Gut microbiome shifts in people with type 1 diabetes are associated with glycaemic control: an INNODIA study.

AIMS/HYPOTHESIS: The gut microbiome is implicated in the disease process leading to clinical type 1 diabetes, but less is known about potential changes in the gut microbiome after the diagnosis of type 1 diabetes and implications in glucose homeostasis. We aimed to analyse potential associations between the gut microbiome composition and clinical and laboratory data during a 2 year follow-up of people with newly diagnosed type 1 diabetes, recruited to the Innovative approaches to understanding and arresting type 1 diabetes (INNODIA) study. In addition, we analysed the microbiome composition in initially unaffected family members, who progressed to clinical type 1 diabetes during or after their follow-up for 4 years. METHODS: We characterised the gut microbiome composition of 98 individuals with newly diagnosed type 1 diabetes (ND cohort) and 194 autoantibody-positive unaffected family members (UFM cohort), representing a subgroup of the INNODIA Natural History Study, using metagenomic sequencing. Participants from the ND cohort attended study visits within 6 weeks from the diagnosis and 3, 6, 12 and 24 months later for stool sample collection and laboratory tests (HbA1c, C-peptide, diabetes-associated autoantibodies). Participants from the UFM cohort were assessed at baseline and 6, 12, 18, 24 and 36 months later. RESULTS: We observed a longitudinal increase in 21 bacterial species in the ND cohort but not in the UFM cohort. The relative abundance of Faecalibacterium prausnitzii was inversely associated with the HbA1c levels at diagnosis (p=0.0019). The rate of the subsequent disease progression in the ND cohort, as assessed by change in HbA1c, C-peptide levels and insulin dose, was associated with the abundance of several bacterial species. Individuals with rapid decrease in C-peptide levels in the ND cohort had the lowest gut microbiome diversity. Nineteen individuals who were diagnosed with type 1 diabetes in the UFM cohort had increased abundance of Sutterella sp. KLE1602 compared with the undiagnosed UFM individuals (p=1.2 × 10-4). CONCLUSIONS/INTERPRETATION: Our data revealed associations between the gut microbiome composition and the disease progression in individuals with recent-onset type 1 diabetes. Future mechanistic studies as well as animal studies and human trials are needed to further validate the significance and causality of these associations.

Discordance between mean glucose and time in range in relation to HbA1c in individuals with type 1 diabetes: results from the GOLD and SILVER trials.

AIMS/HYPOTHESIS: Previous studies have shown that individuals with similar mean glucose levels (MG) or percentage of time in range (TIR) may have different HbA1c values. The aim of this study was to further elucidate how MG and TIR are associated with HbA1c. METHODS: Data from the randomised clinical GOLD trial (n=144) and the follow-up SILVER trial (n=98) of adults with type 1 diabetes followed for 2.5 years were analysed. A total of 596 paired HbA1c/continuous glucose monitoring measurements were included. Linear mixed-effects models were used to account for intra-individual correlations in repeated-measures data. RESULTS: In the GOLD trial, the mean age of the participants (± SD) was 44±13 years, 63 (44%) were female, and the mean HbA1c (± SD) was 72±9.8 mmol/mol (8.7±0.9%). When correlating MG with HbA1c, MG explained 63% of the variation in HbA1c (r=0.79, p<0.001). The variation in HbA1c explained by MG increased to 88% (r=0.94, p value for improvement of fit <0.001) when accounting for person-to-person variation in the MG-HbA1c relationship. Time below range (TBR; <3.9 mmol/l), time above range (TAR) level 2 (>13.9 mmol/l) and glycaemic variability had little or no effect on the association. For a given MG and TIR, the HbA1c of 10% of individuals deviated by >8 mmol/mol (0.8%) from their estimated HbA1c based on the overall association between MG and TIR with HbA1c. TBR and TAR level 2 significantly influenced the association between TIR and HbA1c. At a given TIR, each 1% increase in TBR was related to a 0.6 mmol/mol lower HbA1c (95% CI 0.4, 0.9; p<0.001), and each 2% increase in TAR level 2 was related to a 0.4 mmol/mol higher HbA1c (95% CI 0.1, 0.6; p=0.003). However, neither TIR, TBR nor TAR level 2 were significantly associated with HbA1c when accounting for MG. CONCLUSIONS/INTERPRETATION: Inter-individual variations exist between MG and HbA1c, as well as between TIR and HbA1c, with clinically important deviations in relatively large groups of individuals with type 1 diabetes. These results may provide important information to both healthcare providers and individuals with diabetes in terms of prognosis and when making diabetes management decisions.

Effects of maternal type 1 diabetes and confounding factors on neonatal microbiomes.

