The rising number of obese individuals has become a major burden to the healthcare systems worldwide. Obesity includes not only the increase of adipose tissue mass but importantly also the altered cellular functions that collectively lead to a chronic state of adipose tissue inflammation, insulin resistance and impaired wound healing. Adipose tissue undergoing chronic inflammation shows altered cytokine expression and an accumulation of adipose tissue macrophages (ATM). The macrophage migration inhibitory factor (MIF) superfamily consists of MIF and the recently identified homolog D-dopachrome tautomerase (D-DT or MIF-2). MIF and D-DT, which both bind to the CD74/CD44 receptor complex, are differentially expressed in adipose tissue and have distinct roles in adipogenesis. MIF positively correlates with obesity as well as insulin resistance and contributes to adipose tissue inflammation by modulating ATM functions. D-DT, however, is negatively correlated with obesity and reverses glucose intolerance. In this review, their respective roles in adipose tissue homeostasis, adipose tissue inflammation, insulin resistance and impaired wound healing will be reviewed.
Adipose Tissue/*immunology/pathology ; Animals ; Diabetes Mellitus/immunology/pathology ; Humans ; Inflammation/*immunology/pathology ; Insulin Resistance ; Intramolecular Oxidoreductases/analysis/*immunology ; Macrophage Migration-Inhibitory Factors/analysis/*immunology ; Macrophages/immunology/pathology ; Obesity/*immunology/pathology ; *Wound Healing

The rising number of obese individuals has become a major burden to the healthcare systems worldwide. Obesity includes not only the increase of adipose tissue mass but importantly also the altered cellular functions that collectively lead to a chronic state of adipose tissue inflammation, insulin resistance and impaired wound healing. Adipose tissue undergoing chronic inflammation shows altered cytokine expression and an accumulation of adipose tissue macrophages (ATM). The macrophage migration inhibitory factor (MIF) superfamily consists of MIF and the recently identified homolog D-dopachrome tautomerase (D-DT or MIF-2). MIF and D-DT, which both bind to the CD74/CD44 receptor complex, are differentially expressed in adipose tissue and have distinct roles in adipogenesis. MIF positively correlates with obesity as well as insulin resistance and contributes to adipose tissue inflammation by modulating ATM functions. D-DT, however, is negatively correlated with obesity and reverses glucose intolerance. In this review, their respective roles in adipose tissue homeostasis, adipose tissue inflammation, insulin resistance and impaired wound healing will be reviewed.
Adipose Tissue/*immunology/pathology ; Animals ; Diabetes Mellitus/immunology/pathology ; Humans ; Inflammation/*immunology/pathology ; Insulin Resistance ; Intramolecular Oxidoreductases/analysis/*immunology ; Macrophage Migration-Inhibitory Factors/analysis/*immunology ; Macrophages/immunology/pathology ; Obesity/*immunology/pathology ; *Wound Healing

The regional distribution and relative frequency of some endocrine cells in the principal pancreatic islets of two teleosts, Silurus asotus Linne (Siluridae) and Siniperca scherzeri Steindachner (Centropomidae), which have similar feeding habits, were observed using specific antisera against insulin, glucagon, somatostatin and bovine pancreatic polypeptide (bovine PP) using the peroxidase antiperoxidase (PAP) method. Spherical to spindle shaped cells were demonstrated in the principal pancreatic islets in both species of teleost fishes. However, they were not detected in the exocrine portions nor the pancreatic ducts. Insulin-immunoreactive cells were located in the central regions of the principal pancreatic islets at high frequency in both species. Glucagonimmunoreactive cells were restricted to the peripheral regions of the principal pancreatic islets in both species. They formed a mantle zone in the peripheral regions of Silurus asotus with moderate frequency, and occupied a narrower mantle zone in Siniperca scherzeri with moderate frequency. In addition, glucagonimmunoreactive cell cores were also found in the peripheral zone of some principal pancreatic islets of Siniperca scherzeri. Somatostatin-immunoreactive cells were dispersed in the central zone of the principal pancreatic islets of Silurus asotus with moderate frequency, but were located in the peripheral regions with low frequency in Siniperca scherzeri. Bovine PPimmunoreactive cells were found in the peripheral region and the mantle zone of the principal pancreatic islets with low and rare frequency, respectively in both species. In conclusion, the regional distribution and relative frequency of endocrine cells in the principal pancreatic islets of Silurus asotus showed general patterns similar to those of other teleostean fishes. But, some speciesdependent distributional patterns and/or relative frequencies, particularly in glucagon-, somatostatin- and bovine PP-immunoreactive cells, were detected in the principal pancreatic islets of Siniperca scherzeri
Animals ; Catfishes/*anatomy & histology/physiology ; Cattle ; Glucagon/analysis/immunology ; Immune Sera/diagnostic use/immunology ; Immunohistochemistry/veterinary ; Insulin/analysis/immunology ; Islets of Langerhans/*cytology/physiology ; Pancreatic Polypeptide/analysis/immunology ; Perciformes/*anatomy & histology/physiology ; Somatostatin/analysis/immunology

