Comparison between type1 and type 2 diabetes mellitus gevolgen,medical documentation mistakes online,diabetic diet for pregnancy indian,tucson ride to cure diabetes permanently - .

Diabetes mellitus is not one disease, but rather is a heterogeneous group of multifactorial, polygenic syndromes characterized by an elevation of fasting blood glucose that is caused by a relative or absolute deficiency in insulin. The American Diabetes Association (ADA) recognizes four clinical classifications of diabetes: type 1 diabetes (formerly, insulin dependent diabetes mellitus), type 2 diabetes (formerly, non-insulin dependent diabetes mellitus), gestational diabetes, and diabetes due to other causes (for example, genetic defects or medications). Type 1 diabetics must rely on exogenous insulin injected subcutaneously to control hyperglycemia and ketoacidosis.
The goal in treating type 2 diabetes is to maintain blood glucose concentrations within normal limits, and to prevent the development of long-term complications. Gestational diabetes is defined as carbohydrate intolerance with onset or first recognition during pregnancy. ReferenceInternational Diabetes Federation, Lippincott Illustrated Reviews Pharmacology & Biochemistry, American Diabetes Association, National Diabetes Education Program USA, Mayo Clinic. Thankfulness to my father who shared with me regarding this web site, this website is in fact remarkable.
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.
The diverse names given to the polyendocrine autoimmune syndromes reflect the large number of studies and case reports concerning these patients and heterogeneity in their clinical presentation. The knockout of the AIRE gene by two groups in mouse models indicates that mice lacking AIRE develop widespread but clinically mild autoimmunity. A single family has been described with an autosomal dominant form of the disease (thyroiditis prominent in this family) (54), and of note Anderson and colleagues have produced an animal model of the dominant mutation found in this family (55).
Patients with APS-1 express autoantibodies reacting with a remarkable diversity of autoantigens, both autoantibodies specifically only detected in APS-1 patients and autoantibodies found in common isolated examples of the autoimmune disorder (e.g. Particular patterns of anti-adrenal autoantibodies are associated with this syndrome (89-91).
Given that the individual components of disease develop over years to decades, one must be vigilant for other associated autoimmune disorders.
Once the diagnosis of APS-I is established, the individuals should be referred to a center with experience following these patients and enrolled in a systematic screening regimen with the goal of identifying developing autoimmune disease prior to significant clinical sequelae are reached. There has been a marked increase in knowledge concerning genetic determinants of disorders such as Type 1A diabetes given whole genome screens analyzing thousands of patients and controls (106). Genetic abnormalities underlying disease susceptibility for APS-II are partially defined and consist primarily of alleles of genes within the major histocompatibility complex. Several diseases that manifest in patients with polyendocrine autoimmune syndromes are not associated with HLA-B8 or HLA-DR3 in population studies. Initiating factors for the type II syndrome and its component illnesses are not established except for celiac disease (wheat protein gliadin) (141), the insulin autoimmune syndrome (e.g. Controversial data suggest that ingestion of the milk protein bovine albumin in the first few months of life may be associated with type 1 diabetes (152) while other investigators implicate casein, and studies from Denver and Germany (oral reports) implicate early (<3 months) ingestion of wheat. Families with the type II polyendocrine syndrome should be evaluated over time to detect the presence of organ-specific antibodies indicating the possibility of a future endocrine malfunction (Table 8.7). ACTH and cosyntropin (adrenocorticotropin)-stimulated cortisol determination is indicated if 21-hydroxylase autoantibodies are detected (118;158). More than 20 years may elapse between the onset on one endocrinopathy and the diagnosis of the next. Rarely, hypoparathyroidism, a specific endocrine disturbance present in the type 1 syndrome, is identified in a patient with type II syndrome. In the APS-II syndrome, many ICA-positive individuals do not progress to diabetes, and diabetes risk is much lower than for ICA-positive first-degree relatives of patients with type 1 diabetes (159;160). Antibodies to specific receptors are characteristic of given disorders (anti-acetylcholine receptor antibodies of myasthenia gravis, anti-TSH receptor antibodies of Graves’ disease or hypothyroidism (176), and oocyte sperm receptor autoantibodies associated with oophoritis). One hypothesis is that different tissues share the same autoantigen and thus when autoimmunity is directed at one organ it will also affect other organs. Both autoreactive T cells and autoantibodies are pathogenic, depending on the specific disease.
T cell autoimmunity has been much more difficult to study and correlate with disease compared to autoantibodies. In addition, studies by Tung and associates and Wucherpfennig and colleagues suggests one mechanism whereby properties of T cell recognition may lead to multiple autoimmune disorders (78;182).
Very important animal models of polyendocrine autoimmunity indicate that loss of regulatory T lymphocytes can result in widespread autoimmunity. Kriegel and co-workers reported that patients with APS-II have a defect in terms of lymphocyte response to CD4+CD25+ T cell suppression (209). Individuals with a single autoimmune disease are at increased risk for the development of a second disease over the general population.
The therapy of the APS-II syndrome depends upon the specific disease manifestation with a few caveats (225). There are a large number of new potent immunosuppressive and immunomodulatory therapies being used in non-endocrine autoimmune diseases and in various stages of clinical development.
The IPEX syndrome presents in neonates with fatal autoimmunity and this very rare disorder has multiple different names reflecting endocrinopathy, allergic manifestations, intestinal destruction and immune dysregulation (e.g. The disease results from mutations that inactivate the Foxp3 transcription factor and the same gene is also mutated in a mouse model (the Scurfy mouse) (4).
In that the mouse model is cured with bone marrow transplantation, such therapy has recently been tested in children with the disorder. The presence of anti-insulin receptor autoantibodies is characterized by marked insulin resistance, but paradoxically, patients can also have severe hypoglycemia (6). Thymomas and thymic hyperplasia are associated with a series of autoimmune diseases (7-9;248-250). POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes) patients usually present with a sensory motor polyneuropathy, diabetes mellitus (50%), primary gonadal failure (70%), and a plasma cell dyscrasia with sclerotic bony lesions (257) (13;258). The insulin autoimmune syndrome, associated with Graves’ disease and methimazole therapy (or other sulfhydryl containing medications) is of particular interest due to a remarkably strong association with a specific HLA haplotype (11). The Kearns-Sayre syndrome is characterized by onset before age 20, external ophthalmoplegia, pigmentary retinal degeneration, and one or more of ataxia, heart block, or high cerebrospinal fluid protein.
