Quasi-experimental evaluation of a nationwide diabetes prevention programme.

Diabetes is a leading cause of morbidity, mortality and cost of illness1,2. Health behaviours, particularly those related to nutrition and physical activity, play a key role in the development of type 2 diabetes mellitus3. Whereas behaviour change programmes (also known as lifestyle interventions or similar) have been found efficacious in controlled clinical trials4,5, there remains controversy about whether targeting health behaviours at the individual level is an effective preventive strategy for type 2 diabetes mellitus6 and doubt among clinicians that lifestyle advice and counselling provided in the routine health system can achieve improvements in health7-9. Here we show that being referred to the largest behaviour change programme for prediabetes globally (the English Diabetes Prevention Programme) is effective in improving key cardiovascular risk factors, including glycated haemoglobin (HbA1c), excess body weight and serum lipid levels. We do so by using a regression discontinuity design10, which uses the eligibility threshold in HbA1c for referral to the behaviour change programme, in electronic health data from about one-fifth of all primary care practices in England. We confirm our main finding, the improvement of HbA1c, using two other quasi-experimental approaches: difference-in-differences analysis exploiting the phased roll-out of the programme and instrumental variable estimation exploiting regional variation in programme coverage. This analysis provides causal, rather than associational, evidence that lifestyle advice and counselling implemented at scale in a national health system can achieve important health improvements.

Association of prediabetes with clinical outcomes in patients with chronic coronary syndrome: a post hoc analysis of the ISCHEMIA and ISCHEMIA-CKD trials.

BACKGROUND: There is conflicting evidence whether prediabetes is associated with adverse clinical outcomes in patients with chronic coronary syndrome. We aimed to assess the effect of prediabetes in patients with chronic coronary syndrome on clinical outcomes. METHODS: This is a secondary analysis of data from the ISCHEMIA and ISCHEMIA-CKD trials, including patients with chronic coronary syndrome determined by coronary computed tomography angiography or exercise-stress testing. Participants were assigned to the normoglycemia group (HbA1c < 5.7% [< 39 mmol/mol]), prediabetes group (HbA1c 5.7-6.4% [40-47 mmol/mol]), or diabetes group (HbA1c ≥ 6.5% [≥ 48 mmol/mol]). The primary end point of this study was all-cause mortality. Secondary endpoints included major adverse cardiovascular events and composites thereof. RESULTS: Overall, the primary endpoint all-cause mortality occurred in 330 (8.4%) of 3910 patients over a median follow-up time of 3.1 years (IQR 2.1-4.1). The primary endpoint all-cause mortality occurred in 37 (5.2%) of 716 patients in the normoglycemia group, in 63 (6.9%) of 911 in the prediabetes group, and in 230 (10.1%) of 2283 in the diabetes group. In the covariate-adjusted Cox model analysis, the estimated adjusted HR (aHR) in the prediabetes group as compared with the normoglycemia group was 1.45 (95%CI, 0.95-2.20). The aHR in the diabetes group as compared with the normoglycemia group was 1.84 (95%CI, 1.29-2.65). Prediabetes, compared with normoglycemia, was associated with an increased risk of stroke (aHR, 3.44, 95%CI, 1.15-10.25). Subgroup analyses suggested an increased risk of all-cause death associated with prediabetes in males and patients under 65 years. CONCLUSIONS: In patients with chronic coronary syndrome, diabetes but not prediabetes was associated with significantly increased risk of all-cause death within a median follow-up period of 3.1 years. Trial Registration NCT01471522, BioLINCC ID 13936.

The association between the triglyceride-glucose index and the risk of cardiovascular disease in US population aged ≤ 65 years with prediabetes or diabetes: a population-based study.