AIMS/HYPOTHESIS: Body niche-specific microbiota in maternal-neonatal dyads from gravidae with type 1 diabetes have not been quantitatively and functionally examined. Similarly, the impact of pregnancy-specific factors, such as the presence of comorbidities known to occur more frequently among gravidae with type 1 diabetes, including Caesarean delivery, as well as antibiotic prophylaxis, level of glycaemic control during each trimester of pregnancy and insulin administration, has not been adequately considered. The aims of this study were to characterise the maternal and neonatal microbiomes, assess aspects of microbiota transfer from the maternal microbiomes to the neonatal microbiome and explore the impact of type 1 diabetes and confounding factors on the microbiomes. METHODS: In this observational case-control study, we characterised microbiome community composition and function using 16S rRNA amplicon sequencing in a total of 514 vaginal, rectal and ear-skin swabs and stool samples derived from 92 maternal-neonatal dyads (including 50 gravidae with type 1 diabetes) and in-depth clinical metadata from throughout pregnancy and delivery. RESULTS: Type 1 diabetes-specific microbiota were identified among gravidae with type 1 diabetes and their neonates. Neonatal microbiome profiles of ear-skin swabs and stool samples were established, indicating the taxa more prevalent among neonates born to mothers with type 1 diabetes compared with neonates born to control mothers. Without taking into account the type 1 diabetes status of mothers, both delivery mode and intrapartum antibiotic prophylaxis were found to have an influence on neonatal microbiota composition (both p=0.001). In the logistic regression analysis involving all confounding variables, neonatal ear-skin microbiome variation was explained by maternal type 1 diabetes status (p=0.020) and small for gestational age birthweight (p=0.050). Moreover, in women with type 1 diabetes, a relationship was found between HbA1c levels >55 mmol/mol (>7.2%) measured in the first trimester of pregnancy and neonatal ear-skin microbiota composition (p=0.008). In the PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) assessment, pathways concerning carbohydrate biosynthesis were predicted as key elements of the microbial functional profiles dysregulated in type 1 diabetes. Additionally, in SourceTracker analysis, we found that, on average, 81.0% of neonatal microbiota was attributed to maternal sources. An increase in the contribution of maternal rectum microbiota and decrease in the contribution of maternal cervix microbiota were found in ear-skin samples of vaginally delivered neonates of mothers with type 1 diabetes compared with neonates born to control mothers (83.2% vs 59.5% and 0.7% vs 5.2%, respectively). CONCLUSIONS/INTERPRETATION: These findings indicate that, in addition to maternal type 1 diabetes, glycaemic dysregulation before/in the first trimester of pregnancy, mode of delivery and intrapartum antibiotic prophylaxis may contribute to the inoculation and formation of the neonatal microbiomes. DATA AVAILABILITY: The BioProject (PRJNA961636) and associated SRA metadata are available at http://www.ncbi.nlm.nih.gov/bioproject/961636 . Processed data on probiotic supplementation and the PICRUSt analysis are available in the Mendeley Data Repository ( https://doi.org/10.17632/g68rwnnrfk.1 ).

HbA1c variability is independently associated with progression of diabetic kidney disease in an urban multi-ethnic cohort of people with type 1 diabetes.

AIMS/HYPOTHESIS: The role of HbA1c variability in the progression of diabetic kidney disease is unclear, with most studies to date performed in White populations and limited data on its role in predicting advanced kidney outcomes. Our aim was to evaluate if long-term intra-individual HbA1c variability is a risk factor for kidney disease progression (defined as an eGFR decline of ≥50% from baseline with a final eGFR of <30 ml/min per 1.73 m2) in an ethnically heterogeneous cohort of people with type 1 diabetes with a preserved eGFR ≥45 ml/min per 1.73 m2 at baseline. METHODS: Electronic health record data from people attending outpatient clinics between 2004 and 2018 in two large university hospitals in London were collected. HbA1c variability was assessed using three distinct methods: (1) SD of HbA1c (SD-HbA1c); (2) visit-adjusted SD (adj-HbA1c): SD-HbA1c/√n/(n-1), where n is the number of HbA1c measurements per participant; and (3) CV (CV-HbA1c): SD-HbA1c/mean-HbA1c. All participants had six or more follow-up HbA1c measurements. The eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration equation and clinical/biochemical results from routine care were extracted from electronic health records. RESULTS: In total, 3466 participants (50% female, 78% White, 13% African Caribbean, 3% Asian and 6% of mixed heritage or self-reporting as 'other') were followed for a median (IQR) of 8.2 (4.2-11.6) years. Of this cohort, 249 (7%) showed kidney disease progression. Higher HbA1c variability was independently associated with a higher risk of kidney disease progression, with HRs (95% CIs) of 7.76 (4.54, 13.26), 2.62 (1.75, 3.94) and 5.46 (3.40, 8.79) (lowest vs highest HbA1c variability quartile) for methods 1-3, respectively. Increasing age, baseline HbA1c, systolic BP and urinary albumin/creatinine ratio were also associated with kidney disease progression (p<0.05 for all). African Caribbean ethnicity was associated with an increased risk of kidney disease progression (HR [95% CI] 1.47 [1.09, 1.98], 1.76 [1.32, 2.36] and 1.57 [1.17, 2.12] for methods 1-3, respectively) and this effect was independent of glycaemic variability and other traditional risk factors. CONCLUSIONS/INTERPRETATION: We observed an independent association between HbA1c variability, evaluated using three distinct methods, and significant kidney disease progression in a multi-ethnic type 1 diabetes cohort. Further studies are needed to elucidate the mechanisms that may explain our results and evaluate if HbA1c variability is a modifiable risk factor for preventing diabetic kidney disease progression.

