Angiotensin II Type 1 receptor antagonism mediates uncoupling protein 2-driven oxidative stress and ameliorates pancreatic islet beta-cell function in young Type 2 diabetic mice

We recently identified a local pancreatic islet renin-angiotensin system (RAS), and demonstrated that it is upregulated in an animal model of obesity-induced type 2 diabetes mellitus (T2DM). Moreover, angiotensin II type 1 receptor (AT1R) antagonism improves beta-cell function and glucose tolerance in young T2DM mice and delays the onset of diabetes. Meanwhile, obesity-induced T2DM results in oxidative stress-mediated activation of uncoupling protein 2 (UCP2), a negative regulator of islet function. In the present study, we postulated that some of the protective effects of AT1R antagonism might be mediated through interference with this pathway and tested this hypothesis in a T2DM animal model. Losartan, an AT1R antagonist, was given to 4-week-old obese db/db mice for a period of 8 weeks. UCP2-driven oxidative damage and apoptosis were then analyzed in isolated islets. Losartan selectively inhibited oxidative stress via downregulation of NADPH oxidase; this in turn suppressed UCP2 expression, thus improving beta-cell insulin secretion and decreasing apoptosis-induced beta-cell mass loss in db/db mouse islets. These data indicate that islet AT1R activation in young diabetic mice can generate progressive islet beta-cell failure through UCP-driven oxidative damage.     

Isletopathy in Type 2 diabetes mellitus: implications of islet RAS, islet fibrosis, islet amyloid, remodeling, and oxidative stress

This review focuses primarily on islet structural and functional changes related to an activated islet renin- angiotensin system (RAS), islet oxidative-redox imbalance, the concurrence of islet fibrosis (pericapillary, intra- and peri-islet), and islet amyloid deposition (pericapillary, intra- and peri-islet). The islet-acinar-portal vascular pathway and the emerging important anatomical and functional region, the islet-exocrine interface, are also discussed. Because there is an associated histopathological islet disease in type 2 diabetes mellitus (T2DM), the term isletopathy is discussed in detail. The isletopathy in T2DM is equally important as the other complications of diabetes. Special stains and special lighting (bright field and crossed polarized light) are utilized, along with light and transmission electron microscopy, in order to better understand islet structural remodeling in T2DM. The importance of an isletopathy in T2DM is supported by numerous remodeling changes within the islet and the islet-exocrine interface. While some of the structural findings are only preliminary observations, additional investigation in this area should lead to the development of new pathophysiological concepts and new therapies regarding the prevention and treatment of T2DM.     

Endogenous lipoid pneumonia presenting as solitary pulmonary nodule: a case report

A 63-year-old woman complained of hemoptysis was admitted to our hospital. Chest computed tomography (CT) showed a solitary pulmonary nodule (SPN) arising from the lower lobe of the right lung which was considered as lung malignancy. The patient underwent video-assisted thoracoscopic surgery (VATS) of pulmonary wedge resection to remove the nodule. Diagnosis of lipoid pneumonia was established by multiple lipid-laden macrophages found in surgical specimen. As there was no history of inhalation or aspiration of lipid containing substances, she was diagnosed as endogenous lipoid pneumonia. The patient discharged from our hospital after surgery and with no recurrence in 9 months period.     

Exogenous lipoid pneumonia--case report

A 72-year-old patient with a rare disease-exogenous lipoid pneumonia (ELP) was described. One year ago he underwent laryngectomy because of larynx carcinoma and now he was admitted to hospital because of suspicion of cancer progression in the lungs. Chest HRCT and microscopic picture of BALF suggested diagnosis of lipoid pneumonia. His history supported it because he used oil drops to hist tracheostomy outline.     

Three cases of polymyositis/dermatomyositis complicated by pneumomediastinum.

Pneumomediastinum is a rare complication of dermatomyositis (DM) and Polymiositis (PM). We report here three cases of PM/DM who developed pneumomediastinum. First case was 61 years old woman with amyopathic dermatomyositis (aDM). Her aDM was complicated with skin ulceration due to vasculopathy, but complicated interstitial pneumonia was not severe. She developed subcutaneous emphysema and pneumomediastinum. Second case was 57 years old woman with DM, who had intractable skin phenomena and mild interstitial pneumonia. The patient became subcutaneous emphysema and pneumomediastinum following severe vasculopathy of skin. The last case was 63 years old man with PM. His PM was complicated with interstitial pneumonia. He had intractable respiratory symptom. Ten years later, he became subcutaneous emphysema and pneumomediastinum following pneumothorax. First and second cases suggest that their pneumomediastinum were due to vasculopathy. On the other hand, pneumomediastinum of the last patient seemed to be associated with interstitial pneumonia and steroid.     

