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The terms glycemic pentads and glycemic hexads have been introduced to explain the

importance of safely achieving tight glucose control. The efficacy and safety objectives of
the pharmacologic intervention in diabetes management need to consider the individual
patient needs, fears, and comorbidity factors among others. The concept of glycemic hexads
includes three efficacy parameters, namely glycosylated hemoglobin A1c (HbA1c), fasting
plasma glucose (FPG), and postprandial plasma glucose (PPG), along with three safety
parameters, namely hypoglycemia in general, nocturnal hypoglycemia (in special
situations), and glycemic variability. Nocturnal hypoglycemia is reported as an episode of
abnormally low blood glucose (3.5 mmol/L) occurring at nighttime during sleep, especially
in patients with type 1 diabetes mellitus (T1DM). In the 4 years of follow- up after the
Diabetes Control and Complications Trial (DCCT), 43% of all hypoglycemic episodes and
55% of severe episodes were reported to occur during sleep.

In healthy individuals, plasma glucose concentrations keep within a narrow range of about
3.5–7.0 mmol/L throughout the day despite wide fluctuations in nutritional intake, physical
exercise, and other physiological, psychological, and iatrogenic determinants of plasma
glucose concentrations. After food intake, plasma glucose rises to a peak in 30–60 min and
returns to basal or below basal concentrations within 2–3 h. Approximately 50% of the total
daily insulin is secreted during basal periods, suppressing lipolysis and glycogenolysis. The
remainder of insulin secretion is postprandial. In response to a meal, there is a rapid and
sizable release of preformed insulin from storage granules within the b-cell.
The first phase of insulin secretion promotes peripheral utilization of the prandial nutrient
load, suppresses hepatic glucose production, and limits postprandial glucose elevation. The
first phase of insulin secretion begins within 2 min of nutrient ingestion and continues for
10–15 min, giving way to the second phase of insulin secretion. The second phase of
prandial insulin secretion is sustained until normoglycemia is restored. This is pictorially
shown in Fig. 1. It is the loss of b-cells that underlies type 1 diabetes mellitus, and loss of b-
cell glucose sensitivity and responsiveness that underlies the pathogenesis of T2DM.
Between the b-cell loss and ineffective insulin release and function lie other forms of
diabetes.
Various terminologies relating to the use of insulin have been used: augmentation therapy
refers to the addition of basal insulin to a regimen when there is still some b-cell function
present while replacement therapy refers to the use of a regimen that mimics the normal
physiology of insulin secretion and is required when there is b-cell exhaustion. Rescue
therapy refers to the use of replacement regimens for several weeks usually to reverse
glucose toxicity
EADSG Guidelines: Insulin Therapy in Diabetes. Silver, B., et al.
https://doi.org/10.1007/s13300-018-0384-6

Traditionally, T1DM is a condition that affects lean children or adolescents and young adults.
The pathophysiology of T1DM ultimately results in absolute insulin deficiency and hallmark
symptoms such as polyuria and polydipsia, with diabetic ketoacidosis (DKA) presenting in
approximately 30% of patients. Patients with T1DM require exogenous insulin replacement.
Type 1 autoimmune DM (T1ADM) is characterized by β-cell self-destruction. Approximately
70±90% of newly diagnosed cases of T1DM correspond to T1ADM. These patients are
identified by the presence of at least one of the following antibodies: anti-islet cell antibodies
(AICA), anti-insulin antibodies (IAA), antibodies against glutamic acid decarboxylase 65
(GAD-65), insulinoma-associated autoantigen 2 (IA-2 or ICA512) and antibodies against
Zinc transporter 8 (ZnT8). In contrast, patients with type 1 idiopathic DM (T1BDM) do not
exhibit signs of self-autoimmunity.

Insulin sensitivity (IS) was calculated using the equation developed and validated with the
euglycemic-hyperinsulinemic clamp used in the SEARCH diabetes in youth study. The
following equation was used to measure IS: IS = exp [4.64725±0.02032 x waist (cm) -
0.09779 x [HbA1C(%)] - 0.00235 x TG (mg/dL)]. According to this surrogate measurement,
insulin resistance (IR) was defined as IS <8.15 and no insulin resistance (NIR) was defined
as IS_8.15. FCP levels were adjusted by IS; FCP when IS <8.15 and FCP when IS_8.15

Antibodies against glutamic acid decarboxylase 65 (GAD-65) were measured using an


ELISA kit (from AccuDiagTM, CA, USA) with a sensitivity and specificity of 85% and 87.1%,
respectively (antibody-positive was defined as levels >1.05). Anti-insulin antibodies (IAA)
were measured using ELISA kits (BioSystems S.A. Barcelona, Spain) with a sensitivity and
specificity of 86.7% and 98.7%, respectively (antibody-positive was defined as levels >10
U/mL). Anti-islet cell antibodies (AICA) were evaluated using indirect immunofluorescence
methods (monkey pancreas section, BioSystems S.A. Barcelona, Spain) with a sensitivity
and specificity of 65% and 100%, respectively. Pancreatic autoimmunity was defined as at
least one of three autoantibody- positive results.

DM was diagnosed based on ADA criteria. The classification of DM types was made as
follows:
· T1ADM: non-overweight/obese and positive pancreatic autoimmunity,
· T1BDM: non-overweight/obese and negative pancreatic autoimmunity,
· T2DM: overweight/obese and negative pancreatic autoimmunity,
· T1.5DM: overweight/obese and positive pancreatic autoimmunity.

Clinical and Metabolic Characteristics among Mexican Children with Different Types of
Diabetes Mellitus. Evia-Viscarra, ML., et al.

Most of the symptoms are similar in both types of diabetes but they vary in their degree and
develop more rapidly in type 1 diabetes and more typical.

Clinical features of type I diabetes


Some of the symptoms include weight loss, polyurea, polydipsia, polyphagia, constipation
fatigue, cramps, blurred vision, and candidiasis [21]. Long lasting type 1 DM patients may
susceptible to microvascular complications; [22-24] and macrovascular disease (coronary
artery, heart, and peripheral vascular diseases)
Type 1 Diabetes is characterized by autoimmune destruction of insulin producing cells in the
pancreas by CD4+ and CD8+ T cells and macrophages infiltrating the islets [31]. Several
features characterize type 1 diabetes mellitus as an autoimmune disease [32]:
1. Presence of immuno-competent and accessory cells in infiltrated pancreatic islets;
2. Association of susceptibility to disease with the class II (immune response) genes of the
major histocompatibility complex (MHC; human leucocyte antigens HLA);
3. Presence of islet cell specific autoantibodies;
4. Alterations of T cell mediated immunoregulation, in particular in CD4+ T cell compartment;
5. The involvement of monokines and TH1 cells producing interleukins in the disease
process;
6. Response to immunotherapy and;
7. Frequent occurrence of other organ specific auto- immune diseases in affected individuals
or in their family members. Approximately 85% of patients have circulating islet cell
antibodies, and the majorities also have detectable anti-insulin antibodies before receiving
insulin therapy. Most islet cell antibodies are directed against glutamic acid decarboxylase
(GAD) within pancreatic B cells [33]. The autoimmune destruction of pancreatic β-cells,
leads to a deficiency of insulin secretion which results in the metabolic derangements
associated with T1DM. In addition to the loss of insulin secretion, the function of pancreatic
α-cells is also abnormal and there is excessive secretion of glucagons in T1DM patients.
Normally, hyperglycemia leads to reduced glucagons secretion, however, in patients with
T1DM, glucagons secretion is not suppressed by hyperglycemia. The resultant
inappropriately elevated glucagons levels exacerbate the metabolic defects due to insulin
deficiency. Although insulin deficiency is the primary defect in T1DM, there is also a defect
in the administration of insulin. Deficiency in insulin leads to uncontrolled lipolysis and
elevated levels of free fatty acids in the plasma, which suppresses glucose metabolism in
peripheral tissues such as skeletal muscle [34]. This impairs glucose utilization and insulin
deficiency also decreases the expression of a number of genes necessary for target tissues
to respond normally to insulin such as glucokinase in liver and the GLUT 4 class of glucose
transporters in adipose tissue explained that the major metabolic derangements, which
result from insulin deficiency in T1DM are impaired glucose, lipid and protein metabolism.