The possible involvement of phospholipase C (PLC) in the regulation of insulin secretion is not clearly understood and neither its isozymes expressed nor cellular localization in the pancreatic islets is known. By using specific monoclonal antibodies, we have investigated the expression and localization of eight different PLC isozymes, beta1, beta2, beta3, beta4, gamma1, gamma2, delta1, and delta2, in the pancreatic islets of adult mice. Immunohistochemical analysis carried out on paraffin embedded sections showed a distinct pattern of expression for each of the PLC isozymes. In the central part of the islets containing beta cells, a high level of beta4 and moderate levels of beta3 and gamma1 were expressed, whereas PLC-beta1 and -gamma1 were abundantly expressed in the exocrine pancreas. These results demonstrated the heterogeneity in expression of the phospholipase C isozymes in pancreatic islets. It is conceivable that these isozymes are coupled to different receptors and perform selective tasks in the regulation of insulin secretion for glucose homeostasis.
Animal ; Antibodies, Monoclonal ; Glucagon/analysis ; Insulin/analysis ; Islets of Langerhans/cytology/*enzymology ; Isoenzymes/analysis/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phospholipase C/*analysis/immunology

BACKGROUND: Insulin assays are affected by varying degrees of interference from anti-insulin antibodies (IAs) and by cross-reactivity with recombinant insulin analogues. We evaluated the usefulness of the E170 insulin assay by assessing IA effects and cross-reactivity with 2 analogues. METHODS: Sera were obtained from 59 type 2 diabetes patients receiving continuous subcutaneous insulin infusion and 18 healthy controls. Insulin levels were determined using an E170 analyzer. To investigate the effects of IAs, we performed IA radioimmunoassays, and analyzed the differences between directly measured insulin (direct insulin) and polyethylene glycol (PEG)-treated insulins (free, IA-unbound; total, IA-bound and unbound insulin). We performed in-vitro cross-reactivity tests with insulin aspart and insulin glulisine. RESULTS: In IA-positive patients, E170 free insulin levels measured using the E170 analyzer were significantly lower than the direct insulin levels. The mean value of the direct/free insulin ratio and IA-bound insulin, which were calculated as the difference between total and free insulin, increased significantly as endogenous IA levels increased. The E170 insulin assay showed low cross-reactivities with both analogues (< 0.7%). CONCLUSIONS: IAs interfered with E170 insulin assay, and the extent of interference correlated with the IA levels, which may be attributable to the increase in IA-bound insulin, and not to an error in the assay. The E170 insulin assay may measure only endogenous insulin since cross-reactivity is low. Our results suggest that the measurement of free insulin after PEG pre-treatment could be useful for beta cell function assessment in diabetic patients undergoing insulin therapy.
Adult ; Aged ; Aged, 80 and over ; Cross Reactions ; Diabetes Mellitus, Type 2/blood/immunology ; Female ; Humans ; Infusions, Subcutaneous ; Insulin/analogs & derivatives/*blood/chemistry/immunology ; Insulin Antibodies/*blood ; Male ; Middle Aged ; Polyethylene Glycols/chemistry ; Radioimmunoassay/instrumentation/*methods ; Recombinant Proteins/analysis/immunology/metabolism

INTRODUCTIONWith advancement in the understanding of the pathogenesis underlying diabetes mellitus (DM), the boundary between type 1 and type 2 DM (T1DM and T2DM) does not seem to be as clear cut as previously thought. This study was designed to test the possibility of overlap between the spectra of immune-mediated DM and insulin resistance.

METHODSTo test for the possibility of overlap, we looked for autoantibodies typical of T1DM in patients with classical T2DM, and insulin resistance in patients with T1DM. Autoantibodies against islet cell antigen, glutamic acid decarboxylase-65 and insulinoma-associated antigen-2 were tested in 82 patients with T2DM and 27 patients with T1DM. The patients had been diagnosed on clinical criteria using standard laboratory techniques. Clinical parameters of diagnostic importance were noted, and homeostatic model assessment of insulin resistance (HOMA-IR) was calculated using fasting insulin and fasting blood glucose ratio.

