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The most common form of diabetes, type 2 diabetes is a chronic illness that is characterized by high blood sugar levels.
Causes of type 2 diabetes are being very overweight with excess body weight around the waist, poor diet and a low activity level.
Diabetes symptoms are not always present but they can include blurred vision, fatigue, increased appetite, thirst and urination, slow-healing or frequent infections and erectile dysfunction. Adult stem cells, undifferentiated and adaptable, are able to change into the cells of countless organs and structures within the human body. Angeles Health developed the Adult Autologous Stem Cell (A-ASC) Therapy program to care for a variety of patients, including those who have type 2 diabetes. Angeles hospital employs stem cells that come from the patient’s own bone marrow and adipose tissue, or fat.
Organs and tissues can be addressed directly with the specialized catheterization procedure. Angeles Health International is a Center of Excellence that offers type 2 diabetes patients the most innovative and high quality treatment. To learn about Stem Cell Application and all the treatment options available for diabetes at Angeles hospital in Mexico please contact us using the form to your right. Stem Cell Application Mexico: What Does It Mean to be a BioHeart Stem Cell Center of Excellence? Science, Technology and Medicine open access publisher.Publish, read and share novel research. Fulminant Type 1 Diabetes Mellitusin IRS-2 Deficient MiceToshiro Arai1, Nobuko Moriand1 and Haruo Hashimoto1[1] Nippon Veterinary and Life Science University, Japan1. 2007 Fulminant type 1 diabetes in Korea: highprevalence among patients with adult-onset type 1 diabetes.
2003 Inflammatory mediators and islet ?-cell failure: a link between type 1and type 2 diabetes. 2009 Reconsideration of 2sulin signals induced by improved laboratory animal diets, Japanese and American diets, in IRS-2 deficient mice. 2000 A novel subtype of type 1 diabetes mellitus characterized by a rapid onsetand an absence of diabetes-related antibodies.
2005 Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus.
2000 Tissue-specific insulin resistance in mice withmutations in the insulin receptor, IRS-1, and IRS-2.
2000 Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. 2002 Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survivalduring chronic hyperglycemia. 2001 Distict effects of saturated and monosaturated fattyacids on beta-cell turnover and function. 1997 Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cell. Altering Trends in the Epidemiology of Type 1 Diabetes Mellitus in Children and AdolescentsElisavet Efstathiou1 and Nicos Skordis2[1] Paediatric Endocrine Unit, Department of Paediatrics,Makarios Hospital, Nicosia, Cyprus1. Worldwide increase in incidence of Type I diabetes--the analysis of the data on published incidence trends. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Geographical variation in the incidence of diabetes mellitus in Scottish children during the period 1977-1983. Incidence of childhood diabetes in children aged less than 15 years and its clinical and metabolic characteristics at the time of diagnosis: data from the Childhood Diabetes Registry of Saxony, Germany. The incidence of type 1 diabetes mellitus in Greek-Cypriot children and adolescents in 1990-2000.
Rising incidence of type 1 diabetes mellitus in children and adolescents in Cyprus in 2000-2004. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Genetic interaction among three genomic regions creates distinct contributions to early- and late-onset type 1 diabetes mellitus. Epidemiology of type I diabetes mellitus in Switzerland: steep rise in incidence in under 5 year old children in the past decade.
UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. The incidence of type 1 diabetes in the age group 0-39 years has not increased in Antwerp (Belgium) between 1989 and 2000: evidence for earlier disease manifestation. The incidence of Type I diabetes has not increased but shifted to a younger age at diagnosis in the 0-34 years group in Sweden 1983-1998.
Seasonality of birth in children and young adults (0-29 years) with type 1 diabetes in Ukraine.
The association between ultraviolet B irradiance, vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Particular HLA-DQ molecules play a dominant role in determining susceptibility or resistance to type 1 (insulin-dependent) diabetes mellitus. Type 2 diabetes quiz question 9: Out of 10 cases of diabetes diagnosed about how many are type 2 diabetes? Damiano whose 15-year-old son was diagnosed with type 1 diabetes at the age of 11 months Read this article to learn what can cause diabetes lower back pain.
Diabetes mellitus type 2 (or adult-onset diabetes) is a metabolic disorder where high blood sugar levels occur which can cause heart attacks strokes type 2 diabetes diet regime ohio cleveland Diabetic Foot Care Handout Texas Lubbock blindness and kidney failure if not treated. The sooner the Diabetic Foot Care Handout Texas Lubbock your are diagnosed the sooner the treatment process can be implemented and the better your chance of overcoming this condition.
Ada sea diabetes guidelines 2012 diretriz diabetes pdf standards of care diabetes 2012 pdf. This disease is less common than CEA in Collies but more difficult to eed away from as symptoms are not usually detectable until the affected dog is Thus began the eed’s transformation from working farm dog similar to the modern Border collie to the largely pet and show dog monitoring ketones diabetes jackson mississippi we know today. Predictors of Adherence, Metabolic Control and Quality of Life in Adolescents with Type 1 DiabetesM. Clinical, Socio-Demographic Questionnaire (Pereira et al., 2010) that reports gender and age in adolescents and their family members as well as metabolic control (glycated hemoglobin) and duration of disease, in the adolescent.
2008 Questionario de Avaliacao da Qualidade de Vida para Adolescentes com Diabetes: Estudo de validacao do DQOL. 1997 Parental Involvement in Diabetes Management Tasks: Relations to Blood Glucose Monitoring and Metabolic Control in Adolescents with Insulin-Dependent Diabetes-Mellitus. Please note that we are unable to respond back directly to your questions or provide medical advice. As the fastest growing consumer health information site a€” with 65 million monthly visitors a€” Healthlinea€™s mission is to be your most trusted ally in your pursuit of health and well-being. Many therapies use stem cells as they can restore damaged structures and rejuvenate failing cells very effectively.
Type 2 diabetes patients are treated using autologous adult stem cells, which are harvested from the patient. As adipose tissue extraction is more efficient than bone marrow extraction, the tissue yields up to ten times more stem cells, it is more commonly applied in stem cell application. Collaborative medical practitioners encourage and define best practice by learning together, measuring their outcomes and establishing effective treatment protocols. Effects of modern Japanese and American diets on RNA expression of GLUT4 and PPAR?2 of adipose tissues and plasma adipocytokines concentrations in IRS-2 deficient mice fed with three kinds of diets with different lipid levels. Effects of modern Japanese and American diets on intraperitoneal white adipose tissues, (a) Axial views, (b) Coronal views of MRI, and (c) Adipocytes in white adipose tissues of IRS-2 deficient mice with three kinds of diets with different lipid levels.
IntroductionType 1 diabetes mellitus (T1DM), one of two major forms of diabetes, results from nearly complete destruction of pancreatic beta (?) cells.
Mean Annual Incidence rates for T1DM comparing different countries in the world as seen in reference 1.
