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Type 1 diabetes (T1D), also known as insulin dependent diabetes mellitus (IDDM), is primarily a childhood autoimmune disease with selective destruction of the pancreatic β-cells, leading to insulin insufficiency over time [REF 25..2Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med. 1994;331:1428-1436. [PubMed]. Genetic susceptibility in synergistic combination with environmental triggers leads to the development of immune response towards self antigens expressed by the pancreatic β-cells that produce insulin, resulting over time in the loss of β-cell mass and finally loss of glucose homeostasis .
It is believed that genetic susceptibility is a prerequisite for the development of T1D; however, not all genetically predisposed individuals do develop clinical disease. The vast majority (~90%) of the T1D patients develop autoantibodies against pancreatic β-cells before the clinical onset(REF 25…11-15 Bingley PJ, Bonifacio E, Williams AJ, Genovese S, Bottazzo GF, Gale EA. Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes. 1997;46:1701-1710. [PubMed]Bingley PJ, Christie MR, Bonifacio E, Bonfanti R, Shattock M, Fonte MT, Bottazzo GF, Gale EA. Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives. Diabetes. 1994;43:1304-1310. [PubMed]Bonifacio E, Genovese S, Braghi S, Bazzigaluppi E, Lampasona V, Bingley PJ, Rogge L, Pastore MR, Bognetti E, Bottazzo GF. Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity. Diabetologia. 1995;38:816-822. [PubMed]Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, Chase HP, Eisenbarth GS. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes. 1996;45:926-933. [PubMed]Harrison LC. Risk assessment, prediction and prevention of type 1 diabetes. Pediatr Diabetes. 2001;2:71-82. [PubMed])
Although the time period between the appearance of autoantibodies and clinical onset varies greatly, it usually takes years for the clinical disease to occur [REF 25…15 Harrison LC. Risk assessment, prediction and prevention of type 1 diabetes. Pediatr Diabetes. 2001;2:71-82. [PubMed]
]. Furthermore, only a proportion of the autoantibody-positive individuals will progress to clinical diabetes. This lengthy asymptomatic period, from genetic predisposition to prediabetes marked by autoimmunity (autoantibodies and cellular immunity) and finally to clinical disease, provides excellent opportunities for disease.(REF 25)
The incidence of T1D varies in different countries and populations [REF 25..3,4.
Karvonen M, Tuomilehto J, Libman I, Laporte R. A review of the recent epidemiological data on the worldwide incidence of type 1 (insulin-dependent) diabetes mellitus. World Health Organization DIAMOND Project Group. Diabetologia. 1993;36:883-892. [PubMed]
Tuomilehto J, Lounamaa R, Tuomilehto-Wolf E, Reunanen A, Virtala E, Kaprio EA, Akerblom HK. Epidemiology of childhood diabetes mellitus in Finland-background of a nationwide study of type 1 (insulin-dependent) diabetes mellitus. The Childhood Diabetes in Finland (DiMe) Study Group. Diabetologia. 1992;35:70-76. [PubMed]
] with Finland, Scandinavia and Sardinia having the highest incidences (30-50/100,000 per year). The incidence is much lower in Asian countries (1-2/100,000 per year), while it is 12-15/100,000 per year in the US Caucasians [REF 25..3, 4, 5, 6, 7 Karvonen M, Tuomilehto J, Libman I, Laporte R. A review of the recent epidemiological data on the worldwide incidence of type 1 (insulin-dependent) diabetes mellitus. World Health Organization DIAMOND Project Group. Diabetologia. 1993;36:883-892. [PubMed]Tuomilehto J, Lounamaa R, Tuomilehto-Wolf E, Reunanen A, Virtala E, Kaprio EA, Akerblom HK. Epidemiology of childhood diabetes mellitus in Finland-background of a nationwide study of type 1 (insulin-dependent) diabetes mellitus. The Childhood Diabetes in Finland (DiMe) Study Group. Diabetologia. 1992;35:70-76. [PubMed]. Gorodezky C, Alaez C, Murguia A, Rodriguez A, Balladares S, Vazquez M, Flores H, Robles C. HLA and autoimmune diseases: Type 1 diabetes (T1D) as an example. Autoimmun Rev. 2006;5:187-194. [PubMed]Awdeh ZL, Yunis EJ, Audeh MJ, Fici D, Pugliese A, Larsen CE, Alper CA. A genetic explanation for the rising incidence of type 1 diabetes, a polygenic disease. J Autoimmun. 2006;27:174-181. [PubMed]Kawasaki E, Matsuura N, Eguchi K. Type 1 diabetes in Japan. Diabetologia. 2006;49:828-836. [PubMed]
