Development of ALOHa-G Risk Score for Detecting Postpartum Dyslipidemia Among Normoglycemic Women with Previous Gestational Diabetes: Observational Cohort Study.

INTRODUCTION: Previous gestational diabetes (pGD) is associated with a high risk of postpartum dyslipidemia (pD). Our study was aimed at investigating the prevalence of pD and estimating the risk for pD based on metabolic pregnancy parameters in normoglycemic women with pGD. METHODS: 147 women with pGD and normoglycemia after delivery were divided into groups: A (n = 63) with pD and B (n = 84) with normal lipids, defined by the National Cholesterol Education Program's Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report (NCEP ATP III). We recorded age, body mass index (BMI) at conception, fasting glucose (FG), HbA1c, total cholesterol (TC), triglycerides (Tg), low-density lipoprotein (LDL-c), and high-density lipoprotein cholesterol (HDL-c) measured mid-pregnancy and 1-6 months after delivery. GD was diagnosed by 2 h oral glucose tolerance test (OGTT) between the 24th and the 28th week of gestation, which was repeated after delivery to confirm normoglycemia. RESULTS: 42.8% had pD (group A) while 57.2% had normal lipids (group B). Group A was older (36.8 ± 2.7) than B (33.0 ± 4.2 years, p < 0.001) and had a higher BMI (A 31.2 ± 6.4 vs. B 25.5 ± 2.4 kg/m2, p < 0.001). Simultaneously, HbA1c and FG were higher in group A (5.4 ± 0.3, 5.1 ± 0.4) than B (5.2 ± 0.0%, p = 0.001; 4.8 ± 0.0 mmol/L, p < 0.001). Also, group A had higher TC, LDL-c, and Tg [6.6 (6.1-6.9); 4.2 ± 0.4; 2.9 ± 0.8] compared to B [6.2 (5.4-6.9), p < 0.001; 3.4 ± 0.9, p = 0.001; 2.5 ± 0.6, p < 0.001], while the two groups had comparable HDL-c (A: 1.2 ± 0.3 vs. B: 1.2 ± 0.2 mmol/L, p = 0.998). Calculating the cutoff for age, BMI, HbA1c, FG, LDL-c, and Tg (> 35 years, 26.4 kg/m2, 5.2%, 4.8, 3.9 and 2.7 mmol/L, respectively), univariate regression analysis showed a difference for each (p < 0.001). Allocating 1 point to each predictor, we developed ALOHa G score, which showed high accuracy (AUC 0.931, p < 0.001) for risk of pD in normoglycemic women with pGD. According to the ALOHa-G score, more women in group A were at high risk (≥ 4) and medium risk (= 3) (61.9; 34.9) for pD than in group B (4.8; 14.3), with a lower percentage at low risk for PD (≤ 2) in group A than in group B (3.2 vs. 81.0%). CONCLUSION: Our results implied a remarkable occurrence of pD in normoglycemic women with pGD. Also, the ALOHa-G score was developed based on pregnancy metabolic predictors and could be used to identify normoglycemic women with pGD who are at high risk for pD.

Trends of the Prevalence of Pre-gestational Diabetes in 2030 and 2050 in Belgrade Cohort.

The aim of this study was to analyze the trends in diabetes in pregnancy in Belgrade, Serbia for the period of the past decade and forecast the number of women with pre-gestational diabetes for the years 2030 and 2050. The study included the data on all pregnant women with diabetes from the registry of the deliveries in Belgrade, by the City Institute of Public Health of Belgrade, Serbia for the period between 2010 and 2020 and the published data on the deliveries on the territory of Belgrade. During the examined period the total number of live births in Belgrade was 196,987, and the prevalence of diabetes in pregnancy was 3.4%, with the total prevalence of pre-gestational diabetes of 0.7% and overall prevalence of GDM of 2.7%. The average age of women in our study was significantly lower in 2010 compared to 2020. The forecasted prevalence of pre-gestational diabetes among all pregnant women for 2030 is 2% and 4% for 2050 in our cohort. Our study showed that the prevalence of pre-gestational diabetes has increased both among all pregnant women and among women with diabetes in pregnancy in the past decade in Belgrade, Serbia and that it is expected to increase further in the next decades and to further double by 2050.

