Type 1A diabetes mellitus results from autoimmune destruction of the insulin-producing

beta cells in the islets of Langerhans [1]. This process occurs in genetically susceptible
subjects, is probably triggered by one or more environmental agents, and usually
progresses over many months or years during hich the subject is asymptomatic and
euglycemic. Thus, genetic mar!ers for type 1A diabetes are present from birth, immune
mar!ers are detectable after the onset of the autoimmune process, and metabolic mar!ers
can be detected ith sensitive tests once enough "-cell damage has occurred, but before
the onset of symptomatic hyperglycemia [#]. This long latent period is a reflection of the
large number of functioning beta cells that must be lost before hyperglycemia occurs
Type 1$ diabetes mellitus refers to non-autoimmune islet destruction %Type 1$ diabetes&.
%'ee ()lassification of diabetes mellitus and genetic diabetic syndromes(.&
The pathogenesis of type 1A diabetes is *uite different from that of type # diabetes
mellitus, in hich both decreased insulin release %not on an autoimmune basis& and
insulin resistance play an important role. +enome ide association studies indicate that
type 1 and type # diabetes genetic loci do not overlap, although inflammation %eg,
interleu!in-1 mediated& may play a role in islet beta cell loss in both types [,]. %'ee
(-athogenesis of type # diabetes mellitus(.&
The pathogenesis of type 1 diabetes mellitus ill be revieed here. The diagnosis and
management of type 1 diabetes are discussed separately. %'ee (.pidemiology,
presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents( and
(-revention of type 1 diabetes mellitus( and (/anagement of type 1 diabetes mellitus in
children and adolescents( and (Associated autoimmune diseases in children and
adolescents ith type 1 diabetes mellitus(.&
+.0.T1) '2').-T1$1L1T3
-olymorphisms of multiple genes are reported to influence the ris! of type 1A diabetes
%including, 4LA-56alpha, 4LA-56beta, 4LA-57, preproinsulin, the -T-0## gene,
)TLA-8, interferon-induced helicase, 1L# receptor %)5#9&, a lectin-li!e gene %:1A;;,9&,
.7$$,e, and undefined gene at 1#*& [8-1;]. A meta-analysis of data from genome-ide
association studies confirmed the above associations and identified four additional ris!
loci %$A)4#, -7:)6, )T'4, )16T0<=& associated ith an increased ris! of type 1
diabetes [11].
1n addition, some loci conferring shared ris! for celiac disease %7+'1, 1L1>7A-, ))79,
TA+A-, '4#$,, -T-0#& have been identified [1#]. /ost loci have small effects, and
the variants studied are common. The ))79 association is of interest in that a ,#-base
pair insertion deletion in a chemo!ine receptor, ))79, results in a loss of function, and
hen homo?ygous, a tofold decrease in ris! of type 1 diabetes. %'ee @/4)
genes@ belo and @0on-/4) genes@ belo and @Association ith other autoimmune
diseases@ belo.&
Type 1 diabetes is characteri?ed by destruction of the pancreatic beta cells, leading to
absolute insulin deficiency. This is usually due to autoimmune destruction of the
pancreatic beta cells %type 1A&. Testing for islet-cell antibodies %1)A& or other
autoantibodies %antibodies to glutamic acid decarboAylase [anti-+A5], insulin, and to the
tyrosine phosphatase 1A-#& in serum may be helpful if establishing the diagnosis is
importantB a positive result is indicative of immune-mediated or type 1A diabetes [1].
4oever, some patients have no evidence of autoimmunity and have no other !non
cause for beta-cell destruction. They are said to have idiopathic or type 1$ diabetes
mellitus. Cther classification schemes have also been proposed. %'ee ('yndromes of
!etosis-prone diabetes mellitus( and (-athogenesis of type 1 diabetes mellitus(.&
-atients ith type 1 diabetes have an absolute re*uirement for insulin therapy and ill
develop diabetic !etoacidosis %5:A& if not given insulin. Although !etoacidosis is not a
typical feature of type # diabetes, some patients ith type # diabetes develop diabetic
!etoacidosis under certain circumstances %severe infection or other illness&.
Adult-onset type 1 diabetes D 'ince the discovery of autoantibodies directed against
pancreatic beta-cell antigens, it has been recogni?ed that some adults considered to have
type # diabetes probably have type 1 diabetes. Among adults ith apparent type #
diabetes, approAimately E.9 to 1; percent have type 1 diabetes as defined by the presence
of circulating islet-cell antibodies %1)A&, antibodies to glutamic acid decarboAylase
%+A5&, or careful clinical criteria [#-8]. This is sometimes referred to as (latent
autoimmune diabetes in adults( %LA5A& [9-E]. %'ee (-athogenesis of type 1 diabetes
mellitus(.&
The autoimmune response that leads to destruction of pancreatic islet beta-cells and
insulin-dependent diabetes mellitus %155/& has a genetic basisB hoever, environmental
factors can eAert profound modulating effects on the genetic predisposition to this
autoimmune response. 7ecent studies in animal models for human 155/, the genetically
diabetes-prone 0C5 mouse and $$ rat, have revealed that microbial agents--including
certain viruses and eAtracts of bacteria, fungi, and mycobacteria--often have a protective
action against diabetes development. /any of these microbial preparations are immune
adjuvants, hich are agents that stimulate the immune system. The protective effects of
these agents against diabetes appear to involve perturbations in the production of
cyto!ines, hich are polypeptides produced by and acting on cells of the immune system.
Thus, recent studies in 0C5 mice suggest that the islet beta-cell-directed autoimmune
response may be mediated by a T-helper 1 %Th1& subset of T-cells producing the
cyto!ines interleu!in-# %1L-#& and interferon-gamma. These studies also suggest that the
diabetes-protective effects of administering microbial agents, adjuvants, and a beta-cell
autoantigen %+A5=9 [glutamic acid decarboAylase]& may result from activation of a Th#
subset of T-cells that produce the cyto!ines 1L-8 and 1L-1; and conse*uently
donregulate the Th1-cell-mediated autoimmune response. The clinical implication of
these findings is that the autoimmune response leading to islet beta-cell destruction and
155/ may be amenable to prevention or suppression by therapeutic interventions aimed
at stimulatin
)oAsac!ievirus $ infections have been associated ith clinical manifestation of insulin-
dependent diabetes mellitus %155/& in several studies, but their initiating role in the
sloly progressing beta-cell damage is not !non. This is the first prospective study
designed to assess the role of coAsac!ie $ and other enterovirus infections in the
induction and acceleration of this process. Three separate series ere studiedF 1& an
intrauterine eAposure series comprising G= pregnant mothers hose children
subse*uently manifested 155/ and G= control mothers hose children remained
nondiabeticB #& a cohort of ## initially unaffected siblings of diabetic children ho ere
folloed until they developed clinical 155/ %mean observation time, #G months& and
11; control siblings ho remained nondiabeticB ,& a case-control series comprising G;
children ith nely diagnosed 155/ and G; control subjects. .nterovirus infections
ere identified on the basis of significant increases in serum 1g+, 1g/, or 1gA class
antibodies against a panel of enterovirus antigens %capture radioimmunoassay&.
.nterovirus antibodies ere significantly elevated in pregnant mothers hose children
subse*uently manifested 155/, particularly in cases in hich 155/ appeared at a very
young age, before the age of , years %- H ;.;;9&. 'erologically verified enterovirus
infections ere almost to times more fre*uent in siblings ho developed clinical 155/
than in siblings ho remained nondiabetic %mean, 1.; vs. ;.= infectionsIfollo-up yearB -
H ;.;;1&. This difference as seen both close to the diagnosis of 155/ and several years
before diagnosis.%A$'T7A)T T720)AT.5 AT #9; JC75'& g the host@s on
immunoregulatory mechanisms.