Approximately 90% of cases are sporadic, occurring in individuals with no family history of T1D. However, first degree relatives (FDR) of patients with T1D are at increased risk compared to the general population. In Caucasians, the risk of T1D in the general population is 0.4% and the risk of siblings of affected individuals is about 6%, approximately 15 fold higher than the general population [REF 25 ..8, 9, 10 She JX. Susceptibility to type I diabetes: HLA-DQ and DR revisited. Immunol Today. 1996;17:323-329. [PubMed]She JX, Marron MP. Genetic susceptibility factors in type 1 diabetes: linkage, disequilibrium and functional analyses. Curr Opin Immunol. 1998;10:682-689. [PubMed]Risch N. Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet. 1987;40:1-14. [PubMed])
VARIOUS MARKERS FOR DIAGNOSIS OF TYPE 1 DIABETES:
1.Genetic markers (Human leucocyte antigen linkage)
auto antigens reacting with the auto antigens
type 1 susceptibility genes
C reactive proteins
HUMAN LEUKOCYTE ANTIGEN LINKAGE TO TYPE-I DIABETES:
In humans, the MHC is known as the HLA complex and contains over 200 genes.( marker ref 6 Klein, J., and Sato, A. (2000) N. Engl. J. Med. 343, 702-709)It is located on chromosome 6 and encodes HLA class I and class II molecules. The main function of these molecules, which are heterodimers made up of alpha and beta chains, is to present antigens that have been processed into peptides to antigen-specific receptors on CD4+ and CD8+ T lymphocytes. Class I molecules, expressed on most nucleated cells, are encoded by genes within the HLA-A, -B, and -C loci, whereas class II molecules, expressed primarily on antigen-presenting cells (e.g. macrophages and dendritic cells), are encoded by genes within the HLA-DP, -DQ, and -DR loci.(marker ref 6)
Genetic variants (or alleles) in the highly polymorphic human leukocyte antigen (HLA) on chromosome 6p21.3 (Fig. 1) Can lead to functional differences in how fragments of protein are presented to the immune system. In the early 1970s, several groups investigated [(marker ref 10 Singal DP, Blajchman MA. Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes (1973) 22:429-432. Nerup J, Platz P, Andersen OO, et al. HL-A antigens and diabetes mellitus. Lancet (1974) 2:864-866. Cudworth AG, Woodrow JC. Evidence for HL-A-linked genes in 'juvenile' diabetes mellitus. Br Med J (1975) 3:133-135.]and found [marker ref 10.Singal DP, Blajchman MA. Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes (1973) 22:429-432. Nerup J, Platz P, Andersen OO, et al. HL-A antigens and diabetes mellitus. Lancet (1974) 2:864-866. Cudworth AG, Woodrow JC. Evidence for HL-A-linked genes in 'juvenile' diabetes mellitus. Br Med J (1975) 3:133-135.]associations between T1D and HLA class I. Later, lymphocyte-defined HLA-D antigens, HLA class II DR4 and DR3 were shown to be more closely associated with T1D (marker ref 10 Thomsen M, Platz P, Andersen OO, et al. MLC typing in juvenile diabetes mellitus and idiopathic Addison's disease. Transplant Rev (1975) 22:125-147.) , and the combination of two susceptible alleles together, DR3/DR4, produced a higher risk genetic combination [(marker ref 10 Thomson G, Robinson WP, Kuhner MK, et al. Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. Am J Hum Genet (1988) 43:799-816. Thomson G. HLA disease associations: models for insulin dependent diabetes mellitus and the study of complex human genetic disorders. Annu Rev Genet (1988) 22:31-50. Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature (1987) 329:599-604.)]