Wolfram syndrome (DIDMOAD syndrome) is characterized by optic atrophy and childhood onset diabetes but the diabetes is not of autoimmune etiology. Diabetes develops in a significant number of adolescents and young adults with a history of congenital rubella infection. Karounos and coworkers have described a rubella protein with homology to an islet protein, suggesting that molecular mimicry may initiate disease (280).
Polyendocrine autoimmune syndromes have played an important role in understanding autoimmune disorders and in particular type 1A diabetes.
The existence of families of related autoimmune disorders not only is clinically important but also suggests that these diseases are pathogenically related. Finally, the relationships between these diverse disorders suggest that as disease pathogenesis is elucidated and antigen-specific therapies are developed, the improved understanding of pathogenesis and improvements in therapy will be applicable to many autoimmune diseases. Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields. Citation: Anzai E, Nakajima K, Iwakami Y, Sato M, Ino S, et al (2014) Effects of Foot Arch Structure on Postural Stability.
Methods: [Protocol 1] Thirty-seven healthy subjects participated in a test to determine the relationship between midfoot plantar pressure and arch height.
The foot is a very complex and unique structure, and comprises numerous bones, ligaments and joints. Many studies have evaluated postural control using the inverted pendulum model, which considers the body as a reverse pendulum with a fulcrum at the ankle [3].
To further investigate the role of the foot arch in postural control, we quantified the individual characteristics of the foot arch in many subjects using the Shoe Type Stabilometer [7] developed in this study.
The human foot contains three strong arches; two arranged longitudinally and one transverse arch. Based on results from Protocol 1, the study focused on the effect of foot arch structure on postural control.
All subjects in this study were included if they were able to walk independently and were excluded if they had uncontrolled systemic disease and or a serious heart disease or hemiplegia from cerebrovascular that affected their walking. To determine foot arch structure using the Shoe Type Stabilometer, the ratio of MP obtained from the Shoe Type Stabilometer and ratio of arch height obtained from a 3D Foot Scanner were compared. To evaluate postural control in relation to individual characteristics of the foot arch, verification experiments that used the Shoe Type Stabilometer were conducted. The role of foot structure has not been clarified in research into human posture when compared with the role of the vestibular system, lower limb and visual sensation. To evaluate these individual characteristics, it is necessary to measure many subjects including the frail elderly. To determine arch height using the Shoe Type Stabilometer, the ratio of MP obtained with this device and the ratio of arch height measured with a 3D Foot Scanner were compared. Previous studies reported that foot arch structure, for example high medial longitudinal arch or low medial longitudinal arch (flat foot), related to risk of lower-limb injury [14-17]. To elucidate the influence of foot arch structure on postural control, subjects were measured using the Shoe Type Stabilometer. As shown in Table 1 and Figure 4, the correlations between the ratio of MP and CoP total length, area, AP length, and ML length were significant.
In present study, lower limb muscle activity was considered to have influenced the foot arch, in turn effecting postural control while standing. In many studies into human postural control, the foot arch structure was considered as a rigid body.
3.Correlation between the ratio of MP and ML length, and between the ratio of MP and lower limb strength, indicated that the function of the plantar intrinsic foot muscles, which contributes to the structure of the foot arch. Ker RF, Bennett MB, Bibby SR, Kester RC, Alexander RM (1987) The spring in the arch of the human foot. Kappel-Bargas A, Woolf RD, Cornwall MW, McPoil TG (1998) The windlass mechanism during normal walking and passive first metatarsalphalangeal joint extension. Wright WG, Ivanenko YP, Gurfinkel VS (2012) Foot anatomy specialization for postural sensation and control. Kelly LA, Kuitunen S, Racinais S, Cresswell AG (2012) Recruitment of the plantar intrinsic foot muscles with increasing postural demand. Anjos DM, Gomes LP, Sampaio LM, Correa JC, Oliveira CS (2010) Assessment of plantar pressure and balance in patients with diabetes.
Cobey JC, Sella E (1981) Standardizing methods of measurement of foot shape by including the effects of subtalar rotation. Periyasamy R, Anand S (2013) The effect of foot arch on plantar pressure distribution during standing. Kaufman KR, Brodine SK, Shaffer RA, Johnson CW, Cullison TR (1999) The effect of foot structure and range of motion on musculoskeletal overuse injuries. Simkin A, Leichter I, Giladi M, Stein M, Milgrom C (1989) Combined effect of foot arch structure and an orthotic device on stress fractures. Menz HB, Morris ME, Lord SR (2005) Foot and ankle characteristics associated with impaired balance and functional ability in older people. Melzer I, Benjuya N, Kaplanski J (2004) Postural stability in the elderly: a comparison between fallers and non-fallers.
Diabetes affects 25.8 million people in the United States, yet 7 million people are not aware that they have the disease.
The major cause of blindness in people with diabetes is called diabetic retinopathy, a term used for all the abnormalities of the small blood vessels of the retina caused by diabetes. Fragile, abnormal blood vessels can develop and leak blood into the center of the eye, blurring vision. Fluid can leak into the center of the macula, the part of the eye where sharp, straight-ahead vision occurs. If your eye care professional believes you need treatment for macular edema, he or she may suggest a fluorescein angiogram. During the first three stages of diabetic retinopathy no treatment is needed, unless you have macula edema.
If the bleeding is severe, you may need a surgical procedure called a vitrectomy (described below). Both focal and scatter laser treatment are performed in your doctor's office or eye clinic. If you have a lot of blood in the center of the eye (vitreous gel), you may need a vitrectomy to restore your sight.
Are scatter laser treatment and vitrectomy effective in treating proliferative retinopathy? If you have lost some sight from diabetic retinopathy, ask your eye care professional about low vision services and devices that may help you make the most of your remaining vision. Text, images and photographs taken from National Eye Institute (NEI), National Institutes of Health (NIH). For example, it is estimated that more than 250 million people worldwide are afflicted with diabetes, and the prevalence is expected to exceed 350 million by the year 2030. Diabetes is the leading cause of adult blindness and amputation, and a major cause of renal failure, nerve damage, heart attacks, and stroke.
The disease is characterized by an absolute deficiency of insulin caused by an autoimmune attack on the ? cells of the pancreas.
