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α 2 -Heremans-Schmid Glycoprotein/ Fetuin-A Is Associated With Insulin Resistance and Fat Accumulation in the Liver in Humans Norbert Stefan , MD 1 , Anita M. Hennige , MD 1 , Harald Staiger , PHD 1 , Jürgen Machann , PHD 2 , Fritz Schick , PHD 2 , Stefan M. Kröber , MD 3 , Fausto Machicao , PHD 1 , Andreas Fritsche , MD 1 and Hans-Ulrich Häring , MD 1 1 Department of Internal Medicine, University of Tübingen, Tübingen, Germany 2 Section on Experimental Radiology, University of Tübingen, Tübingen, Germany 3 Department of Pathology, University of Tübingen, Tübingen, Germany Address correspondence and reprint requests to Norbert Stefan, MD, Department of Internal Medicine, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail: norbert.stefan{at}med.uni-tuebingen.de Abstract OBJECTIVE —The α 2 -Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver. RESEARCH DESIGN AND METHODS —Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by 1 H magnetic resonance spectroscopy. RESULTS —AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance ( P = 0.006). AHSG plasma levels were negatively associated with insulin sensitivity ( r = −0.22, P = 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat ( r = 0.27, P = 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity ( P = 0.02). CONCLUSIONS —We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance. AHSG, α2-Heremans-Schmid glycoprotein Footnotes Additional information on this article can be found in an online appendix at http://care.diabetesjournals.org . A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted January 2, 2006. Received October 11, 2005. DIABETES CARE

De novo lymphangiogenesis influences the course of different human diseases as diverse as chronic renal transplant rejection 1 and tumor metastasis 2 , 3 . The cellular mechanisms of lymphangiogenesis in human diseases are currently unknown, and could involve division of local preexisting endothelial cells or incorporation of circulating progenitors. We analyzed renal tissues of individuals with gender-mismatched transplants who had transplant rejection and high rates of overall lymphatic endothelial proliferation as well as massive chronic inflammation. Donor-derived cells were detected by in situ hybridization of the Y chromosome. We compared these tissues with biopsies of essentially normal skin and intestine, and two rare carcinomas with low rates of lymphatic endothelial proliferation that were derived from individuals with gender-mismatched bone marrow transplants. Here, we provide evidence for the participation of recipient-derived lymphatic progenitor cells in renal transplants. In contrast, lymphatic vessels of normal tissues and those around post-transplant carcinomas did not incorporate donor-derived progenitors. This indicates a stepwise mechanism of inflammation-associated de novo lymphangiogenesis, implying that potential lymphatic progenitor cells derive from the circulation, transmigrate through the connective tissue stroma, presumably in the form of macrophages, and finally incorporate into the growing lymphatic vessel.

The nitric oxide/cGMP/cGMP-dependent protein kinase type I (cGKI) signaling pathway regulates cell functions that play a pivotal role in the pathogenesis of type 2 diabetes. However, the impact of a dysfunction of this pathway for glucose metabolism in vivo is unknown. The expression of cGKI in tissues relevant to insulin action was analyzed by immunohistochemistry. The metabolic consequences of a genetic deletion of cGKI were studied in mice that express cGKI selectively in smooth muscle but not in other cell types (cGKI-SM mice). In wild-type mice, cGKI protein was detected in hepatic stellate cells, but not in hepatocytes, skeletal muscle, fat cells, or pancreatic β-cells. Compared with control animals, cGKI-SM mice had higher energy expenditure in the light phase associated with lower body weight and fat mass and increased insulin sensitivity. Mutant mice also showed higher fasting glucose levels, whereas insulin levels and intraperitoneal glucose tolerance test results were similar to those in control animals. Interleukin (IL)-6 signaling was strongly activated in the liver of cGKI-SM mice as demonstrated by increased levels of IL-6, phospho-signal transducer and activator of transcription 3 (Tyr 705), suppressor of cytokine signaling-3, and serum amyloid A2. Insulin-stimulated tyrosine phosphorylation of the insulin receptor in the liver was impaired in cGKI-SM mice. The fraction of Mac-2-positive macrophages in the liver was significantly higher in cGKI-SM mice than in control mice. In contrast with cGKI-SM mice, conditional knockout mice lacking cGKI only in the nervous system were normal with respect to body weight, energy expenditure, fasting glucose, IL-6, and insulin action in the liver. Genetic deletion of cGKI in non-neuronal cells results in a complex metabolic phenotype, including liver inflammation and fasting hyperglycemia. Loss of cGKI in hepatic stellate cells may affect liver metabolism via a paracrine mechanism that involves enhanced macrophage infiltration and IL-6 signaling.

OBJECTIVE:--The alpha(2)-Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver. RESEARCH DESIGN AND METHODS--Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by ¹H magnetic resonance spectroscopy. RESULTS:--AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance (P = 0.006). AHSG plasma levels were negatively associated with insulin sensitivity (r = -0.22, P = 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat (r = 0.27, P = 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity (P = 0.02). CONCLUSIONS:--We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance.