Comparison of Insulin Dose Adjustments Made by Artificial Intelligence-Based Decision Support Systems and by Physicians in People with Type 1 Diabetes Using Multiple Daily Injections Therapy.

Objective: Artificial intelligence-based decision support systems (DSS) need to provide decisions that are not inferior to those given by experts in the field. Recommended insulin dose adjustments on the same individual data set were compared among multinational physicians, and with recommendations made by automated Endo.Digital DSS (ED-DSS). Research Design and Methods: This was a noninterventional study surveying 20 physicians from multinational academic centers. The survey included 17 data cases of individuals with type 1 diabetes who are treated with multiple daily insulin injections. Participating physicians were asked to recommend insulin dose adjustments based on glucose and insulin data. Insulin dose adjustments recommendations were compared among physicians and with the automated ED-DSS. The primary endpoints were the percentage of comparison points for which there was agreement on the trend of insulin dose adjustments. Results: The proportion of agreement and disagreement in the direction of insulin dose adjustment among physicians was statistically noninferior to the proportion of agreement and disagreement observed between ED-DSS and physicians for basal rate, carbohydrate-to insulin ratio, and correction factor (P < 0.001 and P ≤ 0.004 for all three parameters for agreement and disagreement, respectively). The ED-DSS magnitude of insulin dose change was consistently lower than that proposed by the physicians. Conclusions: Recommendations for insulin dose adjustments made by automatization did not differ significantly from recommendations given by expert physicians regarding the direction of change. These results highlight the potential utilization of ED-DSS as a useful clinical tool to manage insulin titration and dose adjustments.

Maternal and Fetal Outcomes among Pregnant Women with Diabetes.

The aim of this study was to examine the differences in pregnancy complications, delivery characteristics, and neonatal outcomes between women with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM). This study included all pregnant women with diabetes in pregnancy in Belgrade, Serbia, between 2010 and 2020. The total sample consisted of 6737 patients. In total, 1318 (19.6%) patients had T1DM, 138 (2.0%) had T2DM, and 5281 patients (78.4%) had GDM. Multivariate logistic regression with the type of diabetes as an outcome variable showed that patients with T1DM had a lower likelihood of vaginal delivery (OR: 0.73, 95% CI: 0.64-0.83), gestational hypertension (OR: 0.47, 95% CI: 0.36-0.62), higher likelihood of chronic hypertension (OR: 1.88, 95% CI: 1.55-2.29),and a higher likelihood ofgestational age at delivery before 37 weeks (OR: 1.38, 95% CI: 1.18-1.63) compared to women with GDM. Multivariate logistic regression showed that patients with T2DM had a lower likelihood ofgestational hypertension compared to women with GDM (OR: 0.37, 95% CI: 0.15-0.92).Our results indicate that the highest percentage of diabetes in pregnancy is GDM, and the existence of differences in pregnancy complications, childbirth characteristics, and neonatal outcomes are predominantly between women with GDM and women with T1DM.

Adjustment of Insulin Pump Settings in Type 1 Diabetes Management: Advisor Pro Device Compared to Physicians' Recommendations.

AIMS: To compare insulin dose adjustments made by physicians to those made by an artificial intelligence-based decision support system, the Advisor Pro, in people with type 1 diabetes (T1D) using an insulin pump and self-monitoring blood glucose (SMBG). METHODS: This was a multinational, non-interventional study surveying 17 physicians from 11 countries. Each physician was asked to provide insulin dose adjustments for the settings of the pump including basal rate, carbohydrate-to-insulin ratios (CRs), and correction factors (CFs) for 15 data sets of pumps and SMBG of people with T1D (mean age 18.4 ± 4.8 years; eight females; mean glycated hemoglobin 8.2% ± 1.4% [66 ± 11mmol/mol]). The recommendations were compared among the physicians and between the physicians and the Advisor Pro. The study endpoint was the percentage of comparison points for which there was an agreement on the direction of insulin dose adjustments. RESULTS: The percentage (mean ± SD) of agreement among the physicians on the direction of insulin pump dose adjustments was 51.8% ± 9.2%, 54.2% ± 6.4%, and 49.8% ± 11.6% for the basal, CR, and CF, respectively. The automated recommendations of the Advisor Pro on the direction of insulin dose adjustments were comparable )49.5% ± 6.4%, 55.3% ± 8.7%, and 47.6% ± 14.4% for the basal rate, CR, and CF, respectively( and noninferior to those provided by physicians. The mean absolute difference in magnitude of change between physicians was 17.1% ± 13.1%, 14.6% ± 8.4%, and 23.9% ± 18.6% for the basal, CR, and CF, respectively, and comparable to the Advisor Pro 11.7% ± 9.7%, 10.1% ± 4.5%, and 25.5% ± 19.5%, respectively, significant for basal and CR. CONCLUSIONS: Considerable differences in the recommendations for changes in insulin dosing were observed among physicians. Since automated recommendations by the Advisor Pro were similar to those given by physicians, it could be considered a useful tool to manage T1D.

