Methods for Measuring Risk for Type 2 Diabetes in Youth: the Oral Glucose Tolerance Test (OGTT)

Purpose of Review The oral glucose tolerance test (OGTT) is used both in clinical practice and research to assess glucose tolerance. In addition, the OGTT is utilized for surrogate measures of insulin sensitivity and the insulin response to enteral glucose and has been widely applied in the evaluation of β-cell dysfunction in obesity, prediabetes, and type 2 diabetes. Here we review the use of the OGTT and the OGTT-derived indices for measurement of risk markers for type 2 diabetes in youth. Recent Findings Advantages of using the OGTT for measures of diabetes risk include its accessibility and the incorporation of physiological contributions of the gut-pancreas axis in the measures of insulin response to glucose. Mathematical modeling expands the potential gains from the OGTT in physiology and clinical research. Disadvantages include individual differences in the rate of glucose absorption that modify insulin responses, imperfect control of the glycemic stimulus, and poor intraindividual reproducibility. Summary Available research suggests the OGTT provides valuable information about the development of impaired glycemic control and β-cell function in obese youth along the spectrum of glucose tolerance

Multi-targeted approach in the treatment of thyroid cancer

While accounting for only 1% of solid organ malignancies (9% in women), thyroid carcinoma is the most common malignancy of the endocrine system. Although most patients have a favorable prognosis, over 1,500 people will die from thyroid carcinoma each year. The spectrum of disease types range from papillary thyroid cancer, which is a well-differentiated indolent tumor, to anaplastic carcinoma, a poorly differentiated fulminant cancer. With advances in diagnostic methods, surgical techniques, and clinical care of patients with thyroid carcinoma, the current management of thyroid cancer demands a multidisciplinary approach. The majority of patients with well-differentiated thyroid carcinoma of follicular cell origin are cured with adequate surgical management; however, some thyroid malignancies such as medullary thyroid carcinoma (MTC) or poorly differentiated thyroid carcinomas frequently metastasize, precluding patients from a curative resection. As such, novel palliative and therapeutic strategies are needed for this patient population. Here, we explore the current management of thyroid carcinoma, including surgical management of the primary tumor, lymph node disease, and locoregional recurrence. Likewise, we explore the application of current molecular techniques, reviewing nearly two decades of data that have begun to elucidate critical genetic pathways and therapeutic drug targets which may be important in specific thyroid tumor types

Medullary Thyroid Carcinoma: Targeted Therapies and Future Directions

Medullary thyroid cancer (MTC) is a rare neuroendocrine neoplasm that accounts for approximately 5% of all thyroid malignancies. The natural history of MTC is characterized by early lymph node and distant metastases, making complete surgical cure often impossible. Conventional chemotherapy and external beam radiation have been largely ineffective in altering the natural history of MTC. Therefore, there is a great need to develop novel therapeutic strategies to affect symptom control and reduce tumor burden in patients with widely disseminated disease. Here, we review several pathways which have been shown to be vital in MTC tumorigenesis and focus on the pathways of interest for which targeted drug therapies are currently being developed

Characterizing Circumgalactic Gas around Massive Ellipticals at z~0.4 - II. Physical Properties and Elemental Abundances

We present a systematic investigation of the circumgalactic medium (CGM) within projected distances d<160 kpc of luminous red galaxies (LRGs). The sample comprises 16 intermediate-redshift (z=0.21-0.55) LRGs of stellar mass M_star>1e11 M_sun. Combining far-ultraviolet Cosmic Origin Spectrograph spectra from the Hubble Space Telescope and optical echelle spectra from the ground enables a detailed ionization analysis based on resolved component structures of a suite of absorption transitions, including the full HI Lyman series and various ionic metal transitions. By comparing the relative abundances of different ions in individually-matched components, we show that cool gas (T~1e4 K) density and metallicity can vary by more than a factor of ten in in an LRG halo. Specifically, metal-poor absorbing components with <1/10 solar metallicity are seen in 50% of the LRG halos, while gas with solar and super-solar metallicity is also common. These results indicate a complex multiphase structure and poor chemical mixing in these quiescent halos. We calculate the total surface mass density of cool gas, \Sigma_cool, by applying the estimated ionization fraction corrections to the observed HI column densities. The radial profile of \Sigma_cool is best-described by a projected Einasto profile of slope \alpha=1 and scale radius r_s=48 kpc. We find that typical LRGs at z~0.4 contain cool gas mass of M_cool= (1-2) x1e10 M_sun at d<160 kpc (or as much as 4x1e10 M_sun at d<500 kpc), comparable to the cool CGM mass of star-forming galaxies. Furthermore, we show that high-ionization OVI and low-ionization absorption species exhibit distinct velocity profiles, highlighting their different physical origins. We discuss the implications of our findings for the origin and fate of cool gas in LRG halos.Comment: Accepted for publication in MNRAS after a minor revision. 23 pages, 14 figures, and a 29-page Appendix with 27 additional figure

Mitochondrial fission factor (Mff) is required for organization of the mitochondrial sheath in spermatids

Background: Mitochondrial fission counterbalances fusion to maintain organelle morphology, but its role during development remains poorly characterized. Mammalian spermatogenesis is a complex developmental process involving several drastic changes to mitochondrial shape and organization. Mitochondria are generally small and spherical in spermatogonia, elongate during meiosis, and fragment in haploid round spermatids. Near the end of spermatid maturation, small mitochondrial spheres line the axoneme, elongate, and tightly wrap around the midpiece to form the mitochondrial sheath, which is critical for fueling flagellar movements. It remains unclear how these changes in mitochondrial morphology are regulated and how they affect sperm development. Methods: We used genetic ablation of Mff (mitochondrial fission factor) in mice to investigate the role of mitochondrial fission during mammalian spermatogenesis. Results: Our analysis indicates that Mff is required for mitochondrial fragmentation in haploid round spermatids and for organizing mitochondria in the midpiece in elongating spermatids. In Mff mutant mice, round spermatids have aberrantly elongated mitochondria that often show central constrictions, suggestive of failed fission events. In elongating spermatids and spermatozoa, mitochondrial sheaths are disjointed, containing swollen mitochondria with large gaps between organelles. These mitochondrial abnormalities in Mff mutant sperm are associated with reduced respiratory chain Complex IV activity, aberrant sperm morphology and motility, and reduced fertility. Conclusions: Mff is required for organization of the mitochondrial sheath in mouse sperm. General Significance: Mitochondrial fission plays an important role in regulating mitochondrial organization during a complex developmental process

Nkx2-5 and Sarcospan genetically interact in the development of the muscular ventricular septum of the heart

The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (Sspn(KO)) mice do not have heart defects, but Nkx2-5(+/−)/Sspn(KO) mutants have a higher incidence of muscular VSD than Nkx2-5(+/−) mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5(+/−)/Sspn(KO) mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs