Intestinal alkaline phosphatase at the crossroad of intestinal health and disease - a putative role in type 1 diabetes.

BACKGROUND: Patients with type 1 diabetes have shown an increase in circulating cytokines, altered lipoprotein metabolism and signs of vascular dysfunction in response to high-fat meals. Intestinal alkaline phosphatase (IAP) regulates lipid transport and inflammatory responses in the gastrointestinal tract. We therefore hypothesized that changes in IAP activity could have profound effects on gut metabolic homeostasis in patients with type 1 diabetes. METHODS: Faecal samples of 41 nondiabetic controls and 46 patients with type 1 diabetes were analysed for IAP activity, calprotectin, immunoglobulins and short-chain fatty acids (SCFAs). The impact of oral IAP supplementation on intestinal immunoglobulin levels was evaluated in C57BL/6 mice exposed to high-fat diet for 11 weeks. RESULTS: Patients with type 1 diabetes exhibited signs of intestinal inflammation. Compared to controls, patients with diabetes had higher faecal calprotectin levels, lower faecal IAP activities accompanied by lower propionate and butyrate concentrations. Moreover, the amount of faecal IgA and the level of antibodies binding to oxidized LDL were decreased in patients with type 1 diabetes. In mice, oral IAP supplementation increased intestinal IgA levels markedly. CONCLUSION: Deprivation of protective intestinal factors may increase the risk of inflammation in the gut - a phenomenon that seems to be present already in patients with uncomplicated type 1 diabetes. Low levels of intestinal IgA and antibodies to oxidized lipid epitopes may predispose such patients to inflammation-driven complications such as cardiovascular disease and diabetic nephropathy. Importantly, oral IAP supplementation could have beneficial therapeutic effects on gut metabolic homeostasis, possibly through stimulation of intestinal IgA secretion.

Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway.

High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN.

Role of peridomestic birds in the transmission of St. Louis encephalitis virus in southern California.

In response to the 1984 St. Louis encephalitis (SLE) epidemic in the Los Angeles Basin of southern California (USA), an investigative program was initiated to evaluate the interactive components of the SLE virus transmission cycle. From 1987 through 1996 (10 yr), 52,589 birds were bled and their sera tested for SLE and western equine encephalomyelitis (WEE) virus antibodies by the hemagglutination inhibition (HAI) test. Eighty-three percent of the birds tested were house finches (Carpodacus mexicanus) (48.7%) and house sparrows (Passer domesticus) (34.6%); 1.1% of these birds were positive for SLE antibodies. Prevalence of WEE antibodies was negligible. The analysis of 5,481 sera from rock doves (Columbia livia) yielded 3.6% SLE positives and 0.4% WEE positives. Collection sites were maintained as study sites when identified as positive bird, mosquito, and SLE virus activity localities; others were abandoned. Serial serum samples from 7,749 banded house sparrows and 9,428 banded house finches from these selected sites demonstrated year-round SLE virus transmission. One location exhibited significant numbers of house finches undergoing annual SLE seroconversion and a number of seroconversion-reversion-reconversion sequences suggesting either viral reinfection from mosquitoes or recrudescence by latent virus. A proportion of both bird species also lived for longer than 1 yr, thus, increasing the possibility of virus carry-over from autumn to spring. Assessment of concurrently collected mosquitoes indicated no correlative association between mosquito populations and SLE seroconversion and reconversion. European house sparrows introduced in the 1800's may have provided a supplemental link to the existing SLE virus enzootic cycle involving endemic house finches. Meteorological factors are reviewed as possible important correlates of SLE epidemics. The house finch/house sparrow serosurveillance system is also evaluated for use as an "Early Warning" indicator of SLE virus activity.