Ayurvedic treatments for diabetes mellitus: People with diabetes and other chronic diseases often use complementary and alternative medicines. The vaccine successfully tested on mice was designed to stop the autoimmune response responsible for causing Type 1 diabetes in children without damaging immune cells that protect the body against disease and infection. Cushing Disease Hyperadrenokortizismus = zu viel Kortison Diabetes mellitus (D) Daily foot care is essential to the self-management of diabetes and pharmacists can recommend OTC products and techniques to prevent and treat nick jonas diabetes insulin pump virginia richmond infections.
Beta Glucan shows promise in cholesterol reduction infection prevention and appears to reduce glucose and insulin levels. One study showed that people with type 2 diabetes have an insufficient amount of a protein called GLUT4 which is necessary for cells to take in glucose. Normal fasting blood sugar level is 80-120 mg per 100ml of blood; after eating blood sugar level goes up to 160 mg per 100ml anything higher than this can be considered as diabetes. Intensive insulin treatment prolonged life in diabetic patients after a heart attack by more than 2 years according to researchers from the Karolinska Institute in Stockholm Sweden.
Predictors of adherence, metabolic control and quality of life in adolescents on gender, duration of disease, glycated hemoglobin, family support, school support and parental coping4.3.
Predictors of Adherence, Metabolic Control and Quality of Life in Adolescents on Gender, Duration of Disease, Glycated Hemoglobin, Family Support, School Support and Parental Coping (N=85 adolescents; N= 85 family members).
Predictors of Adherence, Metabolic Control and Quality of Life in Adolescents on Glycated Hemoglobin and Illness Representations (N=85 adolescents; N= 85 fam.
DFBS is a 47 items questionnaire that assesses family support given to the adolescent in diabetes self care.
Both of which will support, guide, and inspire you toward the best possible health outcomes for you and your family. Insulin is necessary in transporting blood sugar, or glucose, to cells where it can be stored for later energy use.
Other diabetes risk factors include old age, high blood pressure, history of gestational diabetes, polycystic ovarian syndrome, impaired glucose intolerance and ethnicity, as African Americans, Hispanic Americans, and Native Americans present high diabetes incidences.
Stem cells can be delivered throughout the body, there is no need for anesthesia and it can be executed in less than an hour. The Center of Excellence operates with licensed medical experts who adhere to formally appointed bodies of expertise.
All pancreas specimens were fixed in 10% buffered formalin and embedded paraffin, mounted on amino-silane coated glass slide and stained using the indirect immunoperoxidase method.
Excess calorie and physical inactivity induce hyperglycemia followed by increased insulin secretion, which accelerates fatty acid synthesis via activation of transcriptional factor, SREBP-1c etc. The history of diabetes dates back to 1550 BC as the polyuric states were described in an Egyptian papyrus, where treatment was given with a four day decoction of bones, wheat, grain, grit and earth.
Every year about 2000 children are diagnosed with type 1 diabetes but a quarter of Adolescents may ignore the symptoms. The best deals of Diabetes Treatment Herbal Diabetes Treatment and Professional Diabetes Treatment company in Singapore. Although many different problems can occur as a result of diabetic neuropathy If your child has a family history of high cholesterol or heart disease and is over 2 years old your child’s doctor may do a cholesterol (LDL and HDL) test when type 1 diabetes is diagnosed or as soon as blood sugars are under control. Cristina Almeida2, Liliana Rocha1 and Engracia Leandro2[1] University of Minho, School of Psychology, Portugal[2] University of Minho, Social Sciences Institute, Portugal1. The Brief-IPQ is a 9 items questionnaire, measuring cognitive and emotional representations of illness, that includes nine dimensions of illness perceptions: consequences, timeline, personal control, treatment control, identity, concern, coherence, emotional representation and causal representations. It?s a 14 items questionnaire assessing adherence to diabetes treatment’srecommendations regarding self care that includes four subscales: blood glucose regulation, insulin and food regulation, exercise and emergency precautions.
Stem cell science has seen considerable advancements in the last few years with many new developments and discoveries being made.
Pancreas sections were pretreated with 0.03% H2O2 in methanol to block endogenous peroxidase activity, and incubated for 60 min at room temperature with guinea pig anti-swine insulin (Dako Cytomation), followed by 30 min incubation with peroxidase-conjugate rabbit anti-guinea pig immunoglobulin. For each mouse, sera were treated with 0.03% H2O2 in methanol to measure the endogenous peroxidase activity. Acceleration of fatty acid synthesis induces heterotopic accumulation of lipid, and visceral fat accumulation is increased. The term diabetes was coined by Aretaeus of Cappadocia in the 2nd century AD for conditions causing increased urine output.
Diabetic Foot Care Handout Texas Lubbock why diabetes increases cancer risk” says Edward Giovannucci MD ScD a professor in the departments of nutrition and epidemiology at Harvard School of Public Health in Boston. The most commonly associated risk factors for developing frequent urination at night are: Getting older.
In diabetes mellitus glucose eating with gestational diabetes west covina california (sugar) cannot be utilized by the body because of either a decrease in insulin production or a decreased sensitivity of cells to insulin. The pathophysiology of type 1 diabetes mellitus (DM) involves: A) autoimmune destruction of pancreatic beta cells.
Characteristics of the Adolescents' Sample by Clinical, Socio-demographic and Psychosocial variables. IntroductionDiabetes Mellitus Type I (DM1) is a diagnosed disease that appears before age 35 (Hanas, 2007) and is well known, in the pediatric population, as one of the most common diseases (Serafino, 1990).
Then, the sections were incubated for 60 min at room temperature with rabbit anti-human glucagon (Dako Cytomation), followed by 30 min incubation with alkaline phosphatase-labelled polymer conjugated goat anti-rabbit antibody (Nichirei). The sweet taste of diabetic urine was noted in the 5th century AD by Indian physicians and in 1776, Matthew Dobson confirmed that diabetic serum and urine contained sugar. The main symptoms of low blood sugar are dizziness trembling shakiness extreme hunger confusion headache and eaking out into a cold Pregnancy makes high and low blood sugar levels happen more often.
Vitamin E is occasionally supplemented but its understanding is of prime Diabetic Foot Care Handout Texas Lubbock significance in the treatment of one of the most common toxicities encountered in Diabetes has become a common diagnosis amongst pets striking 1 out of every 400 dogs. The diagnosis occurs mostly in childhood and adolescence, often between ages 5 and 11 (Eiser, 1990). Only the full scale was used in the present study and the alpha, in the present sample, was.93.
For double staining, peroxidase (brown, DAB) and alkaline phosphatase (red, New Fuchsin) were used, respectively. The definition of adolescence is a bit controversial but OMS (1965) establishes adolescence between 10 and 19 years old. Due to the fact that each subscale includes only one item, it is not possible to calculate an alpha.