The goal in administering insulin to Type 1 diabetics is to maintain blood glucose concentrations as close to normal as possible and to avoid wide swings in glucose levels that may contribute to long-term complications. Insulin may also be delivered by a pump, which allows continuous subcutaneous infusion of insulin 24 hours a day at preset levels and the ability to program doses (a bolus) of insulin as needed at meal times. Weight reduction, exercise, and medical nutrition therapy (dietary modifications) often correct the hyperglycemia of newly diagnosed type 2 diabetes. It is important to maintain adequate glycemic control during pregnancy, because uncontrolled gestational diabetes can lead to fetal macrosomia (abnormally large body) and shoulder dystocia (difficult delivery), as well as neonatal hypoglycemia. A team of inspired pharmacists is working to build a free access pharma publication, we call it Pharma Mirror. Pharma Mirror has an International Standard Serial Number ISSN 2219-763X of its own and it has been assigned by ISSN Center, Paris. 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. The two major autoimmune endocrine syndromes, APS-I and APS-II, both have Addison’s disease as a prominent component. Knowledge of disease associations and inheritance pattern facilitates early diagnosis of component illnesses.
Other diseases associated with APS-I include primary hypothyroidism, a malabsorption syndrome (19), vitiligo, pernicious anemia, type 1 diabetes, alopecia (20), primary hypogonadism (21), cutaneous abnormalities (1), and pure red cell aplasia (22;23). Intestinal manifestations associated with APS-1 include both obstipation and severe malabsorption. Chronic mucocutaneous candidiasis is often the first disease detected, followed by the later development of adrenal insufficiency.
The immunodeficiency underlying disease susceptibility is secondary to autosomal recessive mutations of this transcription factor (33). In particular autoantibodies reacting with multiple organs and T cell infiltrates of multiple organs are observed (36;37). It is likely that the cell types expressing these molecules are both thymic epithelial cells and cells of the macrophage, dendritic lineage.
The specific knockin mutation (G228W) of AIRE functioned as a dominant negative recruiting wild type AIRE away from active sites of transcription, decreased thymic messenger RNA for multiple AIRE regulated thymic genes, and develop lachrymal, salivary, and thyroid infiltrates and progressive peripheral neuropathy. It has recently been reported that 100% of patients with APS-1 express autoantibodies reacting with interferon-omega and the great majority express autoantibodies reacting with interferon alpha (94;95). Perheentupa recommends that individuals under the age of 30 years with any of the following: chronic or recurring mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, chronic gastrointestinal disease characterized by obstipation, diarrhea or steatorrhea, alopecia, vitiligo, noninfectious hepatitis, keratoconjunctivitis or urticaria-like erythema with fever should be closely evaluated for signs of ectodermal dysplasia and consideration for AIRE gene mutational analysis entertained.
Ideally, these individuals should be evaluated every six months for maintenance of their current endocrine disorders and surveillance for future disorders.
These individuals often suffer from multiple endocrinopathies and are at risk for the development of further disease. The majority of the genes influencing susceptibility outside of the major histocompatibility complex have extremely small odds ratios (often less than 1.2) and thus their analysis in relatively uncommon disorders such as APS-II is problematic.
The association of HLA markers with disease can correlate with inheritance of a common HLA-haplotype within families, but haplotypes with DR3 are often introduced into the family by more than one relative (118).
These disorders include vitiligo (133), pernicious anemia (134), and autoimmune goitrous thyroiditis (135-137).
A recent study of omega-3 and omega-6 fatty acid ingestion (153) analyzing both dietary history and levels of fatty acids in prospectively obtained red cells associates increased ingestion with decreased risk of developing islet autoimmunity (153). All such relatives should be advised of the early symptoms and signs of the principal component diseases. As many as 40-50% of subjects with Addison’s disease will develop an associated endocrinopathy. Anti-adrenal cortical antibodies have been used to predict adrenal insufficiency in the type 1 syndrome (in particular 21-hydroxylase). Why do some individuals have a single autoimmune disorder while others have multiple diseases? This is highly unlikely given the number of different molecules targeted specifically for many autoimmune disorders and the wide discordance in time relative to the appearance of for instance specific autoantibodies and disease. Recent advances in T cell immunobiology, studies of animal models, and transfer of autoreactive T lymphocytes or affected human organs into immunodeficient mice should lead to progress in understanding T cell autoimmunity (See chapter on T lymphocytes).
These were dependent upon the injection of putative autoantigens into animals in the presence of adjuvants that enhance inflammation (78).
In studying experimental autoimmune oophoritis, Tang and colleagues identified a peptide of the oocyte sperm receptor (ZP3) that upon injection in adjuvant induced disease. These models utilize either neonatal thymectomy or a combination of radiation and immunosuppressive drugs and transfer of T cell subsets to immunodeficient mice to induce autoimmunity (184-190). Studies of NK T cells in man are controversial with tetramer analysis not confirming decreased numbers in patients with type 1A diabetes, but rather stable wide variation in the percentage of such cells between even normal individuals (219). Table 8.9 shows the prevalence of autoimmune endocrine disease in the general population and the co-incidence of a second autoimmune disease given that a first exists.
Once a second autoimmune disease is identified more extensive screening is indicated to identify further disease at an early stage.
Patients with suspected Addison’s disease and hypothyroidism should be evaluated and treated for adrenal insufficiency prior to replacement of thyroid hormone to avoid Addisonian crisis. Rituximab (anti-CD20 antibody) is one of the more interesting having dramatic effects in multiple sclerosis and a relatively large clinical experience for the treatment of B-cell lymphomas. XLAAD: X-Linked Autoimmunity Allergic-Dysregulation Syndrome or XPID, MIM number 304790 and 300292).
The pathway this gene controls in T lymphocytes is now identified as central to basic immunology. A child became chimeric after bone marrow transplantation and a remarkable two-year remission was induced (142), followed by an unusual hematological disease that resulted in death. Temporary remission may result following radiotherapy directed at the plasmacytoma and peripheral blood stem cell transplantation has been utilized (259).
Such patients with elevated titers of anti-insulin autoantibodies frequently present with hypoglycemia.
