Associations of 24 h time-use compositions of sitting, standing, physical activity and sleeping with optimal cardiometabolic risk and glycaemic control: The Maastricht Study.

AIMS/HYPOTHESIS: The associations of sitting, standing, physical activity and sleep with cardiometabolic health and glycaemic control markers are interrelated. We aimed to identify 24 h time-use compositions associated with optimal metabolic and glycaemic control and determine whether these varied by diabetes status. METHODS: Thigh-worn activPAL data from 2388 participants aged 40-75 years (48.7% female; mean age 60.1 [SD = 8.1] years; n=684 with type 2 diabetes) in The Maastricht Study were examined. Compositional isometric log ratios were generated from mean 24 h time use (sitting, standing, light-intensity physical activity [LPA], moderate-to-vigorous physical activity [MVPA] and sleeping) and regressed with outcomes of waist circumference, fasting plasma glucose (FPG), 2 h plasma glucose, HbA1c, the Matsuda index expressed as z scores, and with a clustered cardiometabolic risk score. Overall analyses were adjusted for demographics, smoking, dietary intake and diabetes status, and interaction by diabetes status was examined separately. The estimated difference when substituting 30 min of one behaviour with another was determined with isotemporal substitution. To identify optimal time use, all combinations of 24 h compositions possible within the study footprint (1st-99th percentile of each behaviour) were investigated to determine those cross-sectionally associated with the most-optimal outcome (top 5%) for each outcome measure. RESULTS: Compositions lower in sitting time and with greater standing time, physical activity and sleeping had the most beneficial associations with outcomes. Associations were stronger in participants with type 2 diabetes (p<0.05 for interactions), with larger estimated benefits for waist circumference, FPG and HbA1c when sitting was replaced by LPA or MVPA in those with type 2 diabetes vs the overall sample. The mean (range) optimal compositions of 24 h time use, considering all outcomes, were 6 h (range 5 h 40 min-7 h 10 min) for sitting, 5 h 10 min (4 h 10 min-6 h 10 min) for standing, 2 h 10 min (2 h-2 h 20 min) for LPA, 2 h 10 min (1 h 40 min-2 h 20 min) for MVPA and 8 h 20 min (7 h 30 min-9 h) for sleeping. CONCLUSIONS/INTERPRETATION: Shorter sitting time and more time spent standing, undergoing physical activity and sleeping are associated with preferable cardiometabolic health. The substitutions of behavioural time use were significantly stronger in their associations with glycaemic control in those with type 2 diabetes compared with those with normoglycaemic metabolism, especially when sitting time was balanced with greater physical activity.

Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. RESULTS: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. CONCLUSIONS/INTERPRETATION: Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04109547. FUNDING: Novo Nordisk A/S.

Efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes uncontrolled with metformin: PIONEER 12, a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to assess the efficacy and safety of oral semaglutide vs sitagliptin in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 12 trial was a randomised, double-dummy, active-controlled, parallel-group, Phase IIIa trial conducted over 26 weeks at 90 sites across the China region (including mainland China, Taiwan and Hong Kong) and five other countries. Adults aged ≥18 years (≥20 years in Taiwan) with a diagnosis of type 2 diabetes, HbA1c between 53 and 91 mmol/mol (inclusive) and treated with a stable daily dose of metformin were eligible for inclusion. Participants were randomised (1:1:1:1) using a web-based randomisation system to either once-daily oral semaglutide (3 mg, 7 mg or 14 mg) or once-daily oral sitagliptin 100 mg. Treatment allocation was masked to both participants and investigators. Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary endpoint was change in HbA1c from baseline to week 26. The confirmatory secondary endpoint was change in body weight (kg) from baseline to week 26. All randomised participants were included in the full analysis set (FAS). All participants exposed to at least one dose of trial product were included in the safety analysis (SAS). RESULTS: Of 1839 participants screened, 1441 were randomly assigned to oral semaglutide 3 mg (n=361), 7 mg (n=360), 14 mg (n=361) or sitagliptin 100 mg (n=359) and included in the FAS. A total of 1438 participants were included in the SAS. In total, 75.2% of participants were from the China region. A total of 1372 (95.2%) participants completed the trial and 130 participants prematurely discontinued treatment (8.3%, 8.6% and 15.0% for oral semaglutide 3 mg, 7 mg and 14 mg, respectively; 4.2% for sitagliptin 100 mg). Significantly greater reductions in HbA1c from baseline to week 26 were reported for all doses of oral semaglutide vs sitagliptin 100 mg. For oral semaglutide 3 mg, 7 mg and 14 mg vs sitagliptin 100 mg, the estimated treatment differences (ETDs [95% CI]) were -2 (-4, -1) mmol/mol, -8 (-9, -6) mmol/mol and -11 (-12, -9) mmol/mol, respectively. The corresponding ETDs (95% CI) in percentage points vs sitagliptin 100 mg were -0.2 (-0.3, -0.1), -0.7 (-0.8, -0.6) and -1.0 (-1.1, -0.8), respectively. Reductions in body weight were significantly greater for all doses of oral semaglutide vs sitagliptin 100 mg (ETD [95% CI] -0.9 [-1.4, -0.4] kg, -2.3 [-2.8, -1.8] kg and -3.3 [-3.8, -2.8] kg for 3 mg, 7 mg and 14 mg, respectively). In the subpopulation of participants from the China region (75.2% of trial participants), reductions in HbA1c and body weight from baseline to week 26 were similar to those seen in the overall population. The most frequent adverse events in the semaglutide treatment arms were gastrointestinal, although these were mostly transient and mild/moderate in severity. CONCLUSIONS/INTERPRETATION: Significantly greater reductions in both HbA1c and body weight over 26 weeks were seen with oral semaglutide 3 mg, 7 mg and 14 mg than with sitagliptin 100 mg in a predominantly Chinese population with type 2 diabetes inadequately controlled with metformin treatment. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04017832. FUNDING: This trial was funded by Novo Nordisk A/S, Søborg, Denmark.