Thus adiponectin increases glucose uptake and fatty acid oxidation in muscles via the type 1 adiponectin receptor (Yamauchi et al., 2003), and hepatic gluconeogensis via type 2 adiponectin receptor.
It has been proven that T1DM represents the ending result of an autoimmune destruction of the pancreatic islet beta cells in genetically susceptible individuals exposed to certain but still unclear environmental factors. The beginning of adolescence starts with the appearance of the first biological changes of puberty.
As a result, like in the original version, pearson correlations between dimensions were calculated.
Moreover adiponectin protects against oxidative stress in skeletal muscle by activating nuclear factor (NF)-?B target genes, manganese superoxide dismutase and inducible nitric oxide synthase (Ikegami et al., 2009).
According to Erikson’s theory of psychosocial development (Erikson, 1968), the central task of adolescence is the development of autonomy, identity and self integration (Barros, 2003).
Data analysisFirst, descriptive statistics were performed to find the rate of adherence to self-care, metabolic control and quality of life.
Column 1, 2 and 3 present diabetic NOD, control IRS-2 deficient and diabetic IRS-2 deficient mouse pancreatic sections, respectively. However, epidemiological study of FT1DM is lacking in other Asian populations and its incidence and pathogenesis remain to be elucidated. Decreased adiponectin secretion and increased inflammatory cytokines secretion from swelling adipose tissue deteriorate insulin resistance in obese animals (1st stage). However, multiple genetic and environmental risk factors seem to play an important role in the genesis of the disease. Type 2 Diabetes, Type 1 Diabetes, Gestational Diabetes, Other Types, Information, Treatment, Causes, Symptoms. In fact, identity formation, in adolescence, requires a reorganization of capacities, desires, needs and interests in the adolescent, as well as a quest for more independence towards parents.
Hierarchical regression analyses were later performed to identify the best predictors of adherence to self-care, metabolic control and quality of life. Control NOD mouse serum (A) reacted with diabetic NOD (A1), control IRS-2 deficient (A2) and diabetic IRS-2 deficient mouse (A3) pancreatic sections.
Decreased adiponectin causes depression of activity of AMPK which increases glucose utilization and fatty acid ?-oxidation in skeletal muscle and adipose tissues (Whitehead et al., 2006).
The genetic background is complex and difficult to be explained by the involvement of HLA gene region alone.
Nevertheless, the difficulties, even in the well succeeded resolution of the psychosocial tasks, may result in “identity confusion” (Erikson, 1968).
Due to the size of the sample, regression analysis were first performed taking in consideration all variables,except illness perceptions, and later including only them in the regression equation.
Diabetic NOD (B1-3), control IRS-2 (C1-3) and diabetic IRS-2 (D1-3) mouse sera reacted with pancreatic sections, respectively. Then hyperglycemia, hyperinsulinemia and accelerated lipid synthesis are maintained and hyper-secretion of insulin force excessively heavy work on pancreatic ? cells. On the other hand viral and nutritional factors changing continuously from country to country, may contribute to the etiology of T1DM. In adolescents with diabetes, the disease can be an additional stressor functioning as another factor that requires acceptation and self integration.
The first regression was performed using the method enter since the selection of variables was based on previous research.

In over functional pancreatic islets, ?-oxidation of fatty acid is accelerated resulting in excess amount of reactive oxygen species (ROS) production, which induces ROS stress leading to mitochondrial dysfunction and apoptosis of ?-cells with low scavenging activity of ROS (2nd stage).
There is no doubt that monitoring temporal trends and incidence of T1DM contribute to the international effort to determine the exact pathogenesis of the disease and it is of critical public health importance.
A small population of male IRS-2 deficient mice showed hyperglycemia associated with markedly diminished pancreatic islet size, and these extremely hyperglycemic IRS-2 deficient mice exhibited 1) abrupt onset of diabetes and 2) very short duration of diabetic symptoms, such as polyuria, thirst, and body weight loss. Hellerstrom, (1994, (1994).Cytokines suppress human islet function irrespective of their effects on nitric oxide generation.
On the other hand, physiological and hormonal changes that take place in adolescence may increase insulin resistance contributing to a weak control of diabetes (Duarte, 2002). These symptoms resembled the features of human nonautoimmune FT1DM (Hashimoto et al., 2006). Macrophages (but not T cells) infiltration is observed frequently in FT1DM (Shibasaki et al., 2010).
Incidence-changing trends The prevalence of T1DM greatly varies between different countries, within countries, and between different ethnic populations. In the first regression analysis, the second step included adolescents’ psychosocial variables i.e. Characteristics of abrupt onset of hyperglycemia associated with marked diminished islet mass in IRS-2 deficient mice were investigated to analyze the onset mechanism of FT1DM.2. Infiltrated macrophages may participate in destruction process of pancreatic islets leading to T1DM.
Adherence and metabolic controlAdherence to therapy in chronic disease is considered one of the main problems that may end in treatment failure (Leite, 2005). The ? cell deficit is believed to be due to autoimmune induced ? cell apoptosis mediated by the release of inflammatory cytokines, such as IL-1? and TNF-?, from T lymphocytes and macrophages (Donath et al., 2003). The highest incidence is observed in the Scandinavian countries, where Finland has the highest one reported while there is a gradual decrease in countries located closer to equator [3]. Cytokine-induced ? cell death preferentially affects newly forming beta cells, which implies that replicating beta cells might be more vulnerable to cytokine destruction. However in some areas such as Puerto Rico, Kuwait and Sardinia there is an unexplained highly increased incidence [4]. Throughout these phases, the diabetic acquires control and develops the autonomy necessary in the maintenance phase.
In the second regression analysis, the second step included adolescents’ illness perceptions and the third step included family member’s illness perceptions. Efforts to expand beta cell mass in type 1 diabetes by fostering?? cell replication are likely to fail unless cytokine-induced apoptosis is concurrently suppressed (Meier et al., 2006).
The lowest incidence in the world is observed in China, where an enormous geographic variation in the development risk is observed [5]. Any detour from the treatment plan is defined as non adherence to therapy (Bishop, 1994) and can range from missing appointments, forgetting to take insulin (or take more or less than the prescribed amount) to not following the nutritional or the exercise plan. Inflammatory cytokines from corpulent adipocytes appear to participate in destruction of islets ? cells leading to T1DM. Fas and Fas ligand expression are lacking and the mechanism of ? cell destruction differs from that in autoimmune T1DM.