Distribution of normal and pathological OGTTs among pregnant population and non-pregnant women with PCOS - the cross-sectional study.

ABSTRACT: Both pregnancy, as physiological, and polycystic ovary syndrome (PCOS), as a pathological condition, carry the risk for developing glucose metabolism abnormalities. In this retrospective cross-sectional study, we hypothesized that pregnancy as a physiological condition carries a higher likelihood for abnormal oral glucose tolerance test (OGTT) results than PCOS as a pathological condition.We have compared the prevalence and likelihood ratios for abnormal OGTT results between non-pregnant women with PCOS (Group A) and pregnant women at 24 to 28 weeks of gestation (Group B). Participants of both study groups underwent glucose tolerance testing with 75 g glucose OGTT. During the study period, 7411 women were tested, 3932 women encompassed Group A, and 3479 women comprised Group B.The numbers of yearly tested pregnant women and the corresponding proportion of tested women among all study participants have decreased during the study period, from 766 to 131 and 89.1% to 20.5%, respectively. Group A had a significantly lower prevalence (4.4%) of pathological OGTT results compared to Group B (8.1%). This has resulted in a 45.427 likelihood ratio (P < .001) for abnormal OGTT results in pregnant women compared to non-pregnant women with PCOS.We might conclude that pregnancy could have a more challenging influence on glucose metabolism and that carries higher risks for abnormal glucose metabolism than PCOS. The awareness of obstetricians regarding physiological changes during pregnancy that predisposes abnormal glucose metabolism is decreasing over time and the compliance concerning OGTT testing of pregnant women is decreasing too.

Prevalence and Metabolic Predictors for Early Diagnosed Prediabetes in Women with Previous Gestational Diabetes: Observational Cohort Study.

INTRODUCTION: Women with previous gestational diabetes (pGD) are at higher risk of prediabetes (PD) after delivery. The aim of this study was to determine the prevalence of and predictors for PD among women with pGD. METHODS: The study included 186 women with pGD treated by lifestyle modification. After delivery, the women were divided into group A (n = 80) with PD and group B (n = 106) with normal glucose tolerance (NGT), defined by the results of the 2-h oral glucose tolerance test at 4-12 weeks after delivery. We recorded age, body mass index (BMI) at conception and after delivery, fasting glucose (FG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglycerides (Tg), low density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c) and the Tg/HDL-c ratio measured in the third trimester of pregnancy. RESULTS: Of the 186 women with pGD enrolled in the study, 43% showed prediabetes at 4-12 weeks after delivery, with 13.9% of these women showing impaired FG (IFG), 12.9% showing impaired glucose tolerance (IGT) and 16.2% with IFG/IGT. The groups differed in terms of age and BMI at conception and after delivery. In the third trimester of pregnancy, HbA1c was higher in women in group A than in those in group B (mean ± standard deviation: 5.6 ± 0.4 vs. 5.2 ± 0.3%; p < 0.001), while FG was comparable. Compared to women in group B, women in group A had higher TC (7.1 ± 0.8 vs. 6.6 ± 1.0 mmol/L), Tg (2.7 ± 0.9 vs. 2.1 ± 0.6 mmol/L) and LDL-c (4.7 ± 0.8 vs. 4.3 ± 1.0 mmol/L) (all p < 0.001), lower HDL-c (1.0 ± 0.2 vs. 1.4 ± 1.0; p < 0.001) and higher median Tg/HDL-c (5.4 [range 4.6-14.3] vs. 4.9 [range 1.1-11.5]; p < 0.001). Univariate analysis found an association between prediabetes and age, BMI at conception and after delivery, HbA1c, TC, LDL-c, HDL-c, Tg and Tg/HDL-c ratio. Of these variables, the multivariate analysis showed age (odds ratio [OR] 1.19; p < 0.001), HbA1c (OR 31.06; p < 0.001), Tg (OR 4.09; p < 0.001) and LDL-c (OR 2.00; p = 0.005) as predictors for prediabetes. CONCLUSION: High prevalence of early diagnosed PD in women with pGD was accompanied by advanced age and higher BMI at conception and after delivery. Moreover, age, HbA1c, Tg and LDL-c were predictors for PD.