The HLA contains lots of genes close together that are transferred from the parent to the child in adjacent 'DNA chunks' or haplotypes that are said to be in 'linkage disequilibrium'. It can therefore be difficult to establish exactly which gene is having an observed effect. It is now generally considered that the principal susceptibility markers for T1D are HLA class II DQB1*0302 on the DR4 haplotype and DQB1*0201 on the DR3 haplotype (Fig. 1).(maker ref10)
Fig. 1 MHC genes on chromosome 6 confer almost 50% of genetic susceptibility to T1D
90-95% of the young children with T1D carry either or both susceptibility haplotypes, whereas the protective DR2-DQB1*0602 is present in <0.1%. HLA-mediated susceptibility represents ~50% of the genetic susceptibility to T1D (marker ref 10 Ounissi-Benkalha H, Polychronakos C. The molecular genetics of type 1 diabetes: new genes and emerging mechanisms. Trends Mol Med (2008) 14:268-275.) . HLA class II haplotypes have been ranked in a risk hierarchy (marker ref 10 . Cucca F, Lampis R, Congia M, et al. A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins. Hum Mol Genet (2001) 10:2025-2037.Lambert AP, Gillespie KM, Thomson G, et al. Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. J Clin Endocrinol Metab (2004) 89:4037-4043.)
Those in the general population with the highest risk genotype DRB1*03-DQA1*0501-DQB1*0201/DRB1*0401-DQA1*0301-DQB1*0302 have a 5% absolute risk of getting diabetes by the age of 15 years (marker ref 10 Lambert AP, Gillespie KM, Thomson G, et al. Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. J Clin Endocrinol Metab (2004) 89:4037-4043.)
In type 1 diabetes, certain HLA class II alleles or combinations of alleles (haplotypes) show a strong association with the development of diabetes, whereas other haplotypes show a weak or even protective association. For example, individuals with the HLA haplotype DRB1*0302-DQA1*0301, especially when combined with DRB1*0201-DQA1*0501, are highly susceptible (10-20-fold increase) to type 1 diabetes. In contrast, individuals with the haplotype DRB1*0602-DQA1*0102 rarely develop type 1 diabetes. Many other high and low risk haplotypes have been identified, and the frequency of specific haplotypes differs among ethnic groups. Other genes within the HLA complex, particularly class I genes, also have been linked to type 1 diabetes, but the strongest linkage by far is with the DQ and DR class II genes.[marker ref 6]
It is possible that screening the general population for high-risk HLA genes with islet autoantibody follow-up could represent a strategy to identify most future cases of T1D. This strategy has been used by the DIPP (Diabetes Prediction and Prevention Trial) study in Finland (marker ref 10 Kukko M, Virtanen SM, Toivonen A, et al. Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of beta-cell autoimmunity in a high-incidence country. Diabetes Care (2004) 27:676-681 ) and by Diabetes Autoimmunity Study in the Young (DAISY) study in the USA (marker ref 10 . Barker JM, Barriga KJ, Yu L, et al. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). J Clin Endocrinol Metab (2004) 89:3896-3902 ) As described in a recent report, the DIPP study screened 116 720 consecutively born infants for high-risk HLA DQB1 genes (marker ref 10 Näntö-Salonen K, Kupila A, Simell S, et al. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet (2008) 372:1746-1755 ), and 17 397 (6.7%) infants had increased genetic risk and 11 225 consented to follow-up for islet autoantibody screening.
