stage 2 (multiple islet autoantibodies and dysglycaemia) and early stage 3 (clinical diagnosis) type 1 diabetes, 10−14 persons in each, to a 6-month intervention with liraglutide or placebo with 6-month follow-up in the stage 2 and stage 3 trials and 18-month follow-up in the stage 1 trial. Primary efficacy outcome in the stage 1 and stage 2 trials is a first-phase insulin response in an intravenous glucose tolerance test and C-peptide area under the curve in a 2-h mixed-meal tolerance test in the stage 3 trial. In addition, safety and tolerability of liraglutide treatment will be assessed. Conclusions: Most prevention trials of type 1 diabetes have targeted the immune system. Treatment with GLP-1 analogue liraglutide supports the pancreatic β-cells, which should likewise attenuate islet autoimmunity. Our innovative study design allows simultaneous investigation of an intervention in three groups of people who represent various early stages of type 1 diabetes and maximises the eligibility to participate

Association between levels of persistent organic pollutants in adipose tissue and cryptorchidism in early childhood:a case-control study

BACKGROUND: Congenital cryptorchidism, i.e. failure of the testicular descent to the bottom of the scrotum, is a common birth defect. The evidence from epidemiological, wildlife, and animal studies suggests that exposure to mixtures of endocrine disrupting chemicals during fetal development may play a role in its pathogenesis. We aimed to assess the association between cryptorchidism and prenatal exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs), and polybrominated diphenyl ethers (PBDEs). METHODS: We conducted a case–control study consisting of 44 cryptorchid cases, and 38 controls operated for inguinal hernia, umbilical hernia, or hydrocele at the Turku University Hospital or Rigshospitalet, Copenhagen in 2002–2006. During the operation a subcutaneous adipose tissue biopsy was taken. Samples were analysed for 37 PCBs, 17 PCDD/Fs and 14 PBDEs by gas chromatography-high-resolution mass spectrometry. Chemical concentrations were adjusted for postnatal variation introduced by differences in duration of breastfeeding, age at the operation, and country of origin with a multiple linear regression. Association between adjusted and unadjusted chemical concentrations and the risk of cryptorchidism were analysed with logistic regression to get an estimate for odds ratio (OR) of cryptorchidism per multiplication of chemical concentrations with ca. 2.71 (Napier’s constant). RESULTS: Total-TEq i.e. the WHO-recommended 2,3,7,8-TCDD equivalent quantity of 17 dioxins and 12 dioxin-like PCBs and sum of PCDD/Fs were positively associated with cryptorchidism [OR 3.21 (95 % CI 1.29–9.09), OR 3.69 (95 % CI 1.45–10.9), respectively], when adjusting for country of origin, the duration the child was breastfed, and age at operation. The association between the sum of PCBs and cryptorchidism was close to significant [OR 1.92 (95 % CI 0.98–4.01)], whereas the association between the sum of PBDEs and cryptorchidism was not [OR 0.86 (95 % CI 0.47–1.54)]. There were no associations between unadjusted chemical concentrations and the risk of cryptorchidism. CONCLUSIONS: Prenatal exposure to PCDD/Fs and PCDD/F-like PCBs may be associated with increased risk for cryptorchidism. Our finding does not exclude the possibility of an association between the exposure to PBDEs and cryptorchidism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12940-015-0065-0) contains supplementary material, which is available to authorized users

Exploring minimally invasive approach to define stages of type 1 diabetes remotely

Abstract Objectives: New methods are pivotal in accurately predicting, monitoring, and diagnosing the clinical manifestation of type 1 diabetes (T1D) in high-risk children. Continuous glucose monitoring (CGM) is a valuable tool for patients with T1D, but there is still a knowledge gap regarding its utility in the prediction of diabetes. The current study explored whether 10-day CGM or CGM during an oral glucose tolerance test (OGTT) performed in the laboratory or at home (home-OGTT) could be accurate in detecting stages of T1D. Research Design and Method: Forty-six subjects 4–25 years of age carrying genetic risk for T1D were recruited and classified into the following groups: islet autoantibody (IAb) negative, one IAb, and stages 1–3 of T1D, based on the laboratory OGTT and IAb results at baseline. A 10-day CGM was initiated before the OGTT. Results: In this study, we showed that CGM was sensitive in detecting asymptomatic individuals at stage 3, and dysglycemic individuals in stage 2 of T1D both during OGTT and the 10-day period. CGM also showed significant differences in several variables during the 10-day sensoring among individuals at different stages of T1D. Furthermore, CGM showed different OGTT profiles and detected significantly more abnormal OGTT results when compared with plasma glucose. Conclusions: CGM together with home-OGTT could detect stages of T1D and offer an alternative method to confirm normoglycemia in high-risk individuals