Targeting Mitochondria in Diabetes.

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

Redesigning diabetes care delivery in Serbia, using JA CHRODIS Recommendations and criteria.

INTRODUCTION: Managing non-communicable diseases (NCDs) requires redesigning health care delivery to achieve better coordination of services at all levels of health care. The aim of this study was improving prevention and strengthening high quality of care for NCDs by using type 2 diabetes as a model disease. METHODS: The mix method approach served to analyse the impact of the intervention processes. Source of information were routine health statistics, interviews and observation. Key Performance Indicators in defined Improvement Areas assisted in the quality of diabetes care assessment. RESULTS AND DISCUSSION: During the study the National Diabetes Centre (NDC) was established. The NDC experts organized numerous educational events, 316 physicians and nurses have participated. New electronic data base was implemented in 20 pilot Primary Health Care Centres (PHCCs) with 38,833 electronic diabetes records. CONCLUSIONS: The intervention led to establishment of the NDC, strengthening competences of health care professionals and to the renewal of the Diabetes Care Units in PHCCs included in the study.

The association of tumor necrosis factor alpha, lymphotoxin alpha, tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2 gene polymorphisms and serum levels with periodontitis and type 2 diabetes in Serbian population.

OBJECTIVES: Aiming to show that periodontitis (PD) and type 2 diabetes (T2D) are bidirectionally related and potentially linked by inflammatory cytokines, we searched for association between -308 G/A Tumor necrosis factor-alpha (TNFα), +252A/G Lymphotoxin-alpha (LTα), +36A/G Tumor necrosis factor receptor 1 (TNFR1) and +676 T/G tumor necrosis factor receptor 2 (TNFR2) single nucleotide polymorphisms (SNPs) and: risk of PD or PD + T2D; periodontitis parameters in PD and PD + T2D; serum levels of cytokines/their receptors. Relationship between periodontal inflammation and serum cytokine/receptor levels was also assessed. DESIGN: Subjects were stratified as: 57 healthy controls (HC); 58 PD; 65 PD + T2D. Sociodemographic, environmental, behavioral and periodontal clinical data were recorded. SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism, while cytokines/receptors levels were quantified by enzyme-linked immunosorbent assay. Impact of periodontal inflammation was measured using periodontal inflamed surface area (PISA). RESULTS: TNFα AA genotype showed protective effect in T2D + PD compared to PD, even adjusted for behavioral/environmental factors (OR 0.18; 95 %CI 0.037-0.886; p = 0.035). LTα AG heterozygotes had increased risk of PD (OR 3.27; 95 %CI 1.35-7.96; p = 0.016), while TNFR2 TG genotype had protective effect (OR = 0.44; 95 %CI 0.954-0.9794; p = 0.043). TNFR1 AA was predictor of periodontal pocket depth and clinical attachment loss in PD. Correlation between TNFR2 concentration and PISA was negative in PD, positive in PD + T2D. CONCLUSIONS: None of the SNPs showed cross-susceptibility between PD and T2D. + 252A/G LTα and +676 T/G TNFR2 SNPs are associated with PD risk. Periodontal destruction in healthy individuals is influenced by TNFR1 genotype. Impact of periodontal on systemic inflammation is masked by T2D.

Evaluation of Glycaemic Control, Glucose Variability and Hypoglycaemia on Long-Term Continuous Subcutaneous Infusion vs. Multiple Daily Injections: Observational Study in Pregnancies With Pre-Existing Type 1 Diabetes.