AUTOANTIGENS TRIGGERING AUTOIMMUNE ATTACK:
What are these autoantigens?marker ref 10
Type 1 diabetes isn't an acute rather long term chronic disease in type 1 diabetes (T1D); insulin-producing β-cells are subjects to specific attack by the host immune system. T1D is often considered a condition of the young but is also frequently diagnosed in adults, and markers of autoimmune diabetes have been identified in the slowly progressive form of autoimmune diabetes, latent autoimmune diabetes in adults. Autoimmune diabetes therefore affects an age spectrum from the very young onwards.(marker ref 10)
Marker ref 6
The initial evidence for autoimmunity in patients with type 1 diabetes came from immunofluorescence studies, which showed that a high percentage of sera from newly diagnosed type 1 patients reacted with pancreatic islets. This led to an intensive search for the actual autoantigens with which the islet cell autoantibodies (ICA) reacted. Three major autoantigens now have been identified.
Glutamic acid decarboxylase
IA-2 tyrosine phosphatase
The first is an isoform of glutamic acid decarboxylase (GAD65) [marker ref 6 Baekkeskov, S., Aanstoot, H. J., Christgau, S., Reetz, A., Solimena, M., Cascalho, M., Folli, F., Richter-Olesen, H., DeCamilli, P., and Camilli, P. D. (1990) Nature 347, 151-156] . GAD65 is a protein of 585 amino acids with a molecular weight of 65,000 encoded by a gene on chromosome 10p11. It is expressed in neuroendocrine cells, including pancreatic islets, and is located within neuron-like small vesicles. The function of GAD65 in the islets is not known. Between 60 and 80% of newly diagnosed type 1 diabetes patients have autoantibodies to GAD65. These antibodies are directed primarily to the middle and C-terminal portions of the molecule and recognize conformational epitopes. (marker ref 6)
The second major autoantigen, IA-2 [marker ref 6 Lan, M. S., Wasserfall, C., Maclaren, N. K., and Notkins, A. L. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 6367-6370 ] (also known as ICA512), is a member of the transmembrane protein-tyrosine phosphatase (PTP) family. It is 979 amino acids in length, has a molecular weight of 106,000, and is encoded by a gene on chromosome 2q35. Because of a critical amino acid replacement at position 911 (Asp for Ala), which is required for enzymatic activity, IA-2 is catalytically inactive. IA-2 is a transmembrane protein found in the secretory vesicles of both endocrine and neuronal cells (marker ref 6 Solimena, M., Dirkx, R., Jr., Hermel, J. M., Pleasic-Williams, S., Shapiro, J. A., Caron, L., and Rabin, D. U. (1996) EMBO J. 15, 2102-2114 ) . The function of this molecule has remained a mystery, but recent knock-out experiments suggest that it may play a role in insulin secretion (marker ref 6 . Saeki, K., Zhu, M., Kubosaki, A., Xie, J., Lan, M., and Notkins, A. L. (2002) Diabetes 51, 1842-1850 ) Nearly the same percentages (60-70%) of newly diagnosed patients with type 1 diabetes have autoantibodies against IA-2 as GAD.
The third major autoantigen is insulin. This protein is only 51 amino acids in length, and its gene is on chromosome 11p15. As with IA-2 and GAD65, the majority of the autoantibodies recognize conformational epitopes, mainly on the B chain of insulin. Autoantibodies against insulin are among the first autoantibodies to appear in the prediabetic state and are usually found in very young children. Between 30 and 50% of young children with type 1 diabetes have autoantibodies against insulin (marker ref 6 Atkinson, M. A., and Eisenbarth, G. S. (2001) Lancet 358, 221-229 ) . The frequency of autoantibodies against insulin is substantially lower in individuals who develop type 1 diabetes at an older age.
Autoantibodies and the risk associated?marker ref 6
Studies have showed that the likelihood of developing type 1 diabetes within 5 years was ~10% in the presence of one autoantibody, ~50% in the presence of two autoantibodies, and 60-80% in the presence of three autoantibodies (marker ref 6 Notkins, A. L., and Lernmark, A. (2001) J. Clin. Invest. 108, 1247-1252). By screening a population for individuals who are positive for two or more of these autoantibodies, it is now possible to readily select subjects at high risk of developing type 1 diabetes.