In autoimmune T1DM, ? cells are assumed to be destroyed through a long-standing autoimmune process, whereas in FT1DM, ? cells seem to be destroyed very rapidly, probably by a destructive process triggered by viral infection (Hanafusa & Imagawa, 2008). Nowadays the incidence of T1DM increases dramatically throughout the world and it is estimated that it may reach the status of an epidemic in the 21st century [6]. The relationship between therapy adherence and metabolic control is complex and probably bidirectional i.e. Since IRS-2 deficient mice were maintained under specific pathogen free conditions (Hashimoto et al., 2006), viral infection was deleted from the causes of ? cell destruction. A number of 37 studies from 27 countries confirmed the increased incidence for the period 1960-96 in T1DM with an upward tendency in another 12 countries. The global average annual increase was 3.0% per year with a more pronounced relative increase in the populations with lower incidence [7]. In recent study, macrophages and T cells - but not natural killer cells – had infiltrated the islets and the exocrine pancreas and Toll-like receptor (TLR) 3, a sensor of viral components, was detected in most of macrophages and T cells in FT1DM patients (Shibasaki et al., 2010).
Chronic exposure of human islets to leptin leads to ? cell apoptosis (Donath et al., 2003). If these trends continue, the number of new cases T1DM in children younger than five years of age may double in some regions between 2005 and 2020 and prevalent cases in children under 15 years will rise by 70 % [8].The need for rigorous epidemiological studies to monitor the trends of T1DM in children less than 15 year of age led to the creation of the World Health Organization ( WHO) -sponsored Diabetes Mondiale (DIAMOND) [2] Project and the EURODIAB study [9]. Their study showed remarkably decreased numbers of pancreatic beta and alpha cells, macrophage-dominated insulitis and the expression of TLRs, a signature of viral infection, in FT1DM soon after the disease onset.
TNF?, in combination with other cytokines, accelerates dysfunction and destruction of the ? cell (Eizirik & Mandrup-Poulsen, 2001). The data from the WHO project for the incidence of T1DM worldwide DIAMOND showed a large geographic variability. Warren and Hixenbaugh, in 1998, found demographic variables to weakly predict adherence to self care in diabetes. These results suggest a new mechanism of virus-induced macrophage-dominated inflammatory process, rather than autoimmune T cell response, plays a major role in ? cell destruction in FT1DM.
IL-6 released by adipocytes may be responsible for the increases in plasma IL-6 concentrations observed in obesity and at least in combination with other cytokines, IL-6 has cytotoxic effects on ? cell (Eizirik et al., 1994).
This study group was based on 43,013 cases of T1DM from a study population of 84 million children aged 14 year old or less during the period 1990-1999 in 114 populations from 57 countries.
Some studies have revealed that adolescents typically are less adherent to therapy than children, regarding insulin administration, exercise, nutrition and self monitoring of glucose (Hirschberg, 2001). In our sample, girls reported better adherence to self-care, less social support, higher school support and family social support when compared to boys but differences were non-significant. Increased FFA levels are known to be toxic for ? cell, leading to the concept of lipotoxicity (McGarry & Dobbins, 1999).
Each adolescent apprehends and creates meanings about diabetes and its treatment’s demands and how (s)he deals with them, in the social context, influences adherence to diabetes (Barros, 2003). The toxic effect of FFA is mediated via formation of ceramide, increased nitric oxide production and activation of the apoptotic mitochondrial pathway (Maedler et al., 2001). Moreover, puberty changes, psychological dilemmas characteristic of adolescence (La Greca, 1992) and cognitive development may also contribute to an increase in non-adherence. To date, viral infection has been the most popular speculated cause of acute destruction of the pancreatic ?cell as many patients reported flu-like symptoms prior to the disease onset (Zheng et al., 2011).
Elevated glucose concentrations induced ? cell apoptosis at higher concentration in rodent islet (Efanova et al., 1998). It is of interest that several reports have shown an increase in the incidence of T1DM worldwide. Also, immaturity of thought, in adolescence, based on invulnerability may be one of the main causes of low adherence to diabetes treatment (Santos, 2001; Elkind, 1984), in adolescence.
In human islets glucose-induced ? cell apoptosis and dysfunction are mediated by ? cell production and secretion of IL-1?.
This tendency implicates an increasing influence of environmental trigger factors against a background of genetic susceptibility.
In children and adolescents with diabetes, adherence is higher after diabetes diagnosis and deteriorates over time (Jacobson et al., 1987). Immunohistochemical analyses revealed the presence of enterovirus-capsid protein in all three affected pancreata.
The geographic and ethnic variations mirror the prevalence of susceptibility genes or that of contributing environmental factors, or both. Extensive infiltration of CXCR3 receptor-bearing T-cells and macrophages into islets was observed.
IL-1? and ROS activate the transcription factor nuclear transcription factor (NF) ?B, which plays a critical role in mediating inflammatory responses.
Nevertheless this increasing incidence rate in such a short period cannot be solely attributed to genetic shifts. The EURODIAB ACE study group examined the trends in the incidence of T1DM from 1989 to 1994.
Interferon-? and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including ?cell and ? cells. The study was based on 16,362 cases of T1D in 44 European centres and Israel covering a population of 28 million children [9].
As a result, higher adherence of adolescent to self-care and parental understanding of the medical situation predicted lower levels of glycated hemoglobin (better metabolic control).
Laboratory data in IRS-2 deficient mice with FT1DM reveal hyperglycemia, hyperlipidemia and remarkable decrease in insulin secretion as in human FT1DM patients (Table 3). The above symptoms of T1DM were onset abruptly after hyperglycemia was observed in IRS-2 deficient mice. Higher values of glycated hemoglobin (poor metabolic control) predicted lower quality of life. Expression of MHC class II and hyper-expression of MHC class I was observed in some islet cells.
Insulitis with macrophage dominant infiltration was observed in IRS-2 deficient mice and human FT1DM.
On the other hand, higher adherence and a higher school support predicted better quality of life. These observations strongly suggest the presence of a circuit for destruction of ?cells in FT1DM. Enterovirus infection of the pancreata initiates coexpression of interferon-? and CXCL10 in ?cells. Since FT1DM was observed in only male IRS-2 deficient mice, pregnancy is not associated with onset of FT1DM.
CXCL10 secreted from ?cells activates and attracts autoreactive T-cells and macrophages to the islets via CXCR3. Inflammatory cytokines play a major role in destruction process of pancreatic? cell in both IRS-2 mice and human FT1DM patients. These infiltrating autoreactive T-cells and macrophages release inflammatory cytokines including interferon-? in the islets, not only damaging ?cells but also accelerating CXCL10 generation in residual ?cells and thus further activating cell-mediated autoimmunity until all ?cells have been destroyed.
On the other hand, Shibasaki et al (2010) investigated pathogenesis of FT1DM with special reference to insulitis and viral infection using pancreatic autopsy samples from three patients. Insulin resistance by increase in inflammatory cytokines seemed to be main cause to lead ? cell destruction in IRS-2 deficient mice, whereas viral infection may be a trigger for destruction mechanism in human FT1DM patients.