A number of these patients have Hashimoto’s thyroiditis with the suggestion that hypothyroidism is associated with encephalopathy (272), hypoparathyroidism (273) and diabetes mellitus and adrenal insufficiency (274). The gene mutated (wolframin on chromosome 4p16) encodes a glycosylated transmembrane protein of unknown function (267;277) that is localized to the endoplasmic reticulum (ER) and may function ER-stress induced cell death (278). These patients frequently have thyroiditis, and despite the development of childhood diabetes infrequently express anti-islet autoantibodies (279).
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The human foot is composed of the arch structure, which is characteristic in every person and deforms with aging.
Midfoot plantar pressure distribution (ratio of MP) was measured using the Shoe Type Stabilometer. Using this device, it was found that people with a high ratio of MP, who tends to be flat-foot, displayed an increase in CoP sway. The aim of this study was to elucidate the effects of foot arch structure on postural control in the elderly. The device consists of a shoe insole with seven pressure-sensitive conductive rubber sensors.
This study focused on the longitudinal arch structure, which we hypothesized to be involved in postural control. This device measures the three dimensional geometry of foot structure using laser scanning.
The ratios of MP of the right and left feet were measured with the Shoe Type Stabilometer in standing position. In Protocol 1, Pearson’s correlation coefficient was used to determine the correlation between weight and ratio of MP, and between ratio of MP and the ratio of arch height. All 143 subjects, including frail elderly, were able to be measured using the Shoe Type Stabilometer.
Therefore, this study used the Shoe Type Stabilometer that can measure CoP and plantar pressure in the natural standing position [6,9].
The correlation coefficients between the ratio of MP and ratio of arch height were significant. These include X-rays [10], clinical measurement of navicular drop [11], foot prints and plantar pressure distribution [12,13]. A future clinical application of our research results would be the easy evaluation of these risks using this device.
These findings therefore revealed that the foot arch structure contributed to postural control. It is reported that the major muscular activity while standing appears to occur in the ankle plantar flexors, and is associated with body sway [19]. The present study focused on the role of the foot and evaluated the effects of the foot arch structure on postural control using the Shoe Type Stabilometer.
People with a high ratio of MP, who tends to be flat-foot, were found to have an increase in CoP sway. 25350665, 23300213 and 25242057), the Japanese Osteoporosis Foundation, the Suzuken Memorial Foundation, and a Sasakawa Scientific Research Grant from The Japan Science Society.
It occurs when diabetes damages the tiny blood vessels inside the retina, the light-sensitive tissue at the back of the eye.
That is why everyone with diabetes should get a comprehensive eye exam at least once a year. This is proliferative retinopathy and it is the fourth and most advanced stage of the disease. Mild non-proliferative retinopathy – At this earliest stage, microaneurysms occur, which are small areas of balloon-like swelling in the retina's tiny blood vessels.
Moderate non-proliferative retinopathy – As the disease progresses, some blood vessels that nourish the retina are blocked.
Severe non-proliferative retinopathy – Many more blood vessels are blocked, depriving several areas of the retina with their blood supply.
Proliferative retinopathy – At this advanced stage, the signals sent by the retina for nourishment trigger the growth of new blood vessels.
To prevent progression of diabetic retinopathy, people with diabetes should control their levels of blood sugar, blood pressure, and blood cholesterol. Because your pupil will remain dilated for a few hours, you should bring a pair of sunglasses.

Insulin resistance is the decreased ability of target tissues, such as liver, adipose tissue, and muscle, to respond properly to normal (or elevated) circulating concentrations of insulin. In the absence of a defect in ?-cell function, non -diabetic, obese individuals can compensate for insulin resistance with elevated levels of insulin. Hypoglycemic agents or insulin therapy may be required to achieve satisfactory plasma glucose levels. 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 major autoimmune polyendocrine syndromes have a strong genetic component with the type II syndrome occurring in multiple generations and the type I syndrome in siblings.
Patients with APS-I and APS-II develop multiple diseases over time and approximately one out of seven relatives of such patients have an undiagnosed autoimmune disorder (most often hypothyroidism for the type II syndrome) (14). Of note, in a study by Friedman and coworkers (24) four of nine patients with APS-I were asplenic. Kampe and coworkers have reported that antibodies to Histidine Decarboxylase are associated with a history of intestinal dysfunction (27) and multiple reports document loss of gastric and intestinal endocrine cells (27). The etiology of the mucocutaneous candidiasis in the absence of systemic candidiasis in the APS-I syndrome is unknown.
For instance, with loss of AIRE gene function, insulin message (45) disappears from the thymus (37).
Of note with the mutation on an NOD background diabetes is not accelerated and the mice do not develop pancreatitis (found in NOD mice with homozygous knockouts of AIRE). Kampe and coworkers have recently described the presence of autoantibodies reacting with NALP5 in approximately 50% of patients with APS-1 and hypoparathyroidism, but not found in patients with isolated hypoparathyroidism (82). 21-hydroxylase) is strongly associated with subsequent development of Addison’s disease.
We have developed an ELISA format assay utilizing time resolved fluorescence of Europium to detect autoantibodies and can confirm the very high prevalence of anti-interferon autoantibodies in patients with APS-1 (95). If more than one of these components is identified, the individuals should be closely followed for the development of additional disease. They must be aware of signs and symptoms of new disease and carry with them information about their disease, should emergency care be needed (96). HLA-B8 is in linkage dysequilibrium with HLA-DR3, which is in turn in strong linkage dysequilibrium with DQ2 (DQA1*0501, DQB1*0201).
Other HLA-B8 and DR3 associated illnesses include selective IgA deficiency (126-128) juvenile dermatomyositis, and dermatitis herpetiformis (72), alopecia, scleroderma (129), autoimmune thrombocytopenia purpura (130), hypophysitis (79;80) metaphyseal osteopenia (131), and serositis (73).
Addison’s disease patients also frequently have DQ8, DQB1*0602, and DR5 associated haplotypes (different from patients with type 1 diabetes). The MHC class II transactivator gene on chromosome 16 influences expression of class II molecules. Patients with celiac disease, which is characterized by atrophy of intestinal villi associated with lymphocytic infiltration, have autoantibodies reacting with transglutaminase (the endomysial antigen) (103) and with less specificity and sensitivity with the wheat protein gliadin. Even though signs and symptoms of disease may be absent, patients with multiple disorders should be screened every few years with measurement of anti-islet antibodies, 21-hydroxylase autoantibodies and transglutaminase autoantibodies, a sensitive thyrotropin assay, and measurement of serum B12 levels (157). Approximately 20 percent of APS-II patients expressing 21-hydroxylase autoantibodies progressed to overt Addison’s disease with long-term follow-up (up to approximately 20 years) (166).