INTRODUCTION: We evaluated the effectiveness of long-term continuous subcutaneous insulin infusion (CSII) compared with multiple daily insulin (MDI) injections for glycaemic control and variability, hypoglycaemic episodes and maternal/neonatal outcomes in pregnant women with pre-existing type 1 diabetes (pT1D). METHODS: Our observational cohort study included 128 consecutive pregnant women with pT1D, who were treated from 1 January 2010 to 31 December 2017. Of 128 participants, 48 were on CSII and 80 were on MDI. Glycaemic control was determined by glycated haemoglobin (HbA1c) (captured in preconception and each trimester of pregnancy). Glucose variability (GV) was expressed as the coefficient of variation (CV) [calculated from self-monitoring of blood glucose (SMBG) values], and hypoglycaemia was defined as glucose values < 3.9 mmol/l. The data on maternal and neonatal outcomes were collected from obstetrical records. RESULTS: Duration of the treatment was 8.8 ± 5.3 years in the CSII and 12.6 ± 8.0 years in the MDI group. The CSII lowered HbA1c in preconception (7.1 ± 0.1 vs. 7.9 ± 0.2%, p = 0.03) and the first (6.9 ± 0.1 vs. 7.7 ± 0.2%, p = 0.02), second (6.6 ± 0.1 vs. 7.2 ± 0.1%, p = 0.003) and third (6.5 ± 0.1 vs. 6.8 ± 0.1%, p = 0.02) trimesters significantly better than MDI. Significantly lower CV was observed only for fasting glycaemia in the first trimester (17.1 vs 28.4%, p < 0.001) in favour of CSII. Moreover, the CSII group had significantly lower mean hypoglycaemic episodes/week/patient only during the first trimester (2.0 ± 1.7 vs 4.8 ± 1.5, p < 0.01). In early pregnancy, the majority of women on CSII had less hypoglycaemia than on MDI (0-3: 79.1 vs. 29.1%; 4-6: 18.8 vs. 65.8%; ≥ 7: 2.1 vs. 5.1%, p < 0.01, respectively). We found no difference in the incidence of adverse maternal/neonatal outcomes. CONCLUSIONS: Treatment with CSII resulted in a favourable reduction of HbA1c in the preconception period and each trimester in pregnancy. Moreover, long-term CSII treatment demonstrated more stable metabolic control with less GV of fasting glycaemia and fewer hypoglyacemic episodes only during early pregnancy.

The Inflammatory and Hemostatic Cardiovascular Risk Markers During Acute Hyperglycemic Crisis in Type 1 and Type 2 Diabetes.

BACKGROUND: We analyzed cardiovascular inflammatory (C-reactive protein (CRP), interleukin 6 (IL-6)), haemostatic (homocysteine) risk markers in lean and obese patients at admission and acute hyperglicemic crisis (AHC) resolving, involving diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). METHODS: In that context, we included group A: N = 20 obese, B: N=20 lean patients with DKA; C: N = l0 obese, D: N=10 lean patients with HHS; E: N = 15 obese, F: N=15 lean controls. CRP IL-6, homocysteine were determined by ELISA. RESULTS: Our results showed that CRP IL-6, and homocysteine levels decreased in all groups: (A: p<0.001; B: p<0.001, C: p<0.05; D: p<0.001 mg/L), (A: p<0.001 B: p<0.001, C: p<0.001, D: p<0.01 pg/mL), (A: p<0.001, B: p <0.001; C: p<0.05, D: p=0.001 µmol/L), respectively, at resolving AHC. However, CRP persisted higher (p<0.001, p<0.01), IL-6 lower (p<0.05, p<0.001), while homocysteine levels turned out to be similar to controls. CONCLUSIONS: AHC is associated with increased inflammatory and hemostatic cardiovascular risk markers. Also, insulin therapy in AHC has had more pronounced favorable effect on IL-6 and homocystein than on CRP.

Endothelial dysfunction of coronary arteries in subjects without diabetes: An association with both insulin resistance and impaired insulin secretion response.

