Re: Re: Did King Herod suffer from a rheumatic disease? doi: 10.1007/s10067-017-3583-z

Clinical Rheumatology -     

Developmental Programming by Maternal Insulin Resistance: Hyperinsulinemia,Glucose Intolerance,and Dysregulated Lipid Metabolism in Male Offspring of Insulin-Resistant Mice

Maternal obesity and gestational diabetes mellitus (GDM) are associated with obesity and diabetes risk in offspring. We tested whether maternal insulin resistance, which frequently coexists with GDM and obesity, could independently contribute to dysregulation of offspring metabolism. Female mice haploinsufficient for insulin receptor substrate-1 (IRS1-het) are hyperinsulinemic and insulin resistant during pregnancy, despite normal plasma glucose and body weight, and thus serve as a model of isolated maternal insulin resistance. Wild-type (WT) offspring of IRS1-het dams insulin resistance-exposed [IR-exposed] were compared with WT offspring of WT dams. Despite no differences in adiposity, male IR-exposed pups were glucose intolerant (P = 0.04) and hyperinsulinemic (1.3-fold increase, P = 0.02) by 1 month of age and developed progressive fasting hyperglycemia. Moreover, male IR-exposed pups challenged with high-fat diet exhibited insulin resistance. Liver lipidomic analysis of 3-week-old IR-exposed males revealed increases in the 16:1n7 fraction of several lipid classes, suggesting increased Scd1 activity. By 6 months of age, IR-exposed males had increased lipid accumulation in liver as well as increased plasma refed fatty acids, consistent with disrupted lipid metabolism. Our results indicate that isolated maternal insulin resistance, even in the absence of hyperglycemia or obesity, can promote metabolic perturbations in male offspring.     

Difluoro ketone peptidomimetics suggest a large S1 pocket for Alzheimer's gamma-secretase: implications for inhibitor design

The final step in the generation of the amyloid-beta protein (Abeta), implicated in the etiology of Alzheimer's disease, is proteolysis within the transmembrane region of the amyloid precursor protein (APP) by gamma-secretase. Although considered an important target for therapeutic design, gamma-secretase has been neither well-characterized nor definitively identified. Previous studies in our laboratory using substrate-based difluoro ketone and difluoro alcohol transition-state analogue inhibitors suggest that gamma-secretase is an aspartyl protease with loose sequence specificity. To further characterize the active site of gamma-secretase, we prepared a series of difluoro ketone peptide analogues with varying steric bulkiness in the P1 position and tested the ability of these compounds to inhibit Abeta production in APP-transfected cells. Incorporation of bulky, aliphatic P1 side chains, such as sec-butyl or cyclohexylmethyl, led to increased gamma-secretase inhibitory potency, suggesting a large S1 pocket to accommodate these substituents and providing further evidence for loose sequence specificity. The cyclohexylmethyl P1 substituent allowed N-terminal truncation to a low-molecular-weight compound (<600 Da) that effectively blocked Abeta production (IC(50) approximately 5 microM). This finding suggests that optimal S1 binding may allow the development of potent inhibitors with ideal pharmaceutical properties. Moreover, a difluoro alcohol analogue with a cyclohexylmethyl P1 substituent was equipotent with its difluoro ketone counterpart, providing strong evidence that gamma-secretase is an aspartyl protease. All new analogues inhibited total Abeta and Abeta(42) production with the same rank order of potency and increased Abeta(42) production at low concentrations, providing further evidence for distinct gamma-secretases that are nevertheless closely similar with respect to active site topology and mechanism.     

An immunoradiometric assay for erythrocyte complement (C3b) receptor activity applied to a pediatric population with connective tissue disease

The number of receptors for complement component C3b per erythrocyte reportedly is decreased in over half of adults with systemic lupus erythematosus. We have devised an immunoradiometric assay for C3b receptor (CR1) on erythrocytes, with which one can assess CR1 saturation due to in vivo binding of immune complexes or activated complement fragments (C3b). Using this assay, we examined binding by CR1 in normal adults and newborns, in lupus and juvenile rheumatoid arthritis patients, and in a population of patients with various general medical problems, including other connective tissue diseases. Binding by CR1 was decreased in eight of 15 SLE patients, four of 25 juvenile rheumatoid arthritis patients, and one of 14 patients with other diseases. We found no significant correlation between CR1 binding and either C1q binding, antinuclear antibody titer, results for complement C3 and C4, or the presence of renal disease. Using this assay, we were also able to show that the observed reduction in CR1 binding was not ascribable to prior saturation of CR1 or to blocking antibody against CR1. The assay is precise and easy enough for routine application.     

Gastric adenocarcinoma associated with human immunodeficiency virus (HIV) infection

Gastric adenocarcinoma developed in a 33-year-old homosexual man with human immunodeficiency virus (HIV) infection. This type of cancer is very rare in a man of his young age and in the absence of other factors. The tumor was aggressive and led to rapid death. Whereas Kaposi's sarcoma and lymphomas have been associated with HIV, there are only a few documented cases of adenocarcinoma associated with a suppressed immune system. The association between HIV infection and the virulence of this tumor appears to be strong.