Comparative pharmacodynamic and pharmacokinetic characteristics of subcutaneous insulin glulisine and insulin aspart prior to a standard meal in obese subjects with type 2 diabetes

Aims: A multinational, randomized, double-blind, two-way crossover trial to compare the pharmacokinetic and pharmacodynamic properties of bolus, subcutaneously administered insulin glulisine (glulisine) and insulin aspart (aspart) in insulin-naÏve, obese subjects with type 2 diabetes

Hyperglycemia-Induced Platelet Activation in Type 2 Diabetes Is Resistant to Aspirin but Not to a Nitric Oxide–Donating Agent

OBJECTIVE: Acute, short-term hyperglycemia enhances high shear stress-induced platelet activation in type 2 diabetes. Several observations suggest that platelets in type 2 diabetes are resistant to inhibition by aspirin. Our aim was to assess comparatively the effect of aspirin, a nitric oxide-donating agent (NCX 4016), their combination, or placebo on platelet activation induced by acute hyperglycemia in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a double-blind, placebo-controlled, randomized trial, 40 type 2 diabetic patients were allocated to 100 mg aspirin once daily, 800 mg NCX 4016 b.i.d., both of them, or placebo for 15 days. On day 15, 1 h after the morning dose, a 4-h hyperglycemic clamp (plasma glucose 13.9 mmol/l) was performed, and blood samples were collected before and immediately after it for platelet activation and cyclooxygenase-1 (COX-1) inhibition studies. RESULTS Acute hyperglycemia enhanced shear stress-induced platelet activation in placebo-treated patients (basal closure time 63 +/- 7.1 s, after hyperglycemia 49.5 +/- 1.4 s, -13.5 +/- 6.3 s, P < 0.048). Pretreatment with aspirin, despite full inhibition of platelet COX-1, did not prevent it (-12.7 +/- 6.9 s, NS vs. placebo). On the contrary, pretreatment with the NO donor NCX 4016, alone or in combination with aspirin, suppressed platelet activation induced by acute hyperglycemia (NCX 4016 +10.5 +/- 8.3 s; NCX 4016 plus aspirin: +12.0 +/- 10.7 s, P < 0.05 vs. placebo for both). Other parameters of shear stress-dependent platelet activation were also more inhibited by NCX 4016 than by aspirin, despite lesser inhibition of COX-1. CONCLUSIONS: Acute hyperglycemia-induced enhancement of platelet activation is resistant to aspirin; a NO-donating agent suppresses it. Therapeutic approaches aiming at a wider platelet inhibitory action than that exerted by aspirin may prove useful in patients with type 2 diabetes

Blood Cell Mitochondrial DNA Content and Premature Ovarian Aging.

Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction

Primary ovarian insufficiency: autoimmune causes.

To review the pathogenesis of premature ovarian insufficiency due to steroid cell autoimmunity (SCA-POI).Autoimmune oophoritis is characterized by a selective mononuclear cell infiltration into the theca layer of large, antral follicles, with earlier stage follicles consistently free of lymphocytic infiltration. SCA-POI is caused by the selective autoimmune destruction of theca cells with preservation of granulosa cells that produce low amounts of estradiol because of lack of substrates. Typically, serum concentrations of inhibins are increased in women with SCA-POI, as compared to both healthy fertile women and women with other forms of ovarian insufficiency. Normal serum antim\ufcllerian hormone (AMH) concentrations were detected in two-thirds of women with recently diagnosed SCA-POI, which demonstrates that this form of ovarian insufficiency is associated with a preserved pool of functioning follicles.The combined measurement of autoantibodies and markers of ovarian reserve (as inhibin B and AMH) may permit to identify women with POI due to steroid cell autoimmunity with a preserved proportion of primordial and primary follicles. In the future the development of techniques of in-vitro folliculogenesis may permit new treatment strategies for women with SCA-POI-related infertility

High serum inhibin concentration discriminates autoimmune oophoritis from other forms of primary ovarian insufficiency

