Future Type 2 Diabetes Mellitus Research Articles

Independent association of metabolic syndrome severity score and risk of diabetes: findings from 18 years of follow-up in the Tehran Lipid and Glucose Study

ObjectivesThis study aimed to investigate the association between age-specific and sex-specific continuous metabolic syndrome severity score (cMetS-S) and the risk of developing type 2 diabetes mellitus (T2DM). Additionally, the study...

Relationship between indices of insulin resistance and incident type 2 diabetes mellitus in Chinese adults.

Insulin resistance (IR) is a pivotal pathogenesis characteristic of type 2 diabetes mellitus (T2DM). The current study aimed to explore the association between triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-c), triglyceride-glucose (TyG), and triglyceride glucose-body mass index (TyG-BMI), and T2DM incidence. A total of 116,855 Chinese adults aged over 20 without diabetes were included. Multivariate Cox regression analysis and restricted cubic spine were utilized to investigate the association between IR indicators and T2DM. The T2DM risk across different quartiles of IR parameters was compared using Kaplan-Meier curves. The receiver operating characteristic analysis was used to investigate the predictive potential of each IR indicator for future T2DM. A total of 2685 participants developed T2DM during a median follow-up of 2.98 years. The adjusted hazard ratios (HR) of incident T2DM were 1.177, 2.766, and 1.1018 for TG/HDL-c, TyG, and TyG-BMI, respectively. There were significant increasing trends of T2DM across the quartiles of TG/HDL-c, TyG, and TyG-BMI. The HRs of new-onset T2DM in the highest quartiles versus the lowest quartile of TG/HDL-c, TyG, and TyG-BMI were 3.298, 8.402, and 8.468. RCS revealed the nonlinear relationship between IR and T2DM risk. The correlations between IR and T2DM were more pronounced in subjects aged <40. TyG-BMI had the highest predictive value for incident T2DM (AUC = 0.774), with a cut-off value of 213.289. TG/HDL-c, TyG, and TyG-BMI index were all significantly positively associated with higher risk for future T2DM. Baseline TyG-BMI level had high predictive value for the identification of T2DM.

Challenges in Type 2 Diabetes Prevention among Senior High School Students: A Qualitative Study.

Schools, a place where students spend much more time than home, play an important role in preventing the nation's future generation from type 2 diabetes mellitus (T2DM). This study aimed to explore challenges in T2DM prevention among senior high school students. The study was conducted in Riau Province, Indonesia, from June to August 2023 using a qualitative content analysis. 31 respondents, determined by data saturation, were recruited using purposeful sampling. They were public senior high schools' principals, vice principals, school health services staff, school canteen tenants, students, parents, and primary health care personnel in six districts. Data were collected through semi-structured face-to-face interviews and document review. Graneheim and Lundman's content analysis method was used to analyze the data in Nvivo version 11 software. The Lincoln and Guba Qualitative research criteria for trustworthiness were used to ensure the rigor of the study. The main concepts obtained from the data were classified into three themes entitled, "Nonoptimal existing diabetes prevention programs in schools", "Inadequate knowledge of school community on T2DM", and "Inadequate policies to prevent diabetes in schools". An evidence-based, well-organized, and systematic school-based diabetes prevention program is fundamental to help overcome challenges and prevent future T2DM incidence. It requires relevant stakeholders' high level of awareness, strong collaborations with the school community, and effective school policies.

Additive Interaction Between Insulin Resistance, Chronic Low-Grade Inflammation and Vitamin D Deficiency on the Risk of Type 2 Diabetes Mellitus: A Cohort Study

Objectives The aim of this study was to explore, on an additive scale, the combined effect of the association between insulin resistance (IR), chronic low-grade inflammation (CLGI) and vitamin D deficiency (VDD) on the risk of type 2 Diabetes Mellitus (T2DM). Methods This is a cohort study, including 1484 non-diabetic subjects, followed for a period of four years. 25 hydroxy-vitamin D (25OHD), hypersensitive C-reactive protein (HsCRP) and triglyceride-glucose index were assessed. Based on VDD and CLGI, the population was subdivided into 4 exposure groups. Analysis was performed both in the case of IR and without IR. Cox proportional regression and additive interaction were applied to explore cumulative effects of exposure. Results At follow-up, 162 newly diagnosed cases of T2DM were identified. TYG index (RR = 4.0[2.8–5.6]), HsCRP (RR = 1.6 [1.4–1.7]) and 25OHD (RR = 0.96 [0.39–0.98]) were all significantly associated with the risk of T2DM (p < 0.01). The highest excess risk was recorded in patients cumulating simultaneously IR, CLGI and VDD (RR= 8.4[3.6–19.8], p < 0.0001). The additive interaction was significant, the excess risk linked to the interaction RERI = 10.5[1.43–19.7], the proportion attributable to the combined effect: AP = 0.61[0.37–0.85], and the interaction was synergistic: synergy index: 2.8[1.42–5.69]. Conclusion Baseline levels of TYG index, 25OHD and HsCRP are strongly predictive of future T2DM, and their joint effects are additive and synergistic. Interventional studies are therefore warranted in order to evaluate whether vitamin D supplementation, combined with appropriate anti-inflammatory therapies, is effective as a preventive strategy to reduce the risk of T2DM.

