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.

Predictors of subclinical cardiovascular disease in women with polycystic ovary syndrome: interrelationship of dyslipidemia and arterial blood pressure.

Background. Women with polycystic ovary syndrome (PCOS) could develop subclinical atherosclerosis during life. Purpose. To analyze cardiovascular risk (CVR) factors and their relation to clinical markers of cardiovascular disease (CVD) in respect to their age. Material and Methods. One hundred women with PCOS (26.32 ± 5.26 years, BMI: 24.98 ± 6.38 kg/m(2)) were compared to 50 respective controls. In all subjects, total cholesterol (TC), HDL-C, LDL-C, triglycerides, TC/HDL-C and TG/HDL-C ratios, glucose, insulin and HOMA index, waist-to-hip ratio (WHR), systolic and diastolic blood pressure (SBP and DBP, resp.), and carotid intima-media thickness (CIMT) were analyzed in respect to their age and level of androgens. Results. PCOS over 30 years had higher WHR (P = 0.008), SBP (P < 0.001), DBP (P < 0.001), TC (P = 0.028), HDL-C (P = 0.028), LDL-C (P = 0.045), triglycerides (P < 0.001), TC/HDL-C (P < 0.001), and triglycerides/HDL-C (P < 0.001) and had more prevalent hypertension and pronounced CIMT on common carotid arteries even after adjustment for BMI (P = 0.005 and 0.036, resp.). TC/HDL-C and TG/HDL-C were higher in PCOS with the highest quintile of FAI in comparison to those with lower FAI (P = 0.045 and 0.034, resp.). Conclusions. PCOS women older than 30 years irrespective of BMI have the potential for early atherosclerosis mirrored through the elevated lipids/lipid ratios and through changes in blood pressure.

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.

Type 2 diabetic patients with ischemic stroke: decreased insulin sensitivity and decreases in antioxidant enzyme activity are related to different stroke subtypes.

We analyzed (a) insulin sensitivity (IS) and (b) glutathione peroxidase (GSH-Px), glutathione reductase (GR), and superoxide dismutase (SOD) antioxidant enzyme activity in type 2 diabetic (T2D) patients with atherothrombotic infarction (ATI) (group A), lacunar infarction (LI) (B), or without stroke (C) and in nondiabetics with ATI (D), LI (E), or without stroke (F). ATI and LI were confirmed by brain imaging IS levels were determined by minimal model (Si index), and the enzyme activity by spectrophotometry. In T2D patients, Si was lower in A and B versus C (1.14 ± 0.58, 1.00 ± 0.26 versus 3.14 ± 0.62 min(-1)/mU/l × 10(4), P < 0.001) and in nondiabetics in D and E versus F (3.38 ± 0.77, 3.03 ± 0.72 versus 6.03 ± 1.69 min(-1)/mU/l × 10(4), P < 0.001). Also, GSH-Px and GR activities were lower in A and B versus C (GSH-Px: 21.96 ± 3.56, 22.51 ± 1.23 versus 25.12 ± 1.67; GR: 44.37 ± 3.58, 43.50 ± 2.39 versus 48.58 ± 3.67 U/gHb; P < 0.001) and in D and E versus F (GSH-Px: 24.75 ± 3.02, 25.57 ± 1.92 versus 28.56 ± 3.91; GR: 48.27 ± 6.81, 49.17 ± 6.24 versus 53.67 ± 3.96 U/gHb; P < 0.001). Decreases in Si and GR were significantly related to both ATI and LI in T2D. Our results showed that decreased IS and impaired antioxidant enzymes activity influence ischemic stroke subtypes in T2D. The influence of insulin resistance might be exerted on the level of glutathione-dependent antioxidant enzymes.

Clinical Case Seminar. Peculiar prolactinomas in patients with pituitary developmental gene mutations: from an adult endocrinologist perspective.

CONTEXT: Congenital hypopituitarism is a syndrome which is associated with single or multiple pituitary hormone deficiencies. Mutations in a number of developmental genes have been linked to combined pituitary hormone deficiencies, the most common being mutation in the pituitary homeobox protein prophet of the Pit 1 gene (PROP1). PROP1 exhibits DNA-binding and transcriptional activities. On magnetic resonance imaging, most patients with PROP1 mutation have a hypoplastic pituitary gland. Occasionally, transient pituitary enlargement before definite involution is reported. Kallmann syndrome (KS) is a human developmental genetic disorder which is a clinically (isolated hypogonadotropic hypogonadism-IHH) and genetically heterogeneous disease. Routine neuroimaging in classical IHH is thought to be of limited clinical value and normal anatomy of the hypothalamic-pituitary region is often reported. For neither disorder are there many reports on imaging during adulthood. Nor are there any guidelines concerning long-term imaging follow-up in patients with developmental pituitary disorders. OBJECTIVE: Our aim was to present unusual endocrine and imaging abnormalities which developed in adulthood in two patients with developmental pituitary disorders. CASES: We report a female with combined pituitary hormone deficiencies (GH, TSH, gonadotropin and ACTH), except for prolactin, as a consequence of PROP1 mutation, and a male with KS (anosmia and IHH) due to Kal 2 gene (fibroblast growth factor receptor 1- FGFR1) mutation, both of whom in adulthood presented with prolactinomas. CONCLUSION: Both patients with developmental gene mutations, after long-term correction of their sex steroid status, developed prolactinomas. Although the exact mechanism of pituitary tumorigenesis is not known, we speculate that sex steroids may have facilitated prolactinoma development from the prolactin cell pool which underwent uncontrolled proliferation in the setting of a developmental disorder.