Baynes HW (2015) Classification, Pathophysiology, Diagnosis and Management of


Diabetes Mellitus. J Diabetes Metab 6: 541.doi:10.4172/2155-6156.1000541

The rate of progression is dependent on the age at first detection of antibody, number of
antibodies, antibody specificity, and antibody titer. Glucose and A1C levels rise well before
the clinical onset of diabetes, making diagnosis feasible well before the onset of DKA. Three
distinct stages of type 1 diabetes can be identified and serve as a framework for future
research and regulatory decision-making

Recommendations
c Plasma blood glucose rather than A1C should be used to diagnose the acute onset of type
1 diabetes in individuals with symptoms of hyperglycemia. E
c Screening for type 1 diabetes with a panel of autoantibodies is currently recommended
only in the setting of a research trial or in first-degree family members of a proband with type
1 diabetes. B
c Persistence of two or more autoantibodies predicts clinical diabetes and may serve as an
indication for intervention in the setting of a clinical trial. B

This form, previously called “insulindependent diabetes” or “juvenile-onset diabetes,”


accounts for 5–10% of diabetes and is due to cellular-mediated autoimmune destruction of
the pancreatic b-cells. Autoimmune markers include islet cell autoantibodies and
autoantibodies to GAD (GAD65), insulin, the tyrosine phosphatases IA-2 and IA-2b, and
ZnT8. Type 1 diabetes is defined by the presence of one or more of these autoimmune
markers. The disease has strong HLA associations, with linkage to the DQA and DQB
genes. These HLA-DR/DQ alleles can be either predisposing or protective.
American Diabetes Association. 2. Classification and diagnosis of diabetes Standards of
Medical Care in Diabetesd2018. Diabetes Care 2018;41(Suppl. 1):S13–S27.

Patients with type 1 diabetes are also prone to other autoimmune disorders such as
Hashimoto thyroiditis, Graves disease, Addison disease, celiac disease, vitiligo,
autoimmune hepatitis, myasthenia gravis, and pernicious anemia
The incidence and prevalence of type 1 diabetes is increasing. Patients with type 1 diabetes
often present with acute symptoms of diabetes and markedly elevated blood glucose levels,
and approximately one-third are diagnosed with life-threatening DKA. Several studies
indicate that measuring islet autoantibodies in relatives of those with type 1 diabetes may
identify individuals who are at risk for developing type 1 diabetes. Such testing, coupled with
education about diabetes symptoms and close follow-up, may enable earlier identification
of type 1 diabetes onset. A study reported the risk of progression to type 1 diabetes from the
time of seroconversion to autoantibody positivity in three pediatric cohorts from Finland,
Germany, and the U.S. Of the 585 children who developed more than two autoantibodies,
nearly 70% developed type 1 diabetes within 10 years and 84% within 15 years (31). These
findings are highly significant because while the German group was recruited from offspring
of parents with type 1 diabetes, the Finnish and American groups were recruited from the
general population. Remarkably, the findings in all three groups were the same, suggesting
that the same sequence of events led to clinical disease in both “sporadic” and familial cases
of type 1 diabetes. Indeed, the risk of type 1 diabetes increases as the number of relevant
autoantibodies detected increases. Although there is currently a lack of accepted screening
programs, one should consider referring relatives of those with type 1 diabetes for antibody
testing for risk assessment in the setting of a clinical research study. Widespread clinical
testing of asymptomatic low-risk individuals is not currently recommended due to lack of
approved therapeutic interventions. Individuals who test positive should be counseled about
the risk of developing diabetes, diabetes symptoms, and DKA prevention. Numerous clinical
studies are being conducted to test various methods of preventing type 1 diabetes in those
with evidence of autoimmunity.
American Diabetes Association. 6. Glycemic targets: Standards of Medical Care in
Diabetesd2018. Diabetes Care 2018; 41(Suppl. 1):S55–S64

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES


Recommendations
c Most people with type 1 diabetes should be treated with multiple daily injections of prandial
insulin and basal insulin or continuous subcutaneous insulin infusion. A
c Most individuals with type 1 diabetes should use rapid-acting insulin analogs to reduce
hypoglycemia risk. A
c Consider educating individuals with type 1 diabetes on matching prandial insulin doses to
carbohydrate intake, premeal blood glucose levels, and anticipated physical activity. E
c Individuals with type 1 diabetes who have been successfully using continuous
subcutaneous insulin infusion should have continued access to this therapy after they turn
65 years of age. E

Insulin Therapy
Insulin is the mainstay of therapy for individuals with type 1 diabetes. Generally, the starting
insulin dose is based on weight, with doses ranging from 0.4 to 1.0 units/kg/day of total
insulin with higher amounts required during puberty. The American Diabetes
Association/JDRF Type 1 Diabetes Sourcebook notes 0.5 units/kg/day as a typical starting
dose in patients with type 1 diabetes who are metabolically stable, with higher weight-based
dosing required immediately following presentation with ketoacidosis (1), and provides
detailed information on intensification of therapy to meet individualized needs. The American
Diabetes Association (ADA) position statement “Type 1 Diabetes Management Through the
Life Span” additionally provides a thorough overview of type 1 diabetes treatment (2).

Pramlintide, an amylin analog, is an agent that delays gastric emptying, blunts pancreatic
secretion of glucagon, and enhances satiety. It is FDA-approved for use in adults with type
1 diabetes. It has been shown to induce weight loss and lower insulin doses. Concurrent
reduction of prandial insulin dosing is required to reduce the risk of severe hypoglycemia.

Metformin
Adding metformin to insulin therapy may reduce insulin requirements and improve metabolic
control in patients with type 1 diabetes. In one study, metformin was found to reduce insulin
requirements (6.6 units/day, P , 0.001), and led to small reductions in weight and total and
LDL cholesterol but not to improved glycemic control (absolute A1C reduction 0.11%, P 5
0.42) (22). A randomized clinical trial similarly found that, among overweight adolescents
with type 1 diabetes, the addition of metformin to insulin did not improve glycemic control
and increased risk for gastrointestinal adverse events after 6 months compared with
placebo. The Reducing With Metformin Vascular Adverse Lesions in Type 1 Diabetes
(REMOVAL) trial investigated the addition of metformin therapy to titrated insulin therapy in
adults with type 1 diabetes at increased risk for cardiovascular disease and found that
metformin did not significantly improve glycemic control beyond the first 3 months of
treatment and that progression of atherosclerosis (measured by carotid artery intima-media
thickness) was not significantly reduced, although other cardiovascular risk factors such as
body weight and LDL cholesterol improved. Metformin is not FDA approved for use in
patients with type 1 diabetes.

Incretin-Based Therapies
Due to their potential protection of b-cell mass and suppression of glucagon release,
glucagon-like peptide 1 (GLP-1) receptor agonists (25) and dipeptidyl peptidase 4 (DPP-4)
inhibitors (26) are being studied in patients with type 1 diabetes but are not currently FDA-
approved for use in patients with type 1 diabetes.

Sodium–Glucose Cotransporter 2 Inhibitors


Sodium–glucose cotransporter 2 (SGLT2) inhibitors provide insulin-independent glucose
lowering by blocking glucose reabsorption in the proximal renal tubule by inhibiting SGLT2.
These agents provide modest weight loss and blood pressure reduction in type 2 diabetes.
There are three FDA-approved agents for patients with type 2 diabetes, but none are FDA
approved for the treatment of patients with type 1 diabetes (2). SGLT2 inhibitors may have
glycemic benefits in patients with type 1 or type 2 diabetes on insulin therapy (27). The FDA
issued a warning about the risk of ketoacidosis occurring in the absence of significant
hyperglycemia (euglycemic diabetic ketoacidosis) in patients with type 1 or type 2 diabetes
treated with SGLT2 inhibitors.
Symptoms of ketoacidosis include dyspnea, nausea, vomiting, and abdominal pain. Patients
should be instructed to stop taking SGLT2 inhibitors and seek medical attention immediately
if they have symptoms or signs of ketoacidosis.
SURGICAL TREATMENT FOR TYPE 1 DIABETES
Pancreas and islet transplantation have been shown to normalize glucose levels but require
life-long immunosuppression to prevent graft rejection and recurrence of autoimmune islet
destruction. Given the potential adverse effects of immunosuppressive therapy, pancreas
transplantation should be reserved for patients with type 1 diabetes undergoing
simultaneous renal transplantation, following renal transplantation, or for those with
recurrent ketoacidosis or severe hypoglycemia despite intensive glycemic management

American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment:


Standards of Medical Care in Diabetesd2018. Diabetes Care 2018;41(Suppl. 1): S73–S85