Thus, lower adolescents’ perception of personal control predicted lower adherence to self care and higher family perception of diabetes duration (timeline) predicted higher adherence to self care, in adolescents. Both ? and ?cell area were significantly decreased in comparison with those of normal controls. Macrophages and T cells – but not natural killer cells – had infiltrated the islets and the exocrine pancreas.
Approximately 50% of the genetic susceptibility can be explained by allele in HLA class II region, in particular certain DQ alleles. Therefore, higher adolescents’ perception of emotional representation (diabetes seen as a threatening disease) predicted higher values of glycated hemoglobin (poor metabolic control) and lower family’s comprehension of diabetes predicted higher values of glycated hemoglobin.
More than 95% of type 1 diabetic patients carry these predisposing alleles, but the occurrence of these alleles in the background population is high, approximately 50%. It is believed that the diabetes predisposing DQ antigens have a shape of the antigen presenting groove of the molecule that leads to more efficient presentation of ? cell associated autoantigens (Donath et al., 2003). In order to identify an increase in the incidence of T1DM in our country, as occurred in the majority of the populations worldwide, we had performed an analysis of the newly diagnosed cases until the end of the year 2004.
Higher perception of the consequences of diabetes by adolescents and higher perception of emotional representation (diabetes seen as a threatening disease) predicted lower quality of life. Enterovirus RNA was detected in ?cells positive islets in one of the three patients by in situ hybridization.
In FT1DM patients, the haplotype frequency of HLA DRB1*0901-DQB1*0303 was significantly higher than those in controls (Moreau et al., 2008). We had subsequently extended this work by adding the new cases of the five year period 2005 – 2009 in order to document this rising trend by comparing the incidence between the two decades (1990-1999 vs 2000-2009). HLA phenotyping of these Caucasian patients did not find the specific HLA haplotype (DRB1*0405-DQB1*0401) found to be linked to FT1D in Japanese patients. However if it occurs, the rapid onset is associated with an extremely high risk of fetal death. More investigation about haplotype frequency of MHC was necessary for IRS-2 mice in the destruction process of pancreatic ? cells.6.
According to Wilcoxon two-sample test this increasing trend of incidence during the 20 years analysed is statistically significant (p-value=0.0091).
Therefore, it is important for physicians to make an appropriate diagnosis as early as possible and to begin immediate treatment of both the mother and the fetus (Murabayashi et al., 2009).
ConclusionIRS-2 mice tend to become obese accompanying insulin resistance after 8 weeks of age. The mean incidence rate for each 5 year- period in accordance with the population data (population below the age of 15yr) is presented in figure 2. IRS-2 deficient mice develop diabetes, presumably due to inadequate ? cell proliferation combined with insulin resistance compared to IRS-1 deficient mice with the ? cell hyperplasia to compensate for the insulin resistance. An association between gender and low adherence to diabetes, in adolescents girls, particularly regarding exercise, has been found in the literature (Patino et al., 2005). Heterotopic accumulation of lipid observed frequently in obese IRS-2 mice, and corpulent adipocytes secrete various inflammatory cytokines, such as TNF-? and ILs, whereas production of adiponectin as antidiabetic agent is decreased significantly. A group of patients with PF was compared with a group of patients of child-bearing age with FT1DM that was not associated with pregnancy (NPF) in a nationwide survey conducted from 2000-2004.
In fact, low quality of life, in girls, has been associated to more difficulties and worries regarding diabetes and less satisfaction with metabolic control. Table 1 shows the percentage of newly diagnosed T1DM cases expressed as age group in accordance with the international standards. Girls enter puberty earlier than boys and a weak metabolic control may be associated to physiological changes, normal to adolescence, such as increased levels of hormones responsible for insulin resistance (Carroll & Shade, 2005). In IRS-2 deficient mice with FT1DM, insulitis with macrophage dominated infiltration to islet ? cell area was observed frequently as in human FT1DM patients. In terms of predictors of adherence, taking in consideration the final model,higher values of glycated hemoglobin (poor metabolic control) predicted lower adherence to diabetes self-care and lower quality of life. In 22 PF patients, 18 developed disease during pregnancy, whereas four cases occurred immediately after delivery.
Inflammatory cytokines appear to have important roles in the process of ? cell destruction leading to FT1DM. Twelve cases that developed during pregnancy resulted in stillbirty, and five of the six fetal cases that survived were delivered by cesarean section. IRS-2 deficient mice are considered to be useful animal model for studying the mechanism of ? cell destruction leading to FT1DM. Adolescents have more difficulties with metabolic control suggesting that hormonal changes, associated with puberty and the decline on adherence to self-care, were responsible for these results (Helgeson et al., 2009). The haplotype frequency of HLA DRB1*0901-DQB1*0303 in PF was significantly higher than those in NPF and controls, whereas that of DRB1*0405-DQB1*0401 in NPF was significantly higher than those in PF.
The age of manifestation of childhood onset T1DM has a bimodal allotment with one peak at 4 to 6 years of age and a second in early puberty (10 to 14 years of age) [22-23]. In another study, glycated hemoglobin explained a small variance of quality of life in adolescents with diabetes suggesting that higher levels of glycated hemoglobin (poor metabolic control) had negative effects on the adolescent’s perception of quality of life (Malik & Koot, 2009).
The type 1 diabetes-susceptible HLA class II haplotype is distinct in PF and NPF patients, suggesting that different HLA haplotypes underlie the presentation of PF or NPF. Recent studies report a higher rate of increase among children younger than 5 years than in children between 5 and 15 years of age [24-25]. This may be related to an earlier onset of clinical manifestation or to a true increase in the causative factors of the disease.Although the clinical appearance occurs at all ages [21] one fourth of individuals with T1DM are diagnosed as adults [26].
Up to 10% of adults primarily supposed to have type 2 diabetes are found to have antibodies associated with T1D [27] and beta cell destruction in adults seems to take place at a much slower rate than in young T1D cases, often delaying the need for insulin therapy after diagnosis.4. Family support has been found to be a predictor of good metabolic control (Lewin et al., 2006).
HLA phenotyping of these Caucasian patients did not find the specific HLA haplotype (DRB1*0405-DQB1*0401) found to be linked to FT1DM in Japanese patients. Gender differencesAlthough most autoimmune diseases are more common in females, there appears to be no gender difference in the overall incidence of childhood T1DM [11].However, a gender influence on the age of onset has been reported, in select populations. In fact, low family support was associated to low adherence to diabetes self-care and, indirectly, to a poor metabolic control. Some data reported from Europe suggest a female predominance in lower risk populations, and slight male excess in the high risk groups [3]. La Greca and Bearman, in 2002, suggested that family support predicts adolescents’ adherence to diabetes self-care because family support is an important factor on the daily management of diabetes’ self-care tasks in adolescents.