BACKGROUND: The relationship between the triglyceride-glucose (TyG) index and the risk of cardiovascular disease (CVD) in the U.S. population under 65 years of age with diabetes or prediabetes is unknown. The purpose of this study was to investigate the relationship between baseline TyG index and CVD risk in U.S. patients under 65 years of age with diabetes or prediabetes. METHODS: We used data from the 2003-2018 National Health and Nutrition Examination Survey (NHANES). Multivariate regression analysis models were constructed to explore the relationship between baseline TyG index and CVD risk. Nonlinear correlations were explored using restricted cubic splines. Subgroup analysis and interaction tests were also conducted. RESULTS: The study enrolled a total of 4340 participants with diabetes or pre-diabetes, with a mean TyG index of 9.02 ± 0.02. The overall average prevalence of CVD was 10.38%. Participants in the higher TyG quartiles showed high rates of CVD (Quartile 1: 7.35%; Quartile 2: 10.04%; Quartile 3: 10.71%; Quartile 4: 13.65%). For CVD, a possible association between the TyG index and the risk of CVD was observed. Our findings suggested a linear association between the TyG index and the risk of CVD. The results revealed a U-shaped relationship between the TyG index and both the risk of CVD (P nonlinear = 0.02583) and CHF (P nonlinear = 0.0208) in individuals with diabetes. Subgroup analysis and the interaction term indicated that there was no significant difference among different stratifications. Our study also revealed a positive association between the TyG index and comorbid MetS in the U.S. population under 65 years of age with prediabetes or diabetes. CONCLUSIONS: A higher TyG index was linked to an increased likelihood of CVD in the U.S. population aged ≤ 65 years with prediabetes and diabetes. Besides, TyG index assessment will contribute to more convenient and effective screening of high-risk individuals in patients with MetS. Future studies should explore whether interventions targeting the TyG index may improve clinical outcomes in these patients.

Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus.

BACKGROUND: The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. METHOD: Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13). RESULTS: At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group. CONCLUSION: Weight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

Ingesting probiotic yogurt containing Lactiplantibacillus plantarum OLL2712 improves glycaemic control in adults with prediabetes in a randomized, double-blind, placebo-controlled trial.

AIM: The ingestion of Lactiplantibacillus plantarum OLL2712 (OLL2712) cells has been shown to improve glucose metabolism by suppressing chronic inflammation in murine models and clinical studies. This study aimed to clarify the effect of OLL2712 on glycaemic control in healthy adults with prediabetes. MATERIALS AND METHODS: The study was a randomized, double-blind, placebo-controlled, parallel-group design. Adult participants with prediabetes [n = 148, glycated haemoglobin (HbA1c) range: 5.6%-6.4%, age range: 20-64 years] were assigned randomly to placebo or OLL2712 groups (n = 74/group) and administered daily for 12 weeks either conventional yogurt or yogurt containing >5 × 109 heat-treated OLL2712 cells, respectively. In addition, the participants were followed for 8 weeks after the discontinuation of either yogurt. The primary outcome was the changes in HbA1c levels at weeks 12 and 16 by analysis of covariance. RESULTS: The levels of HbA1c and glycoalbumin decreased significantly in both groups at week 12 in comparison with those at week 0, but only in the OLL2712 group at week 16. HbA1c levels decreased significantly at weeks 12 and 16 in the OLL2712 group in comparison with the placebo group (p = .014 and p = .006, respectively). No significant inter- and intragroup differences in HbA1c levels were observed at week 20. CONCLUSIONS: The ingestion of OLL2712 prevents the deterioration of glycaemic control and maintains the HbA1c levels within the normal range in adults with prediabetes; yogurt probably exhibits similar effects, which may contribute to reducing the risk of developing type 2 diabetes.

Sex-specific associations between haemoglobin glycation index and the risk of cardiovascular and all-cause mortality in individuals with pre-diabetes and diabetes: A large prospective cohort study.

AIM: The aim of this study was to investigate the relationship between the haemoglobin glycation index (HGI), and cardiovascular disease (CVD) and all-cause mortality in adults with pre-diabetes and diabetes. METHODS: This study included 10 267 adults with pre-diabetes and diabetes from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. Sex-differentiated relationships between HGI and mortality were elucidated using multivariate Cox proportional hazards models, restricted cubic splines and a two-piecewise Cox proportional hazards model. RESULTS: During the median follow-up time of 103.5 months, a total of 535 CVD deaths and 1918 all-cause deaths were recorded. After multivariate adjustment, in males with pre-diabetes and diabetes, there was a U-shaped relationship between HGI and CVD mortality and all-cause mortality, with threshold points of -0.68 and -0.63, respectively. Before the threshold point, HGI was negatively associated with CVD mortality [hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.41, 0.89] and all-cause mortality (HR 0.56; 95% CI 0.43, 0.74), and after the threshold point, HGI was positively associated with CVD mortality (HR 1.46; 95% CI 1.23, 1.73) and all-cause mortality (HR 1.40; 95% CI 1.23, 1.59). In contrast, HGI had an L-shaped relationship with all-cause mortality and no significant association with CVD mortality in females. To the left of the threshold points, the risk of all-cause mortality decreased (HR 0.50; 95% CI 0.35, 0.71) progressively with increasing HGI. CONCLUSIONS: In the cohort study, HGI in pre-diabetic and diabetic populations was found to have a U-shaped association with CVD mortality and all-cause mortality in males and an L-shaped association with all-cause mortality only in females. Further prospective and mechanistic studies are warranted.