1n type 1 diabetes, an immune-mediated process leads to the destruction of pancreatic
beta-cells. 1n the last decade, considerable progress has been made in understanding the
cellular and biochemical pathogenic processes of the disease. 4oever, more needs to be
learned about the immune mechanisms leading to the development of autoreactive
immune cells and the molecular mechanisms of beta-cell death. The study of apoptosis of
autoreactive lymphocytes as ell as apoptosis of beta-cells may give ansers to many
still unsolved *uestions. This revie focuses on the possible role of apoptosis both in the
regulation of immune mechanisms involved in the pathogenesis of type 1 diabetes and as
a ay for beta-cells to die. The advancement in the !noledge of the possible role of
apoptosis and its regulation in the pathogenesis of type 1 diabetes may provide ne
therapeutic tools for the prevention of the disease.
%b& Type 1 diabetes, or 1nsulin 5ependent 5iabetes /ellitus %155/&, is a disease
characteri?ed by Kauto-destructionL of the pancreatic beta cells that produce insulin.
Cvertime, the body silently destroys these cells creating an insulin deficiency.
Diagram showing insulin
producing cells destroyed
155/ appears to stem from an inherited defect in the immune system, triggered by some
environmental stimuli.
The eAact cause of the disease is still un!non but a study found that genetic
predisposition, autoimmunity, and viral infection are the main etiological factors
implicated in the pathogenesis of type 1 diabetes mellitus.

/any of the patients ith type 1 5/ have associated autoimmune diseases li!e thyroid
disorders, autoimmune adrenal disorders, celiac disease and connective tissue disorders,
e.g. systemic lupus erythematosus %'L.&.



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