Abstract Context The effect of a lifestyle intervention to reduce liver fat content in nonalcoholic fatty liver disease in humans is influenced by genetics. We hypothesized that the amino acid exchange in human Gly388Arg (mouse homolog: Gly385Arg) in fibroblast growth factor receptor 4 (FGFR4), which regulates bile acid, lipid, and glucose metabolism, could determine hepatic lipid accumulation and insulin sensitivity. Mechanisms of this substitution were studied in mice under normal chow and high-fat diets. Design In humans, the Gly388Arg polymorphism was studied for its relationship with changes in liver fat content and insulin sensitivity during 9 months of a lifestyle intervention. We also studied a knock-in mouse strain with an Arg385 allele introduced into the murine FGFR4 gene under normal chow and high-fat diets. Results In humans, the FGFR4 Arg388 allele was not associated with liver fat content or insulin sensitivity in subjects who were overweight and obese before lifestyle intervention. However, it was associated with less decrease in liver fat content and less increase in insulin sensitivity during the intervention. In mice receiving normal chow, the FGFR4 Arg385 allele was associated with elevated hepatic triglyceride content, altered hepatic lipid composition, and increased hepatic expression of genes inducing de novo lipogenesis and glycolysis. Body fat mass and distribution, glucose tolerance, and insulin sensitivity were unaltered. The FGFR4 Arg385 allele had no effect on glucose or lipid metabolism under the high-fat diet. Conclusion Our data indicate that the FGFR4 Arg388(385) allele affects hepatic lipid and glucose metabolism specifically during healthy caloric intake. We assessed the role of the amino acid exchange Gly388(385)Arg in the fibroblast growth factor receptor 4 in hepatic lipid accumulation and its implications for glucose metabolism.

Isolated splenic infarction in healthy adults can occur in the context of embolic diseases, haematological malignancies, aortic dissection, splenic torsion, vasculitis, or vasculospasm secondary to treatment with vasopressors.1 Fulminant meningococcaemia or purpura fulminans is the most rapidly lethal form of septic shock. Bacterial replication in the peripheral blood leads to septic shock, skin changes, and organ dysfunction, before an invasion of the central nervous system and the development of meningitis.2 Genetic or acquired defects in the innate immune response may be necessary prerequisites for such rapid bacterial replication.3-5 Polymorphisms in two candidate genes-those for the Toll-like receptors (TLR) 2 and 4-may result in an impaired immune response.4,5 We tested our patient for TLR-2 and TLR-4 polymorphisms; she had neither. We do not know why this young woman was susceptible to infection with N meningitidis, or why she had such an unusual presentation.

BackgroundXanthogranulomatous cholecystitis is a macrophage-rich inflammatory condition of the gallbladder that occasionally presents with tumorlike appearance.Case presentationIn the present case the inflammation involved all the layers of the gallbladder, the surrounding connective tissue, and part of the right lobe of the liver and right transverse colon. The clinical and radiological findings were suggestive of advanced carcinoma of the gallbladder. However, intraoperative frozen section investigation revealed xanthogranulomatous cholecystitis, for which simple cholecystectomy is the treatment of choice.ConclusionsThe original cause of the condition is unclear in most cases. In the present case it is possible that rupture of the gallbladder in association with the patient's known history of trauma have initiated the process

The alpha(2)-Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver. Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by (1)H magnetic resonance spectroscopy. AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance (P = 0.006). AHSG plasma levels were negatively associated with insulin sensitivity (r = -0.22, P = 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat (r = 0.27, P = 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity (P = 0.02). We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance.

Posttransplantation lymphoproliferative disorder (PTLD) of the iris is a rare entity with only ten cases having been published as yet. Its clinical aspect is typical. Therapy is multimodal and affords an interdisciplinary approach. A 7-year-old boy developed a lymphoproliferative mass of the iris with uveitis 4 years after heart transplantation and immunosuppression. A progressive, flesh-colored thickening of the iris with secondary angle closure glaucoma necessitated a diagnostic and therapeutic iridectomy. Morphological investigation of the iris specimen disclosed a polymorphic posttransplantation lymphoproliferative disorder (PTLD) and the presence of Epstein-Barr virus (EBV) within the tissue. The EBV load in peripheral blood monocytes was massively elevated, thus indicating a chronic EBV infection. After conservative treatment and radiation therapy, the iris mass quickly resolved. There was no evidence of systemic PTLD. PTLD is a well-known, EBV-induced entity that rarely affects the eye. EBV is principally detectable in specimens of iris PTLD. If conservative, antiviral treatment fails, the iris lesions can be treated by local radiation therapy with very good success. In the near future, patients with PTLD of the eye may benefit from immunologic treatment with ex vivo generation of virus-specific T-lymphocytes.