GENETIC SUSCEPTIBILITY IMPORTANT IN TYPE-I DIABETES:marker ref 10
Genetic susceptibility is important in the development of T1D. The lifetime risk for a member of the general population is often quoted as 0.4%. This increases to >1% if the mother has diabetes and intriguingly to >3% if the father has T1D (marker ref 10 Warram JH, Krolewski AS, Kahn CR. Determinants of IDDM and perinatal mortality in children of diabetic mothers. Diabetes (1988) 37:1328-1334)
.The classic indicator of the role of genetics in any disease is found by comparing concordance rates in monozygotic (MZ) vs. dizygotic (DZ) twins. Calculations to estimate the role of genetic vs. environmental factors showed that 88% of the phenotypic variance was due to genetic factors, and the remaining variance is due to unshared environmental factors. Studies emphasize the importance of genetics in T1D, but also clearly demonstrate that having certain combinations of genes is not sufficient to cause T1D. Environmental triggers therefore modulate the onset of T1D in genetically susceptible individuals. Environmental factors have been implicated in the recent rapid increase in T1D incidence, because the gene pool cannot change quickly enough to account for the rapid rate of increase of T1D. Three independent studies, (marker ref 10 Hermann R, Knip M, Veijola R, et al. Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes-indication of an increased environmental pressure? Diabetologia (2003) 46:420-425.Gillespie KM, Bain SC, Barnett AH, et al. The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet (2004) 364:1699-1700.Fourlanos S, Varney MD, Tait BD, et al. The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care (2008) 31:1546-1549)comparing genetic susceptibility in individuals developing T1D currently compared with those developing diabetes at least a generation ago, show that more people with less genetic susceptibility are now developing autoimmune diabetes. It might therefore be argued that genetic susceptibility is now less important than in previous generations, but the susceptibility genes have not altered; merely, the number that an individual requires to precipitate diabetes in a 'permissive' environment. Identification of these environmental determinants is proving more elusive than the susceptibility genes.(marker ref 10)
AUTO ANTIBODIES :
Antibody Marker in Predicting Type-1 (ref-2)
Type-1, insulin-dependent diabetes mellitus (IDDM) is due to autoimmune disease of the pancreatic B cells. The insulitis leads to gradual destruction of the insulin secreting cells, islet cell failure and clinical diabetes. The prediabetic phase, which may last many years, is symptomless.
Islet cell antibody
(16,Bottazzo GF,Florin-Christensne A,Doniach D.,
17, MacCuish AC, Jordan J, Campbell CJ, Duncan LJP, Irvine WJ.)
Islet cell surface antibody
(18, Baekkeskov S, Nielsen JH, Marner B, et al.)
(19, Van de Winkel M, Smets G, Gepts W, Pipeleers D.)
(20, Palmer JP, Asplin CM, Clemons P, et al.,
21, Wilkin TJ, Nicholson S.)
(22, Triolo G, Giadina E, Rinsidi A, Sedio G, Bompiani GD.)
(23, Di Mario U, Dotta F, Crisa L, et al.)
(24, Dotta F, Wicker L, Peterson A, et al.)
Insulin Autoantibodies (IAA)
Insulin- autoantibodies (IAA) were first described in 18% of newly-diagnosed diabetic children in 1983(20, Palmer JP, Asplin CM, Clemons P, et al.). IAA is measured either by radiobinding (RBA) assay (20, Palmer JP, Asplin CM, Clemons P, et al., 36, Vardi P, Dib SA, Tuppleman M, et al.) or by direct ELISA (21, Wilkin TJ, Nicholson S., 37, Wilkin TJ, Nicholson S, Casey C.). The RBA employs a minimum quantity of high specific activity ligand and is thereby affinity-sensitive in contrast to the antigen excess ELISA which is capacity sensitive. IAA suffers the disadvantage that they are not IDDM specific. They occur, albeit rarely, in other autoimmune diseases (21,Wilkin TJ, Nicholson S.), insulin autoimmune syndrome (40,Hirata Y,-Ishizu H, Ouchi N, et al.), and drug-induced autoimmunity (4l ,Blackshear P, Rotner H, Kriancuinask K, Kahn CR.). Unlike ICA, IAA varies in frequency and titre inversely with age, so that they are rarely detectable in adulthood. Karjalainen et al. recently reported on 82 children (ages 1.3-18.2 years) and 44 adults (20.0-55.8 years) studied at clinical onset of IDDM (42, Karialainen J, Salmela P, Ilonen J,et al). ICA were present in 81% of both groups, but IAA, while detected in 42.5% of the children, were present in only 3.8% of the adults.