A distinction must be made for subjects with isolated thyroid disease (relatively frequent in the general population) who have no family history of polyglandular syndrome type II. In a patient with the type II syndrome, celiac disease is a more frequent cause of hypocalcemia than hypoparathyroidism. Such ICA reacts only with islet B cells (insulin producing), not A cells (glucagon producing) within rat islets and fail to react with mouse islets. Another hypothesis is that different organs may share immunologically related molecules (mimics) and such mimics may be as simple as short peptides recognized by T lymphocytes. Type 1A diabetes is a T cell mediated disorder and an interesting case report describes a child developing diabetes with a mutation eliminating B-lymphocytes and thus autoantibodies  (59). Thus, thyroiditis can readily be induced in selective strains of mice following injection of thyroglobulin or thyroid peroxidase in Freund’s adjuvant. They then identified which of nine amino acids of this peptide were essential to activate autoimmune T cell clones or induce disease. The general concept is that within the thymus, early in development, a subset of essential regulatory T lymphocytes develops and seeds the periphery.
The BB rat develops type 1 diabetes and thyroiditis in association with a severe T cell immunodeficiency (210).
The above abnormalities appear not to be disease specific and may relate to fundamental abnormalities predisposing to autoimmunity or reflect disease activity. In addition, individuals with APS-II syndrome will often develop autoimmunity sequentially over the time course of many years. There is one fascinating case report of a patient with 21-hydroxylase autoantibodies treated for Graves’ eye disease with a 6 month course of glucocorticoids.
In the NOD mouse model of type 1 diabetes anti-CD20 prevents development of diabetes (227).and a clinical trial in new onset patients (Trialnet) is fully enrolled.
In particular the gene controls the regulatory function of CD4+CD25+ regulatory T lymphocytes. Partial lymphoid chimerism following bone marrow transplantation can induce remission (241).
The disease in Japan is essentially confined to DR4-positive individuals with DRB1*0406 (196). The disorder is associated with multiple large-scale (275) deletions as well as mutations of mitochondrial DNA (276). They described long-term T cell subset abnormalities in patients following congenital rubella infection. The first demonstration of cytoplasmic islet cell autoantibodies occurred in patients with polyendocrine autoimmunity (281). The first is inherited abnormalities of immune function, predisposing to the loss of tolerance to a series of self-antigens. Foot arch structure is assumed to effect postural control; however, underlying mechanisms remain unclear. In Protocol 2, a significant correlation was recognized between the ratio of MP and lower limb strength, CoP total length, area anterior-posterior length, and medial-lateral (ML) length. The arches are considered to play functionally significant roles by supporting body weight and reducing the impact of the body during running and walking [1,2]. As previously explained, the Shoe Type Stabilometer was designed to evaluate foot arch structure. The ratios of arch height and foot length the right and left feet were then measured using a 3D Foot Scanner in standing position. The subjects put on the Shoe Type Stabilometer, and plantar pressure distribution was measured for 45 seconds while standing. The physical condition of each subject had been checked and the research was explained to all participants.
In Protocol 2, as in Protocol 1, ratio of MP (average for 45 seconds) was calculated summing the left and right ratio of MP based on plantar pressure distribution. The vertical axis shows ratio of arch height while the horizontal axis displays the ratio of MP. X-rays are accurate; however they are expensive and require attendance at specialized facilities and carry a potential risk of radiation exposure.
In addition, since foot problems are related to decreasing postural stability and risk of fall in the elderly, our device can also quantify these problems.
Because most of the previous studies used a large scale device to investigate the role of the foot arch on postural control, subject selection was limited. The longitudinal foot arch is mainly supported by the inferior calcaneonavicular ligament, the short plantar ligament, the long plantar ligament, and the plantar aponeurosis, with auxiliary roles played by the abductor pollicis muscle, the flexor pollicis brevis, the flexor brevis, the anterior tibialis muscle, the flexor pollicis longus, and the posterior tibial muscle. Diabetes is the leading cause for new cases of blindness among adults in the United States. Between 40-45% of Americans diagnosed with diabetes have some stage of diabetic retinopathy. These areas of the retina send signals to the body to grow new blood vessels for nourishment. Your doctor places up to several hundred small laser burns in the areas of retinal leakage surrounding the macula. People with proliferative retinopathy have less than a 5% chance of becoming blind within five years when they get timely and appropriate treatment. Many community organizations and agencies offer information about low vision counseling, training, and other special services for people with visual impairments. People with proliferative retinopathy can reduce their risk of blindness by 95% with timely treatment and appropriate follow-up care.
The metabolic abnormalities of type 1 diabetes mellitus include hyperglycemia, ketoacidosis, and hyper triacylglycerolemia. They result from a deficiency of insulin and a relative excess of glucagon. Glyburide and metformin may be reasonably safe alternatives to insulin therapy for gestational diabetes. EnjoyIf you enjoyed this post, please consider subscribing to the RSS feed to have future articles delivered to your email inbox or feed reader.
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 individual polyendocrine autoimmune syndromes, their immunogenetics, pathogenesis and selected aspects of therapy will be reviewed in this chapter. Decades may elapse between the diagnosis of one disease and another in the same individual and the order of disease appearance is not invariant.
In contrast, there is evidence that in rare diseases with abnormal T cell development (e.g. AIRE presumably acts by altering transcription of multiple thymic genes and has important interaction with chromatin (55). In addition, anti-GAD autoantibodies of patients with the APS I syndrome differ from anti-GAD autoantibodies of typical patients with type 1 diabetes in terms of being able to react with GAD on Western blots and inhibit enzymatic activity.
The autoantibodies are apparently first to develop and remain throughout the disease course, a very remarkable finding. Siblings of affected individuals need only have one of the above to warrant more aggressive surveillance (96). Organ-specific autoantibodies in the absence of overt disease is also frequently present in patients and their relatives (105).
The primary association of APS-II, similar to many autoimmune disorders appears to be with class II HLA alleles (immune response genes) and in particular with DQ2 and DQ8.