Función de las células presentadoras de antígeno en


la iniciación de la DM1
A pesar de que los linfocitos T son los mayores efectores de la lesión sobre las células beta,
la colaboración de otras células del sistema inmunitario es necesaria para la iniciación y
posterior desarrollo de la enfermedad. Entre estas células destacan las células dendríticas,
los macrófagos y los linfocitos B, que comparten la función común de presentar antígenos
en el contexto del MHC, es decir, de actuar como células presentadoras de antígeno (APC)
para linfocitos T. Para que los linfocitos T se activen, los antígenos deben ser presentados
de forma simultánea con al menos una señal coestimuladora adicional mediante receptores
de membrana (p.ej., CD28/B7) y generalmente en presencia de citocinas tales como la IL-
2 y la IL-4. Este primer contacto entre las APC y los linfocitos T se produce en los ganglios
linfáticos regionales, donde antígenos tisulares y APC «vigilantes» procedentes de los
distintos tejidos del organismo (p.ej., el páncreas) son transferidos por la linfa. En términos
generales, las APC presentan antígenos procedentes del catabolismo proteico interno en
el contexto de moléculas de MHC de clase I a linfocitos T CD8+. Por el contrario, aquellos
antígenos procedentes del espacio extracelular son captados por las APC mediante
fagocitosis, endocitosis o pinocitosis, y posteriormente presentados en el contexto de las
moléculas de MHC de clase II a linfocitos T CD4+. En algunos casos, antígenos
procedentes del espacio intersticial también son presentados por moléculas de clase I,
proceso que conocemos como «presentación cruzada». En otros, la presentación cruzada
determina tolerancia, es decir una no-respuesta por parte del linfocito T. Sin embargo, en
otras situaciones la presentación cruzada de antígenos tiene como resultado la activación
linfocitaria. Esta dualidad funcional vendría determinada por variables como la dosis de
antígeno, el lugar y momento de la presentación, la presencia de otras células auxiliares o
citocinas en el medio, y en particular el estado de activación de la propia APC. Se ha
postulado que la presentación cruzada de antígenos podría estar implicada en la iniciación
de los procesos autoinmunitarios. Actualmente, en la DM1 se desconoce cómo y cuándo
se activan los linfocitos T precitotóxicos, y tampoco se sabe qué APC están implicadas en
esta activación. Distintos estudios han demostrado que los tres tipos de células
presentadora (células dendríticas, macrófagos y linfocitos B) podrían estar implicadas en la
presentación de autoantígenos y que, dependiendo del estado de activación de dicha APC
y del contexto en que tenga lugar la presentación antigénica, el resultado sería activación
o, por el contrario, la supresión de linfocitos T autorreactivos. Las células dendríticas
capturan preferentemente antígenos solubles, aunque también captan antígenos mediante
fagocitosis. Su única función conocida es la de actuar como APC. Las células dendríticas
inmaduras se encuentran normalmente en superficies epiteliales y en la mayoría de órganos
sólidos. Durante este periodo tienen la máxima capacidad para capturar antígenos, aunque
una mínima capacidad de activar linfocitos T dada la poca expresión de moléculas de MHC
de clase I y II, y la nula expresión de moléculas coestimuladoras. En este estado, las células
dendríticas tendrían actividad supresora de la respuesta de los linfocitos T, contribuyendo
al establecimiento de la tolerancia tanto central como periférica. Por el contrario, una vez
se capturan antígenos «extraños», se produce la activación de la célula, conllevando una
alta expresión de moléculas de MHC y de moléculas coestimuladoras (p.ej., B7), y su
migración a los ganglios linfáticos regionales, transformándose así en las APC con la
capacidad estimuladora más potente para linfocitos T vírgenes (naive).
Se ha sugerido que las células dendríticas de ratones NOD tendrían defectos de
maduración y de transcripción del factor NF-kappaB, lo que conllevaría una activación
anormal de la célula y, en último término, el desarrollo de una respuesta inmunitaria
patogénica.
Estudios realizados en ratones NOD han demostrado que antes de que se inicie la insulitis
ya existen células dendríticas en los islotes pancreáticos. Por otra parte, otros estudios
sugieren que serían estas células dendríticas presentes en las fases previas a la insulitis
las responsables del proceso autoinmunitario. Así, tras la captación antigénica y su
posterior activación, las células dendríticas migrarían a los ganglios linfáticos regionales,
donde activarían a los linfocitos T autorreactivos específi cos de célula beta. Una vez
activados, estos linfocitos T proliferarían y posteriormente migrarían al páncreas, donde
iniciarían el proceso lítico de las células beta. Con la destrucción de las primeras células
beta se produciría la liberación de nuevos autoantígenos, que serían captados por nuevas
células dendríticas y otras APC, las cuales, tras su migración a los ganglios regionales,
iniciarían la activación de nuevos linfocitos T autorreactivos. Estos linfocitos T activados
migrarían a su vez al páncreas, donde actuarían destruyendo un mayor número de células
beta, con una nueva liberación de autoantígenos, cerrándose así un
círculo que en último término sólo finalizaría con la destrucción de todas las células beta.
Los macrófagos también aparecen en los islotes pancreáticos antes del infiltrado de
linfocitos T. Los macrófagos se caracterizan por su capacidad fagocítica casi ilimitada,
incluyendo complejos moleculares como bacterias, fragmentos celulares, células necróticas
y apoptóticas. Con esta actuación, los macrófagos retiran de los tejidos todo aquello que
pueda lesionar al organismo. Aunque el papel de los macrófagos en la DM1 parece estar
más relacionado con esta función limpiadora que con su función presentadora de antígenos,
no se puede descartar un defecto en la presentación antigénica que conlleve a la respuesta
autoinmunitaria. De hecho, en ratones NOD se ha descrito un defecto en la función y
maduración de los macrófagos. Además, algunos estudios han señalado que los
macrófagos son necesarios para el desarrollo y activación de linfocitos T citotóxicos con
reactividad contra células beta, y que, en ratones NOD, la
enfermedad puede prevenirse mediante la transferencia de macrófagos tímicos alogénicos,
a través de un mecanismo aún no determinado.
Los linfocitos B como células presentadoras de antígeno y como células productoras de
autoanticuerpos en la DM1 de ratones NOD
Se ha demostrado que los linfocitos B tienen una función crítica en el desarrollo de la DM1.
Así, la depleción de esta población celular en ratones salvajes (wild-type) NOD o la ausencia
congénita de la misma en NOD. Igmnull, acaba en una resistencia y/o retraso en la edad
de debut de la enfermedad. A pesar de que no se conocen con certeza los mecanismos por
los cuales los linfocitos B contribuirían al desarrollo de la diabetes, se ha
propuesto que lo harían mediante su función presentadora de antígeno, es decir que
linfocitos B autorreactivos podrían capturar, mediante las inmunoglobulinas de membrana,
autoantígenos de células beta y, posteriormente, presentarlos a linfocitos T autorreactivos
a nivel de los ganglios linfáticos regionales. Además, se sabe que los linfocitos B, al igual
que sus homólogos los linfocitos T, migran a los islotes pancreáticos durante el desarrollo
de la DM1, lo que sugiere una función clave in situ.
Por otra parte, varios trabajos apoyan la idea de que los propios autoanticuerpos también
podrían contribuir al desarrollo de la DM1. En ratones NOD, al igual que en los humanos,
el desarrollo de DM1 está asociado a la presencia de autoanticuerpos circulantes contra
distintos autoantígenos de células beta, especialmente contra insulina. Además, en ratones
NOD, se ha demostrado que la transferencia vía placentaria de autoanticuerpos reactivos
contra autoantígenos de células beta contribuye a la progresión de la diabetes en la prole.
Autoantígenos de células beta reconocidos en la DM1 del ratón NOD
Un punto clave para la comprensión del ataque autoinmunitario es la búsqueda del o los
autoantígenos contra los que se dirige dicha agresión. En este sentido, se sabe que durante
la evolución de la enfermedad se produce una expansión en la diversidad de linfocitos T
autorreactivos. Esto es debido a que la misma destrucción de las células beta libera nuevos
autoantígenos que pueden ser diana de la respuesta autoinmunitaria (efecto conocido como
«antigenic spreading») y que se refleja también en la diversificación en los autoanticuerpos
detectables en suero. Por esta razón, se han dedicado muchos esfuerzos a buscar los
autoantígenos contra los que se dirige la respuesta inicial. De esta manera, varios grupos
han aislado clonas de linfocitos T autorreactivos procedentes de insulitis incipientes, y han
estudiado su especificidad y su comportamiento cuando su TCR es ampliamente expresado
de forma transgénica. Estos estudios indican que el comportamiento de estos linfocitos T
autorreactivos depende, en gran medida, de la afinidad de su TCR con el autoantígeno en
cuestión, siendo más dependientes de coestímulos aquellos linfocitos cuyo TCR tiene
menor afinidad con el autoantígeno.
Se han descrito varios autoantígenos de células beta como posibles dianas iniciales de la
respuesta autoinmunitaria de linfocitos T en la DM1. Entre ellos, destacan la insulina (y/o la
proinsulina), IA-2 (insulinoma-associated protein 2), GAD (glutamic acid decarboxylase),
HSP-60 (heat shock protein), y el recientemente descrito IGRP (islet-specific glucose-6-
phosphatase catalytic subunit-related protein). En esta respuesta anómala, se han
implicado defectos de tolerancia central y periférica. Como ya se ha mencionado, una
posible causa del defecto de tolerancia central podría ser la presentación antigénica
defectuosa por parte de las APC presentes en el timo, a consecuencia de una inestabilidad
de la molécula H-2 IAg7 o de un defecto en el procesamiento antigénico. De esta forma,
algunos linfocitos T autorreactivos podrían escapar al proceso de selección negativa. Se ha
sugerido también que un defecto de los linfocitos T en las vías de apoptosis, tanto
dependientes como independientes de Fas, podría estar implicado en el escape a los
mecanismos de tolerancia tanto central como periférica. Nuestro conocimiento sobre el
repertorio antigénico de los linfocitos B autorreactivos en la DM1 proviene básicamente de
estudios de la especificidad antigénica de los autoanticuerpos
circulantes reactivos contra islote, pero también del análisis de la especificidad antigénica
de hibridomas de linfocitos B circulantes (p. ej., de sangre en humanos o de bazo en
roedores). En términos generales, dichos estudios han demostrado la existencia en la
periferia de una extensa gama de autoanticuerpos que reconocen antígenos de células
beta, incluyendo GAD, IA-2, insulina, CPE (carboxypeptidase H), ICA69 (islet cell
autoantigen of 69kDa), y gangliósido GM2-1.
Tolerancia y células T reguladoras en el ratón NOD
En condiciones fisiológicas, el timo permite la maduración de timocitos con cierto grado de
autorreactividad. De esta forma, encontramos con cierta frecuencia en sangre periférica de
individuos sanos la presencia de linfocitos T autorreactivos. Estos linfocitos son silenciados
mediante varios mecanismos inmunológicos de tolerancia periférica, como la delección, la
ignorancia inmunológica o la anergia.
En estos últimos años, ha suscitado gran interés el mecanismo de supresión como
mecanismo de tolerancia, que parece estar mediado por un grupo heterogéneo de linfocitos
T reguladores (Treg), de los cuales algunos son células T supresoras
naturales, es decir que se encuentran de manera constitutiva en el organismo, mientras que
otras son inducidas mediante vías específicas de estimulación antigénica. Las células Treg
supresoras naturales requieren el contacto celular directo para realizar su efecto regulador.
En este grupo se incluyen los linfocitos T CD4+/CD25+, los linfocitos T NK (natural killer), y
probablemente los linfocitos T g#d. Por el contrario, la población de células T reguladoras
inducidas pueden obtenerse in vitro después de la unión con el antígeno en presencia de
IL-10 y TGF-b, y también mediante inducción con tolerancia oral. Este grupo de células Treg
está mayoritariamente constituido por dos subpoblaciones de linfocitos T CD4+, las células
Tr1 y Th3, que llevan a cabo su efecto supresor mediante la secreción de IL-10 y/o TGF-b.
Además de linfocitos T CD4+, también se han descrito tres subgrupos de linfocitos T CD8+
capaces de ejercer funciones supresoras sobre linfocitos T antígeno-específicos. El grupo
1 de células Treg CD8+ actúa impidiendo la expresión de moléculas coestimuladoras en
células presentadoras de antígeno, el grupo 2 inhibiendo la secreción de IFN-g e IL-6, y el
grupo 3 a través de la secreción de citocinas especialmente de IL-10. En estos últimos años,
un número importante de estudios ha demostrado la importancia de las células Treg en el
mantenimiento de la tolerancia natural a lo propio, y por ello se ha demostrado también su
importancia en la prevención de las enfermedades autoinmunitarias, incluyendo la DM1. En
el caso del ratón NOD parece existir un defecto en la capacidad de generar un número
suficiente de células Treg, ya que su porcentaje es de aproximadamente sólo la mitad de
las existentes en cepas de ratones resistentes a la autoinmunidad. No deja de ser
interesante observar que la transferencia de células T reguladoras en ratones NOD es
suficiente para suprimir el desarrollo de diabetes. Por otro lado, algunos estudios han
demostrado que la eficacia de la supresión dependería de la especificidad antigénica de las
propias Treg. Así, se ha demostrado que células Treg
específicas para insulina o con especificidad BDC 2,5-TCR pueden suprimir eficazmente el
desarrollo de diabetes cuando éstas se transferían con linfocitos T diabetogénicos en
modelos de transferencia. Aunque es probable que en la periferia se originen células Treg
en respuesta a autoantígenos, la porción principal de estas células parece tener su origen
en el timo, ya que se ha observado que la timectomía en ratones NOD produce una
aceleración en el debut diabético.
Estado funcional de las células beta pancreáticas y DM1 en ratones NOD
Además de los defectos propios en la regulación del sistema inmunitario, la condición
funcional de las propias células beta es decisiva en la patogénesis de la DM1. Así, se han
señalado como causas del proceso autoinmunitario la disfunción y el incremento en la
muerte de la célula beta cuando termina la lactancia y comienza la dieta adulta (2-3
semanas de vida), justo antes de la aparición de los primeros infi ltrados insulares. También
se ha relacionado un incremento de la actividad funcional de las células beta con un
aumento de la incidencia de la enfermedad. Así, en ratones NOD, el tratamiento preventivo
con insulina que reduce la actividad funcional de las células beta insulares conduce a un
descenso en la incidencia de la diabetes.
Estos resultados sugieren que un incremento en la actividad de la célula beta puede llevarla
a un proceso de estrés, y en último término inducir: 1) un incremento de la presentación
antigénica en células beta; 2) una posible producción de nuevos autoantígenos
(neoantígenos); y/o 3) un incremento de la muerte de las células beta con la consiguiente
producción y liberación de señales de peligro (ácido úrico, interferones, heat-shock proteins,
productos de degradación de matriz extracelular, etc.). De hecho,
se ha descrito que las células beta de ratones NOD son constitutivamente más sensibles a
las citocinas proinflamatorias como IL-1b, TNF, y al IFN-g. Todo ello hacer presuponer
que en ratones NOD las posibilidades de presentación de autoantígenos insulares por parte
de células APC a linfocitos T con especificidad por células beta es mayor que en otras cepas
de ratón.