Islet Cell Antibodies
Islet cell antibodies measured as ICA-IgG are detectable by indirect immunofluorescence in 70-80% of newly diagnosed type 1 diabetics and in 0.1-3% of the community (25, Lendrum R, Walker GJ, Cudworth AG, et al.). However, only the highest titre ICA, corresponding to a complement-fixing subgroup (CF-ICA), predict diabetes; this has been a common source of confusion which the recent introduction of ICA standards, and a JDF (Juvenile Diabetes Foundation) unit, should help to resolve (26, Boitard C, Bonifacio E, Bottazzo GF, Gleichmann H, Molenaar J.). Thus, in a recent report from the Barts-Windsor Family Study, 54% of 24 CFICA positive subjects developed IDDM over an 8-year period, though only when the ICA was positive on three or more occasions27. A striking feature of ICA is their temporary character. In most patients the antibodies tend to disappear within a year of diabetes onset. In the more slowly progressive IDDM seen in adults, however, they may persist and ean prove useful in differentiating adult type-1 from type-2 diabetes, and in predicting insulin dependencym.
64 K Antibody
The 64K antibody is a promising current development (18, Baekkeskov S, Nielsen JH, Marner B, et al.). The 64K antibody also appears to be directed against a B cell specific antigen (molecular mass 64 KDa) (18, Baekkeskov S, Nielsen JH, Marner B, et al.). Doubt, however, has been raised against the location of the 64K antigen on the surface of human islets (52, Colman PG, Campbell IL, Kay TWJ, Harrison LC), questioning its relevance as a target antigen in IDDM, though not necessarily its value as an antibody marker. A number of groups are currently attempting to clone the 64K antigen so as to provide unlimited material for the quantification of antibody in more manageable assays than the immunoprecipitation system currently available
BIOCHEMICAL MARKERS :
Elevated C - reactive protein Levels (ref-3)
Children at risk for type 1 diabetes and followed in the Diabetes Autoimmunity Study of the Young (DAISY) had blood samples drawn and frozen serum saved at various intervals after birth. CRP was measured using a high-sensitivity sandwich enzyme immunoassay. Islet autoantibodies (IAs) were measured using biochemical immunoassays. Elevations in CRP concentrations were significantly more frequent (P < 0.01) in children who later developed type 1 diabetes (8 of 16 children) than in children negative for IAs at their last testing (3 of 26). Children with one or more positive IA were more likely to have elevated CRP concentrations (15 of 36) than IA-negative children (3 of 26; P < 0.01). The finding of elevated CRP levels in infants and young children before the onset of type 1 diabetes adds to the evidence that the disease is an immunoinflammatory disorder. The elevated CRP levels may provide an additional marker for risk of progression to type 1 diabetes.
Elevated C-reactive protein (CRP) is known to be a marker of inflammation. Inflammation may also be a factor before the development of diabetes. Increased levels of inflammatory prostaglandins and cyclooxygenase 2 (COX2) have been described in children developing or having type 1 diabetes (9,Chase HP, Williams RL, Dupont J.11,Litherland SA, She J-X, Schatz D, Fuller K, Hutson AD, Peng RH, Li Y, Grebe KM, Whittaker DS, Bahjat K, Hopkins D, Fang Q, Spies PD, North K, Wasserfall C, Cook R, Dennis MA, Crockett S, Sleasman J, Kocher J, Muir A, Silverstein J, Atkinson M, Clare-Salzler MJ).Type 1 diabetes is characterized by a preclinical phase of islet autoimmunity (13,Atkinson MA, Eisenbarth GS). Levels of CRP have not previously been investigated before the development of type 1 diabetes.
……by…Ronak desai and chaini konwar and sahradayi modi