Continuous glucose monitoring in adults with type 2 diabetes: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) is increasingly used in the treatment of type 2 diabetes, but the effects on glycaemic control are unclear. The aim of this systematic review and meta-analysis is to provide a comprehensive overview of the effect of CGM on glycaemic control in adults with type 2 diabetes. METHODS: We performed a systematic review using Embase, MEDLINE, Web of Science, Scopus and ClinicalTrials.gov from inception until 2 May 2023. We included RCTs investigating real-time CGM (rtCGM) or intermittently scanned CGM (isCGM) compared with self-monitoring of blood glucose (SMBG) in adults with type 2 diabetes. Studies with an intervention duration <6 weeks or investigating professional CGM, a combination of CGM and additional glucose-lowering treatment strategies or GlucoWatch were not eligible. Change in HbA1c and the CGM metrics time in range (TIR), time below range (TBR), time above range (TAR) and glycaemic variability were extracted. We evaluated the risk of bias using the Cochrane risk-of-bias tool version 2. Data were synthesised by performing a meta-analysis. We also explored the effects of CGM on severe hypoglycaemia and micro- and macrovascular complications. RESULTS: We found 12 RCTs comprising 1248 participants, with eight investigating rtCGM and four isCGM. Compared with SMBG, CGM use (rtCGM or isCGM) led to a mean difference (MD) in HbA1c of -3.43 mmol/mol (-0.31%; 95% CI -4.75, -2.11, p<0.00001, I2=15%; moderate certainty). This effect was comparable in studies that included individuals using insulin with or without oral agents (MD -3.27 mmol/mol [-0.30%]; 95% CI -6.22, -0.31, p=0.03, I2=55%), and individuals using oral agents only (MD -3.22 mmol/mol [-0.29%]; 95% CI -5.39, -1.05, p=0.004, I2=0%). Use of rtCGM showed a trend towards a larger effect (MD -3.95 mmol/mol [-0.36%]; 95% CI -5.46 to -2.44, p<0.00001, I2=0%) than use of isCGM (MD -1.79 mmol/mol [-0.16%]; 95% CI -5.28, 1.69, p=0.31, I2=64%). CGM was also associated with an increase in TIR (+6.36%; 95% CI +2.48, +10.24, p=0.001, I2=9%) and a decrease in TBR (-0.66%; 95% CI -1.21, -0.12, p=0.02, I2=45%), TAR (-5.86%; 95% CI -10.88, -0.84, p=0.02, I2=37%) and glycaemic variability (-1.47%; 95% CI -2.94, -0.01, p=0.05, I2=0%). Three studies reported one or more events of severe hypoglycaemia and macrovascular complications. In comparison with SMBG, CGM use led to a non-statistically significant difference in the incidence of severe hypoglycaemia (RR 0.66, 95% CI 0.15, 3.00, p=0.57, I2=0%) and macrovascular complications (RR 1.54, 95% CI 0.42, 5.72, p=0.52, I2=29%). No trials reported data on microvascular complications. CONCLUSIONS/INTERPRETATION: CGM use compared with SMBG is associated with improvements in glycaemic control in adults with type 2 diabetes. However, all studies were open label. In addition, outcome data on incident severe hypoglycaemia and incident microvascular and macrovascular complications were scarce. REGISTRATION: This systematic review was registered on PROSPERO (ID CRD42023418005).

Glycaemic control is still central in the hierarchy of priorities in type 2 diabetes management.