Association between napping and type 2 diabetes mellitus.

As the incidence of type 2 diabetes mellitus (T2DM) is increasing rapidly and its consequences are severe, effective intervention and prevention, including sleep-related interventions, are urgently needed. As a component of sleep architecture, naps, alone or in combination with nocturnal sleep, may influence the onset and progression of T2DM. Overall, napping is associated with an increased risk of T2DM in women, especially in postmenopausal White women. Our study showed that napping >30 minutes (min) increased the risk of T2DM by 8-21%. In addition, non-optimal nighttime sleep increases T2DM risk, and this effect combines with the effect of napping. For nondiabetic patients, napping >30 min could increase the risks of high HbA1c levels and impaired fasting glucose (IFG), which would increase the risk of developing T2DM later on. For diabetic patients, prolonged napping may further impair glycemic control and increase the risk of developing diabetic complications (e.g., diabetic nephropathy) in the distant future. The following three mechanisms are suggested as interpretations for the association between napping and T2DM. First, napping >30 min increases the levels of important inflammatory factors, including interleukin 6 and C-reactive protein, elevating the risks of inflammation, associated adiposity and T2DM. Second, the interaction between postmenopausal hormonal changes and napping further increases insulin resistance. Third, prolonged napping may also affect melatonin secretion by interfering with nighttime sleep, leading to circadian rhythm disruption and further increasing the risk of T2DM. This review summarizes the existing evidence on the effect of napping on T2DM and provides detailed information for future T2DM intervention and prevention strategies that address napping.

Fetal loss and long-term maternal morbidity and mortality: A systematic review and meta-analysis.

Evidence suggests common pathways between pregnancy losses and subsequent long-term maternal morbidity, rendering pregnancy complications an early chronic disease marker. There is a plethora of studies exploring associations between miscarriage and stillbirth with long-term adverse maternal health; however, these data are inconclusive. We systematically searched MEDLINE, EMBASE, AMED, BNI, CINAHL, and the Cochrane Library with relevant keywords and MeSH terms from inception to June 2023 (no language restrictions). We included studies exploring associations between stillbirth or miscarriage and incidence of cardiovascular, malignancy, mental health, other morbidities, and all-cause mortality in women without previous pregnancy loss. Studies reporting short-term morbidity (within a year of loss), case reports, letters, and animal studies were excluded. Study selection and data extraction were performed by 2 independent reviewers. Risk of bias was assessed using the Newcastle Ottawa Scale (NOS) and publication bias with funnel plots. Subgroup analysis explored the effect of recurrent losses on adverse outcomes. Statistical analysis was performed using an inverse variance random effects model and results are reported as risk ratios (RRs) with 95% confidence intervals (CIs) and prediction intervals (PIs) by combining the most adjusted RR, odds ratios (ORs) and hazard ratios (HRs) under the rare outcome assumption. We included 56 observational studies, including 45 in meta-analysis. There were 1,119,815 women who experienced pregnancy loss of whom 951,258 had a miscarriage and 168,557 stillbirth, compared with 11,965,574 women without previous loss. Women with a history of stillbirth had a greater risk of ischaemic heart disease (IHD) RR 1.56, 95% CI [1.30, 1.88]; p < 0.001, 95% PI [0.49 to 5.15]), cerebrovascular (RR 1.71, 95% CI [1.44, 2.03], p < 0.001, 95% PI [1.92, 2.42]), and any circulatory/cardiovascular disease (RR 1.86, 95% CI [1.01, 3.45], p = 0.05, 95% PI [0.74, 4.10]) compared with women without pregnancy loss. There was no evidence of increased risk of cardiovascular disease (IHD: RR 1.11, 95% CI [0.98, 1.27], 95% PI [0.46, 2.76] or cerebrovascular: RR 1.01, 95% CI [0.85, 1.21]) in women experiencing a miscarriage. Only women with a previous stillbirth were more likely to develop type 2 diabetes mellitus (T2DM) (RR: 1.16, 95% CI [1.07 to 2.26]; p < 0.001, 95% PI [1.05, 1.35]). Women with a stillbirth history had an increased risk of developing renal morbidities (RR 1.97, 95% CI [1.51, 2.57], p < 0.001, 95% [1.06, 4.72]) compared with controls. Women with a history of stillbirth had lower risk of breast cancer (RR: 0.80, 95% CI [0.67, 0.96], p-0.02, 95% PI [0.72, 0.93]). There was no evidence of altered risk of other malignancies in women experiencing pregnancy loss compared to controls. There was no evidence of long-term mental illness risk in women with previous pregnancy losses (stillbirth: RR 1.90, 95% CI [0.93, 3.88], 95% PI [0.34, 9.51], miscarriage: RR 1.78, 95% CI [0.88, 3.63], 95% PI [1.13, 4.16]). The main limitations include the potential for confounding due to use of aggregated data with variable degrees of adjustment. Our results suggest that women with a history of stillbirth have a greater risk of future cardiovascular disease, T2DM, and renal morbidities. Women experiencing miscarriages, single or multiple, do not seem to have an altered risk.

