Pancreatic betacell function deteriorates continuously in type 2 diabetes patients despite optimal treatment, which has been attributed to hyperglycemia itself via formation of excess reactive oxygen species. Studies of animals with spontaneous autoimmune diabetes have revealed that autoreactive T cells that mediate islet betacell destruction can be manipulated by the administration of cytokines, especially Th2 cytokines. Restoration of self tolerance at certain time period may facilitate islet cell regeneration and may enable complete recovery from diabetes. To overcome short halflives of cytokines, we would like to deliver genes which enable cytokine production in the body. We also induced antiapoptotic molecules in betacells, the protective effect of which we screened systematically, applying new gene/peptide delivery strategies. In this study, the effect of peptide delivery using specific carriers was evaluated both in vitro and in vivo. In view of the immunoregulatory activity of Th2 cytokines, we investigated whether systemic or local cytokine gene therapy stops islet destructive autoimmunity and regenerates betacells of the pancreas in NOD mice. In addition, treatment of betacells with the antioxidant metallothionein resulted in a significant reduction in pathological changes and restored GSIS. Specific inhibition of NF-kappaB activation by retroviral transduction of dominant negative inhibitor of NF-kappaB also protected betacells. Therefore, these results suggest the protective influence of these gene/ peptide delivery as an adjunctive measure to clinical islet transplantation may enable us to improve the results of the cell-based treatment to overcome the battle against the debilitating disease of diabetes mellitus.
Animals ; Autoimmunity ; Cytokines ; Diabetes Mellitus ; Diabetes Mellitus, Type 1 ; Genetic Therapy ; Humans ; Hyperglycemia ; Islets of Langerhans ; Islets of Langerhans Transplantation ; Metallothionein ; Mice ; Mice, Inbred NOD ; NF-kappa B ; Pancreas ; Reactive Oxygen Species ; Regeneration ; Self Tolerance ; T-Lymphocytes ; Zidovudine

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by selective destruction of pancreatic islet betacells causing insulin deficiency. T1D has been shown to be a polygenic trait, associated with several loci, among which the human leukocyte antigen (HLA) region accounts for 40% of the genetic risk to develop T1D. The betacell autoimmune response is triggered by environmental or unknown events in the predisposing genetic background. The triggers of autoimmunity can lead to a localized imbalance between regulatory T cells and autoimmune effector T cells. The macrophages and autoreactive lymphocytes infiltrate the islets and the interaction of betacells and immune cells leads to inductionamplification of insulitis and loss of betacells. T cells destroy betacells in a direct cytotoxic manner or influence the induction of betacell apoptosis through the release of cytotoxic molecules, such as cytokines. The autoimmune process progresses subclinically for many years in the majority of patients, and clinical symptom do not appear until more than 80% of betacells have been destroyed. Although no current "cure" exists, there is a major effort to develop immunotherapies to prevent or halt the disorder that still requires much research to fully understand exact triggering events leading toautoimmune activation. Other strategies involve beta- cell replacement by islet transplantation, but researchs to enhance the islet mass transplanted and preserve beta-cell function are necessary.
Apoptosis ; Autoimmune Diseases ; Autoimmunity ; Cytokines ; Diabetes Mellitus, Type 1 ; Humans ; Immunotherapy ; Insulin ; Islets of Langerhans ; Islets of Langerhans Transplantation ; Leukocytes ; Lymphocytes ; Macrophages ; Multifactorial Inheritance ; T-Lymphocytes ; T-Lymphocytes, Regulatory ; Transplants

Type 2 diabetes has become epidemic in the past several decades owing to advancing age, a substantially increased prevalence of obesity and decreased physical activities etc. Achieving & maintaning glycemic level as close to the nondiabetic range as possible through intensive diabetes therapy has been demonstrated to have a powerful beneficial effect on diabetesspecific microvascular complications in type 1 & type 2 diabetes. However, diabetes is associated with a reduced lifespan, largely as a consequence of cardiovascular disease. Unlike type 1 diabetes, current studies have failed to demonstrate a beneficial effect of intensive diabetes therapy on cardiovascular disease in type 2 diabetes. Accordingly, special consideration may now need to be given to high-risk patients with multiple risk factors & heart disease. Therefore, comprehensive approach to the treatment of type 2 diabetes that include the treatment of all of the coexisting risk factors for cardiovascular disease has to be implemented and achieved
Cardiovascular Diseases ; Heart Diseases ; Humans ; Motor Activity ; Obesity ; Prevalence ; Risk Factors