A panel of primary care and diabetes specialists conducted focused literature searches on the current role of glycaemic control in the management of type 2 diabetes and revisited the evolution of evidence supporting the importance of early and intensive blood glucose control as a central strategy to reduce the risk of adverse long-term outcomes. The optimal approach to type 2 diabetes management has evolved over time as the evidence base has expanded from data from trials that established the role of optimising glycaemic control to recent data from cardiovascular outcomes trials (CVOTs) demonstrating organ-protective effects of newer glucose-lowering drugs (GLDs). The results from these CVOTs were derived mainly from people with type 2 diabetes and prior cardiovascular and kidney disease or multiple risk factors. In more recent years, earlier diagnosis in high-risk individuals has contributed to the large proportion of people with type 2 diabetes who do not have complications. In these individuals, a legacy effect of early and optimal control of blood glucose and cardiometabolic risk factors has been proven to reduce cardiovascular and kidney disease events and all-cause mortality. As there is a lack of RCTs investigating the potential synergistic effects of intensive glucose control and organ-protective effects of newer GLDs, this article re-evaluates the evolution of the scientific evidence and highlights the importance of integrating glycaemic control as a pivotal early therapeutic goal in most people with type 2 diabetes, while targeting existing cardiovascular and kidney disease. We also emphasise the importance of implementing multifactorial management using a multidisciplinary approach to facilitate regular review, patient empowerment and the possibility of tailoring interventions to account for the heterogeneity of type 2 diabetes.

Heterogeneity of glycaemic phenotypes in type 1 diabetes.

AIMS/HYPOTHESIS: Our study aims to uncover glycaemic phenotype heterogeneity in type 1 diabetes. METHODS: In the Study of the French-speaking Society of Type 1 Diabetes (SFDT1), we characterised glycaemic heterogeneity thanks to a set of complementary metrics: HbA1c, time in range (TIR), time below range (TBR), CV, Gold score and glycaemia risk index (GRI). Applying the Discriminative Dimensionality Reduction with Trees (DDRTree) algorithm, we created a phenotypic tree, i.e. a 2D visual mapping. We also carried out a clustering analysis for comparison. RESULTS: We included 618 participants with type 1 diabetes (52.9% men, mean age 40.6 years [SD 14.1]). Our phenotypic tree identified seven glycaemic phenotypes. The 2D phenotypic tree comprised a main branch in the proximal region and glycaemic phenotypes in the distal areas. Dimension 1, the horizontal dimension, was positively associated with GRI (coefficient [95% CI]) (0.54 [0.52, 0.57]), HbA1c (0.39 [0.35, 0.42]), CV (0.24 [0.19, 0.28]) and TBR (0.11 [0.06, 0.15]), and negatively with TIR (-0.52 [-0.54, -0.49]). The vertical dimension was positively associated with TBR (0.41 [0.38, 0.44]), CV (0.40 [0.37, 0.43]), TIR (0.16 [0.12, 0.20]), Gold score (0.10 [0.06, 0.15]) and GRI (0.06 [0.02, 0.11]), and negatively with HbA1c (-0.21 [-0.25, -0.17]). Notably, socioeconomic factors, cardiovascular risk indicators, retinopathy and treatment strategy were significant determinants of glycaemic phenotype diversity. The phenotypic tree enabled more granularity than traditional clustering in revealing clinically relevant subgroups of people with type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our study advances the current understanding of the complex glycaemic profile in people with type 1 diabetes and suggests that strategies based on isolated glycaemic metrics might not capture the complexity of the glycaemic phenotypes in real life. Relying on these phenotypes could improve patient stratification in type 1 diabetes care and personalise disease management.

