Asprosin, a Fasting-Induced Glucogenic Protein Hormone.

Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.

Fetal Hyperthyroidism Secondary to Maternal Basedow-Graves' Disease.

Fetal hyperthyroidism is a rare prenatal disease and can be life-threatening. The diagnosis is based on ultrasound in mothers with a history of Basedow-Graves' disease and elevation of thyrotropin receptor antibodies (TRAbs) levels. The treatment consists of antithyroid drugs. We present a mother with Basedow-Graves' disease, treated with radioactive iodine 16 years ago. She had an unplanned pregnancy at the age of 29 years, and an elevation of TRAbs (21 U/L) was found at the sixth week of pregnancy. At 22 weeks of gestation, fetal ultrasound displayed tachycardia, goiter, exophthalmos, and suspicion of craniosynostosis, hence methimazole was started. Concomitantly, suppressed maternal thyroid-stimulating hormone (TSH) was found. Her daughter was born at 33 + 6 weeks showing clinical and laboratory findings of hyperthyroidism. Consequently, treatment with methimazole was prescribed. Normal thyroid function was documented in the mother after giving birth. Clear explanation has not been found for the alteration of maternal TSH during pregnancy.

Generation of Fbn1 conditional null mice implicates the extracellular microfibrils in osteoprogenitor recruitment.

Loss-of-function experiments in mice have yielded invaluable mechanistic insights into the pathogenesis of Marfan syndrome (MFS) and implicitly, into the multiple roles fibrillin-1 microfibrils play in the developing and adult organism. Unfortunately, neonatal death from aortic complications of mice lacking fibrillin-1 (Fbn1(-/-) mice) has limited the scope of these studies. Here, we report the creation of a conditional mutant allele (Fbn1(fneo) ) that contains loxP sites bordering exon1 of Fbn1 and an frt-flanked neo expression cassette downstream of it. Fbn1(fneo/+) mice were crossed with FLPeR mice and the resulting Fbn1(Lox/+) progeny were crossed with Fbn1(+/-) ;CMV-Cre mice to generate Fbn1(CMV-/-) mice, which were found to phenocopy the vascular abnormalities of Fbn1(-/-) mice. Furthermore, mating Fbn1(Lox/+) mice with Prx1-Cre or Osx-Cre mice revealed an unappreciated role of fibrillin-1 microfibrils in restricting osteoprogenitor cell recruitment. Fbn1(Lox/+) mice are, therefore, an informative genetic resource to further dissect MFS pathogenesis and the role of extracellular fibrillin-1 assemblies in organ development and homeostasis.

Fluoro-Julia olefination as a mild, high-yielding route to alpha-fluoro acrylonitriles.

Synthesis of a novel, stable reagent (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile from readily synthesized ethyl alpha-(1,3-benzothiazol-2-ylsulfanyl)-alpha-fluoroacetate is reported. Aldehydes undergo condensations with (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile in the presence of DBU leading to alpha-fluoro acrylonitriles in high yields and with good Z-stereoselectivity. Lowering of reaction temperature increases the Z selectivity.

Fibrillin-1 microfibrils influence adult bone marrow hematopoiesis.

We have recently demonstrated that fibrillin-1 assemblies regulate the fate of skeletal stem cells (aka, mesenchymal stem cells [MSCs]) by modulating TGFß activity within the microenvironment of adult bone marrow niches. Since MSCs can also influence hematopoietic stem cell (HSC) activities, here we investigated adult hematopoiesis in mice with Cre-mediated inactivation of the fibrillin-1 (Fbn1) gene in the mesenchyme of the forming limbs (Fbn1(Prx1-/-) mice). Analyses of 3-month-old Fbn1(Prx1-/-) mice revealed a statistically significant increase of circulating red blood cells, which a differentiation assay correlated with augmented erythropoiesis. This finding, together with evidence of fibrillin-1 deposition in erythroblastic niches, supported the notion that this extracellular matrix protein normally restricts differentiation of erythroid progenitors. Whereas flow cytometry measurements identified a decreased HSC frequency in mutant relative to wild type mice, no appreciable differences were noted with regard to the relative abundance and differentiation potential of myeloid progenitor cells. Together these findings implied that fibrillin-1 normally promotes HSC expansion but does not influence cell lineage commitment. Since local TGFß hyperactivity has been associated with abnormal osteogenesis in Fbn1(Prx1-/-) mice, 1-month-old mutant and wild type animals were systemically treated for 8weeks with either a pan-TGF-ß-neutralizing antibody or an antibody of the same IgG1 isotype. The distinct outcomes of these pharmacological interventions strongly suggest that fibrillin-1 differentially modulates TGFß activity in HSC vs. erythroid niches.