AIMS: This study was aimed to compare insulin sensitivity and secretion response, lipoprotein and plasminogen activator inhibitor 1 (PAI-1) levels between the subjects with and without coronary artery endothelial dysfunction (ED). METHODS: ED was detected by intracoronary injection of acetylcholine (ACh) in 47 nondiabetes subjects without stenotic coronary arteries, selected from 316 consecutive patients with coronary angiography performed for suspected coronary artery disease. The subjects were divided into two groups: presence of ACh-induced coronary spasm (group ED+, N = 30) and absence of ACh-induced coronary spasm (group ED-, N = 17). Insulin sensitivity (Si) was evaluated by frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis and by HOMA-IR, insulin secretion by acute insulin response (AIR) (calculated from the first 8 min of FSIGTT) and by disposition index (DI) (Si × AIR). Lipids and PAI-1 levels were determined enzymatically, and LDL particle size by gradient gel electrophoresis. RESULTS: Si was significantly lower (4.22 ±â€¯0.62 vs 6.98 ±â€¯1.47 min-1/mU/l × 104; p < 0.05) while HOMA-IR was significantly higher in ED + group vs ED- group (2.8 ±â€¯0.3 vs 1.7 ±â€¯0.2; p < 0.05). Simultaneously, AIR and DI was significantly lower in ED + vs ED- groups (p < 0.05 and p < 0.01, respectively). Investigated groups did not differ in fasting lipid levels but ED+ group had significantly smaller LDL particles (p < 0.01) and higher PAI-1 levels (p < 0.05). Regression analysis shown that DI was a strong independent predictor of appearance of ED, together with PAI-1 and LDL particle size. CONCLUSIONS: Both insulin resistance and impairment in insulin secretion response strongly correlate with coronary ED in subjects without diabetes.

Increased left ventricular mass index is present in patients with type 2 diabetes without ischemic heart disease.

Left ventricular mass index (LVMI) increase has been described in hypertension (HTN), but less is known about its association with type 2 diabetes (T2DM). As these conditions frequently co-exist, we investigated the association of T2DM, HTN and both with echocardiographic parameters, and hypothesized that patients with both had highest LVMI, followed by patients with only T2DM or HTN. Study population included 101 T2DM patients, 62 patients with HTN and no T2DM, and 76 patients with T2DM and HTN, excluded for ischemic heart disease. Demographic and clinical data, biochemical measurements, stress echocardiography, transthoracic 2D Doppler and tissue Doppler echocardiography were performed. Multivariable logistic regression was used to determine the independent association with T2DM. Linear regression models and Pearson's correlation were used to assess the correlations between LVMI and other parameters. Patients with only T2DM had significantly greater LVMI (84.9 ± 20.3 g/m2) compared to patients with T2DM and HTN (77.9 ± 16 g/m2) and only HTN (69.8 ± 12.4 g/m2). In multivariate logistic regression analysis, T2DM was associated with LVMI (OR 1.033, 95%CI 1.003-1.065, p = 0.029). A positive correlation of LVMI was found with fasting glucose (p < 0.001) and HbA1c (p = 0.0003). Increased LVMI could be a potential, pre-symptomatic marker of myocardial structural change in T2DM.

Impaired Insulin Sensitivity and Secretion in Patients with Alzheimer's Disease: The Relationship with Other Atherosclerosis Risk Factors.

BACKGROUND: The growing body of evidence suggests that atherosclerosis risk factors are important in cognitive decline. OBJECTIVE: To analyse insulin sensitivity, insulin secretion capacity, plasma insulin, adiponectin and lipid levels in normoglycaemic, nonobese patients with Alzheimer's disease (AD) (group A, n=62), mild cognitive impairment (MCI) (group B, n=41), and healthy controls (group C, n=25). METHOD: Insulin sensitivity was determined by euglycemic hyperinsulinaemic clamp (M value) and homeostasis model assessment (HOMA-IR), insulin secretion capacity by first-phase insulin response (FPIR), plasma insulin by RIA, adiponectin by ELISA, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides by enzymatic method. RESULTS: Insulin sensitivity was the lowest in group A (M value: A: 6.2±2.5; B:7.7±2.7; C:8.2±1.5 mg/min/kg, p<0.001; HOMA-IR: A: 4.6±2.2; B: 3.3±1.7; C: 1.5±1.0, p<0.001) as well as FPIR (A:68.9±27.8; B:112.5±47.1; C:147.4±56.0 mU/l, p<0.001). Plasma insulin was higher in group A vs B vs C, while adiponectin was lower in group A vs B vs C. Simultaneously, total and LDL-C were higher and HDL-C levels were lower in groups A and B vs C, with no difference between groups A and B. Triglycerides did not differ between the groups. Binary logistic regression analysis identified only M value, FPIR and plasma insulin as independent predictors of AD and MCI. CONCLUSION: These results imply that in AD and MCI insulin resistance with increased plasma insulin and decreased FPIR may be associated with the development of AD and MCI, accompanied with milder influence of low adiponectin levels and atherogenic lipid profile.

