Summary:RFX6 maturity-onset diabetes of the young (RFX6-MODY) is a relatively new MODY subtype, with limited guidance on management, particularly in pregnancy. We report the clinical features and management of two female patients with RFX6-MODY and their progression during and post-pregnancy. These patients were diagnosed with type 2 diabetes mellitus (DM) at ages 13 and 19 years, initially managed on dietary modification alone. They were subsequently diagnosed with RFX6-MODY during pregnancy following calculation of MODY probability. Both required insulin during pregnancy and delivered healthy babies at 38 weeks. Three months post-delivery, tirzepatide was started for one of our patients and she has shown significant glycaemic improvement and weight loss. To our knowledge, this is the first reported use of tirzepatide in RFX6-MODY. Learning points:RFX6-MODY may present at a much earlier age than previously reported in the literature. Many patients with RFX6-MODY do not appear to require insulin at diagnosis. Tirzepatide may be a beneficial therapeutic option for managing patients with RFX6-MODY who have adequate β-cell function. Pregnancy management in patients with RFX6-MODY is similar to type 2 DM, although higher insulin doses may be required.

AIMS:Chronic kidney disease is associated with dysregulation of the insulin-like growth factor (IGF) system. Alterations in IGF bioavailability, driven by IGF binding proteins (IGFBPs), may influence the decline in renal function. However, the longitudinal relationship between baseline IGF-I, IGF-II, IGFBPs and progression of kidney dysfunction remains unclear. We evaluated how IGF/IGFBP profile relates to longitudinal changes in urinary albumin/creatinine ratio (ACR) and serum creatinine level in people with type 2 diabetes (T2D). METHODS:Individuals' measurements were performed in 436 individuals with T2D recruited from primary and secondary care (2002-2004), from the Salford and Manchester Integrated Care Record (GMCR), for laboratory and clinical data, as well as date of death. Baseline IGF/IGFBP profile was related to 2 primary outcomes: (i) change in albumin-to-creatinine ratio over time (urine ACR trend slope) and (ii) change in serum creatinine over time (creatinine trend slope). Trend slopes were derived for each participant, using repeated measures throughout follow-up for up to 24 years. Associations between IGF axis proteins and outcomes were evaluated with multivariate regression models. Cox proportional hazards models were constructed to determine mortality risk associated with the IGF system proteins studied. RESULTS:At baseline, 59.3% of participants were men. Age at baseline was 56.6 ± 9.4 years. Mean follow-up duration was 17.4 ± 5.2 years. IGF-II and IGFBP-3 were strongly correlated (Spearman rho = 0.80), and were therefore not included simultaneously in the multi-variate linear regression model to avoid co-linearity. Higher circulating IGFBP-2 was independently associated with faster rate of ACR progression (normalised beta (Β) = 0.007, p = 0.002), while IGFBP-1 showed an inverse association (B = -0.057, p = 0.009). IGF-II also remained positively associated with ACR trend (B = 0.005, p = 0.013), whereas IGF-I showed no association. IGFBP-1 showed a significant inverse association with creatinine change when adjusted for effects of covariates (unstandardised B = -0.038, p = 0.04). Survival analysis revealed that higher IGFBP-2 levels were independently associated with higher all-cause mortality (hazard ratio [HR] per 1 standard deviation increase 1.306, 95% CI 1.151-1.483 p = 0.0001). CONCLUSION:This longitudinal study indicated that higher baseline IGF-II, lower IGFBP-1 and higher IGFBP-2 are associated with a greater likelihood of albuminuria progression, independent of standard risk factors; lower IGBFP-1 also associated with greater increase in serum creatinine. Higher circulating IGFBP-2 level was also associated with relatively higher mortality. This study demonstrated the relevance of the IGF system to our understanding of renal complications in diabetes and strongly suggests that further exploration of mechanisms underlying these associations is merited.

BACKGROUND:HbA1c targets guide diabetes management to reduce complications, yet their psychological effects are poorly understood. This feasibility study evaluated the practicality of conducting a definitive trial evaluating the impact of explicit HbA1c target-setting in adults with diabetes. METHODS:We conducted a randomised mixed-methods feasibility study. Adults with diabetes were allocated 1:1 to receive an explicit HbA1c target set 5 mmol/mol above (Group A) or below (Group B) their current HbA1c. Biomedical (HbA1c, blood pressure, BMI) and psychometric patient-reported outcomes were measured at baseline and 3 months. Quantitative data were analysed in SPSS using independent-sample t-tests or Mann-Whitney U tests for between-group comparisons, and paired t-tests or Wilcoxon signed-rank tests for within-group changes. Qualitative data from semi-structured interviews with patients and healthcare professionals were analysed using the Framework Method of thematic analysis in NVivo. Acceptability was assessed via interview, and mixed-methods findings were integrated through triangulation to enhance validity. RESULTS:Fifty participants were recruited; 34% withdrew. Though not powered to determine statistical significance, no between-group differences were observed in HbA1c or patient-reported outcomes. Across groups, diabetes distress decreased, self-efficacy improved, and HbA1c improved. Interviews indicated high acceptability and identified key motivators (target achievability, hypoglycaemia avoidance) and demotivators (limited understanding, perceived unattainability). DISCUSSION:A randomised mixed-methods approach to HbA1c target-setting is feasible and acceptable, providing methodological insights for a definitive trial. TRIAL REGISTRATION:The study is registered with the ISRCTN (registration number: 12461724; date registered: 11th June 2021).