RESULTSAutoantibodies against one or more beta cell antigens were detected in 12.19% of patients clinically diagnosed to have T2DM, and insulin resistance (HOMA-IR > 2.5) was diagnosed in 37.03% of patients with T1DM. It was not possible to identify any combination of clinical or biochemical markers that could predict autoantibody positivity in T2DM patients. T1DM patients with insulin resistance had a significantly higher body mass index than their insulin-sensitive counterparts (p = 0.02).

CONCLUSIONAutoantibodies against beta cell antigens are detectable in insulin-resistant T2DM patients, and insulin resistance may be present in relatively overweight T1DM patients. No differentiating clinical features that might predict autoantibody positivity in T2DM patients were found.

Adolescent ; Adult ; Autoantibodies ; blood ; immunology ; Biomarkers ; blood ; Blood Glucose ; analysis ; Body Mass Index ; Cross-Sectional Studies ; Diabetes Mellitus, Type 1 ; classification ; immunology ; Diabetes Mellitus, Type 2 ; classification ; immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Insulin Resistance ; immunology ; Male

Due to their high immunostimulatory ability as well as the critical role they play in the maintenance of self-tolerance, dendritic cells have been implicated in the pathogenesis of autoimmune diseases. The non-obese diabetic (NOD) mouse is an animal model of autoimmune type 1 diabetes, in which pancreatic beta cells are selectively destroyed mainly by T cell-mediated immune responses. To elucidate initiation mechanisms of beta cell-specific autoimmunity, we attempted to generate bone marrow-derived dendritic cells from NOD mice. However, our results showed low proliferative response of NOD bone marrow cells and some defects in the differentiation into the myeloid dendritic cells. NOD dendritic cells showed lower expressions of MHC class II, B7-1, B7-2 and CD40, compared with C57BL/6 dendritic cells. In mixed lymphocyte reactions, stimulatory activities of NOD dendritic cells were also weak. Treatment with LPS, INF-gamma and anti-CD40 stimulated NOD dendritic cells to produce IL-12p70. The amount of IL-12, however, appeared to be lower than that of C57BL/6. Results of the present study indicated that there may be some defects in the development of NOD dendritic cells in the bone marrow, which might have an impact on the breakdown of self tolerance.
Animal ; Autoimmune Diseases/pathology ; Autoimmune Diseases/immunology ; Bone Marrow Cells/pathology* ; Bone Marrow Cells/immunology* ; Bone Marrow Cells/chemistry ; Cell Differentiation/immunology ; Cell Differentiation/drug effects ; Dendritic Cells/pathology* ; Dendritic Cells/immunology* ; Dendritic Cells/chemistry ; Diabetes Mellitus, Insulin-Dependent/pathology* ; Diabetes Mellitus, Insulin-Dependent/immunology ; Enzyme-Linked Immunosorbent Assay ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Interleukin-12/analysis ; Interleukin-4/pharmacology ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Obesity

This study was performed to prove the hypothesis that oncogene expressions would have the same patterns with those of cellular growth to growth factors in FRTL-5 cells. Ribonucleic acids of FRTL-5 were extracted at 15', 30', 60' and 120' after administration of growth factors to quiescent FRTL-5, and blotted to the nitrocellulose membrane. They were hybridized with radiolabelled c-fos, c-myc and beta-actin probes. Hybridized dot blots were autoradiographed and the amount of radioactivity was measured by densitometry. Densitometric readings were used as the indices of oncogene expressions. Expressions of c-fos and c-myc were more prominent in combined administrations of TSH (10 mU/ml) and IGF-I (100 ng/ml) or IgG of Graves' disease (Graves' IgG; 1 mg/ml) and IGF-I than in combined administration of TSH and Graves' IgG. IgG of primary myxedema suppressed oncogene expressions by TSH or Graves' IgG, but not by IGF-I. From the above results, it was suggested that expressions of c-fos and c-myc to growth factors would have similar patterns with those of cell growth to growth factors in FRTL-5, and the actions of TSH and Graves' IgG would be manifested through same signal transduction system, but IGF-I would be manifested by its own.
Animal ; Cell Division/drug effects/genetics ; Cell Line/cytology/physiology ; Gene Expression/drug effects/immunology ; Graves' Disease/immunology ; Growth Substances/genetics/*pharmacology ; Immunoglobulin G/pharmacology ; Insulin-Like Growth Factor I/pharmacology ; Myxedema/immunology ; Proto-Oncogene Proteins c-fos/*genetics ; Proto-Oncogene Proteins c-myc/*genetics ; RNA/analysis ; Rats ; Rats, Inbred F344 ; Support, Non-U.S. Gov't ; Thyroid Gland/cytology ; Thyrotropin/pharmacology ; Time Factors