A recent report implicates HLA-C as having a greater association with Hashimoto’s thyroiditis than class II HLA alleles, though multiple MHC alleles contribute (132).
A single report indicates association of a polymorphism of this gene with a G allele present in 67% of patients with Addison’s disease (n=128) versus 49% of controls (120).
In contrast to the lack of specificity with gliadin antibody assays, assays of antibodies to deamidated gliadin appear highly specific, and respond to removal of gliadin from the diet more rapidly than transglutaminase autoantibodies (149). A number of drugs are associated with induction of autoimmunity including interferon-a (thyroiditis) (154).
Such individuals have a relatively low probability of developing additional autoimmune disorders in comparison with individuals with rare autoimmune disorders such as Addison’s disease or myasthenia gravis. They represent unusual high titer autoantibodies reacting with glutamic acid decarboxylase (GAD), which is no expressed at detectable levels in mouse islets. In addition, antibodies to hormones can be present, including anti-insulin, anti-thyroxine, and anti-intrinsic factor antibodies (pernicious anemia). That is also a possibility (see below), but would not explain the wide time differences of disease appearance and spectrum of different illnesses. T cells recognize only short peptides presented in the groove of class I or class II major histocompatibility complex (MHC) molecules on antigen-presenting cells. Interference with this normal mechanism results in loss of tolerance to multiple molecules, and thus multiple organs are the target of autoimmunity. Neonatal thymectomy induces autoimmunity apparently by removing regulatory T cells (211;212). An individual often will not have polyglandular failure at the onset of clinical symptoms of the initial autoimmune disease.
Once an individual is identified as having APS-II syndrome, regular screening for further development of autoimmune disease is indicated (220). In this patient 21-hydroxylase autoantibodies became negative and adrenal function was restored to normal. Treatment with rituximab induces long-term B cell depletion, but the antibody does not bind to plasma cells, and often has relatively minor effects on autoantibody levels. They manifest neonatal type 1 diabetes, but the cause of death probably relates to massive intestinal involvement and malabsorption. There are now multiple reports of bone marrow transplantation (241-243) and a report of therapy with Sirolimus (244). The IPEX syndrome with lack of CD4-CD25 regulatory T cells is very instructive with 80% of such children developing type 1 diabetes. The aim of this study was to elucidate the relationship between the structure of the foot arch and postural control in the elderly. Correlation between the ratio of MP and ML length, and between the ratio of MP and lower limb strength, indicated that the function of the plantar intrinsic foot muscles, which contributes to foot arch structure. During standing, the arch is thought to not only support weight but also contribute to dynamic postural control and equilibrium maintenance; however, these functions have not been fully elucidated.
Recent research has reported that foot arch deformations and body sway revealed a significant correlation during quiet standing, indicating that the arch of the foot is related to postural sway [4]. This arrangement was based on the mechanism of postural maintenance and the anatomical structure of the foot arch. In this protocol, to quantify arch height using the Shoe Type Stabilometer, a comparison of arch height and midfoot plantar pressure distribution was conducted. Evaluations of the foot arch structure using footprints and plantar pressure distribution are easy techniques, and are used by many researchers.
Toe gap force measured in this study reflects muscle strength of the posterior tibial muscle and flexor pollicis longus that mainly support foot arch structure. If you have diabetic retinopathy, your doctor can recommend treatment to help prevent its progression. It can occur at any stage of diabetic retinopathy, although it is more likely to occur as the disease progresses. The test allows your eye care professional to identify any leaking blood vessels and recommend treatment.
This procedure is called scatter laser treatment, which helps shrink the abnormal blood vessels. A major study has shown that better control of blood sugar levels slows the onset and progression of retinopathy. Rather, type 2 diabetes develops in insulin-resistant individuals who also show impaired ?-cell function. However, larger randomized studies are needed to fully assess neonatal outcomes and optimal dosing regimens. 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). Patients without hypoparathyroidism, despite having the APS-1 syndrome lacked NALP5 autoantibodies which were measured with a fluid phase radioassay. Thus an initial diagnostic screen can be performed for autoantibodies reacting with interferons (a subset of patients with myasthenia gravis and thymoma as well as patients treated with interferons also produce anti-interferon antibodies). Of note, multiple mutations of the AIRE gene have been implicated in the pathogenesis of disease. Of note, aggressive therapy of oral candidiasis (99) is indicated in an effort to prevent the late complication of epithelial carcinoma. This unusual form of ICA confers a lower risk of type 1 diabetes as compared with nonrestricted ICA (reacts with multiple islet molecules) for both polyendocrine patients and relatives of patients with type 1 diabetes.
It is now relatively easy to develop highly specific and sensitive assays for autoantibodies reacting with non-modified proteins with in vitro transcription and translation of cDNAs of the relevant protein. We believe the most likely link between the diverse diseases is genetic propensity to fail to maintain tolerance to multiple self-molecules, and in particular specific self-peptides.
As few as three properly spaced amino acids (of nine) interacting with a T cell receptor can be sufficient to trigger T cell responses. This is a rapidly developing field and except for the XPID syndrome (see below) with its fatal neonatal autoimmunity and loss of a key regulatory molecule (Foxp3) illustrates how this concept can apply to human autoimmune disorders.
Therefore, a high clinical suspicion for the development of sequential autoimmune diseases must be maintained (220). It may act by influencing presentation of autoantigens by B-lymphocytes or altering B cell regulation.
Unique anti-acetylcholine receptor autoantibodies may be present with thymoma (250) and disease may be initiated by transcription of molecules within the tumor related to acetylcholine receptors (254).
Foot structure has individual characteristic in every person and becomes deformed with aging. CoP was calculated based on the pressure value of the 14 sensors and coordinates relative to the position of the foot.
In the present study, we showed that increased the CoP total length may be associated with an increased ratio of MP. Therefore, as shown in Table 1, the ratio of MP and toe strength showed a significant correlation. They grow along the retina and along the surface of the clear, vitreous gel that fills the inside of the eye.
Your doctor places 1,000 to 2,000 laser burns in the areas of the retina away from the macula, causing the abnormal blood vessels to shrink. The people with diabetes who kept their blood sugar levels as close to normal as possible also had much less kidney and nerve disease. The metabolic alterations observed in type 2 diabetes are milder than those described for the insulin-dependent form of the disease, in part, because insulin secretion in type 2 diabetes- although not adequate- does restrain ketogenesis and blunts the development of diabetic ketoacidosis.