More international collaborative epidemiological studies are warranted in order to better understand and characterize FT1DM associated with pregnancy.3. Furthermore many reports showed that older male adults of European origin (?15 to 40 years of age) are more likely to develop T1DM than females of similar age and geographic location with an approximate 3:2 male to female ratio [28-30]. The same 3:2 male to female ratio also was reported in children younger than 6 years of age in an observational study from Boston [31].
In a Portuguese sample of adolescents, family support was found to predict adherence in adolescents with type 1 diabetes (Pereira et al., 2008). IRS-2 deficient mouseInsulin receptor substrate (IRS) disorders are associated with onset of insulin resistance and diabetes mellitus.
Based on our data it seems that more males develop T1DM at younger age, whereas female predominate during the peripubertal period as shown in figure 3. In the present study, a lowerperception of personal control predicted lower adherence to diabetes self-care in adolescents.

Beliefs in the effectiveness of treatment (control over the illness) were found to predict adherence to dietary self-care (Delamater, 2009). IRS-2 deficient mice develop diabetes, presumably due to inadequate ? cell proliferation combined with insulin resistance, and the insulin resistance in IRS-2 deficient mice is ameliorated by reduction of adiposity. Seasonal variation at onset and birthThe first report of seasonal variation in the manifestation of T1DM was presented by Franklin Adams in 1926[32] although a consistent picture on the real seasonality of the disease has not been established.
IRS-2 deficient mice are widely used for analysis of pathophysiology of human type 2 diabetes mellitus (T2DM).
In an attempt to understand if there were differences between illness representations in adults with type 2 diabetes and their partners, a relationship was found between partner’s perceptions of the duration of diabetes (timeline) and treatment suggesting that partners’ perceptions could influence positively patients’ adherence to diabetes self-care (Searle et al., 2007). Based on the average temperature record in our island, the newly diagnosed cased were grouped according to the month of diagnosis as follow: November, December, January, and February were defined as cold months, October, March, April and May as neutral months and, June, July, August and September, as warm months.
In fact, parent’s perception as a long last condition inadolescent’s life may be associated to more parental support regarding diabetes’ management tasks in order to decrease future complications in the adolescent.In terms of predictors ofmetabolic control,higher adherence to diabetes self-care predicted better metabolic control (lower levels of glycated hemoglobin).
The symptoms observed in IRS-2 deficient mice with serious T1DM with insulin-deficient hyperglycemia resembled those of human nonautoimmune FT1DM reported by Imagawa et al. In fact, higher adherence to diabetes self-care has been found to predict good metabolic control in adolescents with type 1 diabetes, and lower quality of life, on the other hand, to predict poor metabolic control (Lewin et al., 2009).
Higher levels of glycated hemoglobin have been associated to more worries regarding diabetes having, therefore, a negative impact on quality of life (Guttmann-Bauman et al., 1998). Parents' understanding of the medical situation (coping with diabetes) predicted lower levels of glycated hemoglobin (better metabolic control) in the adolescent.
Several studies from Europe [35-37] and Israel [38] showed higher rates of T1DM among youth born in spring and lower rates among youth born in winter. At 6 week of age, there was no difference in body weight between wild-type (control) and IRS-2 deficient mice, but IRS-2 deficient mice showed remarkable impaired glucose tolerance and insulin resistance (Hashimoto et al., 2006). Although McKinney maintained that there is no relationship between T1DM diagnosis and date of birth[39]. Family environment is important in the complex mechanism of adaptation to diabetes self-care having also an impact on metabolic control (Grey & Berry, 2004).
IRS-2 deficient mice showed significant increases in plasma glucose, free fatty acid (FFA), triglyceride (TG), total cholesterol (TC) and insulin concentrations compared to wild-type (control) mice at 6-week-old.
It has been suggested that seasonability pattern may be explained by reduced vitamin D production [40] during the critical intrauterine and neonatal periods of life.6. In the livers of male IRS-2 deficient mice, the activities of cytosolic pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G6PD), ATP citrate lyase (ACL), fatty acid synthase (FAS) and malic enzyme (ME) were significantly higher than those of control mice (Table 1). GenotypeThe genetics of T1DM cannot be classified according to a specific model of inheritance. In a study about health beliefs in adolescents with type 1 diabetes, negative illness perception, like illness severity and susceptibility were predictors of poor metabolic control. Increase in activities of G6PD, ACL, FAS and ME, which are crucial enzymes for fatty acid synthesis, means activation of lipid synthesis in liver of IRS-2 deficient mice.
Susceptibility to autoimmune T1DM is determined by multiple genes with HLA genes having the strongest known association. HLA antigens are present on the surface of the leucocytes and participate in some immune reactions.
On the other hand, two of eight male IRS-2 deficient mice each at the ages of 14 and 24 week suddenly showed extreme hyperglycemia, similar to that in case of FT1DM. Another 2 male IRS-2 deficient mice developed extreme hyperglycemia at the age of 11 and 12 week and died.
Plasma glucose and FFA concentrations in the extremely hyperglycemic IRS-2 deficient mice showed abnormal increases compared with moderately hyperglycemic IRS-2 deficient mice.
These class II molecules are involved to the immune destruction of the pancreatic beta cells because they participate in the presentation of the antigen to the helper T cell, which initiates the immune reaction.Inheritance of HLA-DR3 and HLA-DR4 appears to confer a 2 to 3 fold increased risk for the development of T1DM. Plasma insulin concentrations in extremely hyperglycemic IRS-2 deficient mice were below the detection limit. When both HLA-DR3 and HLA-DR4 are inherited the relative risk for the development of T1DM is increased by 7-10 folds. On histopathologic examination, the pancreatic islets of extremely hyperglycemic IRS-2 deficient mice were either absent or decreased in size and number compared with those of moderately hyperglycemic IRS-2 deficient mice.
It is estimated that 48 percent of the familial aggregation can now be ascribed to known loci, and the Major Histocompatibility Complex (MHC) contributes 41 percent [41].
The islets of extremely hyperglycemic IRS-2 deficient mice showed karyorrhexis, cytoplasmic swelling, and partial necrosis.
As an example, siblings with the highest risk HLA DR and DQ alleles, who inherit both HLA regions identical by descent to their diabetic sibling, may have a risk of developing anti-islet autoimmunity as high as 80 percent and a similar long-term risk of diabetes[42].
In addition, the liver of one extremely hyperglycemic IRS-2 deficient mouse showed collagen fibrinoid degeneration and macrophages.In conclusion, at 6 week of age, IRS-2 deficient mice showed profiles compatible with several features of metabolic syndrome, including hyperglycemia, hyperinsulinemia, insulin resistance, hypertriglyceridemia, and high FFA concentrations. Furthermore, stronger associations of DM1 have been reported with other MHC loci: HLA-DQA1 and DQB1 antigens[43].
Moreover, hyperglycemia and insulin resistance in these mice progressed to their highest levels when the animals were 14 week of age.