Is House Dust Allergen a Possible Causal Factor for Relapses in Lipoid Nephrosis?

In three cases of minimal change nephrotic syndrome (lipoid nephrosis), an allergen sensitivity to house dust, cat hair and grass pollen was demonstrated by clinical and biological data. An increase in proteinuria after specific allergen contact and a decrease after withdrawal of the allergens, suggested that the cause was allergenic. Such cases demonstrate the necessity of an etiological investigation of particularly the atopic features in lipoid nephrosis. Results of these investigations can lead to specific therapy in selected cases.     

VARIED PULMONARY LESIONS WITH INTRAALVEOLAR LARGE LAMELLAR BODIES IN AN AUTOPSY CASE WITH BUSULFAN THERAPY

Characteristic pulmonary findings in an autopsy case of a 46-year-old female who presented heavy dyspnea as her chief complaint after 3 months of busulfan therapy for chronic myeloid leukemia were reported. The pulmonary findings were classified into four types: I. alveolar proteinosis type, II. intra-alveolar fibrosis type, III. interstitial fibrosis type, and IV. lipid pneumonia type with cholesterol granuloma. No other case with various findings like this case has been previously reported. It was considered that type I is the basic type, type II is a type that developed from type I, type III is a type with interstitial cell infiltration and fibrosis and type IV is a lipidrich variant of type I. A large lamellar body was first found in the granular material of type I. It is supposed that such a body consists of osmiophllic body which originated from type B alveolar epithelial cells and blood plasma.     

A case of interstitial pneumonia associated with dermatomyositis effectively treated with cyclosporin-A and cyclophosphamide pulse]

A 46-year-old male demonstrated edematous fingers on both hands in November 2003, and interstitial pneumonia was noted on chest X-ray during a medical check-up in December 2003. Since muscular weakness and fever developed thereafter, and interstitial pneumonia was aggravated on chest X-ray and CT, the patient was admitted to our hospital on March 25, 2004. Heliotrope-like erythema, and Gottron's sign were noted. Laboratory findings showed the following ; LDH 876 U/l ; CK 224 U/l ; CRP 5.68 mg/dl ; and KL-6 3270 U/ml. Autoantibodies such as anti-Jo-1 antibody were all negative. Chest X-ray and CT showed ground-glass opacity in the bilateral lower dorsal regions of the lung, and reduced volume of the inferior lobe. He was diagnosed as having dermatomyositis (DM) associated with progressive interstitial pneumonia. Although a combination of steroid pulse therapy and Cyclosporin-A were administered, the pulmonary lesions became aggravated. Additional intravenous Cyclophosphamide (IVCY) was initiated on the 6th hospital day, and interstitial pneumonia was markedly improved. Cases of progressive interstitial pneumonia associated with DM that are negative for anti-Jo-1 antibody and show a low ratio of CK/LDH are resistant to various treatments. Our case suggested that combination therapy with steroid, Cyclosporin-A, and IVCY is useful for the treatment of progressive interstitial pneumonia with DM.     

2型糖尿病胰岛β细胞氧化应激的研究进展

目的:探讨2型糖尿病(T2DM)胰岛β细胞氧化应激的研究进展.方法:从氧化应激的概念、胰岛β细胞发生氧化应激的因素、氧化应激损伤胰岛β细胞的机制三方面来探讨T2DM胰岛β细胞氧化应激的研究进展.结果:T2DM胰岛β细胞内含有较低水平的抗氧化系统, 在高糖、高脂等作用下,容易发生氧化应激反应, 氧化应激通过多种途径损伤胰岛β细胞, 使胰岛素合成分泌减少,加重T2DM.结论:T2DM胰岛β细胞容易发生氧化应激是多因素多途径共同作用的复杂过程,积极应用抗氧化剂治疗,能保护胰岛β细胞功能,预防和治疗T2DM的发生与发展.     

Varied pulmonary lesions with intraalveolar large lamellar bodies in an autopsy case with busulfan therapy.