Metabolic fingerprinting on retinal pigment epithelium thickness for individualized risk stratification of type 2 diabetes mellitus

The retina is an important target organ of diabetes mellitus, with increasing evidence from patients and animal models suggesting that retinal pigment epithelium (RPE) may serve as an early marker for diabetes-related damages. However, their longitudinal relationship and the biological underpinnings remain less well understood. Here, we demonstrate that reduced in vivo measurements of RPE thickness (RPET) represents a significant risk factor for future type 2 diabetes mellitus (T2DM) and its microvascular phenotypes. After performing systematic analyses of circulating plasma metabolites using two complementary approaches, we identify a wide range of RPET metabolic fingerprints that are independently associated with reduced RPET. These fingerprints hold their potential to improve predictability and clinical utility for stratifying future T2DM and related microvascular phenotypes beyond traditional clinical indicators, providing insights into the promising role of retinas as a window to systemic health.

Prolactin does not seem to mediate the improvement on insulin resistance markers and blood glucose levels related to breastfeeding.

The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. Strategies to decrease this risk should be strongly encouraged. Lactation has been associated, for the mother, with reduction in future T2DM risk in several studies. The mechanisms behind this phenomenon, however, are poorly understood. The aims of this study were, first, to compare blood glucose levels and markers of insulin resistance (MIR) in early postpartum women with overweight/obesity according to their breastfeeding status and, second, to evaluate whether prolactin (PRL) levels could mediate improvements in these parameters. The prospective study followed 95 women older than 18 years from early pregnancy for up to 60 to 180 days postpartum. All participants had a BMI > 25 kg/m2 and a singleton pregnancy. At each visit, questionnaires and clinical and biochemical evaluations were performed. Participants were divided into two groups according to the breastfeeding status as "yes" for exclusive or predominant breastfeeding, and "no" for not breastfeeding. Breastfeeding women (n = 44) had significantly higher PRL levels [47.8 (29.6-88.2) vs. 20.0 (12.0-33.8), p< 0.001]. They also had significantly lower fasting blood glucose levels [89.0 (8.0) vs. 93.9 (12.6) mg/dl, p = 0.04], triglycerides (TG) [92.2 (37.9) vs. 122.4 (64.4) mg/dl, p = 0.01], TG/HDL ratio [1.8 (0.8) vs. 2.4 (1.6) mg/dl, p = 0.02], TyG index [8.24 (0.4) vs. 8.52 (0.53), p = 0.005], fasting serum insulin [8.9 (6.3-11.6) vs. 11.4 (7.7-17.0), p = 0.048], and HOMA-IR [2.0 (1.3-2.7) vs. 2.6 (1.6-3.9), p = 0.025] in the postpartum period compared to the non-breastfeeding group. Groups were homogeneous in relation to prevalence of GDM, pre-gestational BMI, as well as daily caloric intake, physical activity, and weight loss at postpartum. Linear regression analysis with adjustments for confounders showed a statistically significant association of breastfeeding with fasting blood glucose [-6.37 (-10.91 to -1.83), p = 0.006], HOMA-IR [-0.27 (-0.51 to -0.04), p = 0.024], TyG index [-0.04 (-0.06 to -0.02), p = 0.001], and TG/HDL ratio [-0.25 (-0.48 to -0.01), p = 0.038]. Mediation analysis showed that PRL did not mediate these effects. Sensitivity analyses considering different cutoffs for PRL levels also did not show modification effect in the mediation analyses. Breastfeeding was associated with improvement in glucose metabolism and MIR 60 to 180 days after birth in overweight and obese women, even when adjusted for confounders. PRL levels were not found to mediate the association between breastfeeding and improvement in MIR.