Effects of vitamin D and/or calcium intervention on sleep quality in individuals with prediabetes: a post hoc analysis of a randomized controlled trial.

PURPOSE: The aim of this study was to evaluate the effects of vitamin D and/or calcium supplementation on sleep quality in individuals with prediabetes. METHODS: A 24-week randomized controlled trial (RCT) was conducted in a 212 Chinese population with prediabetes. Participants were randomly assigned to four groups: vitamin D + calcium group (1600 IU/day + 500 mg/day, n = 53), vitamin D group (1600 IU/day, n = 54), calcium group (500 mg/day, n = 51), and control group (placebo, n = 54). The Pittsburgh Sleep Quality Index (PSQI) was used as the primary outcome to assess sleep quality. Questionnaires and fasting blood samples were collected at baseline and post-intervention for demographic assessment and correlation index analysis. RESULTS: After a 24-week intervention, a significant difference was observed in serum 25(OH)D concentration among the four groups (P < 0.05), and the total PSQI score in vitamin D + calcium group was lower compared to the preintervention levels. Subgroup analyses revealed improved sleep quality with calcium supplementation (P < 0.05) for specific groups, including women, individuals with a low baseline 25(OH)D level (< 30 ng/mL), and individuals in menopause. Moreover, correlation analysis revealed a negative correlation between the extent of change in sleep efficiency scores before and after the calcium intervention and the degree of change in insulin efficiency scores (r = - 0.264, P = 0.007), as well as the magnitude of change in islet beta cell function (r = - 0.304, P = 0.002). CONCLUSIONS: The combined intervention of vitamin D and calcium, as well as calcium interventions alone, exhibits substantial potential for improving sleep quality in individuals with prediabetes. CLINICAL TRIAL REGISTRATION: The trial was registered in August 2019 as ChiCTR190002487.

Role of secreted frizzled-related protein 4 in prediabetes and type 2 diabetes: a cross sectional study.

BACKGROUND: Type 2 diabetes (T2D) has become an epidemic. Delays in diagnosis and as a consequent late treatment has resulted in high prevalence of complications and mortality. Secreted frizzled-related protein 4 (SFRP4), has been recently identified as a potential early biomarker of T2D related to obesity, due to its association with low grade inflammation in adipose tissue and impaired glucose metabolism. We aimed to evaluate the role of SFRP4 in prediabetes and T2D in a Mexican population. METHODS: This was a cross-sectional study that included 80 subjects with T2D, 50 subjects with prediabetes and 50 healthy individuals. Fasting SFRP4 and insulin concentrations were measured by ELISA. Human serum IL-10, IL-6, IL-1ß and IL-8 levels were quantified by flow cytometry. Genotyping was performed by TaqMan® probes. RESULTS: Prediabetes and T2D patients had significantly higher SFRP4 levels than controls (P < 0.05). In turn, prediabetes subjects had higher SFRP4 concentrations than control subjects (P < 0.05). Additionally, the prediabetes and T2D groups had higher concentrations of proinflammatory molecules such as IL-6, IL-1ß and IL-8, and lower concentrations of IL-10, an anti-inflammatory cytokine, than controls (P < 0.001). The serum SFRP4 concentrations were positively correlated with parameters that are elevated in prediabetes and T2D states, such as, HbA1c and homeostasis model assessment insulin resistance (HOMA-IR), (r = 0.168 and 0.248, respectively, P < 0.05). Also, serum SFRP4 concentrations were positively correlated with concentrations of pro-inflammatory molecules (CRP, IL-6, IL-1ß and IL-8) and negatively correlated with the anti-inflammatory molecule IL-10, even after adjusting for body mass index and age (P < 0.001). The genetic variant rs4720265 was correlated with low HDL concentrations in T2D (P < 0.05). CONCLUSIONS: SFRP4 correlates positively with the stage of prediabetes, suggesting that it may be an early biomarker to predict the risk of developing diabetes in people with high serum concentrations of SFRP4, although further longitudinal studies are required.