Ignacio Conget. PREDIABETES Y DIABETES TIPO 1 DE RECIENTE DIAGNÓSTICO.


Sociedad Española de Diabetes (SED). 2006

Although type 1 diabetes can be diagnosed at any age, it is one of the most common chronic
diseases of childhood.4 Peaks in presentation occur between 5–7 years of age and at or
near puberty.5 Whereas most autoimmune disorders disproportionately affect women, type
1 diabetes is slightly more common in boys and men.

A plethora of environmental influences have been purported to affect the epidemiology of


type 1 diabetes,25 with infant and adolescent diets,26 vitamin D and vitamin D pathway
constituents,27–29 and viruses receiving the most focus.30,31 Interest is growing in models
to describe the influence of environment on type 1 diabetes, including the hygiene
hypothesis32 and gut microbiome;

However, not all patients with type 1 diabetes have these characteristics, leading to
proposed classifications of type 1A (autoimmune) diabetes,41 for the 70–90% of patients
with type 1 disease that have immunological, self-reactive autoantibodies, and type 1B
(idiopathic) diabetes, representing the remainder whose specific pathogenesis remains
unclear.

the disorder results from an autoimmune destruction of insulin-secreting pancreatic β cells.


The presence of a chronic inflammatory infiltrate that affects pancreatic islets at symptomatic
onset of type 1 diabetes is the basis of this observation (figure 2). Another dogma is that in
patients with longstanding disease, the pancreas is devoid of insulin-producing cells and the
remaining β cells are incapable of regeneration. Both of these concepts of pathogenesis of
type 1 diabetes have been debated. Recent data suggest that although most patients with
longstanding type 1 diabetes have few β cells, if any, there is evidence for β-cell
regeneration in infants and very young children (but not in adolescents or adults).

From individuals with recent-onset type 1 diabetes suggest that around 70% of islets display
complete insulin absence;51,52 nearly 20% of insulin-containing islets, as opposed to only
1% of insulin-deficient islets, are inflamed (ie, insulitis), and many pancreata have non-
inflamed insulin-containing islets that seem to be normal.58,59 In patients with type 1
diabetes with surviving β cells, insulitic lesions are usually lobular, analogous to the lobular
loss of melanocytes in vitiligo.60 Although it is often stated that symptoms occur when 90–
95% of β cells are lost, diagnosis of type 1 diabetes can occur when roughly two-thirds of
the islets are devoid of insulin-producing cells.61,62 Among individuals who have had type
1 diabetes for more than 5 years, most of the remaining islets are insulin deficient, containing
a normal complement of other hormone secreting cells (ie, α cells that secrete glucagon, δ
cells that secrete somatostatin, and PP cells that secrete pancreatic polypeptide).62 Thus,
type 1 diabetes involves a selective loss of β cells. In terms of potential pathogenic
mechanisms, CD8+ T cells are the most predominant population within the insulitis lesion,
followed by (in declining order) macrophages (CD68+), CD4+ T cells, B lymphocytes
(CD20+), and plasma cells (CD138+).62 Surprisingly, FOXP3+ cells (ie, regulatory T cells;
a population of intense research interest2) and natural killer cells are rare in this lesion.
Although much focus has been directed at infl ammatory-cell composition, other pancreatic
features in type 1 diabetes could have pathogenic significance.