A whole-food, plant-based intensive lifestyle intervention improves glycaemic control and reduces medications in individuals with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: We conducted the largest and longest clinical trial comparing a whole-food, plant-based intervention with standard medical care (SMC) in individuals with type 2 diabetes. METHODS: We randomised (parallel-arm; computerised 1:1 randomisation ratio) 169 adults aged 18-75 years with type 2 diabetes in the Marshall Islands to an intensive whole-food, plant-based intervention with moderate exercise (PB+Ex) or SMC for 24 weeks. The PB+Ex intervention included 12 weeks of meals, exercise sessions and group classes. Primary outcomes were glycaemic control (HbA1c, glucose, insulin and HOMA-IR) and glucose-lowering medication use. Secondary outcomes included lipids, blood pressure, heart rate and C-reactive protein. Only lab analysts were blinded. RESULTS: Compared with SMC (n=90 randomised; n=70 analysed), the PB+Ex (n=79 randomised; n=66 analysed) intervention decreased HbA1c by an additional 14 mmol/mol (1.3%) at week 12 (-22 vs -7 mmol/mol [-2.0% vs -0.7%]; p<0.0001) and 8 mmol/mol (0.7%) at week 24 (-16 vs -8 mmol/mol [-1.4% vs -0.7%]; p=0.01). Concomitantly, 63% of medicated PB+Ex participants reduced their glucose-lowering medications (vs 24%; p=0.006), and 23% of PB+Ex participants with a baseline HbA1c <75 mmol/mol (<9%) achieved remission. Additionally, the PB+Ex intervention reduced weight (-2.7 kg; p<0.0001), C-reactive protein (-11 nmol/l; p=0.005) and cardiovascular medication use compared with SMC. At intermediate timepoints, it improved glucose, insulin, HOMA-IR, cholesterol, triglycerides and heart rate, but not at week 24. CONCLUSIONS/INTERPRETATION: A whole-food, plant-based lifestyle intervention was more effective for improving glycaemic control than SMC. It also reduced the need for diabetes and cardiovascular medications and induced diabetes remission in some participants. Therefore, it is an effective, evidence-based lifestyle option for individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03862963 FUNDING: This research was funded by the Department of the Army (W81XWH-05-1-0547). CJH received support through a National Institutes of Health Predoctoral T32 Obesity Fellowship (T32 HL105349).

Practical considerations for continuous glucose monitoring in elite athletes with type 1 diabetes mellitus: A narrative review.

Type 1 diabetes mellitus (T1DM) refers to a metabolic condition where a lack of insulin impairs the usual homeostatic mechanisms to control blood glucose levels. Historically, participation in competitive sport has posed a challenge for those with T1DM, where the dynamic changes in blood glucose during exercise can result in dangerously high (hyperglycaemia) or low blood glucoses (hypoglycaemia) levels. Over the last decade, research and technological development has enhanced the methods of monitoring and managing blood glucose levels, thus reducing the chances of experiencing hyper- or hypoglycaemia during exercise. The introduction of continuous glucose monitoring (CGM) systems means that glucose can be monitored conveniently, without the need for frequent fingerpick glucose checks. CGM devices include a fine sensor inserted under the skin, measuring levels of glucose in the interstitial fluid. Readings can be synchronized to a reader or mobile phone app as often as every 1-5 min. Use of CGM devices is associated with lower HbA1c and a reduction in hypoglycaemic events, promoting overall health and athletic performance. However, there are limitations to CGM, which must be considered when being used by an athlete with T1DM. These limitations can be addressed by individualized education plans, using protective equipment to prevent sensor dislodgement, as well as further research aiming to: (i) account for disparities between CGM and true blood glucose levels during vigorous exercise; (ii) investigate the effects of temperature and altitude on CGM accuracy, and (iii) explore of the sociological impact of CGM use amongst sportspeople without diabetes on those with T1DM.

Daily blood flow restriction does not preserve muscle mass and strength during 2 weeks of bed rest.

We measured the impact of blood flow restriction on muscle protein synthesis rates, muscle mass and strength during 2 weeks of strict bed rest. Twelve healthy, male adults (age: 24 ± 3 years, body mass index: 23.7 ± 3.1 kg/m2 ) were subjected to 14 days of strict bed rest with unilateral blood flow restriction performed three times daily in three 5 min cycles (200 mmHg). Participants consumed deuterium oxide and we collected blood and saliva samples throughout 2 weeks of bed rest. Before and immediately after bed rest, lean body mass (dual-energy X-ray absorptiometry scan) and thigh muscle volume (magnetic resonance imaging scan) were assessed in both the blood flow restricted (BFR) and control (CON) leg. Muscle biopsies were collected and unilateral muscle strength (one-repetition maximum; 1RM) was assessed for both legs before and after the bed rest period. Bed rest resulted in 1.8 ± 1.0 kg lean body mass loss (P < 0.001). Thigh muscle volume declined from 7.1 ± 1.1 to 6.7 ± 1.0 L in CON and from 7.0 ± 1.1 to 6.7 ± 1.0 L in BFR (P < 0.001), with no differences between treatments (P = 0.497). In addition, 1RM leg extension strength decreased from 60.2 ± 10.6 to 54.8 ± 10.9 kg in CON and from 59.2 ± 12.1 to 52.9 ± 12.0 kg in BFR (P = 0.014), with no differences between treatments (P = 0.594). Muscle protein synthesis rates during bed rest did not differ between the BFR and CON leg (1.11 ± 0.12 vs. 1.08 ± 0.13%/day, respectively; P = 0.302). Two weeks of bed rest substantially reduces skeletal muscle mass and strength. Blood flow restriction during bed rest does not modulate daily muscle protein synthesis rates and does not preserve muscle mass or strength. KEY POINTS: Bed rest, often necessary for recovery from illness or injury, leads to the loss of muscle mass and strength. It has been postulated that blood flow restriction may attenuate the loss of muscle mass and strength during bed rest. We investigated the effect of blood flow restriction on muscle protein synthesis rates, muscle mass and strength during 2 weeks of strict bed rest. Blood flow restriction applied during bed rest does not modulate daily muscle protein synthesis rates and does not preserve muscle mass or strength. Blood flow restriction is not effective in preventing muscle atrophy during a prolonged period of bed rest.