Altered Daytime Fluctuation Pattern of Plasminogen Activator Inhibitor 1 in Type 2 Diabetes Patients with Coronary Artery Disease: A Strong Association with Persistently Elevated Plasma Insulin, Increased Insulin Resistance, and Abdominal Obesity.

This study was aimed at investigating daily fluctuation of PAI-1 levels in relation to insulin resistance (IR) and daily profile of plasma insulin and glucose levels in 26 type 2 diabetic (T2D) patients with coronary artery disease (CAD) (group A), 10 T2D patients without CAD (group B), 12 nondiabetics with CAD (group C), and 12 healthy controls (group D). The percentage of PAI-1 decrease was lower in group A versus group B (4.4 ± 2.7 versus 35.0 ± 5.4%; P < 0.05) and in C versus D (14.0 ± 5.8 versus 44.7 ± 3.1%; P < 0.001). HOMA-IR was higher in group A versus group B (P < 0.05) and in C versus D (P < 0.01). Simultaneously, AUCs of PAI-1 and insulin were higher in group A versus group B (P < 0.05) and in C versus D (P < 0.01), while AUC of glucose did not differ between groups. In multiple regression analysis waist-to-hip ratio and AUC of insulin were independent determinants of decrease in PAI-1. The altered diurnal fluctuation of PAI-1, especially in T2D with CAD, might be strongly influenced by a prolonged exposure to hyperinsulinemia in the settings of increased IR and abdominal obesity, facilitating altogether an accelerated atherosclerosis.

Decreased Insulin Sensitivity and Impaired Fibrinolytic Activity in Type 2 Diabetes Patients and Nondiabetics with Ischemic Stroke.

We analyzed (a) insulin sensitivity (IS), (b) plasma insulin (PI), and (c) plasminogen activator inhibitor-1 (PAI-1) in type 2 diabetes (T2D) patients with (group A) and without (group B) atherothrombotic ischemic stroke (ATIS), nondiabetics with ATIS (group C), and healthy controls (group D). IS was determined by minimal model (Si). Si was lower in A versus B (1.18 ± 0.67 versus 2.82 ± 0.61 min-1/mU/L × 104; P < 0.001) and in C versus D (3.18 ± 0.93 versus 6.13 ± 1.69 min-1/mU/L × 104; P < 0.001). PI and PAI-1 were higher in A versus B (PI: 19.61 ± 4.08 versus 14.91 ± 1.66 mU/L; P < 0.001, PAI-1: 7.75 ± 1.04 versus 4.57 ± 0.72 mU/L; P < 0.001) and in C versus D (PI: 15.14 ± 2.20 versus 7.58 ± 2.05 mU/L; P < 0.001, PAI-1: 4.78 ± 0.98 versus 3.49 ± 1.04 mU/L; P < 0.001). Si correlated with PAI-1 in T2D patients and nondiabetics, albeit stronger in T2D. Binary logistic regression identified insulin, PAI-1, and Si as independent predictors for ATIS in T2D patients and nondiabetics. The results imply that insulin resistance and fasting hyperinsulinemia might exert their atherogenic impact through the impaired fibrinolysis.

Hypertension in obese type 2 diabetes patients is associated with increases in insulin resistance and IL-6 cytokine levels: potential targets for an efficient preventive intervention.