Mark A Atkinson, George S Eisenbarth, Aaron W Michels. Type 1 diabetes. Lancet 2014;
383: 69–82. http://dx.doi.org/10.1016/ S0140-6736(13)60591-7

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition resulting in absolute


shortage of pancreatic insulin production. Regular and life-long insulin administration is
therefore necessary to prevent hyperglycaemia, metabolic decompensation and life-
threatening diabetic ketoacidosis (DKA). According to the International Diabetes Federation
(IDF), there were approximately 425 million people living with diabetes worldwide in 2017,
out of which 5% to 10% are estimated to have T1DM (42.5 to 95 million).

Insulin administration represents the mainstay of T1DM treatment. The purpose of insulin
administration is to prevent the development of DKA due to the absolute shortage of intrinsic
insulin production and to maintain BG levels within the physiologic range. Insulin
administration should thus ideally prevent, or at least delay development of micro- and
macrovascular complications of hyperglycaemia and, at the same time, should cause as
little hypoglycaemia as possible.

The current National Institute for Health and Care Excellence (NICE) guidelines for
management of T1DM recommend considering metformin in adults with T1DM and a body
mass index (BMI) ≥25 kg/m2 who ‘want to improve glucose control while minimising their
effective insulin dose’ [22]. American Diabetes Association (ADA) also recommend adding
metformin to insulin therapy which may reduce insulin requirements and improve metabolic
control in overweight or obese people with poorly controlled T1DM [23].

A meta-analysis undertaken by Lund et al. [29] in 2010 (only five trials included) reported a
significant reduction of insulin dose (6.6 units/day, P<0.001), but changes in HbA1c were
inconsistent. A recent trial reported that adding metformin (1g twice daily) to titrated insulin
therapy (target HbA1c 53 mmol/mol) in people with T1DM aged 40 years or older and with
three or more cardiovascular (CV) risk factors for duration of 3 years resulted in significant
reduction of progression of caroT1DM artery intima-media thickness, a surrogate marker for
progression of atherosclerosis (P=0.0093) [30]. This approach also led to significant falls in
low density lipoprotein cholesterol (–0.13 mmol/L, P=0.012), sustained weight reduction (–
1.17 kg, P<0.0001) and lower HbA1c at 3 months by 2.6 mmol/mol (P<0.001), although this
was not sustained [30].

In the recently published phase 3 trial DEPICT-1 (Dapagliflozin Evaluation in Patients with
Inadequately Controlled Type 1 Diabetes), dapagliflozin, when given as an oral adjunct to
adjustable insulin in patients with inadequately-controlled T1DM demonstrated significant
reductions from baseline in HbA1c, body weight, and also lowered total daily insulin dose at
24 weeks at both the 5 and 10 mg dose compared to placebo whilst the incidence of
hypoglycaemia, SH and adjudicated ketoacidosis did not differ significantly between both
treatment arms and the placebo arm [35]. Participants in this study were provided with a
combined BG and ketone meter and were asked to measure BG four times a day and
ketonaemia whenever BG readings were consistently elevated. Participants were also
instructed to reduce insulin doses by no more than 20% on initiation of the study medication
and then subsequently to up-titrate insulin doses back to baseline [36]. A 26-week extension
phase of this trial is currently in progress. Sotagliflozin is a novel inhibitor of SGLT1 and
SGLT2. SGLT1 inhibition in the intestine reduces glucose absorption in proximal intestine
resulting in significant blunting and delay of post-prandial hyperglycaemia [37]. Results of a
recently published phase 3 double-blinded RCT show that sotagliflozin versus placebo
added to insulin therapy for 24 weeks in people with T1DM resulted in significantly increased
number of participants who achieved HbA1c levels <7.0% (28.6% vs. 15.2%, P<0.001) with
similar rates of SH in both groups [37]. Sotagliflozin use versus placebo was also linked with
significantly higher reduction of weight (–2.98 kg), systolic blood pressure (–3.5 mm Hg) and
mean daily bolus of insulin (–2.8 units/day) (P<0.002 for all comparisons). The rate of DKA
was higher in the sotagliflozin group (3.0% vs. 0.6%). Mean baseline BMI in the sotagliflozin
group was 28.29±5.13 and in the placebo group 28.10±5.18 [37].
These results suggest that SGLT2/SGLT1 inhibitors may be an appropriate adjunct to insulin
in people with T1DM who monitor BG regularly, have the availability to monitor ketonaemia
in home environment and have good understanding of early signs of ketoacidosis. The risk
of DKA will need to be balanced by the potential benefits. More research is required, par-
ticularly as there is emerging evidence that these agents may provide protection from long-
term renal disease.

Iqbal A, et al. Recent Updates on Type 1 Diabetes Mellitus Management for Clinicians.
Diabetes Metab J 2018;42:3-18

Several therapies given in conjunction with insulin have been investigated in clinical trials,
including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4
inhibitors, sodium glucose cotransporter inhibitors, metformin, sulfonylureas, and
thiazolidinediones. These drugs have pleiotropic effects on glucose metabolism and diff
erent actions complementary to those of insulin—this Review reports the effects of these
drugs on glycaemic control, glucose variability, hypoglycaemia, insulin requirements, and
bodyweight.
Amylin (pramlintide)
The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is a 37-
aminoacid peptide that is synthesised in the pancreatic β cells, stored in the pancreas with
insulin (1:100), and is co-secreted with insulin in a high-frequency, pulsatile manner every 4
to 6 min.25 Amylin seemingly exerts its actions centrally by activating receptors in the area
postrema, stimulating satiety centres and triggering efferent nervous impulses that inhibit
glucagon secretion, and thereby reduce hepatic glucose production and delay gastric
emptying.26–29 These actions imply that amylin reduces postprandial glucose excursions
by modulating the rate of glucose influx into the circulation. Amylin also reduces food intake
and bodyweight.14 Overall, amylin complements the action of insulin by targeting
postprandial hyperglycaemia; type 1 diabetes is a state of deficiency of both amylin and
insulin (fi gure 1). Pramlintide is an injectable amylin analogue that was developed and
approved by the US Food and Drug Administration (FDA) in 2005 for use in individuals with
insulin-treated type 1 diabetes or type 2 diabetes as an adjunct to mealtime insulin.
Pramlintide has the same physiological eff ects in human beings as amylin, including
reducing food intake.15 Its plasma half-life is 26–50 min and maximum concentration occurs
about 15–30 min after injection.30 In individuals with type 1 diabetes, the normal dose is
30–60 μg three to four times per day before main meals or an evening snack. Pramlintide
has a negligible effect on fasting blood glucose concentrations and does not alter the
counter-regulatory hormone responses, symptoms of hypoglycaemia, or glycaemic recovery
time after hypoglycaemia. Recommendations suggest beginning pramlintide therapy as a
15 μg dose before main meals, concurrently reducing the dose of prandial insulin by 50%.
The dose of pramlintide should be escalated by 15 μg at intervals of 3–7 days to a maximum
dose of 60 μg. Pramlintide should not be used in patients with poor compliance, recurrent
hypoglycaemia, gastroparesis, or those unwilling to monitor blood glucose concentrations
frequently. Three studies of pramlintide have included individuals with type 1 diabetes (table
1). In a 52-week double-blind, randomised, placebo-controlled study, Whitehouse and
colleagues assigned 480 participants to preprandial injections of either placebo or 30 μg
pramlintide four times per day in addition to existing insulin regimens. At week 20, patients
in the pramlintide group who did not have a decrease in HbA1c from baseline of at least
1.0% (10・9 mmol/mol) by week 13 were reassigned to either 30 μg or 60 μg pramlintide
four times per day. The reduction in HbA1c at weeks 13 and 52 was significantly greater
with pramlintide compared with placebo (0・5% [5・5 mmol/mol] vs 0・27% [3・0
mmol/mol]). At week 52, the mean total daily insulin doses for the group increased
by 2・3% in the pramlintide group and 10・3% in the placebo group; p=0・0176.
Bodyweight changes were modest, with a weight gain of about 1 kg in the placebo group
and a weight loss of 0・5 kg in the pramlintide
group. In an open-label, 1-year extension phase with all
participants given pramlintide, the mean reduction in
HbA1c from baseline was about –0・35% (–3・8 mmol/mol),
both in patients who continued with pramlintide and in
those who were reassigned to pramlintide from placebo.
Notably, the investigators were allowed to adjust the
insulin regimen consistent with good medical practice,
which might account for the improved glycaemic control
with pramlintide not being associated with an increased
risk of severe hypoglycaemia.