Potential molecular patterns for tuberculosis susceptibility in diabetic patients with poor glycaemic control: a pilot study.

Type 2 diabetes (DM2) is an increasingly prevalent disease that challenges tuberculosis (TB) control strategies worldwide. It is significant that DM2 patients with poor glycemic control (PDM2) are prone to developing tuberculosis. Furthermore, elucidating the molecular mechanisms that govern this susceptibility is imperative to address this problem. Therefore, a pilot transcriptomic study was performed. Human blood samples from healthy controls (CTRL, HbA1c < 6.5%), tuberculosis (TB), comorbidity TB-DM2, DM2 (HbA1c 6.5-8.9%), and PDM2 (HbA1c > 10%) groups (n = 4 each) were analyzed by differential expression using microarrays. We use a network strategy to identify potential molecular patterns linking the differentially expressed genes (DEGs) specific for TB-DM2 and PDM2 (p-value < 0.05, fold change > 2). We define OSM, PRKCD, and SOCS3 as key regulatory genes (KRGs) that modulate the immune system and related pathways. RT-qPCR assays confirmed upregulation of OSM, PRKCD, and SOCS3 genes (p < 0.05) in TB-DM2 patients (n = 18) compared to CTRL, DM2, PDM2, or TB groups (n = 17, 19, 15, and 9, respectively). Furthermore, OSM, PRKCD, and SOCS3 were associated with PDM2 susceptibility pathways toward TB-DM2 and formed a putative protein-protein interaction confirmed in STRING. Our results reveal potential molecular patterns where OSM, PRKCD, and SOCS3 are KRGs underlying the compromised immune response and susceptibility of patients with PDM2 to develop tuberculosis. Therefore, this work paved the way for fundamental research of new molecular targets in TB-DM2. Addressing their cellular implications, and the impact on the diagnosis, treatment, and clinical management of TB-DM2 could help improve the strategy to end tuberculosis for this vulnerable population.

Deterioration of Vestibular Motion Perception: A Risk Factor for Postural Instability and Falls in Elderly With Type 2 Diabetes.

AIMS: To assess whether impaired vestibular perception of self-motion is a risk factor for unsteadiness and falls in elderly patients with type 2 diabetes (T2D). MATERIALS AND METHODS: 113 participants (65-75 years old) with T2D underwent tests of roll and pitch discrimination, postural stability (Berg Balance Scale, Modified Romberg Test, and quantitative posturography), clinical examination and blood chemistry analyses. Falls 1-year after enrolment were self-reported. We performed cluster analysis based on the values of the vestibular motion thresholds, and logistic stepwise regression to compare the clinical-biochemical parameters between clusters. RESULTS: We identified two clusters (VC1 n = 65 and VC2 n = 48 participants). VC2 had significantly (p < 0.001) higher (poorer) thresholds than VC1: mean pitch threshold 1.62°/s (95% CI 1.48-1.78) in VC2 and 0.91°/s (95% CI 0.84-0.98) in VC1, mean roll threshold 1.34°/s (95% CI 1.21-1.48) in VC2 and 0.69°/s (95% CI 0.64-0.74) in VC1. Diabetes duration was significantly (p = 0.024) longer in VC2 (11.96 years, 95% CI 9.23-14.68) than in VC1 (8.37 years, 95% CI 6.85-9.88). Glycaemic control was significantly (p = 0.014) poorer in VC2 (mean HbA1c 6.74%, 95% CI 6.47-7.06) than in VC1 (mean HbA1c 6.34%, 95% CI 6.16-6.53). VC2 had a significantly higher incidence of postural instability than VC1, with a higher risk of failing the Modified Romberg Test C4 (RR = 1.57, χ2 = 5.33, p = 0.021), reporting falls during follow-up (RR = 11.48, χ2 = 9.40, p = 0.002), and greater postural sway in the medio-lateral direction (p < 0.025). CONCLUSIONS: Assessing vestibular motion thresholds identifies individuals with T2D at risk of postural instability due to altered motion perception and guides vestibular rehabilitation.

Care, control and complications of hospitalised patients with type 1 diabetes in China: A nationwide-based registry study.