Increased body weight as well as type 2 diabetes (T2D) are found to be associated with increased incidence of hypertension, although the mechanisms facilitating hypertension in T2D or nondiabetic individuals are not clear. Therefore, in this study we compared the levels of insulin resistance (IR:OGIS), plasma insulin (PI:RIA) levels, and pro-inflammatory cytokines (IL-6 and TNF-α: ELISA), being risk factors previously found to be associated with hypertension, in T2D patients showing increased body weight (obese and overweight, BMI ≥ 25 kg/m²) with hypertension (group A, N = 30), or without hypertension (group B, N = 30), and in nonobese (BMI < 25 kg/m²), normotensive controls (group C, N = 15). We found that OGIS index was the lowest (A: 267 ± 35.42 vs. B: 342.89 ± 32.0, p < 0.01) and PI levels were the highest (A: 31.05 ± 8.24 vs. B: 17.23 ± 3.23, p < 0.01) in group A. In addition, IL-6 levels were higher in group A (A: 15.46 ± 5.15 vs. B: 11.77 ± 6.09; p < 0.05) while there was no difference in TNF-α levels. Our results have shown that appearance of hypertension in T2D patients with increased body weight was dependent on further increase in IR which was associated with the rise in pro-inflammatory IL-6 cytokine. The results imply that lifestyle intervention aimed to decrease IR might be beneficial in reducing the risk for hypertension in those T2D individuals.

Relationship between obesity, adipocytokines and inflammatory markers in type 2 diabetes: relevance for cardiovascular risk prevention.

This study aimed to analyse the impact of obesity in type 2 diabetes (T2D) on adipocytokines (adiponectin, leptin and resistin) and inflammatory markers (TNF-α, IL-6 and hsCRP) as cardiovascular risk factors. A cross-sectional study comparing the basal levels of adipocytokines and inflammatory markers was done in 18 obese (BMI ≥ 30 kg/m²) (group A), 21 overweight (25 kg/m² ≤ BMI < 30 kg/m²) (group B), 25 non-obese T2D patients (group C) and 15 non-obese controls (group D). The lowest levels of adiponectin and the highest levels of leptin, resistin, TNF-α, IL-6 and hsCRP were found in group A. Adiponectin levels were significantly lower, and resistin, TNF-α, and hsCRP levels were elevated in group C vs. D. However, leptin and IL-6 levels differed significantly between groups A and B, but not between groups C and D. Moreover, we found a significant negative correlation between adiponectin and TNF-α, but not with other markers, which was independent of the presence of obesity. In contrast, leptin and resistin correlated with the inflammatory markers, and this correlation was obesity-dependent. Our results suggest that obesity influences cardiovascular risk primarily through changes in leptin and resistin and less efficiently at the level of adiponectin.

High Risk First Degree Relatives of Type 1 Diabetics: An Association with Increases in CXCR3(+) T Memory Cells Reflecting an Enhanced Activity of Th1 Autoimmune Response.

We analyzed the level of (a) CXCR3(+) (Th1) and CCR4(+) (Th2) T memory cells (b) interferon- γ inducible chemokine (IP-10)(Th1) and thymus and activation-regulated chemokine (TARC)(Th2), in 51 first degree relatives (FDRs) of type 1 diabetics (T1D) (17 high risk FDRs (GADA(+), IA-2(+)) and 34 low risk FDRs (GADA(-), IA-2(-))), 24 recent-onset T1D (R-T1D), and 18 healthy subjects. T memory subsets were analyzed by using four-color immunofluorescence staining and flowcytometry. IP-10 and TARC were determined by ELISA. High risk FDRs showed higher levels of CXCR3(+) and lower level of CCR4(+) T memory cells compared to low risk FDRs (64.98 ± 5.19 versus 42.13 ± 11.11; 29.46 ± 2.83 versus 41.90 ± 8.58%, resp., P < 0.001). Simultaneously, both IP-10 and TARC levels were increased in high risk versus low risk FDRs (160.12 ± 73.40 versus 105.39 ± 71.30; 438.83 ± 120.62 versus 312.04 ± 151.14 pg/mL, P < 0.05). Binary logistic regression analysis identified the level of CXCR3(+) T memory cells as predictors for high risk FDRs, together with high levels of IP-10. The results imply that, in FDRs, the risk for T1D might be strongly influenced by enhanced activity of Th1 and diminished activity of Th2 autoimmune response.