GLP-1 receptor agonists


Endogenous GLP-1 is secreted from L cells distributed
throughout the small and large intestine in response to
food ingestion,37,38 and has pleiotropic eff ects such as
enhancement of glucose-induced insulin secretion,
inhibition of glucagon secretion, delayed gastric emptying,
and induced satiety resulting in weight loss (fi gure 2).39–42
In patients with type 1 diabetes, the amount of mealinduced
GLP-1 secretion is similar to that of healthy
individuals, but for therapeutical use supraphysiological
doses are needed.41,43 Use of GLP-1 receptor agonists in
type 2 diabetes is well supported, but little evidence exists
about their effi cacy and safety in type 1 diabetes.
Findings from clinical trials44–53 suggest that GLP-1
receptor agonists induce weight loss and reduce insulin
requirements, with either improved or unaltered
glycaemic control (table 2).

Two phase 3a trials with liraglutide as adjunct therapy


in patients with type 1 diabetes have also been completed
(table 2).54,55 In the 52-week, randomised, double-blind,
placebo-controlled trial ADJUNCT ONE,54 the effi cacy
and safety of 0・6 mg, 1・2 mg, and 1・8 mg liraglutide, and
placebo as adjuncts to insulin treatment were investigated
in 1398 individuals with type 1 diabetes.From a mean
baseline HbA1c of around 8・2%, those given 1・2 mg and
1・8 mg liraglutide achieved the primary objective of noninferiority
to placebo in terms of change in HbA1c. The
reduction in HbA1c was numerically greater with
liraglutide, at around 0・5% (5・5 mmol/mol) compared
with 0・3% (3・3 mmol/mol) for placebo. The primary
objective was not met for the 0・6 mg dose. From a
baseline bodyweight of 86 kg, participants given 1・2 mg
and 1・8 mg liraglutide achieved a signifi cantly greater
weight loss of between 3 kg and 4 kg, whereas the placebo
groups had a weight gain of around 1 kg. The rates of
severe hypoglycaemia seemed numerically, but not
statistically, lower for all doses of liraglutide compared
with placebo. A signifi cantly higher rate of substantiated
symptomatic hypoglycaemia was noted among
participants given liraglutide 1・2 mg and 1・8 mg
compared with those given placebo.54
In the ADJUNCT TWO trial,55 835 participants were
enrolled in a 26-week, double-blind, placebo-controlled
trial and assigned to 0・6 mg, 1・2 mg, and 1・8 mg
liraglutide, and placebo. Maximum insulin dose was fi xed
for all treatment arms. From a baseline HbA1c of about
8・1%, the groups given liraglutide had signifi cantly
improved HbA1c by 0・2% to 0・3% (2・2–3・3 mmol/mol) at
the end of the study compared with unaltered glycaemic
control in the placebo-treated group. Additionally, the total
mean insulin dose was reduced with liraglutide compared with placebo after 26 weeks. From
a baseline bodyweight
of 84 kg, the weight loss in the liraglutide groups was
1–5 kg, whereas weight was stable in placebo-treated
patients. A higher rate of symptomatic hypoglycaemia
occurred among individuals given 1・2 mg liraglutide
compared with those who received placebo. The incidence
of severe hypoglycaemia and nocturnal hypoglycaemia did
not diff er between groups. The adverse events in all trials
were predominantly gastrointestinal—ie, nausea,
obstipation, and vomiting—often transient, and most
pronounced when initiating therapy (appendix).

DPP-4 inhibitors
DPP-4 inhibitors lower blood glucose by extending the
half-life of endogenous GLP-1 and glucose-dependent
insulinotropic polypeptide (GIP).57,58 After secretion from
L cells, GLP-1 is degraded by DDP-4 within 2–3 min,59 thus
DPP-4 inhibition increases the concentration of
endogenous secreted GLP-1 by two to three times. In
patients with type 2 diabetes, DPP-4 inhibitors potentiate
glucose-dependent insulin secretion and inhibit glucagon
release without any clinically relevant eff ect on gastric
emptying or bodyweight (fi gure 2).60,61 Patients with type 1
diabetes have inappropriately raised glucagon secretion;2,4
and the addition of a DPP-4 inhibitor to insulin could
improve glycaemic control and reduce insulin demand in
such patients, and enhance insulin secretion in patients
with residual endogenous insulin secretion.
Six trials with sitagliptin or viladagliptin have been done
assessing the eff ects on HbA1c and postprandial glycaemic excursions (table 3). Three
studies,63–65 all placebocontrolled,
assessed HbA1c concentrations after
4–20 weeks’ treatment; the fi ndings showed signifi cant
reductions of –0・27% and –0・34% compared with placebo
in two studies.63,64 In the third study by Garg and
colleagues,65 the changes in HbA1c after 16 weeks’
treatment with sitagliptin or placebo were similar between
groups. Additionally, in individuals with newly diagnosed
type 1 diabetes, 52 weeks of sitagliptin treatment resulted
in a reduction in HbA1c of –2・1% (–23・0 mmol/mol) from
baseline compared with –2・0% (–21・9 mmol/mol) with
insulin alone, which was not signifi cant between groups.49
Findings from two studies62,64 have suggested
suppression of postprandial glucagon with vildagliptin,
but concentrations were unaltered with sitagliptin.65
However, during hypoglycaemia, DPP-4 inhibitors as
add-on to insulin do not compromise counter-regulatory
hormone responses, including glucagon.62,66

SGLT2 inhibitors and dual inhibitors of SGLT1 and SGLT2


SGLT2 mainly causes renal glucose reabsorption and SGLT1 is pivotal in the intestinal
absorption of glucose.22 Thus, inhibition of SGLT1 and SGLT2 results in decreased blood
glucose through a reduction of glucose absorption in the gastrointestinal tract and increased
renal glucose excretion. SGLT1 inhibition also increases postprandial release of the
gastrointestinal hormones GLP-1 and polypeptide YY (PYY), probably by increasing delivery
of glucose to the distal small intestine, thereby regulating glucose and appetite control (figure
3).67,68
Notably, the mechanisms of actions of both groups of drugs are insulin independent. SGLT2
inhibitors are approved by the FDA and European Medicines Agency to treat type 2 diabetes,
and the dual inhibitor of SGLT1 and SGLT2 sotaglifl ozin is under clinical development
(http://www.lexpharma.com/pipeline/lx4211.html).
In a single arm, open-label trial,69 40 patients with long duration of type 1 diabetes were
treated daily for 8 weeks with 25 mg of the SGLT2 inhibitor empagliflozin (table 4).
A minor decrease in HbA1c from 8・0% (64・0 mmol/mol) at baseline to 7・6% (60・0
mmol/mol) and insulin dose from 54・7 to 45・8 units per day, mainly due to basal insulin
reduction, was reported. Moreover, empagliflozin induced a bodyweight reduction from 72
・6 kg at baseline to 70 kg at the end of the study. The incidence of hypoglycaemia fell from
0・12 to 0・04 events per patient per day. The most frequent adverse events with
empagliflozin were thirst (74%), pollakiuria (79%), and headache (31%),69,72 but the overall
frequency of adverse events did not differ between the empagliflozin and placebo groups.
Two patients withdrew from the study because of ketoacidosis. Accordingly, in a short-term
randomised, double-blind, placebo-controlled study70 investigating the efficacy and safety
of 2・5 mg, 10 mg, or 25 mg empagliflozin as add-on to a basal-bolus insulin regimen,
Pieber and colleagues70 showed a significant placebo-adjusted reduction in the range of
mean HbA1c among the three groups, of 0・35% to 0・49%. Total daily insulin dose and
bodyweight decreased significantly (range of mean placebo-adjusted reactions among the
three groups given empagliflozin 0・07–0・09 U/kg and 1・5−1・9 kg), respectively,
compared with placebo. No cases of diabetic ketoacidosis were reported; however,
increases in fasting concentrations of the ketone body β-hydroxybutyrate were noted with
all doses of empagliflozin.70
In a double-blind, placebo-controlled, 2-week, doseranging pilot study73 of dapagliflozin
(n=70), the 24-h daily blood glucose concentration was reduced by 2・3 mmol/L from
baseline with dapagliflozin 10 mg once per day compared with a reduction of 1・13 mmol/L
with placebo. Moreover, glycosuria increased significantly with dapagliflozin compared with
placebo (p=0・007).
The study was underpowered to test for between-group differences in changes of effi cacy
measures; however, a dose-related tendency was noted in the magnitude of effect on fasting
plasma glucose, glycaemic variability, and reductions in total daily insulin requirements.
The largest randomised trial with a SLGT2 inhibitor in type 1 diabetes,71 was an 18-week
study of 100 mg or 300 mg canagliflozin once per day compared with placebo in 351
individuals with type 1 diabetes. Modest placebo-subtracted reductions in HbA1c from
baseline were reported: –0・29% (3・2 mmol/mol) with 100 mg canagliflozin once per day
and –0・25% (2・7 mmol/mol) with 300 mg canagliflozin once per day. Corresponding total
insulin dose was significantly reduced by –2・5 U/day and –6・0 U/day, respectively,
compared with an increase of 1・6 U/day with placebo. Both doses of canagliflozin were
associated with significant weight loss. The overall frequency of adverse events, including
hypoglycaemia, was similar between canagliflozin and placebo groups. Notably, however,
the incidence of diabetic ketoacidosis was increased with both doses of canagliflozin: 4・
3% (n=5/117) and 6% (n=7/117), respectively.71
Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus. Seerup Frandsen, C,
et al. Lancet Diabetes Endocrinol 2016;4: 766–80

