Adrenal secretion of cortisol and androgens is increased in women with the polycystic ovary syndrome. The increases may be explained by dysregulation of 11 beta-hydroxysteroid dehydrogenase causing increased oxidation of cortisol to cortisone, which cannot be accounted for by obesity.

Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and myotubes. To determine whether loss-of-function mutations in TBC1D4 might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulinresistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in TBC1D4. After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, we further characterized the biological effects of the truncated protein in 3T3L1 adipocytes. Prematurely truncated TBC1D4 protein tended to increase basal cell membrane GLUT4 levels (P ‫؍‬ 0.053) and significantly reduced insulin-stimulated GLUT4 cell membrane translocation (P < 0.05). When coexpressed with wild-type TBC1D4, the truncated protein dimerized with full-length TBC1D4, suggesting that the heterozygous truncated variant might interfere with its wild-type counterpart in a dominant negative fashion. Two overweight family members with the mutation also manifested normal fasting glucose and insulin levels but disproportionately elevated insulin levels following an oral glucose challenge. This family provides unique genetic evidence of TBC1D4 involvement in human insulin action.glucose transport ͉ insulin resistance ͉ AS160 B lood glucose levels are very precisely regulated in healthy people despite enormous variation in the timing and magnitude of carbohydrate ingestion. Postingestive insulinstimulated glucose uptake into skeletal muscle and adipose tissue is an essential element of this tight metabolic regulation. Glucose transporter 4 (GLUT4) selectively mediates insulinstimulated glucose transport into myotubes and adipocytes. The importance of this metabolic step in vivo was demonstrated by generating muscle and adipose tissue-specific GLUT4 knockout mice, both of which are insulin resistant (1). Human physiological studies suggest that defects in insulin-stimulated glucose transport in muscle constitute the earliest abnormality in insulinresistant people (2). GLUT4 is the main insulin-responsive hexose transporter. Insulin rapidly increases the amount of GLUT4 in the plasma membrane by causing specialized GLUT4-containing vesicles to move from an intracellular location to the plasma membrane where the vesicles dock and then fuse with the plasma membrane (3). This process is referred to as GLUT4 translocation. Whilst impaired GLUT4 translocation appears to be common to many different insulin resistance-inducing metabolic insults (4), precisely how insulin triggers GLUT4 vesicle movement and subsequent membrane fusion remains incompletely understood. AKT2 is clearly activated in response to insulin and triggers GLUT4 membrane translocation (5), but until recently the link between proxi...

Type 2 diabetes mellitus (DM) is associated with an increased risk of hip fractures despite patients with this condition having normal to high bone mineral density (BMD). Therefore, nonskeletal risk factors may be important in the etiology of fractures in these patients. The aim of this cross-sectional retrospective study was to determine risk factors for falling and fracture in older women with type 2 DM. We randomly recruited 150 women from a community-based diabetes register. They underwent detailed clinical assessment, and BMD was measured by dual-energy X-ray absorptiometry (DXA) and heel quantitative ultrasound (QUS). Mean age was 74 years, mean duration of DM 11 years, mean body mass index 30 kg/m2, and mean HbA1c 7.6%. Mean BMD Z scores were significantly higher than the manufacturer's reference range for all skeletal sites. Previously, 53/150 (35%) of the women had reported a low trauma fracture. The fracture group did not differ significantly from the nonfracture group by age, diabetes-related risk factors or DXA BMD Z scores. However, QUS variables were lower in the fracture group (P = 0.04). A history of one or more falls in the previous 12 months was reported by 61/89 (41%) women. Fallers had a higher vibration perception threshold vs. nonfallers (mean 21.1 vs. 17.6 volts, respectively; P = 0.05). There were no other differences in diabetes or fall-related risk factors. These data suggest that reduced vibration perception (a measure of peripheral neuropathy) is an important risk factor for falling and that QUS, as opposed to DXA, may be a more useful method for fracture risk prediction in older women with type 2 DM. These findings need to be confirmed prospectively.

No abstract

The concept of perineural lymphatics is widely accepted, particularly in reference to prostatic carcinoma. A study of serial sections of many tissue blocks from 12 prostatic carcinomas revealed involvement of perineurium in only five cases; however, the assumption that these tumor cells are in lymphatics is unlikely because of the absence of an endothelial lining and the involvement of the entire circumference of the nerve by tumor in some instances. Experimental studies were performed to further investigate the perineurium. When India ink was injected into the lymphatics of the prostatic capsule of dogs, none was found in perineural areas either grossly or microscopically. Inoculation of Walker 256 carcinoma directly into the perineurium of femoral nerves of rats resulted in variable spread within the nerve and along tissue spaces in the perineurium, with no evidence of invasion of lymphatics or regional lymph nodes. Electron microscopy of canine and human nerves did not reveal any evidence of lymphatics in the perineurium. Therefore, the authors conclude that spread of malignant tumors along nerves in the prostate and elsewhere is not within performed lymphatics but within tissue planes of least resistance.

No abstract

Continuing investigation of pineal gland function indicates that the anti-gonadotrophic activity of this organ cannot be attributed solely to the postulated hormone melatonin, the concentration of which is negligible in the pineal body compared to quantities required to produce unequivocal physiological effects. A non-melatonin antigonadotrophic substance recently isolated from bovine pineal glands was further purified by organic solvent extraction, ultrafiltration and gel filtration. Studies of partial blockage of compensatory ovarian hypertrophy in unilaterally ovariectomized Charles River CD-1 mice indicated that this substance is significantly more potent than melatonin in this test system.

A study of 147 human pineal glands from autopsy cases of all ages revealed a direct correlation between size and weight and a significant correlation of these with age but not with body weight, brain weight, sex or color. The growth pattern was nonlinear, with a sharp increase in size in the fifth and sixth decades. This increase was reduced but still apparent after removal of malignant cases from the sample. Pineal glands from malignant cases were significantly larger than the others. Histologic studies revealed a striking similarity of pineocytes from pineals of patients between ages 2 and 91, with no apparent differences in malignant cases. The authors conclude that the human pineal does not undergo cellular atrophy after puberty and that there is some relationship between the presence of malignancy and the weight of the human pineal.