In our effort to detect the genetic susceptibility of Greek Cypriot population to DM1, we studied 101 DM1 patients with age of onset less than 15 years through HLA serological typing for the DR and DQ1 alleles and compared them to 209 healthy controls. A small population of male IRS-2 deficient mice developed abrupt onset of hyperglycemia associated with markedly diminished islet mass, resembling the features of human nonautoimmune FT1DM. Obesity with insulin resistance in IRS-2 deficient mice with high-fat diet feedingType 2 diabetes mellitus (T2DM) appears to be increasing mainly in the United States, Africa and Asia.
The protective role of HLA-DR5 was shown, whereas the presence of HLA-DR2 is neutral, in contrast with most findings among Caucasian population where DR2 is protective. In 2000 there were one hundred and fifty million T2DM patients, but they are predicted to increase substantially to two hundred and twenty million world-wide in 2010.
In addition, high resolution testing of the DR4 and DR3 alleles revealed the predominant presence of the DRB1*0403 (0% vs 36%), similar frequency of the DRB1*0402 in both groups (19% vs 14%) and that the DRB1*301 was the only DR3 allele detected.
Since World War II (WWII), T2DM patients have increased markedly with dramatic changes of lifestyle in Japan. The DQB1 alleles present in our T1DM patients as shown in figure 5 were nearly exclusively DQB1*0201 and DQB1*0302 [44]. Typical changes of the lifestyle include the increases in high fat diets, sedentary habit and driving.
Furthermore, although most T1D cases occur in individuals without a family history of the disease, T1D is strongly influenced by genetic factors. Japanese population is predisposed to develop T2DM due to insufficient insulin secretion in spite of no predisposition to obesity. IRS-2 deficient mice show at 6 weeks of age showed profiles compatible with several features of the metabolic syndrome, including hyperglycemia, hyperinsulinemia, insulin resistance, hypertriglyceridemia, and high FFA. To investigate the characteristics in energy metabolism in IRS-2 deficient, three kinds of diets with different lipid concentrations were supplied to IRS-2 deficient mice (4 weeks old) for 2weeks. A monozygotic twin of a patient with type 1 diabetes has a higher risk of diabetes than a dizygotic twin, and the risk in a dizygotic twin sibling is similar to that in non-twin siblings [46]. Additionally age at onset is inversely related to the proportion of HLA haplotypes, and young children with T1DM show the greatest HLA-associated genetic risk. Siblings of children with onset of T1D before the age of 5 years have a 3- to 5-fold greater cumulative risk of diabetes by age 20 years compared with siblings of children diagnosed between 5 and 15 years of age [47]. Several reports suggest a higher proportion of lower risk haplotypes and in association with the decreased age at onset of T1DM are consisted with a major environmental effect on the development of the disease [48-51]. T1DM is associated with other autoimmune diseases such as thyroiditis, celiac disease, autoimmune gastritis and Addison disease [52].
The coexistence of these autoimmune diseases is associated to genes within the MHC complex [52].7. Japanese and American diet increased significantly the body weight of IRS-2 deficient mice when compared with regular diet. Ad group showed severely impaired glucose tolerance, and Jd and Ad group showed deterioration of insulin resistance.
They include: viral infections in infancy and early childhood, maternal viral infection during pregnancy [53], early exposure to cow’s milk and other nutritional factors [54], chemical contamination of food and water [55], high birth weight and an increase in body mass index [56]. Viruses that have been associated with T1DM as environmental triggers include enteroviruses, mumps, rubella, cytomegalovirus, rotavirus and Epstein-Barr virus.
Many epidemiological studies have been supported the involvement of enteroviruses, especially the Coxsackie B viruses in the aetiology which appears to trigger ? cell autoimmunity [58-59].
Furthermore it has been hypothesized that excessive weight gain and increase in insulin resistance in early childhood is trigger event which initiates the autoimmunity leading to ? cell destruction and this Accelerator Hypothesis has been supported by several epidemiological studies [56, 60-61]. Figure 1 shows expression of mRNA in WAT and plasma cytokine concentrations in IRS-2 deficient mice.
A number of dietary factors may influence the development of T1DM in infants at high risk for T1DM. Early introduction to the infant diet of cattle proteins, lack or short lasting breast feeding might be reasons for development of immunological reaction leading to the destruction of pancreatic beta cells [62]. In two large prospective cohort studies of newborns at high risk for T1DM diabetes (either a first degree relative [63-64] or a high risk HLA genotype) [63], first exposure to cereal before age three months [63-64] or after seven months [63] was associated with an increased risk of developing autoantibodies (IA) compared to infants whose first exposure was between ages four to six months. The increased risk was associated with gluten-containing cereals in one study [64], but with either gluten or rice-containing cereals in the other [63].On the other hand Vitamin D and omega-3 fatty acids may have a protective role. A case control study in seven European countries suggested that supplementation with vitamin D in early infancy can protect against development of T1DM [65]. A similar protective effect was found in a birth-cohort study of over 10,000 children [66]. Moreover preliminary studies in animals sustain a protective role of omega-3 fatty acids in the inflammatory reaction associated with autoimmune islet cell damage [67-68].In conclusion there is no doubt that the incidence of T1DM is increasing dramatically. Data from large epidemiological studies worldwide indicate that the incidence of T1DM has been increasing by 2% to 5% worldwide [69] and this is of concern because of its health and resource implications.
This rising incidence of T1DM in young children has been confirmed to a genetically susceptible subgroup of the population (48).
MRI showed the effects of Japanese and American diets on intraperitoneal WAT in IRS-2 deficient mice. The heightened proportion of lower risk hapltotypes and decreased median age at onset of T1DM within the subgroup are consistent with a major environmental effect on Diabetes development (50). WAT around the kidney and testes in the Jd and Ad groups increased in proportion to fat concentrations of diets when compared with the Rd group. EpilogueIt is a an actuality that significant advances have been made in the clinical care of T1DM, which ultimately improved the clinical outcomes. In addition, adipocytes of the Jd and Ad groups were corpulent when compared with those of the Rd group (Figure 2c).
In the absence of an ideal therapy Diabetes will always be a hurdle in the quality of life of these children. Moreover the increasing incidence is of concern because of its health and resource implications. On histopathologic examination of islets, insulin secretion was observed in all three groups.In conclusion, high-fat diet feeding induced rapid accumulation of fat intraperitoneal cavity of IRS-2 deficient mice.
There is a great research potential and more studies are required to identify the environmental factors that trigger the autoimmune destruction of the pancreatic beta cell particularly in some populations and individuals, who are not genetically predisposed to develop T1DM.
