Maternal prediabetes as a risk factor of preeclampsia and placental dysfunction in pregnant female Sprague-Dawley rats.

BACKGROUND: Prediabetes (PD) is associated with intermediate hyperglycaemia, dyslipidaemia, reduced nitric oxide (NO) bioavailability and moderate hypertension. All these factors are risk factor for preeclampsia (PE). However, the effects of the PD on placental function have not been shown. Accordingly, this study sought to investigate a possible link between maternal PD and the risk of developing PE. METHODS: Pregnant female Sprague-Dawley rats (N = 18) were divided into normal, preeclamptic and prediabetic groups (n = 6 in each group) to study the effects of maternal PD on placenta function over the period of 19 days. Blood glucose and blood pressure were measured on gestational day (GND) 0, 9 and 18. Placental vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) mRNA expression were measured terminally. Data were analysed using ANOVA followed by the Tukey-Kramer post hoc test. Values of p < .05 were used to indicate statistical significance. RESULTS: Maternal PD and PE significantly increased blood glucose, decrease NO concentration and increase in MAP by comparison to the normal pregnant control group. Maternal PD significantly decreased VEGF, PlGF mRNA expression with a slight increase in sFlt-1 mRNA expression comparison to the normal pregnant control group. CONCLUSIONS: Maternal PD is associated with placental dysfunction due to impaired glucose handling, endothelial dysfunction and an imbalance in angiogenic and antiangiogenic factors. Therefore, maternal PD is a risk factor of PE.

People with prediabetes (PD) are at risk of developing type 2 diabetes. Studies have shown that PD can cause blood vessel problems in both men and women. However, there have not been any studies on prediabetic pregnant women, so we do not know much about the pregnancy problems they might face. Looking into new factors related to blood vessel growth and health in PD could help us understand how to diagnose and manage PD during pregnancy. This could reduce the risk of problems similar to pre-eclampsia. Research in this area will help mothers and their doctors be more aware of the complications PD can cause during pregnancy. This could lead to fewer health problems and deaths for both mothers and babies linked to type 2 diabetes.

MAFLD and glomerular hyperfiltration in subjects with normoglycemia, prediabetes and type 2 diabetes: A cross-sectional population study.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD, 2020 diagnostic criteria) and glomerular hyperfiltration share common risk factors, including obesity, insulin resistance, impaired glucose tolerance, diabetes, dyslipidemia, and hypertension. AIMS: To assess the prevalence of MAFLD and its association with glomerular hyperfiltration and age-related worsening of kidney function in subjects with normoglycemia, prediabetes and type 2 diabetes mellitus (T2DM). METHODS: We analysed data recorded during occupational health visits of 125,070 Spanish civil servants aged 18-65 years with a de-indexed glomerular filtration rate (GFR) estimated with the chronic-kidney-disease-epidemiological (CKD-EPI) equation (estimated glomerular filtration rate [eGFR]) ≥60 mL/min. Subjects were categorised according to fasting plasma glucose levels <100 mg/dL (normoglycemia), ≥100 and ≤ 125 mg/dL (prediabetes), or ≥126 mg/dL and/or antidiabetic treatment (T2DM). The association between MAFLD and glomerular hyperfiltration, defined as a de-indexed eGFR above the age- and gender-specific 95th percentile, was assessed by multivariable logistic regression. RESULTS: In the whole study group, MAFLD prevalence averaged 19.3%. The prevalence progressively increased from 14.7% to 33.2% and to 48.9% in subjects with normoglycemia, prediabetes and T2DM, respectively (p < 0.001 for trend). Adjusted odds ratio (95% CI) for the association between MAFLD and hyperfiltration was 9.06 (8.53-9.62) in the study group considered as a whole, and 8.60 (8.03-9.21), 9.52 (8.11-11.18) and 8.31 (6.70-10.30) in subjects with normoglycemia, prediabetes and T2DM considered separately. In stratified analyses, MAFLD amplified age-dependent eGFR decline in all groups (p < 0.001). CONCLUSIONS: MAFLD prevalence increases across the glycaemic spectrum. MAFLD is significantly associated with hyperfiltration and amplifies the age-related eGFR decline.

Patellar tendon biomechanical and morphologic properties and their relationship to serum clinical variables in persons with prediabetes and type 2 diabetes.