Prevalence of type 2 diabetes diagnoses in the perioperative and survivorship periods following surgical management of endometrial cancer: An opportunity for screening and intervention?

ObjectiveTo determine the prevalence of Type 2 diabetes mellitus (T2DM) diagnoses during the peri-operative and survivorship periods in patients following surgical management of endometrial cancer (EC). MethodsAn IRB-approved, retrospective single-institution cohort study was performed in patients who underwent surgical management of EC from 2014 to 2020. The perioperative period was defined as the 30 days before and after surgery. T2DM diagnoses occurring during survivorship were recorded. T2DM diagnoses were defined by a HgbA1c ≥6.5% or a random blood glucose ≥200 mg/dL. Sequelae of peri-operative T2DM and predictors of future T2DM were examined utilizing univariate analysis. ResultsOf 519 patients meeting inclusion criteria, 37 (7.1%) were diagnosed with T2DM in the perioperative period. Patients diagnosed with T2DM in the perioperative period had significantly higher BMI (p = 0.006) compared to no T2DM, but there were no significant differences in age (p = 0.20), ethnicity/race (p > 0.05) or ECOG score (p = 0.19). The rates of intraoperative complications between groups did not significantly differ, except for vascular complications (p = 0.005), and the incidence of any postoperative complication was higher in the perioperative T2DM group (p = 0.01). With a median follow-up of 29 months [range 11.6–49.0 months], an additional 18.3% (n = 88) of the cohort met diagnostic criteria for T2DM. BMI (p < 0.001), perioperative glucose (p < 0.001), and HgbA1c (p = 0.002) demonstrate risk for a T2DM diagnosis during survivorship. Conclusion(s)In this retrospective cohort of EC patients, 25.4% were diagnosed with T2DM, with the majority diagnosed in the survivorship period. Surgical management and subsequent surveillance of EC presents an opportunity to diagnose at-risk patients with T2DM.

Correlation of ChREBP Gene Methylation with Pathological Characteristics of Type 2 Diabetes Mellitus.

The objective of this study is to investigate the expression of the carbohydrate response element binding protein (ChREBP) gene in type 2 diabetes mellitus (T2DM) and its correlation with pathological features.For obtaining and exploring the pathological features in patients, sixty T2DM patients (the research group) and thirty healthy controls (the control group) presented to our hospital between January 2019 and June 2019 were selected as the research participants. After DNA extraction from peripheral blood mononuclear cells (PBMCs) and modification of target gene methylation with bisulfite, differences in methylation were verified, and the correlation of ChREBP methylation level with T2DM pathological features and single nucleotide polymorphism (SNP) typing was discussed.According to the prediction results of UCSC Genome Browser Home, there were two CpG islands in the promoter region of the ChREBP gene, and the first exon was selected for research. The ChREBP methylation rate was statistically higher in the research group versus the control group (P < 0.05). Age, FPG, TC, and TG were confirmed by the multiple linear regression analysis to be correlated with the ChREBP methylation rate (P < 0.05). Finally, there was no difference in ChREBP methylation level between CT- and CC-type patients at rs17145750 and rs1051921 loci (P > 0.05).Peripheral blood ChREBP methylation is elevated in T2DM patients and is closely related to age, blood glucose, and blood-lipid level, which is expected to be a new direction for future T2DM diagnosis and treatment.

Effects of the synbiotic composed of mangiferin and Lactobacillus reuteri 1-12 on type 2 diabetes mellitus rats.