Autoimmune comorbidity in type 1 diabetes and its association with metabolic control and mortality risk in young people: a population-based study.

AIMS/HYPOTHESIS: This register-based study aimed to describe autoimmune comorbidity in children and young adults from type 1 diabetes onset, and to investigate whether such comorbidity was associated with a difference in HbA1c or mortality risk compared with children/young adults with type 1 diabetes without autoimmune comorbidity. METHODS: A total of 15,188 individuals from the Swedish National Diabetes Register, registered with type 1 diabetes before 18 years of age between 2000 and 2019, were included. Five randomly selected control individuals from the Swedish population (Statistics Sweden) were matched to each individual with type 1 diabetes (n=74,210 [346 individuals with type 1 diabetes were not found in the Statistics Sweden register at the date of type 1 diabetes diagnosis, so could not be matched to control individuals]). The National Patient Register was used to attain ICD-10 codes on autoimmune diseases and the Cause of Death Register was used to identify deceased individuals. RESULTS: In the total type 1 diabetes cohort, mean±SD age at onset of type 1 diabetes was 9.5±4.4 years and mean disease duration at end of follow-up was 8.8±5.7 years. Of the individuals with type 1 diabetes, 19.2% were diagnosed with at least one autoimmune disease vs 4.0% of the control group. The HRs for comorbidities within 19 years from onset of type 1 diabetes were 11.6 (95% CI 10.6, 12.6) for coeliac disease, 10.6 (95% CI 9.6, 11.8) for thyroid disease, 1.3 (95% CI 1.1, 1.6) for psoriasis, 4.1 (95% CI 3.2, 5.3) for vitiligo, 1.7 (95% CI 1.4, 2.2) for rheumatic joint disease, 1.0 (95% CI 0.8, 1.3) for inflammatory bowel disease, 1.0 (95% CI 0.7, 1.2) for systemic connective tissue disorder, 1.4 (95% CI 1.1, 1.9) for uveitis, 18.3 (95% CI 8.4, 40.0) for Addison's disease, 1.8 (95% CI 0.9, 3.6) for multiple sclerosis, 3.7 (95% CI 1.6, 8.7) for inflammatory liver disease and 19.6 (95% CI 4.2, 92.3) for atrophic gastritis. Autoimmune disease in addition to type 1 diabetes had no statistically significant effect on HbA1c or mortality risk. CONCLUSIONS/INTERPRETATION: To our knowledge, this is the first comprehensive study where young individuals with type 1 diabetes were followed regarding development of a wide spectrum of autoimmune diseases, from onset of type 1 diabetes. In this nationwide and population-based study, there was already a high prevalence of autoimmune diseases in childhood, especially coeliac and thyroid disease. The presence of autoimmune comorbidity did not have a statistically significant effect on metabolic control or mortality risk.

Integration of a fasting-mimicking diet programme in primary care for type 2 diabetes reduces the need for medication and improves glycaemic control: a 12-month randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the impact on metabolic control of periodic use of a 5-day fasting-mimicking diet (FMD) programme as an adjunct to usual care in people with type 2 diabetes under regular primary care surveillance. METHODS: In this randomised, controlled, assessor-blinded trial, people with type 2 diabetes using metformin as the only glucose-lowering drug and/or diet for glycaemic control were randomised to receive 5-day cycles of an FMD monthly as an adjunct to regular care by their general practitioner or to receive regular care only. The primary outcomes were changes in glucose-lowering medication (as reflected by the medication effect score) and HbA1c levels after 12 months. Moreover, changes in use of glucose-lowering medication and/or HbA1c levels in individual participants were combined to yield a clinically relevant outcome measure ('glycaemic management'), which was categorised as improved, stable or deteriorated after 1 year of follow-up. Several secondary outcome measures were also examined, including changes in body weight. RESULTS: One hundred individuals with type 2 diabetes, age 18-75 years, BMI ≥27 kg/m2, were randomised to the FMD group (n=51) or the control group (n=49). Eight FMD participants and ten control participants were lost to follow-up. Intention-to-treat analyses, using linear mixed models, revealed adjusted estimated treatment effects for the medication effect score (-0.3; 95% CI -0.4, -0.2; p<0.001), HbA1c (-3.2 mmol/mol; 95% CI -6.2, -0.2 and -0.3%; 95% CI -0.6, -0.0; p=0.04) and body weight (-3.6 kg; 95% CI -5.2, -2.1; p<0.001) at 12 months. Glycaemic management improved in 53% of participants using FMD vs 8% of control participants, remained stable in 23% vs 33%, and deteriorated in 23% vs 59% (p<0.001). CONCLUSIONS/INTERPRETATION: Integration of a monthly FMD programme in regular primary care for people with type 2 diabetes who use metformin as the only glucose-lowering drug and/or diet for glycaemic control reduces the need for glucose-lowering medication, improves HbA1c despite the reduction in medication use, and appears to be safe in routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03811587 FUNDING: The project was co-funded by Health~Holland, Top Sector Life Sciences & Health, the Dutch Diabetes Foundation and L-Nutra.