AIMS: To evaluate the status quo of type 1 diabetes (T1D) management and characteristics of hospitalised patients with T1D in China through a nationwide multicentre registry study, the China Diabetes Type 1 Study (CD1S). MATERIALS AND METHODS: Clinical data from the electronic hospital records of all people with T1D were retrospectively collected in 13 tertiary hospitals across 7 regions of China from January 2016 to December 2021. Patients were defined as newly diagnosed who received a diagnosis of diabetes for less than 3 months. RESULTS: Among the 4993 people with T1D, the median age (range) at diagnosis was 23.0 (1.0-87.0) years and the median disease duration was 2.0 years. The median haemoglobin A1c (HbA1c) level was 10.7%. The prevalence of obesity, overweight, dyslipidemia, and hypertension were 2.5%, 10.8%, 62.5% and 25.9%, respectively. The incidence rate of diabetic ketoacidosis at disease onset was 41.1%, with the highest in children <10 years of age (50.6%). In patients not newly diagnosed, 60.7% were diagnosed with at least one chronic diabetic complication, with the highest proportion (45.3%) of diabetic peripheral neuropathy. Chronic complications were detected in 79.2% of people with T1D duration ≥10 years. CONCLUSIONS: In the most recent years, there were still unsatisfactory metabolic control and high incidence of diabetic ketoacidosis as well as chronic diabetic complications among inpatients with T1D in China. The ongoing CD1S prospective study aims to improve the quality of T1D management nationally.

Comparative Effects of Diabetes Self-Management Programs on Type 2 Diabetes Clinical Outcomes: A Systematic Review and Network Meta-Analysis.

AIMS: This systematic review and network meta-analysis compared the effects of various diabetes self-management programs: Diabetes Self-Management Education (DSME), Diabetes Self-Management Support (DSMS), and Diabetes Self-Management Education and Support (DSMES). METHODS: We searched four electronic databases for eligible articles up to March 1, 2023. Only randomized controlled trials investigating the effects of DSME, DSMS, or DSMES on glycated haemoglobin (HbA1c) level, fasting blood glucose (FBG), total cholesterol (TC), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in adults with type 2 diabetes were included. Cochrane Risk of Bias 2.0 tool was used to assess each study quality, and Confidence in Network Meta-Analysis was applied to evaluate the certainty of the evidence. Data were pooled with a random-effects model under a frequentist framework. RESULTS: A total of 108 studies encompassing 17,735 participants (mean age 57.4 years) were analysed. DSMES, compared with usual care, significantly reduced HbA1c level (mean difference = -0.61%, 95% confidence interval [CI] = -0.74 to -0.49; certainty of evidence = moderate), FBG (-23.33 mg/dL; -31.33 to -15.34; high), TC (-5.62 mg/dL; -8.69 to -2.55; high), SBP (-3.05 mmHg; -5.20 to -0.91; high), and DBP (-2.15 mmHg; -3.36 to -0.95; high). Compared with DSME, DSMES showed significantly greater improvements in HbA1c levels (-0.23%; -0.40 to -0.07; high) and DBP (-1.82 mmHg; -3.47 to -0.17; high). DSMES was ranked as the top treatment for improving diabetes clinical outcomes (0.82-0.97) in people with type 2 diabetes. CONCLUSIONS: DSMES, in people with type 2 diabetes, yields the greatest improvement in the key clinical outcomes of HbA1c, fasting blood glucose, and blood pressure levels. Healthcare providers should incorporate the DSMES approach into their daily care routines. Approximately 30% of the studies reviewed raised some concerns about their quality, underscoring the need for high-quality studies in this area.

The use of dietary supplements, and the association between supplemental vitamin D and glycaemic control in adult individuals with type 1 diabetes.

AIMS: To assess the dietary supplement use in adult individuals with type 1 diabetes, and to study the association between vitamin D supplementation and glycaemic control in an observational cross-sectional study. METHODS: The study subjects were participants of the Finnish Diabetic Nephropathy Study. Data were included from all individuals with type 1 diabetes with estimated glomerular filtration rate ≥60 mL/min/1.73 m2, who had completed a diet questionnaire. In the questionnaire, the participants reported dietary supplement use for the past 30 days. A thorough investigation with an assessment of the blood panel was conducted at the study visit. RESULTS: Data were available from 1181 individuals (43% men, mean ± SD age 45 ± 13 years). Altogether 62% of the sample reported supplement use; 56% reported some vitamin or mineral and 27% reported non-vitamin and non-mineral supplement use. Supplement use was more frequent among women and those supplementing had better overall health. In the study sample, of the vitamins and minerals, vitamin D (45%) and magnesium (31%), respectively, were the most frequently reported. In the multivariable models, vitamin D supplementation was associated with better glycaemic control. Starting from a daily dose of ≥30 µg, there was evidence of improving glycaemic control with higher doses of supplemental vitamin D (e.g., for 30 µg: B [Wald Confidence Internal], p-value, -2.76 [-5.03 to -0.49], 0.017). CONCLUSIONS: Supplement use was frequent in this sample of adult individuals with type 1 diabetes. Due to potential drug-supplement interactions, the attending physicians should be aware of their patients' supplement use. The causality between vitamin D supplementation and glycaemic control should be assessed in a randomized controlled trial.