Tendon biomechanical properties and fibril organization are altered in patients with diabetes compared to healthy individuals, yet few biomarkers have been associated with in vivo tendon properties. We investigated the relationships between in vivo imaging-based tendon properties, serum variables, and patient characteristics across healthy controls (n = 14, age: 45 ± 5 years, body mass index [BMI]: 24 ± 1, hemoglobin A1c [HbA1c]: 5.3 ± 0.1%), prediabetes (n = 14, age: 54 ± 5 years, BMI: 29 ± 2; HbA1c: 5.7 ± 0.1), and type 2 diabetes (n = 13, age: 55 ± 3 years, BMI: 33 ± 2, HbA1c: 6.7 ± 0.3). We used ultrasound speckle-tracking and measurements from magnetic resonance imaging (MRI) to estimate the patellar tendon in vivo tangent modulus. Analysis of plasma c-peptide, interleukin-1ß (IL-1ß), IL-6, IL-8, tumor necrosis factor-α (TNF-α), adiponectin, leptin, insulin-like growth factor 1 (IGF-1), and C-reactive protein (CRP) was completed. We built regression models incorporating statistically significant covariates and indicators for the clinically defined groups. We found that tendon cross-sectional area normalized to body weight (BWN CSA) and modulus were lower in patients with type 2 diabetes than in healthy controls (p < 0.05). Our regression analysis revealed that a model that included BMI, leptin, high-density lipoprotein (HDL), low-density lipoprotein (LDL), age, and group explained ~70% of the variability in BWN CSA (R2 = 0.70, p < 0.001). For modulus, including the main effects LDL, groups, HbA1c, age, BMI, cholesterol, IGF-1, c-peptide, leptin, and IL-6, accounted for ~54% of the variability in modulus (R2 = 0.54, p < 0.05). While BWN CSA and modulus were lower in those with diabetes, group was a poor predicter of tendon properties when considering the selected covariates. These data highlight the multifactorial nature of tendon changes with diabetes and suggest that blood variables could be reliable predictors of tendon properties.

Blood-derived miRNA levels are not correlated with metabolic or anthropometric parameters in obese pre-diabetic subjects but with systemic inflammation.

As blood-derived miRNAs (c-miRNAs) are modulated by exercise and nutrition, we postulated that they might be used to monitor the effects of a lifestyle intervention (LI) to prevent diabetes development. To challenge this hypothesis, obese Asian Indian pre-diabetic patients were submitted to diet modifications and physical activity for 4 months (LI group) and compared to a control group which was given recommendations only. We have considered 2 periods of time to analyze the data, i.e.; a first one to study the response to the intervention (4 months), and a second one post-intervention (8 months). At basal, 4 months and 8 months post-intervention the levels of 17 c-miRNAs were quantified, selected either for their relevance to the pathology or because they are known to be modulated by physical activity or diet. Their variations were correlated with variations of 25 metabolic and anthropometric parameters and cytokines. As expected, fasting-glycaemia, insulin-sensitivity, levels of exercise- and obesity-induced cytokines were ameliorated after 4 months. In addition, the levels of 4 miRNAs (i.e.; miR-128-3p, miR-374a-5p, miR-221-3p, and miR-133a-3p) were changed only in the LI group and were correlated with metabolic improvement (insulin sensitivity, cytokine levels, waist circumference and systolic blood pressure). However, 8 months post-intervention almost all ameliorated metabolic parameters declined indicating that the volunteers did not continue the protocol on their own. Surprisingly, the LI positive effects on c-miRNA levels were still detected, and were even more pronounced 8 months post-intervention. In parallel, MCP-1, involved in tissue infiltration by immune cells, and Il-6, adiponectin and irisin, which have anti-inflammatory effects, continued to be significantly and positively modified, 8 months post-intervention. These data demonstrated for the first time, that c-miRNA correlations with metabolic parameters and insulin sensitivity are in fact only indirect and likely associated with the level systemic inflammation. More generally speaking, this important result explains the high variability between the previous studies designed to identify specific c-miRNAs associated with the severity of insulin-resistance. The results of all these studies should take into account the level of inflammation of the patients. In addition, this finding could also explain why, whatever the pathology considered (i.e.; cancers, diabetes, neurodegenerative disorders, inflammatory diseases) the same subset of miRNAs is always found altered in the blood of patients vs healthy subjects, as these pathologies are all associated with the development of inflammation.

Beta cell function, incretin hormones, and incretin effect in obese children and adolescents with prediabetes.