Association of neutrophil-lymphocyte ratio with all-cause and cardiovascular mortality in US adults with diabetes and prediabetes: a prospective cohort study.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is a novel hematological parameter to assess systemic inflammation. Prior investigations have indicated that an increased NLR may serve as a potential marker for pathological states such as cancer and atherosclerosis. However, there exists a dearth of research investigating the correlation between NLR levels and mortality in individuals with diabetes and prediabetes. Consequently, this study aims to examine the connection between NLR and all-cause as well as cardiovascular mortality in the population of the United States (US) with hyperglycemia status. METHODS: Data were collected from a total of 20,270 eligible individuals enrolled for analysis, spanning ten cycles of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. The subjects were categorized into three groups based on tertiles of NLR levels. The association of NLR with both all-cause and cardiovascular mortality was evaluated using Kaplan-Meier curves and Cox proportional hazards regression models. Restricted cubic splines were used to visualize the nonlinear relationship between NLR levels and all-cause and cardiovascular mortality in subjects with diabetes after accounting for all relevant factors. RESULTS: Over a median follow-up period of 8.6 years, a total of 1909 subjects with diabetes died, with 671 deaths attributed to cardiovascular disease (CVD). And over a period of 8.46 years, 1974 subjects with prediabetes died, with 616 cases due to CVD. The multivariable-adjusted hazard ratios (HRs) comparing high to low tertile of NLR in diabetes subjects were found to be 1.37 (95% CI, 1.19-1.58) for all-cause mortality and 1.63 (95% CI, 1.29-2.05) for CVD mortality. And the correlation between high to low NLR tertile and heightened susceptibility to mortality from any cause (HR, 1.21; 95% CI, 1.03-1.43) and CVD mortality (HR, 1.49; 95% CI, 1.08-2.04) remained statistically significant (both p-values for trend < 0.05) in prediabetes subjects. The 10-year cumulative survival probability was determined to be 70.34%, 84.65% for all-cause events, and 86.21%, 94.54% for cardiovascular events in top NLR tertile of diabetes and prediabetes individuals, respectively. Furthermore, each incremental unit in the absolute value of NLR was associated with a 16%, 12% increase in all-cause mortality and a 25%, 24% increase in cardiovascular mortality among diabetes and prediabetes individuals, respectively. CONCLUSIONS: The findings of this prospective cohort study conducted in the US indicate a positive association of elevated NLR levels with heightened risks of overall and cardiovascular mortality among adults with diabetes and prediabetes. However, potential confounding factors for NLR and the challenge of monitoring NLR's fluctuations over time should be further focused.

MicroRNAs Associated with Metformin Treatment in the Diabetes Prevention Program.

The Diabetes Prevention Program (DPP) randomized controlled trial demonstrated that metformin treatment reduced progression to type 2 diabetes (T2D) by 31% compared to placebo in adults with prediabetes. Circulating micro-ribonucleic acids (miRs) are promising biomarkers of T2D risk, but little is known about their associations with metformin regimens for T2D risk reduction. We compared the change in 24 circulating miRs from baseline to 2 years in a subset from DPP metformin intervention (n = 50) and placebo (n = 50) groups using Wilcoxon signed rank tests. Spearman correlations were used to evaluate associations between miR change and baseline clinical characteristics. Multiple linear regression was used to adjust for covariates. The sample was 73% female, 17% Black, 13% Hispanic, and 50 ± 11 years. Participants were obese, normotensive, prediabetic, and dyslipidemic. Change in 12 miR levels from baseline to 2 years was significantly different in the metformin group compared with placebo after adjusting for multiple comparisons: six (let-7c-5p, miR-151a-3p, miR-17-5p, miR-20b-5p, miR-29b-3p, and miR-93-5p) were significantly upregulated and six (miR-130b-3p, miR-22-3p, miR-222-3p, miR-320a-3p, miR-320c, miR-92a-3p) were significantly downregulated in the metformin group. These miRs help to explain how metformin is linked to T2D risk reduction, which may lead to novel biomarkers, therapeutics, and precision health strategies.