Context: Primary ovarian insufficiency (POI) is defined by hypergonadotropic amenorrhea occurring before the age of 40 yr. In 4–5% of women with POI, an ovarian autoimmune process can be demonstrated. Design: We have determined the serum concentrations of total inhibin and inhibin B by sensitive ELISAs in 22womenwith autoimmune POI (aPOI), 71womenwith non-autoimmune idiopathic POI (iPOI), 77 postmenopausal women, and 90 healthy, fertile women (HW). Diagnosis of aPOI was made according to the presence of steroid cell autoantibodies and/or 17-hydroxylase autoantibodies and/or cytochrome P450 side-chain cleavage autoantibodies. All aPOI patients were also positive for adrenal autoantibodies. Results: Total inhibin levels were significantly higher inwomenwith aPOI (median, 281 pg/ml) than in women with iPOI (median, 74 pg/ml) or HW (median, 133.5 pg/ml) (P 0.001). Levels of inhibin B were also significantly higher in women with aPOI (median, 109 pg/ml) than in women with iPOI (median, 18 pg/ml) (P 0.001) orHW(median, 39 pg/ml) (P 0.05). Serum concentrations of total inhibin and inhibin B were significantly higher inwomenwith POI than in postmenopausalwomen (P 0.001), irrespective of the presence/absence of autoantibodies. At receiver-operating characteristic analysis, cutoff values of 133 pg/ml for total inhibin and 60.5 pg/ml for inhibin B ensured 86.4% sensitivity and 81–84.5% specificity for aPOI vs. iPOI. Conclusions: We conclude that a variable degree of ovarian function is preserved in women with POI and that aPOI is characterized by increased inhibin production resulting from a selective theca cell destruction, with initial preservation of granulosa cells

Autoantibody responses in autoimmune ovarian insufficiency and in Addison's disease are IgG1 dominated and suggest a predominant, but not exclusive, Th1 type of response

none13noneBrozzetti A;Marzotti S;La Torre D;Bacosi ML;Morelli S;Bini V;Ambrosi B;Giordano R;Perniola R;De Bellis A;Betterle C;Falorni A;Italian Addison NetworkBrozzetti, A; Marzotti, S; La Torre, D; Bacosi, Ml; Morelli, S; Bini, V; Ambrosi, B; Giordano, R; Perniola, R; De Bellis, A; Betterle, Corrado; Falorni, A; Italian Addison, Networ

Primary ovarian insufficiency due to steroidogenic cell autoimmunity is associated with a preserved pool of functioning follicles

Context: Primary ovarian insufficiency (POI) is defined as hypergonadotropic amenorrhea before the age of 40 yr. In 4-5% of patients with POI, an ovarian autoimmune process is present. Design: Serum concentrations of antimüllerian hormone (AMH) have been determined in 26 women with POI due to steroidogenic cell autoimmunity (SCA-POI), 66 with nonautoimmune idiopathic POI (iPOI), 40 postmenopausal women (PMW), and 44 healthy fertile women (HW). SCA-POI was diagnosed according to presence of steroidogenic enzyme autoantibodies (17α-hydroxylase, side chain cleavage, and 21-hydroxylase autoantibodies). Results: AMH concentrations were significantly higher in women with SCA-POI than women with iPOI (P = 0.018) orPMW(P = 0.03) but significantly lower thanHW(P < 0.0001). AMH was detected in 11 of 26 women with SCA-POI (42%) and seven of 66 with iPOI (11%) (P = 0.002). Serum concentrations above the fifth percentile of the normal range (0.6 ng/ml) were detected in nine of 26 women with SCA-POI (35%) and four of 66 with iPOI (6%) (P = 0.001). Eight of 12 women with SCA-POI with less than 5 yr (67%) and one of 14 with longer disease duration (7%) had AMH concentrations within the normal range (P = 0.003). AMH concentrations correlated inversely with disease duration in women with SCA-POI (rho = -0.563, P = 0.003) but not women with iPOI. AMH correlated inversely with FSH serum concentrations inHW(rho = -0.584, P < 0.001) but not PMW or women with POI. Conclusions: Two thirds of women with recent-onset SCA-POI had normal AMH concentrations. Women with SCA-POI, differently from those with iPOI, present a preserved ovarian follicle pool for several years after diagnosis of ovarian insufficiency. Copyright © 2009 by The Endocrine Society