BACKGROUND: Defects of incretin hormones and incretin effect may be underlying mechanisms of abnormal glucose metabolism in youth. OBJECTIVE: To assess incretin hormone dynamics during an oral glucose tolerance test (OGTT) and incretin effect in obese children with prediabetes in comparison with those with normal glucose tolerance (NGT). METHODS: Overweight and obese children were enrolled and classified according to OGTT results as NGT and prediabetes. Insulin sensitivity, insulin secretion, incretin hormone concentrations during OGTT; and incretin effect derived from OGTT and intravenous glucose tolerance test were determined and compared between NGT and prediabetes groups. RESULTS: Sixty-three patients (43 NGT and 20 prediabetes) were enrolled. Their median (interquartile range) age was 12.5 (11.1, 13.8) years. Peak glucagon-like peptide-1 (GLP-1) was demonstrated at 30 min during OGTT and was higher in the prediabetes group (49.2 [35.6, 63.6] versus 36.5 [27.6, 44.2] pmol/L, p = 0.009). However, incremental areas under the curves (iAUCs) of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were not different between the two groups. There was no difference in incretin effect between NGT and prediabetes (NGT: 66.5% [60.2%, 77.5%] vs. prediabetes: 70.0% [61.5%, 75.0%], p = 0.645). Incretin effect had positive correlations with iAUCs of both GLP-1 and GIP (GLP-1: r = 0.40, p = 0.004 and GIP: r = 0.37, p = 0.009). CONCLUSIONS: Comparing between obese children with prediabetes and NGT, there were no differences in overall incretin hormone changes during OGTT and incretin effect. Incretin effect was positively correlated with iAUCs of GLP-1 and GIP.

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.

Effects of volume-matched resistance training with different loads on glycemic control, inflammation, and body composition in prediabetic older adults.

The purpose of the investigation was to examine the influence of resistance training (RT) with equal volume and varying load on glycemic control, inflammation, and body composition in non-obese prediabetic older adults. Non-obese older adults with prediabetes were randomized into 2 groups, high-load (80% of 1RM) and low-load (40% of 1RM) RT (n = 12/group), both with the same training volume. Oral glucose tolerance test (OGTT) and blood samples were collected at baseline and again after 10 weeks of RT. Fasting blood glucose (103.8 vs. 99.9 mg/dL) and the area under the curve (AUC) of OGTT (0-30 min) decreased significantly in older adults with prediabetes after 10 weeks of volume-matched RT (p < 0.05). Serum levels of MCP-1 (138.7 vs. 98.5 pg/mL) and TNF-α (1.8 vs. 1.3 pg/mL) showed significant decrease after 10 weeks of high-load RT (p < 0.05). There were no changes in IL-10, IL-6, and CRP levels in both groups. Leptin showed significant decrease after 10 weeks of low-load RT (p < 0.05). Changes in fasting glucose and AUC of OGTT (0-120 min) were positively correlated with changes in MCP-1 and TNF-α (p < 0.05). Lean body mass (39.6 vs. 40.3 kg) increased significantly after 10 weeks of volume-matched RT (p < 0.05). Results indicate that equal-volume RT at different loads is beneficial to glycemic control and muscle growth, and high-load RT shows more prominent anti-inflammatory effects. Novelty: Short-term high-load resistance training can help older adults bring their blood sugar level back to normal. High-load resistance training attenuates aging-associated chronic inflammation.

Measures of Left Ventricular Diastolic Function and Cardiorespiratory Fitness According to Glucose Metabolism Status: The Maastricht Study.

Background This cross-sectional study evaluated associations between structural and functional measures of left ventricular diastolic function and cardiorespiratory fitness (CRF) in a well-characterized population-based cohort stratified according to glucose metabolism status. Methods and Results Six hundred seventy-two participants from The Maastricht Study (mean±SD age, 61±9 years; 17.4% prediabetes and 25.4% type 2 diabetes mellitus) underwent both echocardiography to determine left atrial volume index, left ventricular mass index, maximum tricuspid flow regurgitation, average e' and E/e' ratio; and submaximal cycle ergometer test to determine CRF as maximum power output per kilogram body mass. Associations were examined with linear regression adjusted for cardiovascular risk and lifestyle factors, and interaction terms. After adjustment, in normal glucose metabolism but not (pre)diabetes, higher left atrial volume index (per 1 mL/m2), left ventricular mass index (per 1 g/m2.7), maximum tricuspid regurgitation flow (per 1 m/s) were associated with higher CRF (maximum power output per kilogram body mass; ß in normal glucose metabolism 0.015 [0.008-0.023], Pinteraction (pre)diabetes <0.10; 0.007 [-0.001 to 0.015], Pinteraction type 2 diabetes mellitus <0.10; 0.129 [0.011-0.246], Pinteraction >0.10; for left atrial volume index, left ventricular mass index, maximum tricuspid regurgitation flow, respectively). Furthermore, after adjustment, in all individuals, higher average E/e' ratio (per unit), but not average e', was associated with lower CRF (normal glucose metabolism -0.044 [-0.071 to -0.016]), Pinteraction >0.10). Conclusions In this population-based study, structural and functional measures of left ventricular diastolic function were independently differentially associated with CRF over the strata of glucose metabolism status. This suggests that deteriorating left ventricular diastolic function, although of small effect, may contribute to the pathophysiological process of impaired CRF in the general population. Moreover, the differential effects in these structural measures may be the consequence of cardiac structural adaptation to effectively increase CRF in normal glucose metabolism, which is absent in (pre)diabetes.