Association of Glutathione Peroxidase 3 (GPx3) and miR-196a with Carbohydrate Metabolism Disorders in the Elderly.

The escalating prevalence of carbohydrate metabolism disorders (CMDs) prompts the need for early diagnosis and effective markers for their prediction. Hyperglycemia, the primary indicator of CMDs including prediabetes and type 2 diabetes mellitus (T2DM), leads to overproduction of reactive oxygen species (ROS) and oxidative stress (OxS). This condition, resulting from chronic hyperglycemia and insufficient antioxidant defense, causes damage to biomolecules, triggering diabetes complications. Additionally, aging itself can serve as a source of OxS due to the weakening of antioxidant defense mechanisms. Notably, previous research indicates that miR-196a, by downregulating glutathione peroxidase 3 (GPx3), contributes to insulin resistance (IR). Additionally, a GPx3 decrease is observed in overweight/obese and insulin-resistant individuals and in the elderly population. This study investigates plasma GPx3 levels and miR-196a expression as potential CMD risk indicators. We used ELISA to measure GPx3 and qRT-PCR for miR-196a expression, supplemented by multivariate linear regression and receiver operating characteristic (ROC) analysis. Our findings included a significant GPx3 reduction in the CMD patients (n = 126), especially in the T2DM patients (n = 51), and a decreasing trend in the prediabetes group (n = 37). miR-196a expression, although higher in the CMD and T2DM groups than in the controls, was not statistically significant, potentially due to the small sample size. In the individuals with CMD, GPx3 levels exhibited a negative correlation with the mass of adipose tissue, muscle, and total body water, while miR-196a positively correlated with fat mass. In the CMD group, the analysis revealed a weak negative correlation between glucose and GPx3 levels. ROC analysis indicated a 5.2-fold increased CMD risk with GPx3 below 419.501 ng/mL. Logistic regression suggested that each 100 ng/mL GPx3 increase corresponded to a roughly 20% lower CMD risk (OR = 0.998; 95% CI: 0.996-0.999; p = 0.031). These results support the potential of GPx3 as a biomarker for CMD, particularly in T2DM, and the lack of a significant decline in GPx3 levels in prediabetic individuals suggests that it may not serve reliably as an early indicator of CMDs, warranting further large-scale validation.

IGF-1 and IGFBP-1 as Possible Predictors of Response to Lifestyle Intervention-Results from Randomized Controlled Trials.

Lifestyle interventions can prevent type 2 diabetes (T2DM). However, some individuals do not experience anticipated improvements despite weight loss. Biomarkers to identify such individuals at early stages are lacking. Insulin-like growth factor 1 (IGF- 1) and Insulin-like growth factor binding protein 1(IGFBP-1) were shown to predict T2DM onset in prediabetes. We assessed whether these markers also predict the success of lifestyle interventions, thereby possibly guiding personalized strategies. We analyzed the fasting serum levels of IGF-1, IGFBP-1, and Insulin-like growth factor binding protein 2 (IGFBP-2) in relation to changes in metabolic and anthropometric parameters, including intrahepatic lipids (IHLs) and visceral adipose tissue (VAT) volume, measured by magnetic resonance imaging (MRI), in 345 participants with a high risk for prediabetes (54% female; aged 36-80 years). Participants were enrolled in three randomized dietary intervention trials and assessed both at baseline and one year post-intervention. Statistical analyses were performed using IBM SPSS Statistics (version 28), and significance was set at p < 0.05. Within the 1-year intervention, overall significant improvements were observed. Stratifying individuals by baseline IGF-1 and IGFBP-1 percentiles revealed significant differences: higher IGF-1 levels were associated with more favorable changes compared to lower levels, especially in VAT and IHL. Lower baseline IGFBP-1 levels were associated with greater improvements, especially in IHL and 2 h glucose. Higher bioactive IGF-1 levels might predict better metabolic outcomes following lifestyle interventions in prediabetes, potentially serving as biomarkers for personalized interventions.

Predictive performance of triglyceride glucose index (TyG index) to identify glucose status conversion: a 5-year longitudinal cohort study in Chinese pre-diabetes people.