Diabetes Mellitus is a metabolic disease caused by impaired insulin secretion of pancreatic beta cells and increased insulin resistance of peripheral tissues. In Asian T2DM, progressive loss of beta cells mass and concomitant reduction of insulin secretion are more fundamental problems than peripheral insulin resistance. To solve this problem, research fields about investigation how stimulated islet cell growth and block the islet cell death is getting more important. Recently introduced drug, Glucagon like peptide-1 (GLP-1) has many beneficial roles in treatment of diabetes. GLP-1 stimulated glucose dependent insulin secretion and also can preserve beta cell mass through stimulation of beta cell growth and differentiation and protection of beta cell death from hyperglycemic stress. After treatment of GLP-1 or Exendin-4 (GLP-1 receptor agonist), beta cell mass is increased in animal models. This can be achieved through beta cell proliferation in islet or differentiation from intrapancreatic progenitor cells like ductal epithelium. The mechanism of beta cell proliferation is mediated by the PKA-CREB pathway. After activation of GLP-1 receptor, intracellular cAMP is elevated and then it activates PKA and CREB phosphorylation. Translocation of CREB into the nucleus up-regulates PDX-1 andIRS-2. Another pathway for beta cell proliferation is trans-activation of EGFR via c-Src after GLP-1 receptor activated. The notch pathway, major determinant of pancreas development in the embryonic stage, can be participate beta mass preservation through activation of gamma secretase in the beta cell membrane. Cleaved intracellular part of the notch translocates to the nucleus and binds to the pdx-1 promoter region. In hyperglycemia, oxidative and endoplasmic reticulum (ER) stress can be caused by apoptosis of the beta cell. Protection of apoptosis is another tool for beta cell mass preservation. After treatment of GLP-1 or exendin-4, beta cell apoptosis induced by oxidative and ER stress can be protected. GLP-1 can modulate JNK and GSK 3beta activation and ER chaperone and ER stress response. In treatment of diabetes, GLP-1 increases insulin secretion with glucose dependent manner and also preserves beta cell mass against progressive beta cell loss
Amyloid Precursor Protein Secretases ; Apoptosis ; Asian Continental Ancestry Group ; Cell Death ; Cell Membrane ; Cell Proliferation ; Diabetes Mellitus ; Endoplasmic Reticulum ; Epithelium ; Glucagon ; Glucagon-Like Peptide 1 ; Glucose ; Humans ; Hyperglycemia ; Insulin ; Insulin Resistance ; Insulin-Secreting Cells ; Islets of Langerhans ; Metabolic Diseases ; Models, Animal ; Pancreas ; Peptides ; Phosphorylation ; Promoter Regions, Genetic ; Receptors, Glucagon ; Stem Cells ; Venoms ; Glucagon-Like Peptide-1 Receptor

No abstract available.
Asia ; Insulin ; Insulin Resistance ; Risk Factors

Insulin resistance is the main pathophysiologic abnormality of type 2 diabetes mellitus. Insulin resistance and resultant compensatory hyperinsulinemia are closely associated with other important cardiovascular risk factors such as hypertension, dyslipidemia and artherosclerosis. Genetic factors and environmental factors such as obesity and physical inactivity contribute to the development of insulin resistance. Recently mitochondrial dysfunction, ER (endoplasmic Reticulum) stress and inflammation has been known to be linked with insulin resistance. At present, lifestyle modification and metformin and thiazolidinediones are known to reduce insulin resistance with some limitations. Considering both clinical importance of insulin resistance and rapid advances in our understanding of pathogenesis of insulin resistance, new therapeutic strategies based on novel molecular mechanisms of insulin resistance are anticipated
Diabetes Mellitus, Type 2 ; Dyslipidemias ; Hyperinsulinism ; Hypertension ; Inflammation ; Insulin ; Insulin Resistance ; Life Style ; Metformin ; Obesity ; Risk Factors ; Thiazolidinediones