Many synbiotics are effective for the prevention and treatment of type 2 diabetes mellitus (T2DM). In the treatment of T2DM, synbiotics often regulate the composition of intestinal flora, which autoinducer-2 (AI-2) may play an important role. Whether the changes of intestinal flora are related to AI-2 during synbiotics treatment of T2DM is a topic worth studying. We elucidated the effects of synbiotic composed of mangiferin and Lactobacillus reuteri 1-12 (SML) on T2DM rats. Male Spraque-Dawley rats were injected intraperitoneally with streptozotocin (STZ) and randomly grouped. After that, biochemical parameters, intestinal flora, fecal AI-2, and intestinal colonization of L. reuteri were detected. The results showed that SML had a hypoglycemic effect and mitigated the organ lesions of the liver and pancreas. Also, SML regulated biochemical parameters such as short chain fatty acids (SCFAs), lipopolysaccharides (LPS), intercellular cell adhesion molecule-1 (ICAM-1), and tumor necrosis factor-α (TNF-α). On the other hand, the proportion of probiotics, such as Lactobacillus acidophilus, L. reuteri, Bifidobacterium pseudolongum, Lactobacillus murinus, and Lactobacillus johnsonii, were elevated by the treatment of SML. In addition, SML promoted the colonization and proliferation of L. reuteri in the gut. Another thing to consider was that AI-2 was positively correlated with the total number of OTUs sequences and SML boosted AI-2 in the gut. Taken together, these results supported that SML may modulate intestinal flora through AI-2 to treat T2DM. This study provided a novel alternative strategy for the treatment of T2DM in future.

Growth trajectories in lipid profile and fasting blood sugar in prediabetic people over a 16- year follow-up and future risk of type2 diabetes mellitus: A latent growth modeling approach

ABSTRACT Introduction The current study aimed to investigate whether the pattern of changes in lipid profile and fasting blood sugar (FBS) can predict the future risk of type 2 diabetes mellitus (T2DM) incidence in prediabetic people. Methods In a prospective cohort study, 1228 prediabetic patients were followed from 2003 until 2019 and longitudinal data on lipid indices (CHOL: cholesterol; HDL: high-density lipoprotein; LDL: low-density lipoprotein; TG: triglyceride) and fasting blood sugar (FBS) were recorded. The latent class growth model (LCGM) was used to estimate growth trajectories and to determine distinct subgroups (latent class) with a similar trajectory for lipid profile and FBS over time. The incidence of T2DM in extracted latent classes was compared. Results Finally, 946 people with complete data were included in statistical analysis. Two latent classes were identified based on the change in FBS including high-risk and low-risk classes (class size: 5.2% vs. 94.8%) with T2DM incidence rates 100% and 35.9%, respectively (P < 0.001). Two distinct subgroups were identified based on changes in lipid profile. Latent classes with abnormal TG, CHOL, HDL, and LDL included 18.8%, 21.8%, 38.8%, and 24% of study participants, respectively. The incidence rates of T2DM and remaining prediabetic in abnormal TG latent class were 57.2% and 30.8%, and in abnormal HDL latent class were 41.5% and 31.7% were significantly different from normal latent classes (P < 0.001). While in the extracted latent classes based on CHOL and LDL the incidence rates were not statistically significant differences (P > 0.05). Conclusions We identified two subgroups with high and low risk of future T2DM based on the changes in FBS and lipid profile by applying LCGM. The incidence of T2DM in extracted latent classes was significantly different. LCGM is a reliable approach for predicting the risk of T2DM incidence based on trajectories of risk factors.

A Cross-Sectional Study on the Health Profile and Nutritional Status of Adults at Risk of Type 2 Diabetes Mellitus in Kuala Nerus, Terengganu

Surprisingly, 541 million people have impaired glucose tolerance (IGT) worldwide[1]. Prediabetes has been associated with an elevated risk of composite cardiovascular disease, coronary heart disease, stroke and all-cause mortality2 as well as an increased risk of type 2 diabetes mellitus (T2DM) than normal glycaemia[1]. In Malaysia, the undiagnosed diabetes prevalence has increased3. Health profile and nutritional status play a crucial role in prediabetes development. However, there is a scarcity of related health profile characteristics and nutritional status data in Kuala Nerus, Terengganu.&#x0D; &#x0D; This cross-sectional study aimed to identify the health profile and nutritional status of adults at risk of T2DM in Kuala Nerus, Terengganu. A total of 30 respondents at moderate and high risk of T2DM (Finnish Type 2 Diabetes Risk Assessment Tool (FINDRISC) score &gt; 4) aged 18 to 59 years old were recruited from Kuala Nerus using a convenience sampling method. Information on socio-demographic, anthropometric, fasting plasma glucose (FPG) level, clinical profile, FINDRISC score, dietary intake, and physical activity level were obtained. The data were analyzed using IBM SPSS system version 21.0 and Nutritionist ProTM software (Version 7.0.0, Axxya Systems). A descriptive statistic was used to present all outcomes. The continuous data were described as mean ± standard deviation (SD) whereas for categorical variables, the data were reported as the number of frequency and percentage.&#x0D; &#x0D; The respondents (mean age: 36.1 ± 8.7 years) were predominantly female (76.7%), Malay (96.7%), married (43.3%), with tertiary education (60.0%), and employed (83.3%) with a monthly income ranging below RM 1000. Half of the respondents were from the obese class I category. However, they had a normal FPG (5.6 ± 0.5 mmol/L) and were normotensive with a normal heart rate. Also, they had an average FINDRISC score of 6.3 ± 1.8. The respondents had excessive energy, fat, vitamin C, and selenium intake with insufficient dietary fibre, vitamin A, E, and K, calcium, and magnesium intake. Most of them (63.3%) were minimally active.&#x0D; The mean energy intake of this study was in accord with Malaysian Adult Nutrition Survey (MANS) 2003 (2097 kcal) and MANS 2014 (2123 kcal) after excluding under-reporters [3]. The National Health Morbidity Survey (NHMS) 2019 stated that 25.1% of Malaysian adults were physically inactive which was slightly higher than the current study finding. On the contrary, a higher percentage (80.0%) of the study respondents were physically active than 74.9% as reported by NHMS (2019) [4].&#x0D; &#x0D; It is vital to determine the health profile and nutritional status, which can provide important information for planning future cost-effective T2DM preventive strategies. This is because a strategic method of primary prevention for T2DM is by managing risk factors through lifestyle modification.