For double staining, peroxidase (brown, DAB) and alkaline phosphatase (red, New Fuchsin) were used, respectively. There is no association of the overall syndrome with specific HLA class II alleles, though there is increasing evidence that specific HLA alleles determine the probability of the specific organs targeted by an individual (35). Prospective studies are needed to define when autoantibodies to NALP5 appear and whether they disappear following the development of hypoparathyroidism in a subset of patients, thus correlating with lack of the autoantibodies in approximately 50% of the APS-1 patients with hypoparathyroidism. Final diagnosis is usually dependent upon direct sequencing, with difficulty arising in defining mutations on both genes in the presence of deletions. Therefore, the sensitivity of mutational analysis is dependent upon the number of mutations screened for and the underlying prevalence of the mutations in the population (30). Individuals with symptoms of dysphasia or chest pain should be evaluated by endoscopy to identify strictures.
There is a well developed hypothesis in terms of the pathogenesis of celiac disease with the deamidation of gliadin by transglutaminase leading to increased binding of the deamidated peptide to HLA DQ2 and DQ8 class II molecules and activation of the disease by presentation of the peptides to T lymphocytes (151).
Apparently non-multiple sclerosis patients treated with the same monoclonal do not develop Graves’ disease.
If multiple anti-islet autoantibodies (of GAD, insulin and IA-2) are present, there is a high risk of diabetes.
The specificity of ELISA format assays can be enhanced with competition with fluid phase molecules and detection with fluorescence assays (174).
T cell clones reacting with these molecules, or other selected peptides, are generated, and such clones when transferred into naive animals induce disease. Noting that a peptide of the acetylcholine receptor had the appropriate T cell binding motif associated with experimental oophoritis, they demonstrated that this peptide stimulated an oophoritis-derived T cell clone in vitro and when administered in vivo induced oophoritis. Studies in Graves’ disease suggest a potential role, but also potential complications (228-230). This suggests that in the absence of regulatory T lymphocytes most humans will target and destroy beta cells. There is a 1997 report of treatment of a patient with thymoma and pure red cell aplasia with octreotide and prednisone (248). Some patients have monoclonal anti-insulin autoantibodies that also induce hypoglycemia and for these patients there is not an HLA association (264).
However, previous studies have not revealed the effects of foot characteristics on postural control. Center of pressure (CoP) was quantified based on the pressure value from the 14 sensors and coordinates indicating a relative position of the foot.
The correlations between the ratio of MP and parameters (age, weight, height, toe gap force, CoP total length, area, ML length and AP length) were analyzed with Pearson’s correlation coefficients.
The foot arch is also believed to have a role in postural sway since the plantar intrinsic foot muscles form the foot arch. Therefore, in addition to previous studies, it is possible to assess body sway using foot arch structure. In addition, a previous study reported that the muscle activity of the abductor pollicis is especially associated with CoP ML sway [5]. To protect vision, every pregnant woman with diabetes should have a comprehensive eye exam as soon as possible. Because a high number of laser burns are necessary, two or more sessions usually are required to complete treatment. Available treatments for diabetes moderate the hyperglycemia, but fail to completely normalize metabolism.
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.
Patients are at risk for developing esophageal and oral cancers presumably related to chronic candida infections.
In particular DQB1*0602 appears to protect from type 1 diabetes and DR3 increase the risk of type 1 diabetes in patients with the APS-I syndrome, as it does for the common variety of type 1A diabetes. APS-I syndrome) cause loss of peripheral antigen expression in the thymus (52) and probably decreased deletion of autoreactive T lymphocytes that target such peripheral antigens. Why NALP5 should be highly expressed in the parathyroid glands and why they are such a prominent target of autoantibodies in this particular syndrome are unknown.
Patients expressing multiple anti-islet autoantibodies are at higher risk for progression to diabetes. Of note, sudden hypercalcemia in hypoparathyroid individuals may mark the beginning of adrenal insufficiency and deserves evaluation (97). Keratoconjunctivitis must also be aggressively treated to prevent a decrease in visual acuity (74). Of note, several forms of immunization with such autoreactive clones can be used to make animals refractory to disease induction (181).
The requirement for sharing of as few as three of nine amino acids of a linear sequence for activation of autoreactive T cells provides a mechanism whereby inflammation directed at one organ may spread to additional tissues by T cell cross reactions to distinct peptides of different tissues. Of note the Foxp3 molecule is essential for regulatory T lymphocytes and when it is mutated (IPEX syndrome-see below) neonatal autoimmune diabetes results (214;215). Significant controversy exists regarding the screening tests that should be employed and the frequency of testing performed. Trials of modified anti-CD3 monoclonal antibodies in new onset type 1 diabetes are very advanced with the potential that such antibodies induce regulatory T lymphocytes as well as acutely and transiently depleting T lymphocytes (231-236).
Many thymomas lack AIRE expression within the thymoma a potential factor in the development of autoimmunity (255;256). In that T cell clones can respond to peptides that share no identical amino acids (283), depending upon their three dimensional structure, the potential for such T-cell cross-reactivity must be enormous (282).
One reason for this lack of findings may be that subjects in these studies were restricted to patients with disease or several young participants able to use large equipment (e.g. CoP waveforms measured by the Shoe Type Stabilometer were strongly correlated with a stationary type stabilometer.
The ratio of midfoot pressure (ratio of MP) was calculated by dividing midfoot pressure by the sum total of the 14 point sensor pressure values (Total Pressure). In this study, we focused on the effects of individual characteristics of foot arch structure on postural control. As shown in Figure 4, we found that ML length was highly correlated with the ratio of MP rather than AP length.
You need to be examined by your eye care professional at the first sign of blurred vision, before more bleeding occurs. Although you may notice some loss of your side vision, scatter laser treatment can save the rest of your sight. Because the vitreous gel is mostly water, you will notice no change between the salt solution and the original vitreous gel. This level of blood sugar control may not be best for everyone, including some elderly patients, children under age 13, or people with heart disease.