Diabetes mellitus is an epidemic worldwide. The worldwide prevalence of diabetes has risen rapidly over the past two decades, from an estimated 30 million cases in 1985 to 177 million in 2000. Especially, the prevalence of diabetes in Korea has explosively increased six to sevenfold from 1.5% to almost 10% during the past 30 years. Furthermore, diabetic patients in Korea suffered from various diabetic complications and diabetes-related mortality has rapidly increased over the last decades. However, the current status of diabetes management was not good. According to an analysis of Korean National Health Insurance Database on Diabetes (2003), only 53% of diabetic patients visited clinics for diabetes management. The proportion of diabetic patients with optimally controlled glycemia (HbA1c<7%), blood pressure (<130/80 mmHg) and dyslipidema (LDL cholesterol <100 mg/dL) were only 40%, 19% and 38%, respectively. If the current trend continues, diabetes would be a disaster in Korea, leading to a greater loss of human and financial resources. To reduce this harmful epidemic, comprehensive and improved public health strategies should be implemented
Blood Pressure ; Cholesterol ; Diabetes Complications ; Diabetes Mellitus ; Disasters ; Humans ; Korea ; National Health Programs ; Prevalence ; Public Health

Helicobacter pylori (H. pylori) infection is mainly acquired in childhood. Although the majority of H. pylori-infected individual remain asymptomatic, it may cause some diseases including peptic ulcer disease, MALT lymphoma, subnormal growth, and iron deficiency anemia in children. H. pylori infection in children differs from that in adults in many aspects including clinical manifestations, pathologic features, diagnosis, and treatment. In this article, characteristic features of H. pylori infection in children were presented with special emphasis on different features from adult infection.decreased to 59.6% from 66.9% in the adult (16-79 yrs) over the period of 7 years, especially, in young subjects less than 50 years, Seoul and Gyeonggi suggesting that this decrease may be due to the improvement of socioeconomic status and hygiene.
Adult ; Anemia, Iron-Deficiency ; Child* ; Diagnosis ; Gyeonggi-do ; Helicobacter pylori ; Humans ; Hygiene ; Lymphoma, B-Cell, Marginal Zone ; Peptic Ulcer ; Seoul ; Social Class

Helicobacter pylori (H. pylori) infection is a common bacterial infection for humans. Current knowledge implies that acquisition of H. pylori seems to occur predominantly in childhood and that a major role of intrafamilial spread is not controversial. However, the major route of transmission remains poorly understood. According to the nation-wide seroprevalence study for 5,732 asymptomatic Korean population in 1998, the seroprevalence of H. pylori infection was 46.6%, showing the transition from a developing country to a developed country. The seroprevalence in children (neonate-15 yr) and adult (16-79 yrs) were 17.2% and 66.9%, respectively. According to multivariate analysis, variables such as sex, age, geographic area, crowding (number of person per room) in childhood, economic status in childhood, and types of housing in childhood were significantly and independently associated with H. pylori seroprevalence of adults. In children, age, geographic area, household income, mother's education, and drinking water source were significant factors of H. pylori infection. The seroprevalence survey in 2005 showed that it decreased to 59.6% from 66.9% in the adult (16-79 yrs) over the period of 7 years, especially, in young subjects less than 50 years, Seoul and Gyeonggi suggesting that this decrease may be due to the improvement of socioeconomic status and hygiene.
Adult ; Bacterial Infections ; Child ; Crowding ; Developed Countries ; Developing Countries ; Drinking Water ; Education ; Family Characteristics ; Gyeonggi-do ; Helicobacter pylori ; Housing ; Humans ; Hygiene ; Multivariate Analysis ; Prevalence* ; Seoul ; Seroepidemiologic Studies ; Social Class

Patients can be tested for the H. pylori infection via invasive or non-invasive methods. At present, no single test is absolutely relied upon to detect colonization of H. pylori, and a combination of two tests is recommended if feasible. A growing interest in non-invasive tests for the detection of Helicobacter pylori has been observed recently. Although serology for IgG often is chosen in the outpatient setting because of its convenience, it is less accurate than either the urea breath test (UBT) or stool antigen test. In addition, the UBT and stool antigen test can be used to confirm eradication, whereas serology remains positive for months after eradication. The test should be used in the basis of the clinical circumstances, the likelihood ratio of positive and negative tests, the cost-effectiveness of the testing strategy, and the availability of the tests.
Breath Tests ; Colon ; Diagnosis* ; Helicobacter pylori* ; Helicobacter* ; Humans ; Immunoglobulin G ; Outpatients ; Urea