The TOTUM-63 Supplement and High-Intensity Interval Training Combination Limits Weight Gain, Improves Glycemic Control, and Influences the Composition of Gut Mucosa-Associated Bacteria in Rats on a High Fat Diet.

Obesity and prediabetes are the two strongest risk factors of type 2 diabetes. It has been reported that TOTUM-63, a polyphenol-rich plant extract, has beneficial effects on body weight (BW) and insulin resistance in mice fed a high fat diet (HFD). The study aim was to determine whether high-intensity interval training (HIIT) and/or TOTUM-63 supplementation improved body composition and glycemic control and gut microbiota composition in a Western diet-induced obesity rat model. Wistar rats received a standard diet (CTRL; control; n = 12) or HFD (HFD; n = 48) for 16 weeks. Then, HFD rats were divided in four groups: HFD, HFD + TOTUM-63 (T63), HFD + HIIT (HIIT), and HFD + HIIT +T63 (HIIT + T63). Training was performed 4 days/week for 12 weeks. TOTUM-63 was included in diet composition (2%). The HIIT + T63 combination significantly limited BW gain, without any energy intake modulation, and improved glycemic control. BW variation was correlated with increased α-diversity of the colon mucosa microbiota in the HIIT + T63 group. Moreover, the relative abundance of Anaeroplasma, Christensenellaceae and Oscillospira was higher in the HIIT + T63 group. Altogether, these results suggest that the HIIT and TOTUM-63 combination could be proposed for the management of obesity and prediabetes.

Advanced glycation end-products, measured as skin autofluorescence, associate with vascular stiffness in diabetic, pre-diabetic and normoglycemic individuals: a cross-sectional study.

BACKGROUND: Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. We aimed to investigate the relationships between advanced glycation end-products, measured as skin autofluorescence, and vascular stiffness in various glycemic strata. METHODS: We performed a cross-sectional analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, comprising n = 3535 participants (median age 67 years, 60% women). Advanced glycation end-products were measured as skin autofluorescence with AGE-Reader™, vascular stiffness was measured as pulse wave velocity, augmentation index and ankle-brachial index with Vascular Explorer™. A subset of 1348 participants underwent an oral glucose tolerance test. Participants were sub-phenotyped into normoglycemic, prediabetes and diabetes groups. Associations between skin autofluorescence and various indices of vascular stiffness were assessed by multivariable regression analyses and were adjusted for age, sex, measures of adiposity and lifestyle, blood pressure, prevalent conditions, medication use and blood biomarkers. RESULTS: Skin autofluorescence associated with pulse wave velocity, augmentation index and ankle-brachial index, adjusted beta coefficients (95% CI) per unit skin autofluorescence increase: 0.38 (0.21; 0.55) for carotid-femoral pulse wave velocity, 0.25 (0.14; 0.37) for aortic pulse wave velocity, 1.00 (0.29; 1.70) for aortic augmentation index, 4.12 (2.24; 6.00) for brachial augmentation index and - 0.04 (- 0.05; - 0.02) for ankle-brachial index. The associations were strongest in men, younger individuals and were consistent across all glycemic strata: for carotid-femoral pulse wave velocity 0.36 (0.12; 0.60) in normoglycemic, 0.33 (- 0.01; 0.67) in prediabetes and 0.45 (0.09; 0.80) in diabetes groups; with similar estimates for aortic pulse wave velocity. Augmentation index was associated with skin autofluorescence only in normoglycemic and diabetes groups. Ankle-brachial index inversely associated with skin autofluorescence across all sex, age and glycemic strata. CONCLUSIONS: Our findings indicate that advanced glycation end-products measured as skin autofluorescence might be involved in vascular stiffening independent of age and other cardiometabolic risk factors not only in individuals with diabetes but also in normoglycemic and prediabetic conditions. Skin autofluorescence might prove as a rapid and non-invasive method for assessment of macrovascular disease progression across all glycemic strata.

Increasing glycaemia is associated with a significant decline in HDL cholesterol in women with prediabetes in two national populations.

