Dynamics of insulin secretion and the clinical implications for obesity and diabetes

Insulin secretion is a highly dynamic process regulated by various factors including nutrients, hormones, and neuronal inputs. The dynamics of insulin secretion can be studied at different levels: the single β cell, pancreatic islet, whole pancreas, and the intact organism. Studies have begun to analyze cellular and molecular mechanisms underlying dynamics of insulin secretion. This review focuses on our current understanding of the dynamics of insulin secretion in vitro and in vivo and discusses their clinical relevance.     

Mature acinar cells are refractory to carcinoma development by targeted activation of Ras oncogene in adult rats

Pancreatic ductal adenocarcinoma (PDA) is one of the most debilitating malignancies in humans. A thorough understanding of the cytogenesis of this disease will aid in establishing successful treatments. We have developed an animal model which uses adult Hras^G12V and Kras^G12V transgenic rats in which oncogene expression is regulated by the Cre/loxP system and neoplastic lesions are induced by injection of adenovirus‐expressing Cre recombinase. When adenovirus with Cre recombinase under the control of the CMV enhancer/chicken β‐actin (CAG) promoter (Ad‐CAG‐Cre) is injected into the pancreatic duct of these animals, pancreatic neoplasias develop. Pathologically, the origin of these lesions is duct, intercalated duct, and centroacinar cells, but not acinar cells. The present study was undertaken to test the effect of acinar cell‐specific oncogenic ras expression. Adult transgenic rats were injected with adenovirus with Cre recombinase under the control of the acinar cell‐specific promoters amylase (Ad‐Amy‐Cre) and elastase‐1 (Ad‐Ela‐Cre) or under the control of the non‐specific CAG promoter. Injection of either Ad‐Amy‐Cre or Ad‐Ela‐Cre into the pancreatic ducts of transgenic animals in which oncogenic Kras is tagged with hemagglutinin (HA), HA‐Kras^G12V rats resulted in expression of oncogenic ras in acinar cells but not in duct, intercalated duct, or centroacinar cells. Notably, injected animals did not develop any observable proliferative or neoplastic lesions. In marked contrast, injection of Ad‐CAG‐Cre resulted in pancreatic cancer development within 4 weeks. These results indicate that adult acinar cells are refractory to Ras oncogene activation and do not develop neoplasia in this model. (Cancer Sci2009)     

Prevalence of 'obesity disease' and 'metabolic syndrome' in obese pediatric outpatients at the University Hospital of Occupational and Environmental Health, Japan

'Obesity Disease for Japanese Children' was defined in 2002, and very recently 'Metabolic Syndrome (MS) for Japanese Children' was also defined. We therefore aimed to determine the prevalence of these two among the obese pediatric outpatients at our university hospital. The subjects were 97 children, 58 boys and 39 girls, ranging in age from 5 to 15 years. A child was considered to be obese when the body weight exceeded 120% of the standard body weight. All the subjects exceeded 120% overweight, and 58 children (35 boys and 23 girls) were over 150% overweight. Eighty five children (53 boys and 32 girls) were diagnosed with obesity disease (87.6%). Sixteen children (12 boys and 4 girls) were diagnosed with metabolic syndrome, which was 16.5% of all the subjects and 18.8% of the children with obesity disease. Fourteen of the 16 children with MS were over 10 years old. Obesity disease is diagnosed when the child has an obesity disease score of more than 6. The obesity disease score was significantly correlated with the waist circumference and the visceral adipose tissue area measured by computed tomography. The mean score of the children with MS was significantly higher than that of the non-MS group (30.2 vs. 12.3 points). In this study, it was clear that about 90% of our clinic patients are in the obesity disease group, and need therapeutic interventions. The prevalence of MS in the pediatric age is very low compared with that of adults, but MS is a high-risk category of obesity disease.     

A revisit of mucosal IgA immunity and oral tolerance.

Induction of mucosal immunity by oral immunization with protein antigen alone is difficult: potent mucosal adjuvants, vectors, or other special delivery systems are required. Cholera toxin (CT) has been shown to be an effective adjuvant for the development of mucosal vaccines and, when given with vaccine, induces both mucosal and systemic immune responses via a Th2 cell-dependent pathway. However, and in addition to potential type-I hypersensitivity, a major concern for use of mucosal adjuvants such as CT is that this molecule is not suitable for use in humans because of its inherent toxicity. When we examined the potential toxicity of CT for the central nervous system, both CT and CT-B accumulated in the olfactory nerves/epithelium and olfactory bulbs of mice when given by the nasal route. The development of effective mucosal vaccines for the elderly is also an important issue; however, only limited information is available. When mucosal adjuvanticity of CT was evaluated in aged mice, an early immune dysregulation was evident in the mucosal immune system. The present review discusses these potential problems for effective mucosal vaccine development. Tolerance represents the most common and important response of the host to environmental antigens, including food and commensal bacterial components, for the maintenance of an appropriate immunological homeostasis. We have examined whether Peyer patches could play a more important role for the maintenance of oral tolerance. Using Peyer patch-null mice, we found that mice lacking this gut-associated lymphoid tissue retained their capability to produce secretory IgA antibodies but did not develop normal oral tolerance to protein antigens.     