Obese IRS-2 deficient mice showed higher activities of lipid synthesis in their livers and the increase in TNF-? of corpulent adipocyte origin further aggravated insulin resistance and the increase in resistin also aggravated the impaired glucose tolerance, leading to aggravation of T2DM. These environmental triggers if ever identified could potentially be targeted for new preventive strategies and optimal intervention. Plasma adiponectin concentrations decreased significantly in obese IRS-2 deficient mice fed on high-fat diet, and decreased adiponectin concentrations might worsen T2DM to severe diabetic condition.4. Onset of FT1DM in IRS-2 deficient miceTwo of eight male IRS-2 deficient mice each at 14 and 24 weeks of age suddenly showed extreme hyperglycemia associated with markedly diminished pancreatic islet size. These extremely hyperglycemic mice had greatly diminished activities of hepatic ACL, FAS, and ME.
In these mice, plasma ALT activities were elevated and histochemical analysis of the liver confirmed inflammation. These cases of extreme diabetes resemble the human nonautoimmune FT1DM (Hashimoto et al., 2006). Occurrence rate of FT1D appears to be ~20% in male IRS-2 deficient mice after the age of 8 weeks, and is not observed in the female mice. Characteristics of plasma metabolite and hormones in IRS-2 deficient mice with FT1DMBecause over 50% of male IRS-2 deficient mice after 10 weeks of age tended to show glycosuria with obesity, male IRS-2 deficient mice (8 weeks old) without glycosuria according to Diasticks (Bayer Medical Ltd., Tokyo, Japan) were used as the control. Plasma glucose, FFA, TG, TC, insulin and C-peptide concentrations and hepatic enzyme activities were compared between control and diabetic mice. As the diabetic mice (8-24 weeks old) were older than the control mice (8 weeks old), the reduction of body weights in the diabetic mice was significant.
In the diabetic mice, the plasma glucose and TC concentrations were significantly higher than those in the controls, whereas plasma insulin and C-peptide concentrations decreased significantly under one third of the control values. Existence of the islet-related antibodies was investigated immunohistochemically in sera of NOD mice as autoimmune type 1 diabetic model and IRS2-deficient mice using pancreatic sections prepared from mice before (control mice) and after (diabetic mice) onset of FT1DM. Activities of HK and GK in glycolysis and MDH in the malate-aspartate shuttle in cytosolic fraction of liver in the diabetic mice were significantly lower than those of the control mice.
Activities of FBPase in gluconeogenesis and ME in fatty acid synthesis in liver of the diabetic mice were significantly higher than those of the controls. In the mitochondrial fraction of liver of the diabetic mice, activities of 3-HBD were significantly higher than the controls, whereas activities of AST and PC were significantly lower than those of the controls.
In the liver of the diabetic mice, activities of cytosolic LDH, G6PD, AST and mitochondrial GLDH were lower than those of the control mice.
The clinical symptoms of FT1DM observed in male IRS-2 deficient mice are significant increase in plasma glucose and cholesterol concentrations and a significant decrease in plasma insulin and C-peptide concentrations. All diabetic mice showed reduction of body weight, glycosuria and ketonuria and they were considered to fall into complete insulin deficiency. In the diabetic mice with insulin deficiency, their plasma TG and FFA concentrations were expected to increase generally, however those concentrations were not changed in IRS-2 deficient diabetic mice.
In our previous report (Hashimoto et al., 2006), plasma TG and FFA concentrations decreased significantly notwithstanding plasma glucose and cholesterol concentrations increased significantly in the diabetic IRS-2 deficient mice at 14 weeks old.
Liver-specific insulin receptor knockout (LIR-KO) mice with remarkable insulin resistance showed a significant decrease in their plasma TG and FFA concentrations. As IRS-2 deficient mice seemed to have unique regulation mechanism of plasma TG and FFA concentrations, their characteristics in lipid metabolism should be further studied in more IRS-2 deficient mice. In livers of the diabetic IRS-2 deficient mice, activities of enzymes in glycolysis and the malate-aspartate shuttle were significantly decreased, whereas those in gluconeogenesis and ketone body synthesis were significantly elevated. Decreased activities of pyruvate carboxylase, supplying oxaloacetate to the TCA cycle, suggested depression of citrate synthesis, the rate limiting reaction of TCA cycle, and activation of ketone body synthesis. Decrease in glycolysis or increase in gluconeogenesis and ketone body synthesis may be typical metabolic changes induced by complete insulin deficiency.
Decreased activities of LDH, MDH, AST and GLDH in the diabetic IRS-2 deficient mice reflected depression of liver function frequently observed in the diabetic animals. Pathology and islet antibodies in IRS-2 deficient mice with FT1DMOn histopathological examination, the pancreatic islets of the diabetic mice were significantly decreased in size and number compared to those of the control mice. In particular, size and number of insulin secreted ? cells in the diabetic mice decreased significantly compared to those in the controls, whereas number of glucagon secreted ? cells decreased a little.
Remarkable insulitis by autoimmunity was not observed in pancreatic sections in the diabetic mice (Figure 3). In the sera of the diabetic NOD mice, the islet-related antibodies reacted with their own islets (Figure 4, B1) and IRS2-deficient mouse islets before (Figure 4, B2) and after (Figure 4, B3) onset of FT1DM. In the serum of the control NOD mouse without glycosuria, the islet-related antibodies were not observed (Figure 4, A1-3). In sera of control and diabetic IRS2-deficient mice, the islet-related antibodies were not observed (Figure 4, C1-3 and D1-3). The cause of this degeneration might be increased adiposity due to increased activities of lipogenic enzymes (such as ACL, FAS, and ME) before the change of glucose tolerance in IRS-2 deficient mice. We consider that macrophages noted on histopathologic examination likely appeared to phagocytize the degraded collagen fibrinoid induced by fatty degeneration.In the diabetic IRS-2 deficient mice, hepatic steatosis is frequently observed. The finding of severe, selective destruction of pancreatic ? cells was considered to be one of the characteristics in FT1DM in IRS-2 deficient mice. The diabetic IRS-2 deficient mice did not show the islet-related antibodies observed in the diabetic NOD mice as autoimmune T1DM model.
The destruction mechanism of pancreatic islet cells in IRS-2 deficient mice may differ clearly from that in the diabetic NOD mice.
IRS-2 deficient mice develop diabetes because of insulin resistance in the liver and failure to undergo ? cells hyperplasia.
Progress of changes in islet mass should be further studied to investigate pancreatic ? cells destruction. At the moment abrupt increase in plasma concentrations and appearance of ketonuria are available indicators to decide complete insulin deficiency caused by pancreatic ? cells destruction in diabetic mice. In IRS-2 deficient mice, the sterol regulatory element binding protein (SREBP)-1 downstream genes, such as ATP citrate lyase and fatty acid synthase genes, are significantly increased and an excess amount of lipid is accumulated in their tissues. Accumulated lipid is also considered to be one of the causes of injury to their pancreatic islets. Diabetic NOD (B1-3), control IRS-2 (C1-3) and diabetic IRS-2 (D1-3) mouse sera reacted with pancreatic sections, respectively.5.

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