Internationally, studies have shown associations between lipids and glycemia; however, whether the link varies by gender and population has been rarely examined. We investigated relationships between glycemia and HDL- and Non-HDL-cholesterol and their modification by gender. We undertook a cross-sectional analysis from the National Health Examination Survey for Thailand (NHES-Thailand) and the Health Survey for England (HS-England) in adults aged 18-75 year. Glycaemia was assessed by FPG in Thailand and by HbA1c in the UK. In population- and gender-stratified analyses, the relationships between glycemia and lipids were explored. A total of 15,145 Thai and 3484 UK adults with blood measurement were included. The prevalences of prediabetes were: in NHES-Thailand, 16% (SE = 0.004), based on FPG (5.6 to < 7.0 mmol/L) and in HS-England, 19% (0.007) based on HbA1c (39 to < 48 mmol/mol). Increasingly abnormal glucose homeostasis was associated with increasing age, adiposity, SBP, proportion of antihypertensive and lipid-lowering agent use and with decreasing HDL-cholesterol. Independent of age, adiposity, smoking, alcohol, physical activity, and lipid and BP lowering drug use, increasing glycemia was associated with decreasing HDL-cholesterol specifically in women with prediabetes (NHES-Thailand, beta-coefficient - 0.07 (95% CI - 0.15, - 0.001) p = 0.04 and HS-England, - 0.03 (- 0.04, - 0.006) p = 0.01). In both populations, among those with prediabetes, increasing glycaemia is associated with an adverse, significant decline in HDL cholesterol, specifically in women. These adverse effects are apparent in widely-differing international populations.

Circulating microRNA-122, microRNA-126-3p and microRNA-146a are associated with inflammation in patients with pre-diabetes and type 2 diabetes mellitus: A case control study.

The prevalence of type 2 diabetes mellitus (T2DM) is increasing dramatically worldwide. Dysregulation of microRNA (miRNA) as key regulators of gene expression, has been reported in numerous diseases including diabetes. The aim of this study was to investigate the expression levels of miRNA-122, miRNA-126-3p and miRNA-146a in diabetic and pre-diabetic patients and in healthy individuals, and to determine whether the changes in the level of these miRNAs are reliable biomarkers in diagnosis, prognosis, and pathogenesis of T2DM. Additionally, we examined the relationship between miRNA levels and plasma concentrations of inflammatory factors including tumor necrosis factor alpha (TNF-α) and interleukin 6 (Il-6) as well as insulin resistance. In this case-control study, participants (n = 90) were allocated to three groups (n = 30/group): T2DM, pre-diabetes and healthy individuals as control (males and females, age: 25-65, body mass index: 25-35). Expression of miRNA was determined by real-time polymerase chain reaction (RT-PCR). Furthermore, plasma concentrations of TNF-α, IL-6 and fasting insulin were measured by enzyme-linked immunosorbent assay. Homeostatic model assessment for insulin resistance (HOMA-IR) was calculated as an indicator of insulin resistance. MiRNA-122 levels were higher while miRNA-126-3p and miRNA-146a levels were lower in T2DM and pre-diabetic patients compared to control (p<0.05). Furthermore, a positive correlation was found between miRNA-122 expression and TNF-α (r = 0.82), IL-6 (r = 0.83) and insulin resistance (r = 0.8). Conversely, negative correlations were observed between miRNA-126-3p and miRNA-146a levels and TNF-α (r = -0.7 and r = -0.82 respectively), IL-6 (r = -0.65 and r = -0.78 respectively) as well as insulin resistance (r = -0.67 and r = -0.78 respectively) (all p<0.05). Findings of this study suggest the miRNAs can potentially contribute to the pathogenesis of T2DM. Further studies are required to examine the reproducibility of these findings.

ADMA (asymmetric dimethylarginine) and angiogenic potential in patients with type 2 diabetes and prediabetes.

Asymmetric dimethylarginine is an endogenous competitive inhibitor of nitric oxide synthase and marker of endothelial dysfunction, but the question remains as to whether asymmetric dimethylarginine is a marker of cardiovascular episodes or their independent risk factor. ADMA/DDAH (dimethylaminohydrolase) pathway regulates vascular endothelial growth factor (VEGF)-mediated angiogenesis due to its impact on the NO formation. The aim of the study was to assess the concentrations of asymmetric dimethylarginine and the angiogenic potential in the blood of subjects with type 2 diabetes (T2DM, n = 33) and patients with prediabetes (n = 32)-impaired fasting glycemia and/or impaired glucose tolerance (WHO criteria). The study found that both the prediabetes group and subjects with T2DM had significantly elevated concentrations of asymmetric dimethylarginine, significantly high levels of VEGF-A, low ratio of sVEGF-R1/VEGF-A, and sVEGF-R2/VEGF-A. This may suggest endothelial damage at early stages of carbohydrate metabolism dysfunction-before T2DM is diagnosed. Higher proangiogenic potential in prediabetes and T2DM patients than in healthy subjects, is not only the effect of an increase in VEGF-A levels, but also reduced inhibition of circulating receptors.