OBJECTIVE: Triglyceride glucose index (TyG index) has been recommended as an alternative indicator of insulin resistance. However, the association between TyG and regression from prediabetes to normoglycemia remains to be elucidated. METHODS: This retrospective cohort study involved 25,248 subjects with prediabetes at baseline conducted from 2010 to 2016. A Cox proportional hazard regression model was designed to evaluate the role of TyG in identifying people at converting from prediabetes to normoglycemia. Cox proportional hazards regression with cubic spline functions and smooth curve fitting was used to dig out the nonlinear relationship between them. Detailed evaluations for TyG were also performed using sensitivity and subgroup analyse. RESULTS: Among the included prediabetes subjects (n = 25,248), the mean age was 49.27 ± 13.84 years old, and 16,701 (66.15%) were male. The mean TyG was 8.83 ± 0.60. The median follow-up time was 2.96 ± 0.90 years. 11,499 (45.54%) individuals had a final diagnosis of normoglycemia. After adjusting for covariates, TyG was negatively affecting the results of glucose status conversion in prediabetes people (HR 0.895, 95% CI 0.863, 0.928). There was a nonlinear connection between TyG and normoglycemia in prediabetes people, and the inflection point was 8.88. The effect sizes (HR) on the left and right sides of the inflection point were 0.99 (0.93, 1.05) and 0.79 (0.74, 0.85), respectively. Sensitivity analysis confirmed the robustness of these results. Subgroup analysis showed that TyG was more strongly associated with incident glucose status conversion in male, BMI ≥ 25. In contrast, there was a weaker relationship in those with female, BMI < 25. CONCLUSION: Based on sample of subjects evaluated between 2010 and 2016, TyG index appears to be a promising marker for predicting normoglycemic conversion among prediabetes people in China. This study demonstrates a negative and non-linear association between TyG and glucose status conversion from prediabetes to normoglycemia. TyG is strongly related to glucose status conversion when TyG is above 8.88. From a therapeutic point of view, it is meaningful to maintain TyG levels within the inflection point to 8.88.

Association of prediabetes with reduced brain volume in a general elderly Japanese population.

OBJECTIVES: Diabetes frequently results in cognitive impairment, but it is less clear if brain health is adversely affected during the prediabetic stage. Our aim is to identify possible changes in brain volume as measured by magnetic resonance imaging (MRI) in a large elderly population stratified according to level of "dysglycemia." METHODS: This is a cross-sectional study of 2144 participants (median age 69 years, 60.9% female) who underwent 3-T brain MRI. Participants were divided into 4 dysglycemia groups based on HbA1c levels (%): normal glucose metabolism (NGM) (< 5.7%), prediabetes (5.7 to < 6.5%), undiagnosed diabetes (6.5% or higher), and known diabetes (defined by self-report). RESULTS: Of the 2144 participants, 982 had NGM, 845 prediabetes, 61 undiagnosed diabetes, and 256 known diabetes. After adjustment for age, sex, education, body weight, cognitive status, smoking, drinking, and disease history, total gray matter volume was significantly lower among participants with prediabetes (0.41% lower, standardized ß = - 0.0021 [95% CI - 0.0039, - 0.00039], p = 0.016), undiagnosed diabetes (1.4% lower, standardized ß = - 0.0069 [95% CI - 0.012, - 0.002], p = 0.005), and known diabetes (1.1% lower, standardized ß = - 0.0055 [95% CI - 0.0081, - 0.0029], p < 0.001) compared to the NGM group. After adjustment, total white matter volume and hippocampal volume did not differ significantly between the NGM group and either the prediabetes group or the diabetes group. CONCLUSION: Sustained hyperglycemia may have deleterious effects on gray matter integrity even prior to the onset of clinical diabetes. KEY POINTS: • Sustained hyperglycemia has deleterious effects on gray matter integrity even prior to the onset of clinical diabetes.

One-week sorghum (Sorghum bicolor L.) grain consumption is insufficient to increase adiponectin levels in prediabetic adults.