Association between prediabetes and breast cancer: a comprehensive meta-analysis.

BACKGROUND: Breast cancer accounts for up to 30% of cancer cases in women in the US. Diabetes mellitus has been recognized as a risk factor for breast cancer. Some studies have suggested that prediabetes may also be associated with breast cancer whereas other studies have shown no or an inverse association; thus, we conducted a meta-analysis to assess the risk of breast cancer in prediabetes. METHODS: We searched PubMed/Medline, EMBASE, Google Scholar, and Scopus to identify studies that reported breast cancer risks in patients having prediabetes compared to normoglycemic patients. Binary random-effects model was used to calculate a pooled odds ratio (OR) with 95% confidence intervals. I2 statistics were used to assess heterogeneity. Leave-one-out sensitivity analysis and subgroup analyses were performed. RESULTS: We analyzed 7 studies with 24,586 prediabetic and 224,314 normoglycemic individuals (783 and 5739 breast cancer cases, respectively). Unadjusted odds ratio (OR) for breast cancer was 1.45 (95% CI = 1.14, 1.83); adjusted OR was 1.19 (95% CI = 1.07, 1.34) in prediabetes. Subgroup analysis revealed a higher breast cancer risk in individuals aged less than 60 years (OR = 1.86, 95% CI = 1.39, 2.49) than in those aged 60 years or more (OR = 1.07, 95% CI = 0.97, 1.18). Subgroup analysis by median follow-up length indicated a higher risk of breast cancer for follow-ups of less than or equal to 2 years (OR = 2.34, 95% CI = 1.85, 2.95) than in those of over 10 years (OR = 1.1, 95% CI = 0.99, 1.23) and 6 to 10 years (OR = 1.03, 95% CI = 0.88, 1.21). CONCLUSIONS: In conclusion, individuals with prediabetes have higher risk of developing breast cancer than those with normoglycemia, especially younger prediabetes patients. These individuals may benefit from early identification, monitoring, and interventions to reverse prediabetes.

The impact of major depressive disorder on glycaemic control in type 2 diabetes: a longitudinal cohort study using UK Biobank primary care records.

BACKGROUND: This study evaluates longitudinal associations between glycaemic control, measured by mean and within-patient variability of glycated haemaglobin (HbA1c) levels, and major depressive disorder (MDD) in individuals with type 2 diabetes (T2D), focusing on the timings of these diagnoses. METHODS: In UK Biobank, T2D was defined using self-report and linked health outcome data, then validated using polygenic scores. Repeated HbA1c measurements (mmol/mol) over the 10 years following T2D diagnosis were outcomes in mixed effects models, with disease duration included using restricted cubic splines. Four MDD exposures were considered: MDD diagnosis prior to T2D diagnosis (pre-T2D MDD), time between pre-T2D MDD diagnosis and T2D, new MDD diagnosis during follow-up (post-T2D MDD) and time since post-T2D MDD diagnosis. Models with and without covariate adjustment were considered. RESULTS: T2D diagnostic criteria were robustly associated with T2D polygenic scores. In 11,837 T2D cases (6.9 years median follow-up), pre-T2D MDD was associated with a 0.92 increase in HbA1c (95% CI: [0.00, 1.84]), but earlier pre-T2D MDD diagnosis correlated with lower HbA1c. These pre-T2D MDD effects became non-significant after covariate adjustment. Post-T2D MDD individuals demonstrated increasing HbA1c with years since MDD diagnosis ( ß = 0.51 , 95% CI: [0.17, 0.86]). Retrospectively, across study follow-up, within-patient variability in HbA1c was 1.16 (95% CI: 1.13-1.19) times higher in post-T2D MDD individuals. CONCLUSIONS: The timing of MDD diagnosis is important for understanding glycaemic control in T2D. Poorer control was observed in MDD diagnosed post-T2D, highlighting the importance of depression screening in T2D, and closer monitoring for individuals who develop MDD after T2D.

HbA1c-dependent projection of long-term renal outcomes.