AbstractBackgroundGlycated haemoglobin (HbA1c) targets are commonly used to guide patient management in diabetes to reduce future risk of diabetes complications, but little is known of the psychological impact of HbA1ctarget-setting. We explored the feasibility of undertaking a conclusive study evaluating the impact of setting explicit HbA1ctargets in adults with diabetes.MethodsA randomised, mixed-methods study design was used to quantitatively and qualitatively evaluate the psychometric and biomedical impact of intensified or relaxed glycaemic targets in adults with diabetes. Alongside baseline measurement of HbA1c, blood pressure and body mass index, patients completed baseline validated psychometric questionnaires (EuroQoL-5D-5L, Problem Areas In Diabetes, Summary of Diabetes Self-Care Activities, Well-Being Quetionnaire-12, Diabetes Empowerment Scale-Long Form) and were randomised 1:1. Participants in group A received explicit HbA1ctarget intervention targets 5 mmol/mol above current HbA1c. Participants in group B received explicit HbA1ctargets 5 mmol/mol below current HbA1c. Rates of eligibility, recruitment, retention and questionnaire response were recorded. Outcomes were re-measured 3-months post-intervention. Patients and healthcare professionals attended semi-structured interviews for qualitative evaluation.ResultsFifty participants were recruited. Withdrawal rate was 34% (n=17). Endpoint evaluation revealed no significant between-group differences in patient-reported outcome measures or HbA1clevels. Overall, levels of distress (-4.4, p=.009), self-efficacy (.25 [.09–.41], p=.004) and subsequent HbA1creadings (-2.8 [-5.0–-.7], p=.012) improved, with non-significant changes seen in health-related quality of life, wellbeing, and self-care. Patients and healthcare professional interviews demonstrated study acceptability alongside specific motivators (e.g., target achievability, hypoglycaemia avoidance) and demotivators (e.g., lack of understanding, lack of target achievability) for striving to reach glycaemic targets. Combined qualitative data from patient and healthcare professional interviews and quantitative study aspects triangulated, enhancing data trustworthiness, and informing future hypotheses and methodologies.DiscussionThis mixed-methods study demonstrates feasibility and provides a novel insight into the psychological implications of HbA1ctarget-setting.Trial registrationThe study is registered with the ISRCTN (registration number:12461724; date registered: 11thJune 2021).

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background Weight change is often seen in people with diabetes. We investigated the effects of genes associated with weight change/glucose handling/insulin-signalling. Materials/methods DNA from diabetes individuals and non-diabetes individuals, plus clinical data, were available from the DARE study (n = 379 individuals: T1D n = 111; T2D n = 222; controls n = 46). Weight gain was assessed by temporal change of Body Mass Index (BMI). Genotyping was performed for CAV1rs926198, LEPRrs1137101, BDNFrs6265 and FTOrs9939609. Results No differences in genotype distributions were observed for the four SNPs in all groups un-stratified by weight gain. Following stratification differences in genotype distribution were observed. For those BMI relatively stable; controls showed a difference in genotype distributions versus T1D (CAV1rs926198, LEPRrs1137101). In T2D vs controls, significant differences were observed in genotype distribution for all four genes. For BMI increase, the only difference by category was LEPRrs1137101 (bothT1D/T2D vs controls). In BMI-stable groups, CAV1rs926198, T1D individuals showed lower T allele frequency (p=0.004) vs non-diabetes and for LEPRrs1137101 a higher G allele frequency versus controls (p=0.002). For T2D, CAV1rs926198, T allele frequency was lower in T2D than controls (p=0.005). For LEPR rs1137101, the G allele frequency was higher than in controls (p=0.004). In those with BMI increase, LEPRrs1137101 T1D individuals had higher G allele frequency versus controls (p=0.002) as did T2D vs controls (p=0.03). Conclusion Differences in allele frequency were seen between diabetes individuals and non-diabetes diagnosed at baseline in relation to the likelihood of BMI increase of >10%. It is established that the G allele of LEPRrs1137101 is associated with weight gain/obesity. However, this is the first report of CAV1rs926198 polymorphism being associated with weight stability/gain in diabetes.