Objective. Adiponectin is an internally produced bioactive compound with a protective role against the insulin resistance-related diseases. Finding an adiponectin modifier can play a beneficial role in preventing the progression of the diseases, particularly in the prediabetic patients, as a high-risk population. This study was undertaken to examine the effect of dietary sorghum grain for a week on the plasma adiponectin levels in prediabetic patients. Methods. The study involved 26 (13+13) participants in both control and intervention groups. The control group maintained their habitual diet of white rice, while the intervention group replaced their habitual diet of white rice with sorghum grain for seven consecutive days. In all participants, the adiponectin concentration was measured before and after the intervention period. Results. Most study subjects had central obesity and dyslipidemia. Adiponectin levels after the intervention period decreased from the baseline in the control and sorghum groups including in all BMI groups. The change of decreasing adiponectin level was greater in the control than the sorghum group and in line with greater BMI in the sorghum group, but statistically insignificant. No significant difference in adiponectin concentrations was found among BMI groups. Conclusion. Sorghum grain consumption for a week is insufficient to increase adiponectin levels in the prediabetic patients. Insulin resistance, central obesity, and dyslipidemia may be the confounding variables that alter the favorable effect of sorghum on adiponectin. Longer sorghum consumption or other interventions may be needed to increase the adiponectin levels in people under these conditions.

Diagnosis and Management of Prediabetes: A Review.

Importance: Prediabetes, an intermediate stage between normal glucose regulation and diabetes, affects 1 in 3 adults in the US and approximately 720 million individuals worldwide. Observations: Prediabetes is defined by a fasting glucose level of 100 to 125 mg/dL, a glucose level of 140 to 199 mg/dL measured 2 hours after a 75-g oral glucose load, or glycated hemoglobin level (HbA1C) of 5.7% to 6.4% or 6.0% to 6.4%. In the US, approximately 10% of people with prediabetes progress to having diabetes each year. A meta-analysis found that prediabetes at baseline was associated with increased mortality and increased cardiovascular event rates (excess absolute risk, 7.36 per 10 000 person-years for mortality and 8.75 per 10 000 person-years for cardiovascular disease during 6.6 years). Intensive lifestyle modification, consisting of calorie restriction, increased physical activity (≥150 min/wk), self-monitoring, and motivational support, decreased the incidence of diabetes by 6.2 cases per 100 person-years during a 3-year period. Metformin decreased the risk of diabetes among individuals with prediabetes by 3.2 cases per 100 person-years during 3 years. Metformin is most effective for women with prior gestational diabetes and for individuals younger than 60 years with body mass index of 35 or greater, fasting plasma glucose level of 110 mg/dL or higher, or HbA1c level of 6.0% or higher. Conclusions and Relevance: Prediabetes is associated with increased risk of diabetes, cardiovascular events, and mortality. First-line therapy for prediabetes is lifestyle modification that includes weight loss and exercise or metformin. Lifestyle modification is associated with a larger benefit than metformin.

Vitamin D Supplementation and Prevention of Type 2 Diabetes.

BACKGROUND: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).

Effects of an acute exercise bout in hypoxia on extracellular vesicle release in healthy and prediabetic subjects.

The purpose of this study is to investigate exosome-like vesicle (ELV) plasma concentrations and markers of multivesicular body (MVB) biogenesis in skeletal muscle in response to acute exercise. Seventeen healthy [body mass index (BMI): 23.5 ± 0.5 kg·m-2] and 15 prediabetic (BMI: 27.3 ± 1.2 kg·m-2) men were randomly assigned to two groups performing an acute cycling bout in normoxia or hypoxia ([Formula: see text] 14.0%). Venous blood samples were taken before (T0), during (T30), and after (T60) exercise, and biopsies from m. vastus lateralis were collected before and after exercise. Plasma ELVs were isolated by size exclusion chromatography, counted by nanoparticle tracking analysis (NTA), and characterized according to international standards, followed by expression analyses of canonical ELV markers in skeletal muscle. In the healthy normoxic group, the total number of particles in the plasma increased during exercise from T0 to T30 (+313%) followed by a decrease from T30 to T60 (-53%). In the same group, an increase in TSG101, CD81, and HSP60 protein expression was measured after exercise in plasma ELVs; however, in the prediabetic group, the total number of particles in the plasma was not affected by exercise. The mRNA content of TSG101, ALIX, and CD9 was upregulated in skeletal muscle after exercise in normoxia, whereas CD9 and CD81 were downregulated in hypoxia. ELV plasma abundance increased in response to acute aerobic exercise in healthy subjects in normoxia, but not in prediabetic subjects, nor in hypoxia. Skeletal muscle analyses suggested that this tissue did not likely play a major role of the exercise-induced increase in circulating ELVs.

Plasma apolipoprotein concentrations and incident diabetes in subjects with prediabetes.