Therefore, we assume that T cells can recognize Beta cells and act (i.e. become activated,
engage, or differentiate) accordingly, based upon contact of the T cell receptor (TCR) and
the MHC class I, which is typically located on the surface of Beta cells [6]. Similarly, memory
T cells are produced through differentiation from effector T cell parents. The memory T cells
can acquire effector function upon coming into contact with their cognate antigen.
The migration rate of CD8+ T cells into the pancreas from the pancreatic lymph node (PLN)
was taken as 1.7% per day based on the population dynamics study of islet infiltrating cells
carried out by Magnuson et al. [38]. Furthermore, intravital two-photon imaging studies
conducted on mice demonstrated that the T cells moved autonomously and independently
within the pancreatic tissue, suggesting a random walk behavior rather than collective
migration induced by chemotactic gradients [42, 43]. In the light of these studies, the
movement of CD8+ T cells was modeled as random walk with a persistence time of 1 to 4
minutes and a movement speed of 10 μm/min [43]. The lifespan of naive T cells was chosen
to be 8 weeks [44]. Although there does not seem to be a consensus on the lifespan of
effector CD8+ T cells, most studies on mice and humans suggest a lifespan of 5±8 days [45,
46]. Therefore, the lifespan of effector CD8+ T cells was chosen to be 6 days. In the case of
memory CD8+ T cells, the lifespan was reported to be between 6 months to 1 year in mice
[47] and was set to be 6 months in the simulations. Although the different subsets of T cells
in the simulation have different lifetimes, all T cell types can disappear from the simulation
by moving beyond the boundaries of the simulated tissue, in which case they are assumed
to have migrated to the neighboring tissue sections. Similarly, new T cells can appear near
the boundaries to mimic the incoming migration of T cells from the surrounding tissue
sections. T cell proliferation rules were implemented based on the findings of Kinjyo et al.
[48] (Fig 1). According to this study, naive T cells enter a fast cell cycle upon contact with
cognate antigen (i.e. Beta cells). This event is followed by fast proliferation of the naive T
cells and starting from the 8th generation, the progeny has a 20% probability of
differentiating into a memory T cell. Memory T cells have two subpopulations consisting of
effector memory T cells, which exert rapid effector function, and central memory T cells,
which lack immediate effector function and requires re-stimulation [49]. Since effector
memory T cells display a similar function as the effector T cells, the model considers only
the central memory T cells under the memory T cell designation.

· All T cell types exhibit random walk


· Naive T cells enter the cell cycle shown in Fig 1 upon contact with Beta cells.
· Effector T cells form a conjugate with up to two Beta cells upon contact, and kill with a 55%
probability
· Memory T cells acquire effector function upon contact with its cognate antigen, i.e. Beta
cells
Beta cells trigger activation in naive T cells, and they can be recognized by all subsets of
the T cell population in the simulation. The diameter of Beta cells was set as 10 μm [53] and
a single cell was assumed to occupy a single grid (i.e. 10 μm × 10 μm). Also, insulin secretion
from Beta cells was not considered.
Lately, there have been studies that suggest the presence of a residual pool of Beta cells in
people with long-standing T1D, concomitant with the continual regeneration and subsequent
destruction of Beta cells [31, 54±56]. Although Beta cell regeneration during T1D is still
controversial, modeling is a strong tool to test this hypothesis, and therefore a parameter for
Beta cell regeneration was incorporated into the model. Depending on the value of this
parameter, Beta cells can start to proliferate at a set rate (as specified by the simulated
scenario) upon encountering the autoimmune attack.
The rules for Beta cells can be summarized as follows:
· Proliferate at a set rate under immune attack (if Beta cell proliferation is enabled)
· Recognized by all T cell types and trigger proliferation or differentiation in T cells

Basement membrane
Basement membrane is a key structure around the islets, which serves to prevent cell
migration into the islet. Consequently, its destruction during the onset of the autoimmunity
is a critical event that determines the fate of the islet. Some studies in the literature point
towards reduced or delayed incidence of T1D through inhibition of enzymes such as
heparanese, which degrade heparan sulfate, a key component of the basement membrane
[57, 58]. Based on its role, the basement membranes for individual islets were also
incorporated into the model. The basement membrane is represented by local values
surrounding the islets, initially set to a predetermined value. This value is considered to be
the same on all locations around the islet, initially. Over time, local values are gradually
reduced by effector T cells, leading
to the formation of openings in the basement membrane. Eventually, this allows the invasion
of the islet by all T cell types and typically triggers a wave of proliferation in T cells. The
representation of the basement membrane by an arbitrary and uniform initial value allows
the calibration of the model against clinical data. Furthermore, this arrangement provides
flexibility for simulating scenarios where basement membrane destruction is delayed
through inhibition of degradative enzymes [57, 58]. Lastly, we do not consider the
regeneration of the basement membrane as we assume the autoimmune response to be
severe enough to prevent any regeneration.
Overall, the basement membrane is governed by the following rules:
· Constitute a barrier between all T cell types and the Beta cells
· Represented by local, arbitrary values around the islet, which are decreased by the effector
T cells in the vicinity
· Repair of the membrane was not considered

We developed a model of the interactions between CD8+ T cells and Beta cells, which
allows the observation of temporal variations in the cell populations, as well as the spatial
interactions between individual cells. Beyond mimicking the clinical observation, the agent-
based model has shown promise as a tool for testing various hypotheses in silico, providing
capabilities to save time and resources for the experimental researchers, and facilitate
knowledge discovery.
The model predicted the emergence of a phenomena that is similar to epitope spreading,
which illustrates an important advantage of ABM. Despite no explicit effort to include such a
mechanism in the model, an ABM allows the emergence of certain phenomena that is
analogous to the actual system under investigation. Modification of key model parameters
may lead to the emergence of better outcomes from the in silico simulations, which would
direct clinicians toward the design of the corresponding therapies. In the example of Beta
cell regeneration and epitope spreading, this could indicate interventions involving
immunosuppression along with the control of Beta cell proliferation.

Ozturk MC, Xu Q, Cinar A (2018) Agent- based modeling of the interaction between CD8+
T cells and Beta cells in type 1 diabetes. PLoS ONE 13(1): e0190349.
https://doi.org/10.1371/journal. pone.0190349

Recientemente, el estudio Diabetes Control and Complications Trial / Epidemiology of