BACKGROUND: Diabetes mellitus is a major risk factor for the development of chronic kidney disease (CKD). There is limited data addressing the value of glycated hemoglobin (HbA1c) to predict renal outcomes independent of diabetes status. METHODS: This single-center retrospective observational study presents data of 19,285 subjects, irrespective of initial CKD or diabetes status. The primary endpoint was defined as the time to manifestation of moderate CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 ) in subjects with eGFR ≥60 mL/min/1.73 m2 at baseline. The secondary endpoint was defined as time to progression of CKD (eGFR <30 mL/min/1.73 m2 ) in subjects with eGFR 30-60 mL/min/1.73 m2 . Multivariate time-to-event and logistic regression models were applied to estimate the influences of HbA1c, sex, age, eGFR, triglycerides, and cholesterol on both endpoints. RESULTS: Lowest baseline HbA1c levels were associated with the slowest decline of kidney function (median time to manifestation of moderate CKD for HbA1c <5.7%: 15.9 years [95% confidence interval (CI): 15.2-16.7]; for HbA1c 5.7%-6.5%: 14.5 years [95% CI: 14.0-15.1]; for HbA1c 6.5%-8.5%: 11.1 years [95% CI: 10.4-11.7]; for HbA1c >8.5%: 8.3 years [95% CI: 7.8-9.2]; p < 0.001). Similar results were observed for the secondary endpoint. Covariate-adjusted time-to-event analysis demonstrated an almost linear correlation between continuous baseline HbA1c levels and the probabilities of reaching both endpoints. CONCLUSIONS: HbA1c levels are a strong predictor for eGFR decline, irrespective of diabetes status or CKD stage, demonstrating a tight concentration-dependent relationship. This association becomes apparent in the prediabetic HbA1c range and remains constant over the entire HbA1c spectrum.

A Mutagen Acts as a Potent Reducing Agent of Glycated Hemoglobin: a Combined Ultrafast Electron Transfer and Computational Studies.

Glycated hemoglobin (GHb) found in mammals undergoes irreversible damage when exposed to external redox agents, which is much more vulnerable than its normal counterpart hemoglobin (Hb). Besides the oxygen regulation throughout the body, Hb plays a vital role in balancing immunological health and the redox cycle. Photoinduced ultra-fast electron transfer phenomena actively participate in regulation of various kind of homeostasis involved in such biomacromolecules. In the present study we have shown that a well-known mutagen Ethidium Bromide (EtBr) reduces GHb in femtosecond time scale (efficiently) upon photoexcitation after efficient recognition in the biomolecule. We have performed similar experiment by colocalizing EtBr and Iron (Fe(III)) on the micellar surface as Hb mimic in order to study the excited state EtBr dynamics to rationalize the time scale obtained from EtBr in GHb and Hb. While other experimental techniques including Dynamic Light Scattering (DLS), Zeta potential, absorbance and emission spectroscopy have been employed for the confirmation of structural perturbation of GHb compared to Hb, a detailed computational studies involving molecular docking and density functional theory (DFT) have been employed for the explanation of the experimental observations.

HIV and type 2 diabetes: An evolving story.

INTRODUCTION: Diabetes is widely reported to be more common in people living with HIV (PLWH). Much of the data supporting this originated during the earlier HIV era. The perceived increased risk of type 2 diabetes is reflected in HIV clinical guidelines that recommend screening for diabetes in PLWH on anti-retroviral therapy (ART). However, international HIV clinical guidelines do not agree on the best marker of glycaemia to screen for diabetes. This stems from studies that suggest HbA1c underestimates glycaemia in PLWH. METHODS: Within this review we summarise the literature surrounding the association of HIV and type 2 diabetes and how this has changed over time. We also present the evidence on HbA1c discrepancy in PLWH. CONCLUSION: We suggest there is no basis to any international guidelines to restrict HbA1c based on HIV serostatus. We recommend, using the current evidence, that PLWH should be screened annually for diabetes in keeping with country specific guidance. Finally, we suggest future work to elucidate phenotype and natural history of type 2 diabetes in PLWH across all populations.

Glycemic Trends in Patients with Thyroid Eye Disease Treated with Teprotumumab in 3 Clinical Trials.

PURPOSE: Assess incidence, severity, and glucose excursion outcomes in thyroid eye disease (TED) patients receiving the insulin-like growth factor-1 receptor inhibitor teprotumumab from 3 clinical trials. DESIGN: Analysis of pooled glycemic data over time. PARTICIPANTS: Eighty-four teprotumumab- and 86 placebo-treated active TED patients from the phase 2 and phase 3 (OPTIC) controlled clinical trials and 51 teprotumumab-treated patients from the OPTIC extension (OPTIC-X) trial. METHODS: Eight intravenous infusions were given over 21 weeks. Phase 2 serum glucose was measured at weeks 1, 4, 15, and 21, with fasting measurements at weeks 1 and 4. Serum glucose was measured at each study visit in OPTIC and OPTIC-X, with fasting measurements at weeks 1 and 4 (in patients without diabetes) or all visits (in patients with diabetes). In all studies, hemoglobin A1c (HbA1c) was measured at baseline, 12, and 24 weeks plus weeks 36 and 48 in OPTIC-X. MAIN OUTCOME MEASURES: Serum glucose and HbA1c. RESULTS: In the phase 2 and 3 studies, 9 hyperglycemic episodes occurred in 8 teprotumumab patients; mean HbA1c level increased 0.22% from baseline to week 24 (to 5.8%; range, 5.0%-7.9%) versus 0.04% in patients receiving the placebo (to 5.6%; range, 4.6%-8.1%). At study end, 78% (59/76) of teprotumumab patients and 87% (67/77) of patients receiving placebo had normoglycemic findings. Normoglycemia was maintained in 84% (57/68) of patients receiving teprotumumab and 93% (64/69) of patients receiving placebo. Among baseline prediabetic patients, 43% (3/7) remained prediabetic in both groups, and 29% (2/7) of teprotumumab patients and 14% (1/7) of patients receiving placebo had diabetic findings at week 24. OPTIC-X patients trended toward increased fasting glucose and HbA1c whether initially treated or retreated with teprotumumab. Fasting glucose commonly rose after 2 or 3 infusions and stabilized thereafter. Most hyperglycemic incidents occurred in patients with baseline prediabetes/diabetes but were controlled with medication. No evidence was found for progression or increased incidence of hyperglycemia with subsequent doses. CONCLUSIONS: Serious glycemic excursions are uncommon in patients with normoglycemia before teprotumumab therapy. Patients with controlled diabetes or impaired glucose tolerance can be treated safely if baseline screening, regular monitoring of glycemic control, and timely treatment of hyperglycemia are practiced. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

