Decreased occurrence of ketoacidosis and preservation of beta cell function in relatives screened and monitored for type 1 diabetes in Australia and New Zealand

Published December 2022Aims: Islet autoantibody screening of infants and young children in the Northern Hemisphere, together with semi-annual metabolic monitoring, is associated with a lower risk of ketoacidosis (DKA) and improved glucose control after diagnosis of clinical (stage 3) type 1 diabetes (T1D). We aimed to determine if similar benefits applied to older Australians and New Zealanders monitored less rigorously. Methods: DKA occurrence and metabolic control were compared between T1D relatives screened and monitored for T1D and unscreened individuals diagnosed in the general population, ascertained from the Australasian Diabetes Data Network. Results: Between 2005 and 2019, 17,105 relatives (mean (SD) age 15.7 (10.8) years; 52% female) were screened for autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2. Of these, 652 screened positive to a single and 306 to multiple autoantibody specificities, of whom 201 and 215, respectively, underwent metabolic monitoring. Of 178 relatives diagnosed with stage 3 T1D, 9 (5%) had DKA, 7 of whom had not undertaken metabolic monitoring. The frequency of DKA in the general population was 31%. After correction for age, sex and T1D family history, the frequency of DKA in screened relatives was >80% lower than in the general population. HbA1c and insulin requirements following diagnosis were also lower in screened relatives, consistent with greater beta cell reserve. Conclusions: T1D autoantibody screening and metabolic monitoring of older children and young adults in Australia and New Zealand, by enabling pre-clinical diagnosis when beta cell reserve is greater, confers protection from DKA. These clinical benefits support ongoing efforts to increase screening activity in the region and should facilitate the application of emerging immunotherapies.John M. Wentworth, Helena Oakey, Maria E. Craig, Jennifer J. Couper, Fergus J. Cameron, Elizabeth A. Davis, Antony R. Lafferty, Mark Harris, Benjamin J. Wheeler, Craig Jefferies, Peter G. Colman, Leonard C. Harriso

Analysis of the transcriptional program induced by Raf in epithelial cells

Activation of the Raf/MAP kinase pathway is a critical event in tumorigenesis induced by RAS and other oncogenes, a major role of this signaling system being the regulation of cellular transcription factors. To address the contribution of MAP kinase mediated transcriptional changes to the transformed phenotype, we used an inducible form of Raf to analyze early changes in the transcription of some 6000 genes following activation of the kinase in a normal human breast epithelial cell line. Of the more than 120 significant changes in mRNA level detected, genes promoting cell proliferation, invasiveness, and angiogenesis featured prominently. Some of the most strongly induced genes encoded growth factors of the EGF family: Autocrine activation of the EGF receptor was shown to be responsible for the ability of Raf activation to protect these cells from apoptosis induced by detachment of cells from extracellular matrix (anoikis), which is a critical component of the transformed phenotype

Phosphorylation of the LIR Domain of SCOC Modulates ATG8 Binding Affinity and Specificity

Autophagy is a highly conserved degradative pathway, essential for cellular homeostasis and implicated in diseases including cancer and neurodegeneration. Autophagy-related 8 (ATG8) proteins play a central role in autophagosome formation and selective delivery of cytoplasmic cargo to lysosomes by recruiting autophagy adaptors and receptors. The LC3-interacting region (LIR) docking site (LDS) of ATG8 proteins binds to LIR motifs present in autophagy adaptors and receptors. LIR-ATG8 interactions can be highly selective for specific mammalian ATG8 family members (LC3A-C, GABARAP, and GABARAPL1-2) and how this specificity is generated and regulated is incompletely understood. We have identified a LIR motif in the Golgi protein SCOC (short coiled-coil protein) exhibiting strong binding to GABARAP, GABARAPL1, LC3A and LC3C. The residues within and surrounding the core LIR motif of the SCOC LIR domain were phosphorylated by autophagy-related kinases (ULK1-3, TBK1) increasing specifically LC3 family binding. More distant flanking residues also contributed to ATG8 binding. Loss of these residues was compensated by phosphorylation of serine residues immediately adjacent to the core LIR motif, indicating that the interactions of the flanking LIR regions with the LDS are important and highly dynamic. Our comprehensive structural, biophysical and biochemical analyses support and provide novel mechanistic insights into how phosphorylation of LIR domain residues regulates the affinity and binding specificity of ATG8 proteins towards autophagy adaptors and receptors

Determinants of cardiovascular risk in 7,000 youth with type 1 diabetes in the Australasian Diabetes Data Network