Influence of pre-diabetic and pancreatic exocrine states on pulmonary and nutritional status in adults with Cystic Fibrosis.

BACKGROUND: In 1992, a landmark study demonstrated clinical deterioration in respiratory function and nutritional status prior to the onset of cystic fibrosis-related diabetes (CFRD). We re-evaluated this outcome. METHODS: The Montreal Cystic Fibrosis Cohort is a prospective CFRD screening study. We performed a 6-year retrospective analysis of nutritional parameters and FEV1 (%) in subjects who developed incident CFRD and in controls who maintained normoglycemia (NG). In the former group, data was collected over 6 years prior to diabetes onset. RESULTS: Subjects (n = 86) had a mean age of 31.7 ± 8.1 years, BMI of 23.0 ± 4.0 kg/m2, and FEV1% of 70.1 ± 24.2%. Eighty-one percent had pancreatic insufficiency (PI). Patients were grouped as follows: NG+PS (pancreatic sufficient) (n = 16), NG+PI (pancreatic insufficient) (n = 21), CFRD+PS (n = 3) and CFRD+PI (n = 46). At their most recent screen NG+PS subjects had significantly greater BMI, as compared to NG+PI and CFRD+PI groups (26.2 ± 3.6 kg/m2 vs 22.6 ± 4.2 kg/m2 vs 22.1 ± 3.5 kg/m2, p = 0.0016). FEV1 was significantly greater in the NG+PS group (91.5 ± 16.8% vs 67.8 ± 25.3% vs 63.5 ± 22.2%, p = 0.0002). The rates of change in weight, BMI, fat mass (%), and FEV1 prior to the most recent visit (NG+PS, NG+PI groups) or to the diagnosis of de novo CFRD were similar between groups. CONCLUSION: In a contemporary context, CFRD onset is not preceded by deterioration in BMI, fat mass, or pulmonary function. Low BMI and FEV1 are more closely associated with PI than a pre-diabetic state.

Relationships among pancreatic beta cell function, the Nrf2 pathway, and IRS2: a cross-sectional study.

OBJECTIVES: This study aimed to investigate the relationships among islet function, the Nrf2 pathway, and insulin receptor substrate 2 (IRS2) in type 2 diabetes mellitus (T2DM), prediabetes mellitus (IGR), and normal glucose tolerance (NGT) populations. METHODS: Three hundred cases each were selected for the NGT, IGR, and T2DM groups; FBG, 2hPG, HbA1 c, FINS, TG, TC, HDL-C, and LDL-C levels and serum levels of nuclear factor in E2-related factor 2 (Nrf2), insulin receptor substrate 2 (IRS2), tumor necrosis factor alpha (TNF-α), and heme oxygenase 1 (HO-1) were evaluated. RESULTS: The T2DM group had lower islet ß-cell function index and insulin sensitivity index than the NGT and IGR groups (P < 0.05). The Nrf2, IRS2, and HO-1 levels in the NGT, IGR, and T2DM groups followed a decreasing trend in the order mentioned, whereas the TNF-α levels followed an increasing trend. CONCLUSIONS: Upon impairment of glucose regulation, the expression of TNF-α in the human body increased, which indicated the aggravation of oxidative stress (OS) and the inflammatory response. Islet function was maintained in the pre-diabetic population, and concurrently, the TNF-α, Nrf2, and HO-1 levels were moderately elevated, the expression of IRS2 was marginally inhibited, and the Nrf2 pathway was activated under mild OS stimulus to resist OS, inflammation, and injury, which may have been mediated through PI3 K/AKT. In patients with T2DM, islet function was significantly poorer, TNF-α amplification was enhanced significantly, and Nrf2, HO-1, and IRS2 expression reduced significantly; this suggested that, along with the aggravation of OS and the inflammatory response, Nrf2 pathway activation and HO-1 expression were both inhibited, the antioxidant capacity of the body was reduced, IRS2 degradation increased, and islet function was impaired.

Small changes in glucose variability induced by low and high glycemic index diets are not associated with changes in ß-cell function in adults with pre-diabetes.