Do-it-yourself continuous glucose monitoring in people aged 16 to 69 years with type 1 diabetes: A qualitative study.

AIMS: In many countries, real-time continuous glucose monitoring (rt-CGM) is not funded, and cost presents a barrier to access. A do-it-yourself conversion of intermittently scanned CGM (DIY-CGM) is a cheaper alternative. This qualitative study aimed to explore user experiences with DIY-CGM in people aged 16 to 69 years with type 1 diabetes (T1D). METHODS: Convenience sampling was used to recruit participants for semi-structured virtual interviews exploring experiences of DIY-CGM use. Participants were recruited after completing the intervention arm of a crossover randomised controlled trial that evaluated DIY-CGM versus intermittently scanned CGM (isCGM). Participants were previously naive to DIY-CGM and rt-CGM but not isCGM. The DIY-CGM intervention consisted of a Bluetooth bridge connected to isCGM, adding rt-CGM functionality over 8 weeks. Interviews were transcribed, then thematic analysis was performed. RESULTS: Interviews were with 12 people aged 16 to 65 years, with T1D: mean age ± SD 43 ± 14 years; baseline mean HbA1c ± SD 60 mmol/mol ± 9.9 (7.6 ± 0.9%) and time in range 59.8% ± 14.8%. Participants perceived that using DIY-CGM improved both glycaemic control and aspects of quality of life. Alarm and trend functionality allowed participants to perceive reduced glycaemic variability overnight and following meals. The addition of a smartwatch increased discrete access to glucose information. There was a high degree of trust in DIY-CGM. Challenges while using DIY-CGM included signal loss during vigorous exercise, alarm fatigue and short battery life. CONCLUSIONS: This study suggests that for users, DIY-CGM appears to be an acceptable alternative method of rt-CGM.

A register-based study describing time trends in risk factor control and serious hypoglycaemia together with the effects of starting continuous glucose monitoring in people with type 1 diabetes in Norway.

AIMS: To describe trends in risk factor control and serious hypoglycaemia in people with type 1 diabetes and to assess the effect of starting continuous glucose monitoring (CGM) in the real-world setting. METHODS: Two cross-sectional surveys including 5746 individuals in 2012 and 18,984 individuals in 2020 based on data recorded in the Norwegian Diabetes Register for Adults (NDR-A) and an analysis of a longitudinal cohort of 2057 individuals where data on CGM and HbA1c were available in the NDR-A in 2012 and 2020. RESULTS: In the cross-sectional surveys mean HbA1c decreased from 66 mmol/mol (99% CI 65, 66) (8.2%) in 2012 to 61 mmol/mol (99% CI 61, 61) (7.7%) in 2020 (p < 0.0001). The proportion reporting serious hypoglycaemia decreased from 16.9 to 6.2% in 2020 (p < 0.0001). Mean LDL-cholesterol decreased from 2.80 (99% CI 2.78, 2.83) to 2.63 (99% CI 2.61, 2.65) mmol/l in 2020 (p < 0.0001). Mean blood pressure increased slightly. In the CGM cohort, we found a 3 mmol/mol (0.3%) greater improvement in mean HbA1c and a greater reduction in serious hypoglycaemia (-12.3% vs. -6.2%) among individuals that had started using CGM between 2013 and 2020 when compared with individuals that had not started using CGM. CONCLUSIONS: Between 2012 and 2020, we found marked improvements in glycaemic control and a considerable decrease in the proportion of individuals reporting serious hypoglycaemia. The proportion of individuals using CGM increased substantially and individuals that had started using CGM by 2020 showed greater improvement in glycaemic control and less serious hypoglycaemia.

Diabetes duration, perceived comfort with self-management and glycaemic control in adolescents with type 1 diabetes: A cross-sectional study.