Transitioning to active-controlled trials to evaluate cardiovascular safety and efficacy of medications for type 2 diabetes

Cardiovascular (CV) outcome trials (CVOTs) of type 2 diabetes mellitus (T2DM) therapies have mostly used randomized comparison with placebo to demonstrate non-inferiority to establish that the investigational drug does not increase CV risk. Recently, several glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium glucose cotransporter 2 inhibitors (SGLT-2i) demonstrated reduced CV risk. Consequently, future T2DM therapy trials could face new ethical and clinical challenges if CVOTs continue with the traditional, placebo-controlled design. To address this challenge, here we review the methodologic considerations in transitioning to active-controlled CVOTs and describe the statistical design of a CVOT to assess non-inferiority versus an active comparator and if non-inferiority is proven, using novel methods to assess for superiority versus an imputed placebo. Specifically, as an example of such methodology, we introduce the statistical considerations used for the design of the “Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events (MACE) in Patients with Type 2 Diabetes” trial (SURPASS CVOT). It is the first active-controlled CVOT assessing antihyperglycemic therapy in patients with T2DM designed to demonstrate CV efficacy of the investigational drug, tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA, by establishing non-inferiority to an active comparator with proven CV efficacy, dulaglutide. To determine the efficacy margin for the hazard ratio, tirzepatide versus dulaglutide, for the composite CV outcome of death, myocardial infarction, or stroke (MACE-3), which is required to claim superiority versus an imputed placebo, the lower bound of efficacy of dulaglutide compared with placebo was estimated using a hierarchical Bayesian meta-analysis of placebo-controlled CVOTs of GLP-1 RAs. SURPASS CVOT was designed so that when the observed upper bound of the 95% confidence interval of the hazard ratio is less than the lower bound of efficacy of dulaglutide, it demonstrates non-inferiority to dulaglutide by preserving at least 50% of the CV benefit of dulaglutide as well as statistical superiority of tirzepatide to a theoretical placebo (imputed placebo analysis). The presented methods adding imputed placebo comparison for efficacy assessment may serve as a model for the statistical design of future active-controlled CVOTs.

The prognostic value of the oral glucose tolerance test for future type-2 diabetes in nulliparous pregnant women testing negative for gestational diabetes

AimTo determine the prognostic value of the antepartum 75g-oral glucose tolerance test (OGTT) for future type 2 diabetes mellitus (T2DM) in nulliparous pregnant women who tested negative for GDM. MethodsA population-based retrospective cohort study of nulliparous pregnant women who underwent testing for GDM using a 75g-OGTT in Ontario, Canada (2007-2017). The overwhelming majority of women in Ontario undergo screening using the preferred 2-step approach where the 75g-OGTT is performed following an abnormal non-fasting 1 h 50g-glucose challenge test. The relationship between the 75g-OGTT results in women who tested negative for GDM (defined as normal glucose at fasting, 1 and 2 h post 75g-glucose load) and future T2DM (as recorded in the Ontario Diabetes Database by the end date of follow up period) was explored. FindingsOf the 162,622 women who underwent 75g-OGTT during the study period, there were 41,507 (75.0%) who met the study criteria. In women without GDM, the adjusted hazard ratios (aHR) for T2DM were–At fasting 2.82 (95%-CI 2.18-3.64), at 1 h 1.26 (1.15-1.37), at 2 h 1.14 (1.04-1.25) for a 1 mmol/L increase in glucose. A model that combined all 3 OGTT values and clinical characteristics could detect 43% (42.6%-43.4%) of those who developed T2DM at 5-years post the index pregnancy for a false-positive rate of 20%. InterpretationThe results of the antepartum OGTT can be used to refine the future risk of T2DM even in nulliparous pregnant women who tested negative for GDM.