BACKGROUND: The identification of circulating biomarkers associated with the risk of type 2 diabetes (T2D) is useful for improving the current prevention strategies in the most at-risk patients. Here, we aimed to investigate the association of plasma apolipoprotein concentrations in prediabetes subjects with the incidence of new-onset T2D during follow-up. METHODS: In the IT-DIAB prospective study, 307 participants with impaired fasting glucose levels (fasting plasma glucose [FPG]: 110-125 mg/dL) were followed yearly for 5 years. The onset of T2D was defined as a first FPG value ≥ 126 mg/dL during follow-up. Apolipoprotein (apo)A-I, A-II, A-IV, B100, C-I, C-II, C-III, C-IV, D, E, F, H, J, L1, M, and (a) plasma concentrations were determined by mass spectrometry. Correlations between apolipoproteins and metabolic parameters at baseline were assessed by Spearman's coefficients. Kaplan-Meier curves were drawn using a ternary approach based on terciles and incident T2D. The association between plasma apolipoproteins concentrations and the incidence of T2D was determined using Cox proportional-hazards models. RESULTS: During a median follow-up of 5-year, 115 participants (37.5%) developed T2D. After adjustment for age, sex, body mass index, FPG, HbA1c, and statin use, the plasma levels of apoC-I, apoC-II, apoC-III, apoE, apoF, apoH, apoJ, and apoL1 were positively associated with a high risk for T2D. After further adjustment for plasma triglycerides, only apoE (1 SD natural-log-transformed hazard ratio: 1.28 [95% confidence interval: 1.06; 1.54]; p = 0.010), apoF (1.22 [1.01; 1.48]; p = 0.037), apoJ (1.24 [1.03; 1.49]; p = 0.024), and apoL1 (1.26 [1.05; 1.52]; p = 0.014) remained significantly associated with the onset of T2D. Kaplan-Meier survival curves also showed that the lower third of plasma apoE levels (< 5.97 mg/dL) was significantly associated with a lower risk of conversion to T2D (log-rank test, p = 0.002) compared to the middle and upper thirds. CONCLUSIONS: The plasma apoE levels are positively associated with the risk of T2D in prediabetes subjects, independently of traditional risk factors. The possible associations of apoF, apoJ, and apoL1 with T2D risk also pave the way for further investigations. Trial registration This trial was registered at clinicaltrials.gov as NCT01218061 and NCT01432509.

Detecting dysglycaemia in compensated liver cirrhosis: Comparison of oral glucose tolerance test and glycated haemoglobin, with continuous glucose monitoring.

AIMS: Liver cirrhosis increases the risk of developing dysglycaemia (pre-diabetes and diabetes), thus people with cirrhosis should undergo regular screening for dysglycaemia. The utility of screening using the laboratory glycated haemoglobin (HbA1c ) test has been questioned in this setting. This study examines the relationship between different potential screening modalities: 75 g oral glucose tolerance test (OGTT) and HbA1c , using continuous glucose monitoring (CGM) as a comparator. METHODS: Participants ≥18 years with no known diabetes, were recruited from a gastroenterology cirrhosis surveillance register. Study measurements included a 75 g OGTT, laboratory HbA1c and two weeks of 'blinded' CGM (Freestyle Libre Pro). The possibility of intravascular haemolysis affecting HbA1c interpretation was also assessed. RESULTS: All 20 participants had compensated cirrhosis. OGTT tended to diagnose more dysglycaemia (N = 7) than did HbA1c (N = 4). Bland-Altman analysis showed laboratory and CGM-estimated HbA1c were broadly comparable, with a difference of 4mmol/mol (95% CI -3 to 12), or 0.4% (95% CI -0.3 to 1.1). Laboratory HbA1c tended to be higher than the CGM-estimated HbA1c , perhaps reflecting positive lifestyle changes in participants during their two weeks of wearing 'blinded' CGM (Hawthorne effect). In the population studied, there was no evidence that haemolysis affected interpretation of HbA1c results. CONCLUSIONS: In the setting of compensated cirrhosis, the OGTT and HbA1c remain standard screening test for diabetes, but multiple studies show the OGTT diagnoses more people with dysglycaemia than does the HbA1c . Blinded CGM in an ambulatory, real world setting provides additional insights into glycaemic excursions but cannot be used to diagnose dysglycaemia.