BMI variability and cardiovascular outcomes within clinical trial and real-world environments in type 2 diabetes: an IMI2 SOPHIA study.

BACKGROUND: BMI variability has been associated with increased cardiovascular disease risk in individuals with type 2 diabetes, however comparison between clinical studies and real-world observational evidence has been lacking. Furthermore, it is not known whether BMI variability has an effect independent of HbA1c variability. METHODS: We investigated the association between BMI variability and 3P-MACE risk in the Harmony Outcomes trial (n = 9198), and further analysed placebo arms of REWIND (n = 4440) and EMPA-REG OUTCOME (n = 2333) trials, followed by real-world data from the Tayside Bioresource (n = 6980) using Cox regression modelling. BMI variability was determined using average successive variability (ASV), with first major adverse cardiovascular event of non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death (3P-MACE) as the primary outcome. RESULTS: After adjusting for cardiovascular risk factors, a + 1 SD increase in BMI variability was associated with increased 3P-MACE risk in Harmony Outcomes (HR 1.12, 95% CI 1.08-1.17, P < 0.001). The most variable quartile of participants experienced an 87% higher risk of 3P-MACE (P < 0.001) relative to the least variable. Similar associations were found in REWIND and Tayside Bioresource. Further analyses in the EMPA-REG OUTCOME trial did not replicate this association. BMI variability's impact on 3P-MACE risk was independent of HbA1c variability. CONCLUSIONS: In individuals with type 2 diabetes, increased BMI variability was found to be an independent risk factor for 3P-MACE across cardiovascular outcome trials and real-world datasets. Future research should attempt to establish a causal relationship between BMI variability and cardiovascular outcomes.

Predictors of efficacy of Sodium-GLucose Transporter-2 inhibitors and Glucagon-Like Peptide 1 receptor agonists: A retrospective cohort study.

AIMS: The aim of the present study was to verify predictors of HbA1c reduction with Sodium-GLucose Transporter-2 (SGLT2) inhibitors and Glucagon-Like Peptide 1 (GLP1) receptor agonists in routine clinical practice. MATERIALS AND METHODS: A retrospective cohort study was performed, enrolling patients with type 2 diabetes aged ≥18 years who received a prescription of an SGLT2 inhibitor or a long-acting GLP1 receptor agonist with at least 6 months of persistence in therapy. Therapeutic success was defined as HbA1c reduction >10 mmol/mol or attainment of the recommended HbA1c target. RESULTS: Out of 236 patients receiving SGLT2 inhibitors, 148 were categorised as successes: successes had a mean lower age and higher estimated Glomerular Filtration Rate than failures, but only age retained statistical significance at multivariate analysis (Odds Ratio with 95% confidence interval: 0.94 [0.91-0.98], p = 0.006). In the GLP1 receptor agonists cohort (N = 214) there were 146 successes, showing a significantly shorter duration of diabetes even after adjusting for age, and baseline HbA1c (HR 0.96 [0.91-0.99], p = 0.02). CONCLUSIONS: The present study is a preliminary exploration of factors associated with HbA1c response to SGLT2 inhibitors and GLP1 receptor agonists. Differences in predictors of HbA1c changes across different classes of drugs could be useful in identifying the most suitable drug in individual patients. SGLT2 inhibitors seem to be associated with a greater reduction of HbA1c in younger subjects, and GLP1 agonists in those with a shorter duration of diabetes.

HbA1c and the risk of developing peripheral neuropathy in childhood-onset type 1 diabetes: A follow-up study over 3 decades.