Consumption of Different Egg-Based Diets Minimally, yet Differentially, Impacts Markers Insulin Resistance in Young Healthy Adults

ObjectivesPrevious epidemiological studies have reported conflicting associations between egg consumption and type 2 diabetes mellitus (T2DM) risk. However, many observational, survey-based studies do not fully characterize intake of additional egg-based foods or clearly differentiate between type of egg consumed. Thus, we investigated whether daily intake of whole eggs, egg whites, or an egg-free diet differentially altered markers of T2DM risk in young healthy adults. MethodsYoung, healthy men and women (18–35 y, BMI < 30 kg/m2 or <30% body fat for men and < 40% body fat for women, n = 26) participated in a randomized, crossover intervention trial where they followed an egg-free diet for 4 weeks, then were randomized to consume either 3 whole eggs or 3 egg whites per day for 4 weeks. Participants then followed a 4-week egg-free diet washout period, before switching to the alternative whole egg or egg white diet treatment. Additional egg-based foods were restricted. Fasting serum samples were collected at the end of each diet period to measure markers of T2DM risk. ResultsAverage fasting serum glucose was 90.7 mg/dL at baseline, and did not significantly change between the egg-free, egg white, or whole egg diet periods. Similarly, there were no changes in pro-inflammatory N-acetylglucosamine/galactosamine (GlycA), which is an independent predictor of insulin resistance (IR). Serum amino acids levels were further assessed, as elevated branched-chain amino acids and reduced glycine levels are predictors of prediabetes, IR, and future T2DM. Interestingly, isoleucine levels were increased following the egg white and whole egg diet as compared to the egg-free diet, whereas glycine levels were increased in by the whole egg diet only. Despite these differences, lipoprotein IR index (LP-IR) scores, which take into account NMR lipoprotein particle profiles, and diabetes risk index scores, which are calculated from LP-IR and branched-chain amino acid measures, did not change over the course of the intervention. ConclusionsOur findings indicate that eggs minimally impact IR markers in young healthy adults, with egg whites yielding more adverse changes than whole eggs. Funding SourcesThis study was funded by an Agriculture and Food Research Initiative Grant from the USDA National Institute of Food and Agriculture.

Characteristics of pregnancy with gestational diabetes mellitus and the consecutive pregnancy as predictors for future diabetes mellitus type 2

AimTo explore possible obstetrical history-related, modifiable risk factors of future type 2 diabetes mellitus (T2DM), with focus on characteristics of the index gestational diabetes mellitus (GDM) pregnancy and the consecutive pregnancy. MethodsThis retrospective, population-based, cohort study included 788 women with GDM, who had consecutive deliveries at Emek Medical Center during 1991–2012. Women with pre-existing diabetes were excluded. Factors associated with T2DM development were examined using stepwise multiple Cox regression model. ResultsOverall 178 women developed T2DM (23%). Multivariable analysis demonstrated that the most significant independent risk factors for T2DM development were birth weight ≥ 4000 g (HRadj1.7 95% CI [1.001–2.8]), fasting oral glucose tolerance test value (OGTT, HRadj1.03 95% CI [1.01–1.04], 1-hour post-OGTT glucose value (HRadj1.01 95% CI [1.006–1.02]), earlier gestational week in which GDM was diagnosed (HRadj 0.96 95% CI [0.93–0.99]), higher parity (HRadj 1.15 95% CI [1.06–1.25] and GDM recurrence in the consecutive delivery (HRadj2.4 95% CI [1.6–3.7]). Kaplan Meier survival curve of the time from the consecutive pregnancy until T2DM development showed a statistically significant effect of GDM recurrence and the risk for T2DM. Body mass index (BMI) gain between pregnancies and inter-pregnancy interval were not independent risk factors for T2DM. ConclusionsObstetric characteristics of women with GDM and particularly GDM recurrence are associated with increased risk for T2DM. Strategies to prevent those factors and especially GDM recurrence might reduce the risk of future T2DM.

Associations of oral hygiene with incident hypertension and type 2 diabetes mellitus: A population based cohort study in Southwest China.

