| 1. |
- Martinez, Maria Månsson, et al.
(författare)
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Beta cell function in participants with single or multiple islet autoantibodies at baseline in the TEDDY Family Prevention Study : TEFA
- 2021
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Ingår i: Endocrinology, Diabetes & Metabolism. - : Wiley. - 2398-9238. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The 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 methods: Healthy 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. Results: All 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 (<42 mmol/mol). Insulin responses to the glucose challenge on OGTT ranged between 13.0 and 143 mIU/L after 120 minutes with C-peptide values between 0.74 and 4.60 nmol/L. In Swedish participants, the first-phase insulin response (FPIR) on IvGTT was lower in those positive for three or more autoantibodies (n = 13; median 83.0 mIU/L; range 20.0-343) compared to those with two autoantibodies (n = 15; median 146 mIU/L; range 19.0-545; P =.0330). Conclusion: Participants 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.
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| 2. |
- Martinez, Maria Månsson, et al.
(författare)
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Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA
- 2022
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Ingår i: Clinical diabetes and endocrinology. - : Springer Science and Business Media LLC. - 2055-8260. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.METHODS: Subjects (n = 57) at 2-50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24).RESULTS: Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2-4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was - 1.88 (- 2.71, - 1.05) p = 3.49 × 10-5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (- 0.80 (- 1.58, - 0.02), p = 0.046).CONCLUSIONS: The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02605148 , November 16, 2015.
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| 3. |
- Schoultz, Elin, et al.
(författare)
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Tissue architecture delineates field cancerization in brafv600e-induced tumor development
- 2022
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Ingår i: DMM Disease Models and Mechanisms. - 1754-8403 .- 1754-8411. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAFmutant lineage becomes a cancerized lineage. The TgCreERT2; BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution.
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