Characteristic pulmonary findings in an autopsy case of a 46-year-old female who presented heavy dyspnea as her chief complaint after 3 months of busulfan therapy for chronic myeloid leukemia were reported. The pulmonary findings were classified into four types: I. alveolar proteinosis type, II. intra alveolar fibrosis type, III. interstitial fibrosis type, and IV. lipid pneumonia type with cholesterol granuloma. No other case with various findings like this case has been previously reported. It was considered that type I is the basic type, type II is a type that developed from type I, type III is a type with interstitial cell infiltration and fibrosis and type IV is a lipidrich variant of type I. A large lamellar body was first found in the granular material of type I. It is supposed that such a body consists of osmiophilic body which originated from type B alveolar epithelial cells and blood plasma.     

4-苯基丁酸抗内质网应激诱导胰岛β细胞凋亡

目的 探讨4-苯基丁酸（4-PBA）对2型糖尿病（T2DM）大鼠胰岛β细胞内质网应激（ERS）诱导的细胞凋亡的保护作用。方法 高脂饮食喂养加小剂量链脲佐菌素（STZ）腹腔注射建立SD大鼠T2DM模型,造模成功后取其中10只给予4-PBA灌胃20d。放射免疫法检测各组大鼠游离脂肪酸（FFA）、血糖及胰岛素的变化。醛品红染色观察胰岛形态改变,RT-PCR检测内质网相关蛋白（Caspase-3、GRP78、CHOP）的mRNA表达变化。结果 高脂对照组（EM> n/EM>＝10）和T2DM组（ EM>n/EM>＝8）大鼠血清FFA比正常对照组（EM>n/EM>＝10）显著增加,4-PBA治疗后显著下降（ EM>n/EM>＝8）。4-PBA治疗升高了T2DM造成的     

Involvement of collagen-binding heat shock protein 47 and procollagen type I synthesis in idiopathic pulmonary fibrosis: contribution of type II pneumocytes to fibrosis

The most common pathologic form of idiopathic pulmonary fibrosis is usual interstitial pneumonia, which is characterized by patchy fibrotic areas, marked increase in the number of fibroblasts and type II pneumocytes, and excessive deposition of extracellular matrix proteins, especially collagen. Heat shock protein 47 is a collagen-binding stress protein and has a specific role in intracellular processing of procollagen molecules as a collagen-specific molecular chaperone. However, its role in the causation of fibrosis in usual interstitial pneumonia is unknown. In this study, we examined the expression of heat shock protein 47 and type I procollagen in 12 patients with usual interstitial pneumonia by immunohistochemistry on sequential sections. Heat shock protein 47 was localized predominantly in alpha-smooth muscle actin-positive myofibroblasts and surfactant protein-A-positive type II pneumocytes in active fibrotic areas of usual interstitial pneumonia. Type I procollagen was also expressed in those cells. In contrast, heat shock protein 47 and type I procollagen were weakly or not at all expressed in myofibroblasts and type II pneumocytes in bronchiolitis obliterans organizing pneumonia and normal lung tissue samples obtained from excised lung cancer tissues. The numbers of heat shock protein 47- and type I procollagen-positive cells to type II pneumocytes or myofibroblasts were significantly higher in usual interstitial pneumonia than in bronchiolitis obliterans organizing pneumonia and normal lung tissue specimens. Our results suggest that myofibroblasts and type II pneumocytes play an important role in the progression of fibrosis through the induction of heat shock protein 47, which regulates the synthesis/assembly of type I procollagen in usual interstitial pneumonia. HUM PATHOL 31:1498-1505.     

Attenuation of islet‐specific T cell responses is associated with C‐peptide improvement in autoimmune type 2 diabetes patients

The clinical efficacy of peroxisome proliferator‐activated receptor gamma (PPAR‐γ) agonists in cell‐mediated autoimmune diseases results from down‐regulation of inflammatory cytokines and autoimmune effector cells. T cell islet autoimmunity has been demonstrated to be common in patients with phenotypic type 2 diabetes mellitus (T2DM) and islet‐specific T cells (T⁺) to be correlated positively with more severe beta cell dysfunction. We hypothesized that the beneficial effects of the PPAR‐γ agonist, rosiglitazone, therapy in autoimmune T2DM patients is due, in part, to the immunosuppressive properties on the islet‐specific T cell responses. Twenty‐six phenotypic T2DM patients positive for T cell islet autoimmunity (T⁺) were identified and randomized to rosiglitazone (n = 12) or glyburide (n = 14). Beta cell function, islet‐specific T cell responses, interleukin (IL)‐12 and interferon (IFN)‐γ responses and islet autoantibodies were followed for 36 months. Patients treated with rosiglitazone demonstrated significant (P < 0·03) down‐regulation of islet‐specific T cell responses, although no change in response to tetanus, a significant decrease (P < 0·05) in IFN‐γ production and significantly (P < 0·001) increased levels of adiponectin compared to glyburide‐treated patients. Glucagon‐stimulated beta cell function was observed to improve significantly (P < 0·05) in the rosiglitazone‐treated T2DM patients coinciding with the down‐regulation of the islet‐specific T cell responses. In contrast, beta cell function in the glyburide‐treated T2DM patients was observed to drop progressively throughout the study. Our results suggest that down‐regulation of islet‐specific T cell autoimmunity through anti‐inflammatory therapy may help to improve beta cell function in autoimmune phenotypic T2DM patients.     