Fibrillin-1 Regulates Skeletal Stem Cell Differentiation by Modulating TGFß Activity Within the Marrow Niche.

A full understanding of the microenvironmental factors that control the activities of skeletal stem cells (also known as mesenchymal stem cells [MSCs]) in the adult bone marrow holds great promise for developing new therapeutic strategies to mitigate age-related diseases of bone and cartilage degeneration. Bone loss is an understudied manifestation of Marfan syndrome, a multisystem disease associated with mutations in the extracellular matrix protein and TGFß modulator fibrillin-1. Here we demonstrate that progressive loss of cancellous bone in mice with limbs deficient for fibrillin-1 (Fbn1(Prx1-/-) mice) is accounted for by premature depletion of MSCs and osteoprogenitor cells combined with constitutively enhanced bone resorption. Longitudinal analyses of Fbn1(Prx1-/-) mice showed incremental bone loss and trabecular microarchitecture degeneration accompanied by a progressive decrease in the number and clonogenic potential of MSCs. Significant paucity of marrow fat cells in the long bones of Fbn1(Prx1-/-) mice, together with reduced adipogenic potential of marrow stromal cell cultures, indicated an additional defect in MSC differentiation. This postulate was corroborated by showing that an Fbn1-silenced osteoprogenitor cell line cultured in the presence of insulin yielded fewer than normal adipocytes and exhibited relatively lower PPARγ levels. Consonant with fibrillin-1 modulation of TGFß bioavailability, cultures of marrow stromal cells from Fbn1(Prx1-/-) limb bones showed improper overactivation of latent TGFß. In line with this finding, systemic TGFß neutralization improved bone mass and trabecular microarchitecture along with normalizing the number of MSCs, osteoprogenitor cells, and marrow adipocytes. Collectively, our findings show that fibrillin-1 regulates MSC activity by modulating TGFß bioavailability within the microenvironment of marrow niches.

[Polycystic ovary syndrome and pregnancy: clinical experience]. / Síndrome de ovario poliquístico (SOP) y embarazo: Experiencia clínica.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications. AIM: To report a prospective clinical experience in PCOS patients who became pregnant after diet, exercise and metformin treatment intervention, and were followed up during the whole pregnancy. PATIENTS AND METHODS: Seventy pregnant PCOS (PPCOS) women and forty normal pregnant (NP) women of similar age and with singleton pregnancies were included in the study. During gestational ages 10-16 and 22-28 weeks, a 2h, 75 g oral glucose tolerance test (OGTT) was performed with measurement of glucose and insulin in each sample. RESULTS: No differences were found in duration of gestation, weight gain during pregnancy, or systolic and diastolic blood pressure between PPCOS and NP women. There were significant differences in body mass index (BMI) at the initiation and in the third trimester of pregnancy between both groups. The incidence of gestational diabetes was significantly higher (p <0.01) in the PCOS group (35.2%) compared to the control group (5.0%). The prevalence of small for gestational age (SGA) infants tended to be higher (p =0.09) in the PCOS group. During pregnancy, 2h glucose and insulin were significantly higher in PPCOS than in NP women. CONCLUSIONS: PCOS mothers showed a higher prevalence of gestational diabetes and SGA newborns, which cannot be attributed to the weight gain during pregnancy, and seems to be more related to the BMI at the initiation of pregnancy, and to the PCOS condition of the mother.