Oscillating glucose levels can increase oxidative stress and may contribute to ß-cell dysfunction. We tested the hypothesis that increased glycemic variability contributes to ß-cell dysfunction by experimentally altering glucose variability with controlled diets varying in glycemic index (GI). Fifty-two adults with prediabetes received a 2-week moderate GI (GI = 55-58) control diet followed by randomization to a four-week low GI (LGI: GI < 35) or high GI (HGI HI > 70) diet. Those on the HGI diet were randomized to placebo or the antioxidant N-acetylcysteine (NAC). Participants underwent blinded CGMS, fasting oxidative stress markers and an intravenous glucose tolerance test to estimate ß-cell function (disposition index: DI). On the control diet, DI was inversely correlated with SD glucose (r = -0.314, p = 0.03), but neither DI nor glucose variability were associated with oxidative stress markers. The LGI diet decreased SD glucose (Control 0.96 ±â€¯0.08 vs. LGI 0.79 ±â€¯0.06, p = 0.02) while the HGI diet increased it (Control 0.88 ±â€¯0.06 vs. HGI 1.06 ±â€¯0.07, p = 0.03). Neither DI nor oxidative stress markers changed after the LGI or HGI diets. NAC had no effect on DI, glucose variability or oxidative stress markers. We conclude small changes in glucose variability induced by dietary GI in adults with pre-diabetes are unlikely to contribute to ß-cell dysfunction.

A 2 Adenosine Receptors Mediate Whole-Body Insulin Sensitivity in a Prediabetes Animal Model: Primary Effects on Skeletal Muscle.

Epidemiological studies showed that chronic caffeine intake decreased the risk of type 2 diabetes. Previously, we described that chronic caffeine intake prevents and reverses insulin resistance induced by hypercaloric diets and aging, in rats. Caffeine has several cellular mechanisms of action, being the antagonism of adenosine receptors the only attained with human coffee consumption. Here, we investigated the subtypes of adenosine receptors involved on the effects of chronic caffeine intake on insulin sensitivity and the mechanisms and sex differences behind this effect. Experiments were performed in male and female Wistar rats fed either a chow or high-sucrose (HSu) diet (35% of sucrose in drinking water) during 28 days, to induce insulin resistance. In the last 15 days of diet the animals were submitted to DPCPX (A1 antagonist, 0.4 mg/kg), SCH58261 (A2A antagonist, 0.5 mg/kg), or MRS1754 (A2B antagonist, 9.5 µg/kg) administration. Insulin sensitivity, fasting glycaemia, blood pressure, catecholamines, and fat depots were assessed. Expression of A1, A2A, A2B adenosine receptors and protein involved in insulin signaling pathways were evaluated in the liver, skeletal muscle, and visceral adipose tissue. UCP1 expression was measured in adipose tissue. Paradoxically, SCH58261 and MRS1754 decreased insulin sensitivity in control animals, whereas they both improved insulin response in HSu diet animals. DPCPX did not alter significantly insulin sensitivity in control or HSu animals, but reversed the increase in total and visceral fat induced by the HSu diet. In skeletal muscle, A1, A2A, and A2B adenosine receptor expression were increased in HSu group, an effect that was restored by SCH58261 and MRS1754. In the liver, A1, A2A expression was increased in HSu group, while A2B expression was decreased, being this last effect reversed by administration of MRS1754. In adipose tissue, A1 and A2A block upregulated the expression of these receptors. A2 adenosine antagonists restored impaired insulin signaling in the skeletal muscle of HSu rats, but did not affect liver or adipose insulin signaling. Our results show that adenosine receptors exert opposite effects on insulin sensitivity, in control and insulin resistant states and strongly suggest that A2 adenosine receptors in the skeletal muscle are the majors responsible for whole-body insulin sensitivity.

Prediabetes, diabetes, metabolic syndrome, and small fiber neuropathy.

INTRODUCTION: This study was conducted to evaluate the association between prediabetes (PD), elements of the metabolic syndrome (MetS), and small fiber neuropathy (SFN). METHODS: A total of 268 patients with SFN symptoms and normal electrophysiology underwent tests to assess small fibers. SFN was diagnosed based on abnormality of at least two among intraepidermal nerve fiber density (IEFND), quantitative sensory testing, and quantitative sudomotor axon reflex testing. RESULTS: There was no difference in IENFD or abnormal skin biopsy frequency between PD and normoglycemia (NG). However, IENFD was lower in people with diabetes mellitus (DM) than in those with NG. An association between HbA1C and IENFD was observed only if DM patients were included. Attributes of the MetS were more common in those with an abnormal skin biopsy but not among those with autonomic dysfunction or meeting SFN criteria. DISCUSSION: DM, but not PD alone, is associated with SFN. Other MetS elements appear to preferentially impact small fiber structure over function.

Effect of a family and interdisciplinary intervention to prevent T2D: randomized clinical trial.