AIMS: We have evaluated long-term weighted mean HbA1c (wHbA1c), HbA1c variability, diabetes duration, and lipid profiles in relation to the development of diabetic peripheral neuropathy (DPN), nephropathy, and retinopathy in childhood-onset type 1 diabetes. MATERIALS AND METHODS: In a longitudinal cohort study, 49 patients (21 women) with childhood-onset type 1 diabetes were investigated with neurophysiological measurements, blood tests, and clinical examinations after a diabetes duration of 7.7 (±3.3) years (baseline) and followed with repeated examinations for 30.6 (±5.2) years. We calculated wHbA1c by integrating the area under all HbA1c values since the diabetes diagnosis. Lipid profiles were analysed in relation to the presence of DPN. Long-term fluctuations of HbA1c variability were computed as the standard deviation of all HbA1c measurements. Data regarding the presence of other diabetes complications were retrieved from medical records. RESULTS: In this follow-up study, 51% (25/49) of the patients fulfilled electrophysiological criteria for DPN. In nerve conduction studies, there was a deterioration in the amplitudes and conduction velocities for the median, peroneal, and sural nerves over time. Patients with DPN had a longer duration of diabetes, higher wHbA1c, and increased HbA1c variability. The lowest wHbA1c value associated with the development of DPN was 62 mmol/mol (7.8%). The presence of albuminuria and retinopathy was positively correlated with the presence of neuropathy. CONCLUSIONS: More than half of the patients had developed DPN after 30 years. None of the patients who developed DPN had a wHbA1c of less than 62 mmol/mol (7.8%).

Circadian alignment of food intake and glycaemic control by time-restricted eating: A systematic review and meta-analysis.

Daily rhythms of metabolic function are supported by molecular circadian clock systems that are strongly regulated by feeding and fasting. Intermittent fasting diets have been associated with weight loss and improved metabolism. However, the effects of time-restricted eating (TRE) on glycemic parameters are still under debate. In this review, we aim to systematically analyze the effects of TRE on glycemic parameters. We searched on PubMed, EMBASE, and the Cochrane Library for controlled studies in which subjects followed TRE for at least 4 weeks. 20 studies were included in the qualitative systematic review, and 18 studies (n = 1169 subjects) were included in the meta-analysis. Overall, TRE had no significant effect on fasting glucose (Hedges's g = -0.08; 95% CI:-0.31,0.16; p = 0.52), but it did reduce HbA1c levels (Hedges's g = -0.27; 95% CI: -0.47, -0.06; p = 0.01). TRE significantly reduced fasting insulin (Hedges's g = -0.40; 95% CI: -0.73,-0.08; p = 0.01) and showed a tendency to decrease HOMA-IR (Hedges's g = -0.32; 95% CI:-0.66,0.02; p = 0.06). Interestingly, a cumulative analysis showed that the beneficial effects of TRE regarding glucose levels were less apparent as studies with later TRE windows (lTRE) were being included. Indeed, a subgroup analysis of the early TRE (eTRE) studies revealed that fasting glucose was significantly reduced by eTRE (Hedges's g = -0.38; 95% CI:-0.62, -0.14; p < 0.01). Our meta-analysis suggests that TRE can reduce HbA1c and insulin levels, and that timing of food intake is a crucial factor in the metabolic benefit of TRE, as only eTRE is capable of reducing fasting glucose levels in subjects with overweight or obesity.PROSPERO registration number CRD42023405946.

Vitamin D supplementation modulates glycated hemoglobin (HBA1c) in diabetes mellitus.

Diabetes is a metabolic illness that increases protein glycosylation in hyperglycemic conditions, which can have an impact on almost every organ system in the body. The role of vitamin D in the etiology of diabetes under RAGE (receptor for advanced glycation end products) stress has recently received some attention on a global scale. Vitamin D's other skeletal benefits have generated a great deal of research. Vitamin D's function in the development of type 1 and type 2 diabetes is supported by the discovery of 1,25 (OH)2D3 and 1-Alpha-Hydroylase expression in immune cells, pancreatic beta cells, and several other organs besides the bone system. A lower HBA1c level, metabolic syndrome, and diabetes mellitus all seems to be associated with vitamin D insufficiency. Most of the cross-sectional and prospective observational studies that were used to gather human evidence revealed an inverse relationship between vitamin D level and the prevalence or incidence of elevated HBA1c in type 2 diabetes. Several trials have reported on the impact of vitamin D supplementation for glycemia or incidence of type 2 diabetes, with varying degrees of success. The current paper examines the available data for a relationship between vitamin D supplementation and HBA1c level in diabetes and discusses the biological plausibility of such a relationship.

Metabolic and Skeletal Characterization of the KK/Ay Mouse Model-A Polygenic Mutation Model of Obese Type 2 Diabetes.