CONTEXT:Cardiovascular disease occurs prematurely in type 1 diabetes. The additional risk of overweight is not well characterised. OBJECTIVE:Primary aim was to measure the impact of BMI in youth with type 1 diabetes on cardiovascular risk factors. Secondary aim was to identify other determinants of cardiovascular risk. DESIGN:Observational longitudinal study of 7061 youth with type 1 diabetes followed for median 7.3 (IQR 4-11) years over 41 (IQR 29-56) visits until March 2019. SETTING:15 tertiary care diabetes centres in the Australasian Diabetes Data Network. PARTICIPANTS:aged 2 - 25 years at baseline, with at least two measures of BMI and blood pressure. MAIN OUTCOME MEASURE:Standardised systolic and diastolic blood pressure scores and non-HDL cholesterol were co-primary outcomes. Urinary albumin/creatinine ratio was the secondary outcome. RESULTS:BMI z-score related independently to standardised blood pressure z- scores and non-HDL cholesterol. An increase in 1 BMI z-score related to an average increase in systolic/diastolic blood pressure of 3.8/1.4mmHg and an increase in non -HDL cholesterol (coefficient + 0.16mmol/L, 95%CI 0.13-0.18; p<0.001) and in LDL cholesterol. Females had higher blood pressure z-scores, higher non-HDL and LDL cholesterol, and higher urinary albumin/creatinine than males. Indigenous youth had markedly higher urinary albumin/creatinine (coefficient +2.15 mg/mmol, 95% CI 1.27-3.03; p<0.001) and higher non-HDL cholesterol than non-indigenous youth. Continuous subcutaneous insulin infusion was associated independently with lower non-HDL cholesterol and lower urinary albumin/creatinine. CONCLUSIONS:BMI had a modest independent effect on cardiovascular risk. Females and indigenous Australians in particular had a more adverse risk profile.Jenny J Couper, Timothy W Jones, Melissa Chee, Helen L Barrett, Philip Bergman, Fergus Cameron ... et al

Longitudinal audit of assessment and pharmaceutical intervention for cardiovascular risk in the Australasian Diabetes Data Network

OnlinePubl.Abstract not available.Claire A. Robertson, Arul Earnest, Melissa Chee, Maria E. Craig, Peter Colman, Helen L. Barrett, Philip Bergman, Fergus Cameron, Elizabeth A. Davis, Kim C. Donaghue, P. Gerry Fegan, P. Shane Hamblin, D. Jane Holmes–Walker, Craig Jefferies, Stephanie Johnson, Meng T. Mok, Bruce R. King, Richard Sinnott, Glenn Ward, Benjamin J. Wheeler, Anthony Zimmermann, Timothy W. Jones, Jenny J. Couper, the ADDN Study Grou

Diabetic Ketoacidosis at Onset of Type 1 Diabetes and Long-term HbA1c in 7,961 Children and Young Adults in the Australasian Diabetes Data Network

Objective: The relationship between diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes and long-term glycemic control varies between studies. We aimed, firstly, to characterize the association of DKA and its severity with long-term HbA1c in a large contemporary cohort, and secondly, to identify other independent determinants of long-term HbA1c. Research Design and Methods: Participants were 7,961 children and young adults diagnosed with type 1 diabetes by age 30 years from 2000 to 2019 and followed prospectively in the Australasian Diabetes Data Network (ADDN) until 31 December 2020. Linear mixed-effect models related variables to HbA1c. Results: DKA at diagnosis was present in 2,647 participants (33.2%). Over a median 5.6 (interquartile range 3.2, 9.4) years of follow-up, participants with severe, but not moderate or mild, DKA at diagnosis had a higher mean HbA1c (+0.23%, 95% CI 0.11,0.28; [+2.5 mmol/mol, 95% CI 1.4,3.6]; P < 0.001) compared with those without DKA. Use of continuous subcutaneous insulin infusion (CSII) was independently associated with a lower HbA1c (−0.28%, 95% CI −0.31, −0.25; [−3.1 mmol/mol, 95% CI −3.4, −2.8]; P < 0.001) than multiple daily injections, and CSII use interacted with severe DKA to lower predicted HbA1c. Indigenous status was associated with higher HbA1c (+1.37%, 95% CI 1.15, 1.59; [+15.0 mmol/mol, 95% CI 12.6, 17.4]; P < 0.001), as was residing in postcodes of lower socioeconomic status (most vs. least disadvantaged quintile +0.43%, 95% CI 0.34, 0.52; [+4.7 mmol/mol, 95% CI 3.4, 5.6]; P < 0.001). Conclusions: Severe, but not mild or moderate, DKA at diagnosis was associated with a marginally higher HbA1c over time, an effect that was modified by use of CSII. Indigenous status and lower socioeconomic status were independently associated with higher long-term HbA1c.Helen F. Clapin, Arul Earnest, Peter G. Colman, Elizabeth A. Davis, Craig Jefferies, Kym Anderson, Melissa Chee, Philip Bergman, Martin de Bock, Kung-Ting Kao, P. Gerry Fegan, D. Jane Holmes-Walker, Stephanie Johnson, Bruce R. King, Meng Tuck Mok, Kruthika Narayan, Alexia S. Peña Vargas, Richard Sinnott, Benjamin J. Wheeler, Anthony Zimmermann, Maria E. Craig, Jenny J. Couper, the ADDN Study Grou