Oral health has been previously reported to be related with cardiovascular diseases (CVD). This study aimed to evaluate whether oral hygiene could reduce the risk of incident hypertension and type 2 diabetes mellitus (T2DM) in a population‐based cohort. A total of 9280 people aged 18 years or above in Guizhou province were recruited from November 20th, 2010 to December 19th, 2012. Sociodemographic characteristics, lifestyles, anthropometric measurements, oral health status and care were collected by trained interviewers. The occurrences of hypertension and T2DM were ascertained until 2020. Cox proportional hazard models were used to evaluate the associations between oral hygiene and the occurrence of hypertension and T2DM, respectively. Compared with almost no tooth brushing, tooth brushing at least twice a day was associated with a 45% reduction (HR: .55; 95% CI: .42–.73) in hypertension events and reduced diabetes risk by 35% (HR: .65; 95% CI: .45–.94). For hypertension, those associations tended to be more pronounced in participants with Han ethic, or living in urban area, while those aged less than 60 or without baseline hypertension were more likely to have T2DM when they brush teeth less than twice a day. Frequent tooth brushing was associated with reduced risks of incident hypertension and T2DM. Tooth brushing at least twice a day may prevent future hypertension and T2DM events.

Microengineered Multi-Organoid System from hiPSCs to Recapitulate Human Liver-Islet Axis in Normal and Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is a systematic multi‐organ metabolic disease, which is characterized by the dynamic interplay among different organs. The increasing incidence of T2DM reflects an urgent need for the development of in vitro human‐relevant models for disease study and drug therapy. Here, a new microfluidic multi‐organoid system is developed that recapitulates the human liver‐pancreatic islet axis in normal and disease states. The system contains two compartmentalized regions connected by a microchannel network, enabling 3D co‐culture of human induced pluripotent stem cells (hiPSC)‐derived liver and islet organoids for up to 30 days under circulatory perfusion conditions. The co‐cultured liver and islet organoids exhibit favorable growth and improved tissue‐specific functions. Transcriptional analyses reveal the activation of metabolically relevant signaling pathways in the co‐cultured organoids. Notably, the co‐culture system facilitates sensitive glucose‐stimulated insulin secretion from islet organoids and increased glucose utilization in liver organoids by glucose tolerance tests. Both liver and islet organoids display mitochondrial dysfunction and decreased glucose transport capacity under high glucose conditions, which can be alleviated by metformin treatment. This novel multi‐organoid system can recapitulate human‐relevant liver‐islet axis under both physiological and pathological conditions, providing a unique platform for future T2DM research and drug development.

Associations of visit-to-visit variabilities and trajectories of serum lipids with the future probability of type 2 diabetes mellitus

BackgroundSerum lipid abnormalities are generally considered as a major risk factor for type 2 diabetes mellitus (T2DM). However, evidence for the effect of long-term serum lipid fluctuations on future T2DM probability remains limited.MethodsA total of 4475 nondiabetic participants who underwent annual health examinations between 2010 and 2013 were followed for the subsequent 5-year risk of T2DM. The Cox proportional hazards model was performed to evaluate the associations of visit-to-visit variabilities and trajectories of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) with T2DM probability.ResultsDuring the five-year follow-up, 223 newly developed T2DM cases were identified. Compared with the “Low” TG trajectory, “Moderate” and “Moderate-High” TG trajectories were significantly associated with T2DM incidence, with adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs) of 1.51 (1.12-2.03) and 2.55 (1.62-4.03), respectively. Additionally, participants in the third and fourth quartiles of TG/standard deviation (SD) were associated with increased T2DM probability when compared with those in the lowest quartile. After excluding individuals with prediabetes, participants with “Moderate-High” TG trajectory still had a 2.43-fold greater risk of T2DM compared with those with “Low” TG trajectory (95 % CI: 1.28-4.63). In addition, compared with participants in “Low” HDL-c trajectory, the future T2DM probability was significantly reduced in those with “Moderate” and “High” HDL-c trajectories, with HR (95 % CI) of 0.52 (0.37-0.72) and 0.38 (0.18-0.80), respectively. After excluding individuals with prediabetes, the “Moderate” HDL-c trajectory remained associated with decreased T2DM probability when compared with “Low” HDL-c trajectory (HR: 0.55, 95 % CI: 0.35-0.88). However, the incidence of T2DM was not associated with the long-term fluctuations of TC and LDL-c.ConclusionsLong-term visit-to-visit variability of TG, and the change trajectories of TG and HDL-c were significantly associated with future T2DM probability. Moreover, these associations were not affected after excluding individuals with prediabetes.