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Fat distribution was assessed by a series of ten skinfold measurements in 7,717 persons voluntarily undergoing a multiphasic health screening examination. From this total, in 360 diabetic and 934 nondiabetic control subjects matched for race, sex, age, height, and weight, fat distribution patterns were compared by direct skinfold measurements, and by triceps ratios and subscapular ratios: thickness of each of the individual's skinfolds relative to his triceps or his subscapular skinfold respectively. Diabetic subjects, especially women, showed a significant shift toward centripetal distribution of fat. The data indicated that centripetal fat distribution is a masculine characteristic. It is suggested that in diabetes there is a disturbance of male/female hormonal balance, responsible for centripetal fat distribution in women, and for exaggeration of centripetal fat distribution in men. Furthermore, the data suggested that persons with diabetes have more total fat than their nondiabetic counterparts.

In addition to its central role in energy production, oxygen has pervasive regulatory actions. Hypoxia (oxygen limitation) triggers the shutdown of major cellular processes, including gene expression. We carried out a genome-wide RNA interference (RNAi) screen in Drosophila S2 cells for functions required to down-regulate translation during hypoxia. RNAi knockdown of specific genes allowed induction of a green fluorescent protein (GFP) reporter gene and continued protein synthesis during hypoxia. Among the identified genes, Tsc1 and Tsc2, which together form the tuberose sclerosis complex that negatively regulates target of rapamycin (TOR) kinase, gave an especially strong effect. This finding is consistent with the involvement of TOR in promoting translation. Another gene required for efficient inhibition of protein translation during hypoxia, the protein tyrosine phosphatase 61F (Ptp61F), down-regulates TOR activity under hypoxia. Lack of Ptp61F or Tsc2 improves cell survival under prolonged hypoxia in a TOR-dependent manner. Our results identify Ptp61F as a novel modulator of TOR activity and suggest that its function during hypoxia contributes to the down-regulation of protein synthesis. INTRODUCTIONOxygen is a pivotal component in metabolism and physiology. Damage caused by limited oxygen supply, as occurs in stroke and myocardial infarction, is one of the leading causes of death in the United States. Limited oxygen availability, called hypoxia, is also a key feature of the microenvironment in solid tumors, and tumor cell survival of hypoxia is important in progression to malignancy.When a shortfall in oxygen is modest, cells and organisms can adjust their metabolism and physiology to compensate, a response that includes adjustments in gene expression mediated by hypoxia-inducible factor (HIF) (Semenza, 2007). However, when reductions in oxygen levels are more severe, cells cannot continue to function, and survival depends on inducing quiescence. Indeed, organisms that tolerate severe hypoxia do so by entering a state resembling suspended animation, in which energy-consuming activities are curtailed. The embryos of many organisms, including Danio rerio (Padilla and Roth, 2001), Caenorhabditis elegans (Padilla et al., 2002), and Drosophila melanogaster (Wingrove and O'Farrell, 1999;DiGregorio et al., 2001;Teodoro and O'Farrell, 2003), instantly enter such a state under severe hypoxia. Our laboratory showed that abrupt loss of oxygen causes inhibition of DNA replication, gene transcription and protein translation, cell cycle arrest in either interphase or metaphase, and stabilization of mRNA and proteins in Drosophila embryos (Wingrove and O'Farrell, 1999;DiGregorio et al., 2001;Teodoro and O'Farrell, 2003).Similar hypoxia responses have been observed in mammalian cell culture systems. Among them, hypoxia-induced inhibition of protein translation has been studied in detail (Liu and Simon, 2004;Wouters et al., 2005;Koumenis, 2006;Koumenis and Maxwell, 2006;Liu et al., 2006). Hypoxia engages several regulatory ...

Normal rabbits immunized with bovine insulin in adjuvant produce circulating autoantibodies that bind large amounts of endogenous insulin (measured by an immunoassay which distinguishes endogenous and exogenous insulin). In a series of nine immunized animals, two not only produced autoantibody but also, as a result of the autoimmune phenomenon, became acutely diabetic. Their blood sugar, circulating antibody, endogenous insulin bound to antibody and morphologic lesions in the islets of Langerhans observed by light and electron microscopy were compared to those of immunized but nondiabetic rabbits for a period of sixty-five weeks. Diabetes was characterized by weight loss, lipemia and blood sugar levels maintained at 350 to 600 mg. per 100 ml. throughout an experimental period of twenty-one weeks after immunization with insulin. Although circulating antibody levels were unusually high in the diabetic animals, little antibody-bound insulin was evidenced in contrast to the nondiabetic immunized rabbits whose bound endogenous insulin ranged fiom 390 to 2,340 μU. per ml. Histologic examination by light and electron microscopy at twenty-one weeks revealed absence of beta cell granules and severe damage to the beta cells. Lymphocytic infiltration of the islets was noted in the less severe diabetic in which some beta cells remained, but neither lymphocytes nor beta cells could be detected in the most severely diabetic animal. Alpha cells in each rabbit were normal. Significantly, the nondiabetic immunized rabbits also showed specific changes in their beta cells detectable by electron microscopy. The surviving, less severely diabetic rabbit remained diabetic and had detectable antibody until sacrificed fourteen months after immunization. Improvement of the animal at this time was indicated by a blood sugar level of 174 mg. per 100 ml., an increase in antibody-bound endogenous insulin, extractable pancreatic insulin in an amount two thirds of normal, and demonstrable granules in most of the beta cells. It was concluded thai an autoimmune diabetes that closely resembles the early juvenile form can be created in rabbits by immunization with insulin. The possibility that autoimmunity can not only contribute to the diabetic state in insulin-treated subjects but may prove important as an underlying cause in some forms of diabetes is discussed.

The efficacy, safety, and effects on hemostasis and coagulation of two doses of human tissue-type plasminogen activator in patients with acute and subacute peripheral arterial occlusion were compared. Seven patients with lower extremity ischemia and one patient with upper extremity ischemia had peripheral arterial thromboses (five arteries, three grafts) confirmed by clinical history, physical examination, and angiography. The duration of occlusion ranged from 31 hours to 30 days (mean 11.9 days). Tissue-type plasminogen activator was infused via a catheter directly into the thrombus at a randomly assigned dose of 0.05 mg/kg/hr (n = 4) or 0.025 mg/kg/hr (n = 4). Thrombolysis was complete in seven patients and partial in one. Duration of infusion ranged from 1 hour to 21 hours (mean 7.4 hours). The low dose required a longer infusion than did the high dose, but they were both successful in achieving thrombolysis. The one patient with partial thrombolysis had abrupt discontinuation of infusion when extravasation through a recently endarterectomized femoral artery developed. Otherwise there were no significant complications from tissue-type plasminogen activator therapy. Secondary procedures to correct underlying arterial disease were performed in five of the seven patients (71%) who had complete thrombolysis. Even at low dosages, infusion of tissue-type plasminogen activator into arteries or bypass graft thrombus produced complete thrombolysis, and no major complications occurred. This allowed more systematic effects to diagnose and treat underlying arterial disease.