BACKGROUND: Lifestyle changes can reduce the risk of T2D; however, no study has evaluated the effect of a lifestyle intervention involving patients´ family. The aim of this study was to compare the impact of an interdisciplinary family (FI) Vs individual intervention (II) on glucose metabolism, insulin resistance (IR), pancreatic ß-cell function and cardiovascular risk markers in patients with prediabetes, as well as to measure the impact on their families' metabolic risk. METHODS: Randomized Clinical Trial (RCT) to compare the impact of FI and II on IR and pancreatic ß-cell function in subjects with prediabetes. There were 122 subjects with prediabetes (and 101 family members) randomized to FI or II. Data were collected in 2015-2016 and analyzed in 2017-2018. FI group had the support of their family members, who also received personalized diet and exercise recommendations; patients and their family members attended monthly a lifestyle enhancement program. II group received personalized diet and exercise recommendations. The follow-up was for 12 months. Glucose, IR, pancreatic ß-cell function and secondary outcomes (body composition and lipid profile) were assessed at baseline, 6 and 12 months. RESULTS: FI group improved area under the glucose curve (AUC) (from 18,597 ± 2611 to 17,237 ± 2792, p = 0.004) and the Matsuda index (from 3.5 ± 2.3 to 4.7 ± 3.5, p = 0.05) at 12 months. II group improved Disposition Index (from 1.5 ± 0.4 to 1.9 ± 0.73, p < .0001) at 12 months. The improvements achieved in weight and lipids at 6 months, were lost in II group at 12 moths, whereas in FI persisted. Adherence up to 12 months was not different between the study groups (FI 56% Vs II 60%). CONCLUSIONS: FI intervention was more effective by improving glucose AUC, insulin sensitivity and lipid profile, besides that, metabolic risk in family members of the FI group was maintained, while the risk of II group was increased. TRIAL REGISTRATION: This study was retrospectively registered at clinicaltrials.gov on December 15, 2015 (NTC026365646).

Association of insulin resistance and ß-cell dysfunction with incident diabetes among adults in China: a nationwide, population-based, prospective cohort study.

BACKGROUND: National investigations on the interaction of insulin resistance, ß-cell dysfunction, and obesity with the development of diabetes are scarce in China. We aimed to investigate the individual and joint associations of insulin resistance and ß-cell dysfunction with incident diabetes, and to examine the modifying effect of BMI and waist circumference on these associations among adults with normal glucose tolerance and with prediabetes. METHODS: In this nationwide, population-based, prospective cohort study, we analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, which recruited adults aged 40 years or older during 2011-12 (baseline) and invited participants to attend follow-up visits in 2014-16. Patients with diabetes at baseline, missing data for baseline measures of glucose tolerance status, missing data for baseline homoeostasis model assessment (HOMA) indexes, missing data for baseline covariates, and missing data for measures of glucose tolerance status at follow-up visits were excluded. At baseline and follow-up visits, a comprehensive set of questionnaires, clinical measurements, oral glucose tolerance tests, and laboratory examinations were carried out following standardised protocols. Glucose tolerance status and prediabetes were defined according to the American Diabetes Association 2010 criteria. In the main analysis, we examined the contributions of insulin resistance (HOMA of insulin resistance [HOMA-IR]) and ß-cell dysfunction (HOMA of ß-cell function [HOMA-B]) to diabetes risk, and evaluated the impact of obesity on these associations. FINDINGS: 94 952 participants (31 517 men and 63 435 women) were included in the analysis. High HOMA-IR was associated with a greater hazard of diabetes (quartile 4 vs 1: hazard ratio [HR] 6·70, 95% CI 6·08-7·39; per unit increase in Z score: HR 2·17, 95% CI 2·10-2·24) than low HOMA-B (quartile 1 vs 4: 4·08, 3·72-4·48; per unit decrease in Z score: 1·92, 1·85-2·00). Approximately 24·4% (95% CI 23·6-25·2) of the incident diabetes could be attributed to insulin resistance and 12·4% (11·2-13·7) could be attributed to ß-cell dysfunction. The HRs for diabetes were 1·83 (95% CI 1·72-1·95) per unit increase in Z score of HOMA-IR and 2·03 (1·86-2·21) per unit decrease in Z score of HOMA-B among participants with normal weight; the corresponding HRs for diabetes were 2·02 (1·93-2·11) and 1·88 (1·79-1·98) among participants with obesity (pinteraction=0·0091). These associations and interactions were similar for participants with normal glucose tolerance or prediabetes. INTERPRETATION: Insulin resistance shows a stronger association with incident diabetes than does ß-cell dysfunction in Chinese adults, and this association pattern was more prominent among adults with obesity. Given the limitations of HOMA indexes as surrogate measures of insulin resistance and ß-cell dysfunction, these findings should be interpreted with caution. FUNDING: National Natural Science Foundation of China.