Highly purified mutant E112K of cholera toxin elicits protective lung mucosal immunity to diphtheria toxin.

We demonstrated that the mutant of cholera toxin (mCT) E112K which was LPS-free supported the induction of protective immunity in mucosal (e.g. lung lavage) and systemic (e.g. serum) compartments when given nasally with vaccine-grade diphtheria toxoid (DT) to mice. Significant DT-specific mucosal IgA antibody (Ab) and serum IgG, IgA and IgM Ab responses were induced when LPS-depleted mCT E112K or native CT (nCT) was co-administered nasally with DT. The analysis of DT-specific Ab-forming cell (AFC) responses supported the Ab titers and significant numbers of DT-specific IgA AFC were present in the lungs, nasal passages and submandibular glands. Furthermore, DT-specific IgG AFC in cervical lymph nodes (CLN) and the spleen were induced in mice administered with DT nasally with either mCT or nCT. The analysis of antigen-specific T cell responses revealed that increased DT-specific CD4+ T cell proliferative and Th2-type cytokine responses were induced in mice nasally-immunized with DT and the LPS-free form of mCT. The neutralization of diphtheria toxin by Abs showed that DT-specific IgG Ab responses in serum and lung lavages of mice immunized with DT and mCT were protective. Furthermore, it was shown that an IgA-enriched fraction of lung lavages possessed diphtheria toxin-specific neutralizing activity. These results are the first demonstration that nasally co-administered mCT E112K can induce DT-specific protective Ab responses in mucosal compartments (e.g. lung lavages and the lungs).     

Formation of advanced glycation end‐product‐modified superoxide dismutase‐1 (SOD1) is one of the mechanisms responsible for inclusions common to familial amyotrophic lateral sclerosis patients with SOD1 gene mutation,and transgenic mice expressing human SOD1 gene mutation

Neuronal Lewy body‐like hyaline inclusions (LBHI) and astrocytic hyaline inclusions (Ast‐HI) are morphological hallmarks of certain familial amyotrophic lateral sclerosis (FALS) patients with superoxide dismutase‐1 (SOD1) gene mutations, and transgenic mice expressing the human SOD1 gene mutation. The ultrastructure of inclusions in both diseases is identical: the essential common constituents are granule‐coated fibrils approximately 15– 25 nm in diameter and granular materials. Detailed immunohistochemical analyses have shown that the essential common protein of the inclusions in both diseases is an SOD1 protein. This finding, together with the immunoelectron microscopy finding that the abnormal granule‐coated fibrils comprising the inclusions are positive for SOD1, indicates that these granule‐coated fibrils containing SOD1 are important evidence for mutant SOD1‐linked disease in human and mouse. For im‐munoelectron microscopy, the granule‐coated fibrils are modified by advanced glycation endproducts (AGE) such as N^?‐carboxymethyl lysine, pyrraline and pentosidine (Maillard reaction). Based on the fact that AGE themselves are insoluble molecules with direct cytotoxic effects, the granule‐coated fibrils and granular materials are not digested by the lysosomal and ubiquitin systems. The neurons and astrocytes of the normal individuals and non‐transgenic mice show no significant immunoreactivity for AGE. Considered with the mutant‐SOD1 aggregation toxicity, a portion of the SOD1 comprising both types of the inclusion is modified by the AGE, and the formation of the AGE‐modified SOD1 (probably AGE‐modified mutant SOD1) is one of the mechanisms responsible for the aggregation (i.e. granule‐coated fibril formation).     

Genetically Diverse Highly Pathogenic Avian Influenza A(H5N1/H5N8) Viruses among Wild Waterfowl and Domestic Poultry,Japan, 2021

Genetic analyses of highly pathogenic avian influenza H5 subtype viruses isolated from the Izumi Plain, Japan, revealed cocirculation of 2 genetic groups of clade 2.3.4.4b viruses among migratory waterfowl. Our findings demonstrate that both continuous surveillance and timely information sharing of avian influenza viruses are valuable for rapid risk assessment.     

The antitumor effects of locally injecting human peripheral blood mononuclear cells treated with OK-432 into the tumor site: The possible role of a tumor growth inhibitory factor (TGIF)

The production of a tumor growth inhibitory factor (TGIF) was induced in human peripheral blood mononuclear cells (PBMC) by a streptococcal preparation, OK-432,in vitro. The antitumor effect of locally injecting PBMC treated with OK-432 into the tumor site was studied. PBMC were collected from patients with gastric cancer 5 to 12 days before their operation, and cultured with OK-432 for 24 hrin vitro. After the culture, the PBMC were washed thoroughly to eliminate the OK-432. The washed PBMC went on producing TGIF for more than 72 hrin vitro in the absence of OK-432. A small number of TGIF-producing PBMC, approximately 10⁷ cells, were injected around the lesion under endoscopic observation. A remarkable antitumor effect was observed in 2 out of 10 cases of resectable gastric cancer. Histological examinations indicated that the antitumor effect is due to antitumor cytokines such as TGIF produced by PBMC rather than to the OK-432-activated PBMC themselves.