Síndrome de ovario poliquístico (SOP) y embarazo: Experiencia clínica / Polycystic ovary syndrome and pregnancy: Clinical experience

Background: Polycystic ovary syndrome (PCOS) is an endocrine metabolic dysfunction closely associated with insulin resistance and obesity, which predisposes to pregnancy complications. Aim: To report a prospective clinical experience in PCOS patients who became pregnant after diet, exercise and metformin treatment intervention, and were followed up during the whole pregnancy. Patients and Methods: Seventy pregnant PCOS (PPCOS) women and forty normal pregnant (NP) women of similar age and with singleton pregnancies were included in the study. During gestational ages 10-16 and 22-28 weeks, a 2h, 75 g oral glucose tolerance test (OGTT) was performed with measurement of glucose and insulin in each sample. Results: No differences were found in duration of gestation, weight gain during pregnancy, or systolic and diastolic blood pressure between PPCOS and NP women. There were significant differences in body mass index (BMI) at the initiation and in the third trimester of pregnancy between both groups. The incidence of gestational diabetes was significantly higher (p <0.01) in the PCOS group (35.2 percent) compared to the control group (5.0 percent). The prevalence of small for gestational age (SGA) infants tended to be higher (p =0.09) in the PCOS group. During pregnancy, 2h glucose and insulin were significantly higher in PPCOS than in NP women. Conclusions: PCOS mothers showed a higher prevalence of gestational diabetes and SGA newborns, which cannot be attributed to the weight gain during pregnancy, and seems to be more related to the BMI at the initiation of pregnancy, and to the PCOS condition of the mothe.

Síndrome de ovario poliquístico, obesidad e hiperinsulinismo: un camino a la diabetes / Polycystic ovary syndrome POS, obesity and hyperinsulinism: a course to diabetes

El síndrome de ovario poliquístico(SOP) es una disfunción endocrinometabólica heterogénea de alta prevalencia, con una probable base genética, que compromete la función reproductiva de la mujer joven y que se encuentra en estrecha asociación a la insulinorresistencia (IR), Dentro de su compleja fisiopatología destacan la hipersecreción de LH e insulina, las cuales agravan una alteración preexistente de la biosíntesis esteroidal. La presencia de IR predispone a estas pacientes a desarrollar complicaciones cardiovasculares y metabólicas, las que suelen ser precoces. Por otro lado, la incidencia de patologías metabólicas asociadas a IR es mayor en los familiares de pacientes SOP que en los de mujeres normales, de ahí que el tratamiento de este síndrome no sólo debe ser sintomático, sino fundamentalmente preventivo. Asimismo, el SOP debería ser considerado un marcador de una patología familiar, un camino a la diabetes y un problema de salud pública

Insulinorresistencia: generalidades e implicancias clínicas / Insulin resistance generalties and clinical approach

La insulinorresistencia, es la base fisiopatológica de múltiples enfermedades de alta prevalencia, entre las que se destacan: la obesidad androide, la intolerancia a la glucosa, la diabetes mellitus, la hipertensión arterial y la dislipidemia. Además, se presenta en otras situaciones patológicas frecuentes, entre otras, diabetes gestacional, ovario poliquístico y en sujetos pequeños para la edad gestacional. Finalmente, está presente en una serie de condiciones fisiológicas y patológicas poco frecuentes o muy excepcionales, ya sea de origen genético, congénitas o adquiridas. Quizás más que por su prevalencia, el principal problema reside en, que esta condición puede permanecer desconocida y el daño metabólico puede ocurrir mucho antes que un exámen fortuito o el cuadro florido de una diabetes 2 nos lleve finalmente a su diagnóstico. El propósito de esta revisión es dar una orientación diagnóstica práctica de este síndrome tanto desde el punto de vista clínico como de las metodologías actualmente en uso