Cholesterol granulomas of the lungs associated with microangiopathic hemolytic anemia and thrombocytopenia in pulmonary hypertension

Cholesterol granulomas unrelated to endogenous lipoid pneumonia, pulmonary alveolar proteinosis, or cholesterol pneumonia are a rare finding during pneumectomy or autopsy. They have been occasionally reported in association with pulmonary hypertension. We report a case where these lesions were associated with long-standing pulmonary hypertension and microangiopathic hemolytic anemia and thrombocytopenia. Plexiform lesions were present in the pulmonary vasculature secondary to pulmonary hypertension, causing hemolysis and thrombocytopenia. We suggest that destruction of red blood cells and platelets could provide membrane lipids that are taken up by phagocytic cells, which promotes the formation of these cholesterol deposits.     

Activated T lymphocytes from patients with high risk of type I diabetes mellitus have different ability to produce interferon-gamma, interleukin-6 and interleukin-10 and undergo anti-CD95 induced apoptosis after insulin stimulation

Type I Diabetes mellitus (DM1) is the effect of T cell dependent autoimmune destruction of insulin producing beta cells in the pancreas islet. T cells are activated in response to islet dominant autoantigens, the result being the development of DM1. Insulin is one of the islet autoantigens responsible for activation of T lymphocyte functions, inflammatory cytokine production and development of DM1. The experiments reported in this study have shown the spontaneous increase of CD95 molecule expression on lymphocytes of the first-degree relatives of DM1 patients. The autoantigen insulin is responsible for stimulation in vitro of potentially hazardous 'memory' lymphocytes to produce interleukin-6 (IL-6) and interleukin-10 (IL-10) interleukins. Insulin induced stimulation of lymphocytes in vitro was observed in patients at high risk of developing diabetes mellitus (prediabetics). Phytohaemagglutinin (PHA) stimulates lymphocytes of all groups in the same way. Stimulated lymphocytes in second cultures undergo apoptosis induced with anti-Fas specific antibodies. The deletion in vitro of resting peripheral lymphocytes is nonfunctional. Insulin activated T lymphocytes, which undergo apoptosis were not observed in peripheral blood of healthy people and in patients with DM1. This observation suggests that insulin is involved as autoantigen in DM1 progression in patients with high risk of diabetes type I. The autoreactive T lymphocytes may persist in peripheral blood of patients with high risk DM1. Defective elimination of autoreactive T cells may result in autodestructive damage of islets beta cells in the prediabetic stage and disease progression to DM1.     

Electron-microscopical immunocytochemical study of a pancreatic islet amyloid polypeptidoma

A 50-year-old man developed a pancreatic islet tumor with liver metastases. High levels of islet amyloid polypeptide (IAPP) were recorded in plasma—35,000 pmol/L—concomitant with the occurrence of type II diabetes mellitus (the clinical syndrome has recently been described in detail) [25]. Light microscopically, the tumor contained considerable amounts of amyloid and displayed IAPP immunoreactivity both in the tumor cells and in the amyloid stroma. Electron-microscopical examination of the liver metastases showed presence of round secretory granules in the tumor cells. The granules were immunoreactive to chromogranin A and B and IAPP but not to insulin. The amyloid deposits were mainly accumulated in the extracellular spaces but were also present in the tumor cell cytoplasm. The intracellufar amyloid fibrils were, as revealed by immunogold labeling, IAPP immunoreactive and seemed to emerge from the secretory granules in the shape of radiating threads. The results show that in this particular case, the amyloid formation started already at the intracellular level and in close proximity to the lAPP-storing secretory granules. The findings may have some significance for understanding the development of pancreatic islet B-cell-related amyloidosis in type II diabetes mellitus.     