Type 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from: https://www.jax.org/strain/002468 ). While numerous mouse models for T2D exist, few effectively stimulate persistent hyperglycemia in both sexes, and even fewer are suitable for bone studies. Commonly used models like db/db and ob/ob have altered leptin pathways, confounding bone-related findings since leptin regulates bone properties (Fajardo et al. in Journal of Bone and Mineral Research 29(5): 1025-1040, 2014). The Yellow Kuo Kondo (KK/Ay) mouse, a polygenic mutation model of T2D, is able to produce a consistent diabetic state in both sexes and addresses the lack of a suitable model of T2D for bone studies. The diabetic state of KK/Ay stems from a mutation in the agouti gene, responsible for coat color in mice. This mutation induces ectopic gene expression across various tissue types, resulting in diabetic mice with yellow fur coats (Moussa and Claycombe in Obesity Research 7(5): 506-514, 1999). Male and female KK/Ay mice exhibited persistent hyperglycemia, defining them as diabetic with blood glucose (BG) levels consistently exceeding 300 mg/dL. Notably, male control mice in this study were also diabetic, presenting a significant limitation. Nevertheless, male and female KK/Ay mice showed significantly elevated BG levels, HbA1c, and serum insulin concentration when compared to the non-diabetic female control mice. Early stages of T2D are characterized by hyperglycemia and hyperinsulinemia resulting from cellular insulin resistance, whereas later stages may feature hypoinsulinemia due to ß-cell apoptosis (Banday et al. Avicenna Journal of Medicine 10(04): 174-188, 2020 and Klein et al. Cell Metabolism 34(1): 11-20, 2022). The observed hyperglycemia, hyperinsulinemia, and the absence of differences in ß-cell mass suggest that KK/Ay mice in this study are modeling the earlier stages of T2D. While compromised bone microarchitecture was observed in this study, older KK/Ay mice, representing more advanced stages of T2D, might exhibit more pronounced skeletal manifestations. Compared to the control group, the femora of KK/Ay mice had higher cortical area and cortical thickness, and improved trabecular properties which would typically be indicative of greater bone strength. However, KK/Ay mice displayed lower cortical tissue mineral density in both sexes and increased cortical porosity in females. Fracture instability toughness of the femora was lower in KK/Ay mice overall compared to controls. These findings indicate that decreased mechanical integrity noted in the femora of KK/Ay mice was likely due to overall bone quality being compromised.

The effect of physical activity on glycaemic control in people with type 1 diabetes mellitus: A systematic literature review and meta-analysis.

AIMS: Type 1 diabetes mellitus (T1DM) is characterised by insulin deficiency. Due to perceived physical activity (PA)-related hypoglycaemia, a minority of people with T1DM exercise regularly. However, the relationship between T1DM and PA remains poorly understood. Our aim was to summarise the existing literature on the effects of PA on short-term glucose control (glycated haemoglobin or time in range) in people with T1DM. METHODS: We searched seven electronic databases (PubMed, Embase, Cochrane library, Cinahl, SPORTDiscus, PEDro and Web Of Science) and two sources of the grey literature (ClinicalTrials.gov and ICTRP). All reviews were screened via title/abstract and full text by two independent reviewers (LE and HT), conflicts were solved by a third independent reviewer (DDC). We excluded animal studies, case reports, non-English articles, qualitative studies, conference abstracts and articles without full-text access. A meta-analysis using random effects model was performed to study the effect of PA on haemoglobin A1c (HbA1c) levels in people with T1DM. RESULTS: We obtained 19,201 unique references across nine different electronic databases. After screening and snowballing, 68 articles were found investigating the effect of PA on glycaemic control in people with T1DM. Overall, HbA1c levels in the PA group (mean difference = 0.29% (0.20%-0.39%)), were lower compared with the control group. CONCLUSION: An overall small beneficial effect of PA on glycaemic control in people with T1DM was found. Caution is advised when interpreting the results of this meta-analysis, given variations in study type, duration, frequency and intensity of physical activity across included studies.

Heterogeneity in glycaemic control in children and adolescents with type 1 diabetes: A latent class trajectory analysis of Danish nationwide data.

AIMS: Suboptimal glycaemic control in children and adolescents with type 1 diabetes is prevalent and associated with increased risk of diabetes-related complications and mortality later in life. First, we aimed to identify distinct glycated haemoglobin (HbA1c) trajectories in children and adolescents (2-19 years) with type 1 diabetes. Second, we examined their associations with clinical and socio-demographic factors. METHODS: Data were obtained from the Danish Registry of Childhood and Adolescent Diabetes (DanDiabKids) comprising all Danish children and adolescents diagnosed with type 1 diabetes from 1996 to 2019. Subgroups of distinct mean trajectories of HbA1c were identified using data-driven latent class trajectory modelling. RESULTS: A total of 5889 children (47% female) had HbA1c measured a median of 6 times (interquartile range 3-8) and contributing to 36,504 measurements. We identified four mean HbA1c trajectories, referred to as 'Stable but elevated HbA1c' (83%), 'Increasing HbA1c' (5%), 'Late HbA1c peak' (7%), and 'Early HbA1c peak' (5%). Compared to the 'Stable but elevated HbA1c' group, the three other groups presented rapidly deteriorating glycaemic control during late childhood or adolescence, had higher HbA1c at study entry, and included fewer pump users, higher frequency of inadequate blood glucose monitoring, more severe hypoglycaemic events, lower proportions with Danish origin, and worse educational status of parents. The groups also represented significant differences by healthcare region. CONCLUSIONS: Children and adolescents with type 1 diabetes experience heterogenous trajectories with different timings and magnitudes of the deterioration of HbA1c levels, although the majority follow on average a stable, yet elevated HbA1c trajectory. The causes and long-term health implications of these heterogenous trajectories need to be addressed.