American Diabetes Association guidelines emphasize the importance of individualized HbA1c target setting in glycemic management, but little is known of the impact of target-setting on patient well-being. We randomized 50 adults (type 1 or 2) to receive HbA1c targets 5 mmol/mol (0.5%) above or below current value and evaluated impact on health-related quality of life: EQ-5D-5L, EQ-VAS, diabetes distress: Problem Areas in Diabetes, PAID, self-efficacy: Diabetes Empowerment Scale Long Form, DES-LF, well-being: Wellbeing Questionnaire-12, W-BQ12 and HbA1c (%) at baseline and 3 months; with thematic analysis of semi-structured interviews in a subset of 14 people. Tabulated results for 33 completers: We hypothesized that individualized target-setting, especially stretch targets, might worsen diabetes distress and compromise wellbeing. Multiple validated questionnaires and thematic analysis of semi-structured interviews showed no evidence of any significant deterioration. Indeed, the process of explicit individualized target setting was associated with improvements in all wellbeing measures except EQ-5D-5L and there were significant improvements in diabetes distress and psychosocial efficacy in the relaxed target group. Our data suggest that the process of setting explicit individualized HbA1c targets is a positive one, regardless of whether the target is ‘relaxed’ or ‘stretch’. Disclosure S.J.Westall: None. S.Watmough: None. R.Narayanan: None. G.Irving: Research Support; Graphnet, Takeda Pharmaceutical Co., Ltd. N.J.Furlong: None. G.A.Lewis: None. K.J.Hardy: Other Relationship; Sanofi, Speaker's Bureau; Napp Pharmaceuticals Limited.

The COVID-19 pandemic globally impacted healthcare provision. Prescribing changes in common medications can be used as a marker for new diagnoses. We describe how the prescribing of specific psychotropics was impacted by the pandemic. Primary Care Prescribing data for different classes of drugs from March 2017 to February 2022 were considered. To capture the impact during periods of restricted access to health services for new diagnoses/existing conditions, repeat prescriptions/episodic prescribing were included with account taken of historical trends. The pre-pandemic prescriptions issued each month from March 2018 to February 2020 were linearly extrapolated forward to give an expected annual growth (EAG). The monthly average expected prescriptions for the pandemic period (March 2020–February 2022) were compared. Physical health medications had lower monthly prescriptions during the pandemic, most markedly for antibiotics − 12.5

Type 2 diabetes mellitus (T2D) is commonly associated with an increasing complexity of multimorbidity. While some progress has been made in identifying genetic and non-genetic risk factors for T2D, understanding the longitudinal clinical history of individuals before/after T2D diagnosis may provide additional insights. In this study, we utilised longitudinal data from the DARE (Diabetes Alliance for Research in England) study to examine the trajectory of clinical conditions in individuals with and without T2D. Data from 1932 individuals (T2D n = 1196 vs. matched non-T2D controls n = 736) were extracted and subjected to trajectory analysis over a period of up to 50 years (25 years pre-diagnosis/25 years post-diagnosis). We also analysed the cumulative proportion of people with diagnosed coronary artery disease (CAD) in their general practice (GP) record with an analysis of lower respiratory tract infection (RTI) as a comparator group. The mean age of diagnosis of T2D was 52.6 (95

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

American Diabetes Association guidelines emphasize the importance of individualized HbA1c target setting in glycemic management, but little is known of the impact of target-setting on patient well-being. We randomized 50 adults (type 1 or 2) to receive HbA1c targets 5 mmol/mol (0.5%) above or below current value and evaluated impact on health-related quality of life: EQ-5D-5L, EQ-VAS, diabetes distress: Problem Areas in Diabetes, PAID, self-efficacy: Diabetes Empowerment Scale Long Form, DES-LF, well-being: Wellbeing Questionnaire-12, W-BQ12 and HbA1c (%) at baseline and 3 months; with thematic analysis of semi-structured interviews in a subset of 14 people. Tabulated results for 33 completers: We hypothesized that individualized target-setting, especially stretch targets, might worsen diabetes distress and compromise wellbeing. Multiple validated questionnaires and thematic analysis of semi-structured interviews showed no evidence of any significant deterioration. Indeed, the process of explicit individualized target setting was associated with improvements in all wellbeing measures except EQ-5D-5L and there were significant improvements in diabetes distress and psychosocial efficacy in the relaxed target group. Our data suggest that the process of setting explicit individualized HbA1c targets is a positive one, regardless of whether the target is ‘relaxed’ or ‘stretch’. Disclosure S.J.Westall: None. S.Watmough: None. R.Narayanan: None. G.Irving: Research Support; Graphnet, Takeda Pharmaceutical Co., Ltd. N.J.Furlong: None. G.A.Lewis: None. K.J.Hardy: Other Relationship; Sanofi, Speaker's Bureau; Napp Pharmaceuticals Limited.