AIMS: Evidence is lacking on whether diabetes duration is associated with type 1 diabetes (T1D) self-management during late adolescence before transfer from paediatric to adult care. We examined associations of diabetes duration with dimensions of perceived comfort with diabetes self-management (self-efficacy, transition readiness, diabetes distress) and glycaemic control in late adolescence. METHODS: Using a cross-sectional design, we conducted a secondary analysis of baseline data of adolescents (ages 16-17 years) with T1D followed at paediatric diabetes academic hospitals in Montreal and enrolled in the Group Education Trial to Improve Transition (GET-IT-T1D). Participants completed validated questionnaires on self-efficacy (Self-Efficacy for Diabetes Self-Management Measure [SEDM], score 1 to 10), diabetes distress and transition readiness, as well as a haemoglobin (HbA1c) capillary blood test. Our primary outcome was self-efficacy. We examined associations of diabetes duration with self-efficacy, diabetes distress, transition readiness and HbA1c using linear and logistic regression models adjusted for sex, socioeconomic status, insulin pump use, glucose sensor use and psychiatric comorbidity. RESULTS: Of 203 adolescents with T1D, mean diabetes duration (SD) was 7.57 (4.44) years. Mean SEDM score was 6.83 (SD 1.62). Diabetes duration was not associated with self-efficacy, diabetes distress or transition readiness. Each additional year of diabetes duration was associated with 0.11% (95% CI, 0.05 to 0.16) higher HbA1c. CONCLUSIONS: Although diabetes duration is not associated with dimensions of perceived comfort with diabetes self-management, adolescents with longer diabetes duration are at risk for higher HbA1c and may need additional support to improve glycaemic control before transition to adult care.

Myths and methodologies: Assessing glycaemic control and associated regulatory mechanisms in human physiology research.

Accurate measurements of glycaemic control and the underpinning regulatory mechanisms are vital in human physiology research. Glycaemic control is the maintenance of blood glucose concentrations within optimal levels and is governed by physiological variables including insulin sensitivity, glucose tolerance and ß-cell function. These can be measured with a plethora of methods, all with their own benefits and limitations. Deciding on the best method to use is challenging and depends on the specific research question(s). This review therefore discusses the theory and procedure, validity and reliability and any special considerations of a range common methods used to measure glycaemic control, insulin sensitivity, glucose tolerance and ß-cell function. Methods reviewed include glycosylated haemoglobin, continuous glucose monitors, the oral glucose tolerance test, mixed meal tolerance test, hyperinsulinaemic euglycaemic clamp, hyperglycaemic clamp, intravenous glucose tolerance test and indices derived from both fasting concentrations and the oral glucose tolerance test. This review aims to help direct understanding, assessment and decisions regarding which method to use based on specific physiology-related research questions.

Strategic exploration of whole grain cereals in modulating the glycaemic response.

In the current context, diabetes presents itself as a widespread and complex global health issue. This study explores the significant influence of food microstructure and food matrix components interaction (protein, lipid, polyphenols, etc.) on the starch digestibility and the glycaemic response of post-prandial glycemia, focusing on the potential effectiveness of incorporating bioactive components from whole grain cereals into dietary strategies for the management and potential prevention of diabetes. This study aims to integrate the regulation of postprandial glycaemic homeostasis, including the complexities of starch digestion, the significant potential of bioactive whole grain components and the impact of food processing, to develop a comprehensive framework that combines these elements into a strategic approach to diabetes nutrition. The convergence of these nutritional strategies is analyzed in the context of various prevalent dietary patterns, with the objective of creating an accessible approach to mitigate and prevent diabetes. The objective remains to coalesce these nutritional paradigms into a coherent strategy that not only addresses the current public health crisis but also threads a preventative approach to mitigate future prevalence and impact.

Real-world evaluation of the effects of tirzepatide in patients with type 2 diabetes mellitus.

AIMS: Tirzepatide is a first-in-class combination glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and glucagon-like peptide 1 receptor agonist (GLP1-RA) approved for treatment of adults with type 2 diabetes mellitus (T2DM) and chronic weight management. The aim of this analysis was to assess the real-world efficacy of tirzepatide in patients with T2DM. METHODS: This retrospective observational study evaluated patients with T2DM from a large urban academic medical centre who received at least 3 months of continuous tirzepatide treatment. The primary outcome was change in A1C from following tirzepatide treatment. Secondary outcomes included change in body weight and body mass index (BMI) after tirzepatide was initiated. RESULTS: A total of 1896 patient charts were reviewed, and 612 patients were evaluated for the primary outcome. Over a median time period of 10.4 months, treatment with tirzepatide resulted in a mean A1C reduction of 1.02 ± 1.48% (p < 0.001). A total of 570 patients were evaluated for the secondary outcomes. Tirzepatide was associated with a mean reduction in body weight of 7.3 ± 9.3 kg (p < 0.001) and a mean reduction in BMI of 2.5 kg/m2. Greater A1C lowering and weight loss was observed in patients without prior GLP1-RA treatment compared to those switched to tirzepatide from GLP1-RA. CONCLUSIONS: In a real-world population of US patients with T2DM, tirzepatide was associated with clinically and statistically significant reductions in A1C and body weight. Greater reductions in both A1C and body weight were observed among patients who were GLP1-RA naïve compared to patients switched from GLP1-RA to tirzepatide.