糖尿病检测谷氨酸脱羧酶抗体、胰岛细胞抗体和胰岛素自身抗体的临床意义

探讨血清谷氨酸脱羧酶抗体(GAD-Ab)、胰岛细胞抗体(ICA)和胰岛素自身抗体(IAA)检测对糖尿病(DM)的临床意义。对46例1型糖尿病(DM1)、78例2型糖尿病(DM2)和50名对照组应用增敏化学发光免疫分析法、RIA法检测其血清中GAD-Ab、ICA和IAA的阳性率并进行分组分析。结果表明DM1组GAD-Ab、ICA和IAA阳性率分别为67.39%、39.13%和23.91%,三者联合检测阳性率为91.30%,均显著高于DM2组(P<0.01)及对照组(P<0.01);DM2组GAD-Ab、ICA和IAA阳性率分别为8.97%、15.39%和10.26%,三者联合检测的阳性率为29.49%,也显著高于对照组(P<0.01)。结论是血清GAD-Ab、ICA和IAA的检测对DM的分型、指导临床用药以及判断预后具有重要的临床应用价值。     

Candidate gene association study of insulin signaling genes and Alzheimer's disease: evidence for SOS2, PCK1, and PPARgamma as susceptibility loci.

Epidemiological evidence supports the existence of a possible link between type II diabetes mellitus (T2DM) and late-onset Alzheimer's disease (LOAD). Polymorphisms from candidate genes for T2DM were genotyped in a two-stage approach to identify novel risk factors for LOAD. One hundred fifty-two polymorphisms were initially genotyped in a case:control cohort: nine SNPs showed individual association with disease status under at least one genetic model, while an additional two SNPs showed a haplotype association. In a replication study, we confirmed significant association of SNPs within three genes--PPARgamma, SOS2, and PCK1--with Alzheimer's disease. In particular, our data suggest that the effect of variants within these genes might be influenced by gender.     

A feline model of experimentally induced islet amyloidosis

The study of the pathogenesis of islet amyloidosis and its relationship to the development and progression of type 2 diabetes mellitus has been hampered by the lack of an experimentally inducible animal model. The domestic cat, by virtue of the fact that it is one of the few species that spontaneously develop a form of diabetes mellitus that closely resembles human type 2 diabetes, including the formation of amyloid deposits derived from islet amyloid polypeptide (IAPP), was considered to be an excellent candidate species in which to attempt to develop a nontransgenic animal model for this disease process. To develop the model, 8 healthy domestic cats were given a 50% pancreatectomy, which was followed by treatment with growth hormone and dexamethasone. Once a stable diabetic state was established, cats were randomly assigned to groups treated with either glipizide or insulin at doses appropriate to control hyperglycemia. Cats were maintained on this treatment regimen for 18 months and then euthanized. Based on light microscopic examination of Congo red-stained sections of pancreas, all cats were negative for the presence of islet amyloid at the time of pancreatectomy. At the end of the study all 4 glipizide-treated cats had islet amyloid deposits, whereas only 1 of 4 insulin-treated cats had detectable amyloid. In addition, the glipizide treated cats had threefold higher basal and fivefold higher glucose-stimulated plasma IAPP concentrations than insulin-treated cats, suggesting an association between elevated IAPP secretion and islet amyloidosis. Blood-glycosylated hemoglobin concentrations were not significantly different between the two treatment groups. This study documents for the first time an inducible model of islet amyloidosis in a nontransgenic animal.     

Lipoid pneumonia with chronic myelomonocytic leukemia

A case of lipoid pneumonia with chronic myelomonocytic leukemia is reported. A 61-year-old man was autopsied after suffering from myelodysplastic syndrome (chronic myelomonocytic leukemia) for 13 years. Interstitial lesions of the lungs were suspected as infiltration of leukemia cells before the autopsy. However, blastic leukemia cells were not observed in the lung, although they were seen in the bone marrow and spleen at autopsy. Instead, an unusual amount of cholesterol deposits was observed with mucormycosis and aspergillosis in the lungs. Cholesterol deposition was observed not only in perihilar but also in subpleural regions without apparent bronchial obstruction in both lungs. It is thought that malfunction of monocytes/macrophages resulted in repeated fungal infection and storage of cholesterol caused by tissue destruction and impaired tissue repairing.