The long standing elevation of blood glucose is associated with the chronic complications of diabetes- premature atherosclerosis, retinopathy, nephropathy, and neuropathy. 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). The molecule NALP5 (NACHT leucine-rich-repeat protein 5) is a member of a family of molecules important for activating the innate immune system as part of the inflammasome pathway and are potent activators of interleukin 1 (83-85). APS-I patients express additional autoantibodies consistent with widespread loss of tolerance to multiple self antigens (92). Between 70 to 80% of DR4 alleles in patients with Addison’s disease have DRB1 allele 0404. Hutton and colleagues utilized identification of tissue specificity followed by development of fluid phase radioassay to define the fourth major islet autoantigen, namely the beta cell Zinc transporter (ZnT8) (175).
For instance, the highest risk (for Type 1 diabetes) HLA genotype DR3-DQ2; DR4-DQ8 is associated with a young age of diabetes onset. For example, in type 1 diabetes, it is generally accepted that routine screening for thyroid disease with biochemical assays should be performed, the frequency of this screening is a source of controversy (221); (222). A long-term goal is the development of antigen specific therapy for each of the major autoimmune disorders.
In the present study, plantar pressure was analyzed and revealed that the ratio of MP correlated to the ratio of arch height. By contrast, the present study used the Shoe Type Stabilometer to evaluate postural control focusing on the individual foot arch structure and conducted measurements in over 100 subjects.
This observation may be a reflection of function of the abductor pollicis muscle that support foot arch structure and associate with lateral sway.
If left untreated, proliferative retinopathy can cause severe vision loss and even blindness.
If you have macular edema in both eyes and require laser surgery, generally only one eye will be treated at a time, usually several weeks apart. You will probably be able to return home after the vitrectomy, however some people stay in the hospital overnight. 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).
They are involved in processes as diverse as autoinflammatory diseases, the inflammation secondary to the sensing of urate crystals in gout (86), and even (NALP3) the adjuvant effects of alum (87). A study by Soderbergh and coworkers have analyzed the prevalence of a series of autoantibodies in patients with APS-1 (93) with for instance IA-2 autoantibodies highly associated with type 1 diabetes, while GAD autoantibodies were more associated with intestinal dysfunction. They must be aggressively identified as described and immunized for hemophilus influenza, meningococcus and pneumococcus. Failure to maintain tolerance can be a result of deficient T regulation or enhanced T cell activation.
In experimental animals regulatory T lymphocytes targeting for instance islet specific molecules can effectively block development of disease in spontaneous animal models (237;238). Therefore, this study demonstrated effects of foot structure based on musculoskeletal system on human postural control. Your eye will be red and sensitive, and you will need to wear an eye patch for a few days or weeks to protect your eye. Other studies have shown that controlling elevated blood pressure and cholesterol can reduce the risk of vision loss. 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). If the individual mounts an inadequate antibody response, daily antibiotics are indicated, as prophylaxis and emergency care should be sought for fever (Table 8.6). Such genotypic associations are likely to vary by country depending on the frequency of specific HLA DR and DQ haplotypes.
An additional hypothesis is that HLA alleles associated with autoimmunity might be inherently contributing to generalized autoreactivity. While the elevated risk of celiac disease in the diabetic population has been well established (103;223)- (224), many of these individuals are asymptomatic at the time of identification and the long term sequelae of untreated asymptomatic celiac disease in regards to growth, pubertal development, bone mineralization and gastrointestinal malignancy is unclear. In addition, this device could measure CoP and foot arch structure at the same time, and can potentially quantify human postural control, with a focus on foot structure.
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. We find that hypothesis unattractive in that specific HLA haplotypes can be protective for one autoimmune disorder and promote another. The Shoe Type Stabilometer also allowed us to apply the structure of the foot and relate it to postural control in various studies. Even if bleeding has started, scatter laser treatment may still be possible, depending on the amount of bleeding. 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).
Evaluation of these symptoms may require investigation for other autoimmune GI disorders such as pernicious anemia and celiac disease, evaluation for fat malabsorption that may be observed with exocrine pancreatic insufficiency and consideration of an autoantibody to endocrine cells of the GI tract, and close consultation with a gastroenterologist.
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. 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). 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. 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).
Cytokine-induced ? cell death preferentially affects newly forming beta cells, which implies that replicating beta cells might be more vulnerable to cytokine destruction. 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).
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). 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.
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).
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). 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).
Increased FFA levels are known to be toxic for ? cell, leading to the concept of lipotoxicity (McGarry & Dobbins, 1999). 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). 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).
In human islets glucose-induced ? cell apoptosis and dysfunction are mediated by ? cell production and secretion of IL-1?. Immunohistochemical analyses revealed the presence of enterovirus-capsid protein in all three affected pancreata. 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. Interferon-? and CXC chemokine ligand 10 (CXCL10) were strongly coexpressed in all subtypes of islet cells, including ?cell and ? cells.
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. 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. 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. 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. 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).
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). 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. 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. 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.
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 IRS-2 deficient mice with FT1DM, insulitis with macrophage dominated infiltration to islet ? cell area was observed frequently as in human FT1DM patients.
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. 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 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.
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. More international collaborative epidemiological studies are warranted in order to better understand and characterize FT1DM associated with pregnancy.3.
IRS-2 deficient mouseInsulin receptor substrate (IRS) disorders are associated with onset of insulin resistance and diabetes mellitus. 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. IRS-2 deficient mice are widely used for analysis of pathophysiology of human type 2 diabetes mellitus (T2DM). 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.
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). 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. 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). 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. 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. Plasma insulin concentrations in extremely hyperglycemic IRS-2 deficient mice were below the detection limit. 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.
The islets of extremely hyperglycemic IRS-2 deficient mice showed karyorrhexis, cytoplasmic swelling, and partial necrosis.
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.
Moreover, hyperglycemia and insulin resistance in these mice progressed to their highest levels when the animals were 14 week of age. 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.
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.
Since World War II (WWII), T2DM patients have increased markedly with dramatic changes of lifestyle in Japan. Typical changes of the lifestyle include the increases in high fat diets, sedentary habit and driving. 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. 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. Figure 1 shows expression of mRNA in WAT and plasma cytokine concentrations in IRS-2 deficient mice. MRI showed the effects of Japanese and American diets on intraperitoneal WAT in IRS-2 deficient mice.
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. In addition, adipocytes of the Jd and Ad groups were corpulent when compared with those of the Rd group (Figure 2c).
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. 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.
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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  1. JanimKa

    Supports the notion that low-carb diets calorically equal diets.



    Other things like cereal and salty.