Diabetes Interventions and Complications (DCCT / EDIC) demostró que la terapia intensiva
de diabetes en T1D durante la DCCT produjo una reducción del 33% en el riesgo de
mortalidad, versus terapia convencional de diabetes, más de 27 año de seguimiento (14).
Aquí comparamos la mortalidad durante el DCCT / EDIC en toda la cohorte con la de la
población general de los EE. UU. Utilizando las tasas actuales (2013) de mortalidad por
edad, sexo y raza de los EE. UU.
mortalidad relativa como una función del nivel de HbA1c y sexo.
DISEÑO Y MÉTODOS DE INVESTIGACIÓN
Durante 1983-1989, el DCCT inscribió a 1,441 pacientes con DT1 entre las edades de 13 y
39 años que fueron asignados aleatoriamente para recibir terapia intensiva o convencional.
El objetivo principal del DCCT fue evaluar los efectos de la terapia intensiva versus
convencional sobre el inicio de la retinopatía en una cohorte de prevención primaria que
ingresó sin retinopatía y sobre la progresión de la retinopatía en una cohorte de intervención
secundaria que ingresó con una enfermedad preexistente de leve a moderada retinopatía
no proliferativa, cada cohorte comprende: 700 sujetos. La cohorte de prevención primaria
también tenía 1-5 años de duración de la diabetes y 40 mg de albuminuria por 24 h. La
cohorte de intervención secundaria tuvo 1-15 años de duración y 200 mg de albuminuria
por 24 h. En ambas cohortes, la edad media fue de 27 años con el 53% de hombres. Al
inicio del estudio, se excluyeron aquellos con antecedentes de ECV, hipertensión o
hipercolesterolemia.
El grupo de terapia intensiva DCCT se trató con bombas de insulina o al menos tres
inyecciones diarias de insulina durante un promedio de 6,5 años durante los cuales
mantuvieron una HbA1c media de; 7%. Por el contrario, el grupo de terapia convencional
DCCT recibió entonces atención estándar con una media de HbA1c de; 9% durante los 6,5
años. El DCCT finalizó en 1993, momento en el cual todos los pacientes fueron remitidos a
sus proveedores privados de atención médica con la recomendación de que siguieran un
régimen intensivo. A partir de entonces, 1.394 participantes (que representan el 97% de la
cohorte completa) se unieron al estudio observacional EDIC (desde 1994 hasta la
actualidad), con atención permanente de la diabetes prestada por sus proveedores locales.
Durante los 21 años de seguimiento en EDIC, la cohorte mantuvo una HbA1c media de;
8%, con poca diferencia entre el DCCT intensivo versus los grupos de terapia convencional.
Los protocolos DCCT y EDIC fueron aprobados por juntas de revisión institucional en todos
los centros participantes.
Los análisis en este documento se basan en 125 muertes ocurridas hasta el 31 de octubre
de 2014. Las muertes, con documentación si está disponible, se informaron al Centro de
Coordinación de Datos y fueron adjudicadas por un Comité de Revisión de Morbilidad y
Mortalidad dentro del estudio (14). Hubo 1.316 sobrevivientes, 1.241 de los cuales estaban
bajo seguimiento activo, cuyo tiempo de observación fue censurado correctamente al 31 de
octubre de 2014 y 75 de los cuales estaban inactivos, cuyo tiempo de observación fue
censurado correctamente en la última fecha que se sabe que está vivo. Los detalles de la
determinación de los resultados y la verificación del estado vital se describieron
recientemente (14).
Las tablas de mortalidad de la población del 2013 del Centro Nacional de Estadísticas de
Salud presentaron riesgos de mortalidad específicos por sexo y raza en la población general
para cada año de edad (18). El número esperado de muertes en la cohorte DCCT
asumiendo estos riesgos poblacionales generales se calculó utilizando el método indirecto.
Para cada sujeto de un determinado sexo y raza, se aplicó la probabilidad de mortalidad de
la población durante cada año de edad durante el seguimiento DCCT / EDIC. La suma de
estas probabilidades para todos los sujetos es el número de muertes en la cohorte DCCT /
EDIC que se esperaban si se hubieran aplicado los riesgos de población específicos por
edad, sexo y raza. La razón de mortalidad estandarizada (TME) se calculó como la relación
entre el número de muertes observadas y esperadas. Todos los SMR presentados aquí se
calcularon de esta manera. Las tasas de mortalidad por 100,000 años-persona (PY) y 95%
Cis se calcularon a partir de modelos de regresión de Poisson robustos (20). Modelos de
Poisson robustos adicionales que utilizan el método PY (21) evaluaron el efecto de las
covariables, incluido el tiempo dependiente
media de HbA1c actualizada, sobre la tasa de mortalidad relativa (RMR) para DCCT / EDIC
frente a la población general, con términos de compensación que representan la mortalidad
esperada en función de la edad, el sexo y la raza.
El RMR se puede ver como una estimación ajustada por covariables de la proporción de
SMR para dos grupos, o como el aumento en el SMR por aumento de unidad en una
covariable cuantitativa. Los gradientes de riesgo de mortalidad semiparamétricos con
respecto a los valores medios de HbA1c dependientes del tiempo se presentan usando
gráficos de modelos de aditivos de Poisson con splines de suavizado (df = 4) (22). Se
usaron análisis similares para investigar si las tasas de mortalidad específicas por edad y
sexo en esta cohorte de participantes con DT1 difería de la población general.
Todos los análisis se realizaron utilizando el software SAS (versión 9.3, SAS Institute, Cary,
NC) y el paquete R. El P _ {0,05} bilateral fue considerado estadísticamente significativo.
RESULTADOS
Las características de la cohorte DCCT / EDIC utilizadas para estos análisis se describieron
recientemente (14). En resumen, al ingresar, los sujetos tenían una edad media de 27 años
(ahora 55 años) con una duración de diabetes de 6 años (ahora 34 años) y el 48% eran
mujeres. Aquellos que murieron posteriormente eran mayores, tenían una edad mayor al
inicio de la diabetes, y eran más propensos a ser varones, ser fumadores y tener una
presión arterial basal más alta, triglicéridos y niveles de HbA1c (13). Entre 125 muertes
observadas, las principales causas subyacentes fueron CVD (n = 29, 23.2%) y cáncer (n =
25, 20%), seguidas por T1D (n = 14, 11.2%), accidente (n = 11, 8.8% ), suicidio (n = 8,
6,4%), enfermedad renal (n = 7, 5,6%) y otros (25, 20%), más 2 pendientes de adjudicación
y 4 no admisibles. SMRs
En relación con las tasas de mortalidad específicas por edad, sexo y raza para la población
general actual de EE. UU., La mortalidad global en la cohorte DCCT / EDIC no aumentó
significativamente (SMR = 1,09 [IC 95%: 0,92, 1,3]). Sin embargo, la mortalidad relativa en
el grupo de terapia intensiva DCCT (SMR = 0,88) no fue significativamente menor (es decir,
neutral), mientras que en el grupo de terapia convencional DCCT fue significativamente
mayor (SMR = 1,31 [IC 95% 1,05, 1,65]) que en la población general. El RMR que comparó
los SMR en los grupos DCCT convencional versus terapia intensiva también fue significativo
(RMR = 1.49 [IC 95% 1.04, 2.14], P = 0.028). La menor mortalidad relativa en la terapia
intensiva DCCT en comparación con el grupo de terapia convencional es probablemente
debido a los efectos residuales de los niveles diferenciales de HbA1c durante la DCCT,
también conocida como memoria metabólica.

En contraste con los hallazgos suecos, las tasas de mortalidad general en la cohorte DCCT
/ EDIC fueron en gran medida similares a las de la población general. Sin embargo, el
aumento de los niveles de HbA1c se asoció fuertemente con el aumento del riesgo de
mortalidad en relación con la población general de EE. UU., Y esto fue más frecuente entre
las mujeres que entre los hombres. En la cohorte DCCT / EDIC completa, una HbA1c 10%
mayor (p. Ej., 8,8 frente a 8%) se asoció con un riesgo de mortalidad 56% mayor (14).
Esta relación entre la HbA1c y la mortalidad puede representar una confusión con otros
factores o un efecto no adherente saludable por el cual los pacientes con una HbA1c muy
baja en ambos grupos pueden ser menos apegados a otras sugerencias terapéuticas como
nutrición, actividad física, tabaquismo y lípidos y adherencia a la medicación para la presión
arterial

Mortality in Type 1 Diabetes in the DCCT/EDIC Versus the General Population. The
DCCT/EDIC Study Research Group. Diabetes Care 2016;39:1378–1383 | DOI:
10.2337/dc15-2399

Complications Trial (DCCT) (8). The two primary aims of the DCCT consensus protocol were
to determine whether, compared with conventional therapy (CON), an intensive treatment
program designed to achieve glycemic control as close to the nondiabetic range as safely
possible would prevent or delay the appearance of early background retinopathy (primary
prevention) and would prevent the progression of early retinopathy to more advanced forms
of retinopathy (secondary intervention).
After the successful completion of a 1-year feasibility phase, during which a substantial
separation of HbA1c levels between the intensive therapy (INT) (“experimental”) and CON
(“standard”) groups was achieved (9), an additional eight centers were added, and full-scale
recruitment began. Recruitment ended in 1989, and the DCCT was halted by its independent
oversight committee in 1993, approximately 1 year ahead of schedule, owing to the uniform
and conclusive results achieved (10). The original CON group was taught INT, and the entire
cohort was invited to join a long-term observational study named the Epidemiology of
Diabetes Interventions and Complications (EDIC) (11). EDIC is now in its 20th year.
The DCCT and its observational EDIC follow-up were designed to determine whether the
long-term complications that affect people with type 1 diabetes could be ameliorated by
intensive glycemic therapy. The DCCT/EDIC convincingly demonstrated that the glucose
hypothesis was correct and that an intervention that aimed to achieve glycemia as close to
the nondiabetic range as safely possible reduced all of the microvascular and cardiovascular
complications of diabetes. Translating the findings of the DCCT/EDIC into clinical care has
substantially improved the long-term health of people with type 1 diabetes.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and


Complications Study at 30 Years: Overview. David M. Nathan, for the DCCT/EDIC Research
Group. Diabetes Care 2014;37:9–16 | DOI: 10.2337/dc13-2112

The proportion of diabetes mellitus patients diagnosed with T1DM is estimated to be 5%–
10% [1] with an annual increase of 3.8–5.6%.
Recently, an increasing number of studies on the topic of DPP-4 inhibitors and T1DM have
discovered their mutual characteristics of immune destruction. Insulitis was alleviated in a
T1DM animal model treated with DPP-4 inhibitors [10], and the numbers of regulatory T
cells, including CD4+ CD25+ Fox P3+ cells, which were reduced in patients with T1DM [11],
increased [10]. Glucagon levels have been shown to be decreased during hyperglycemia
[12–15] in several clinical trials of T1DM. However, controlled clinical trials have reported
controversial effects on postprandial glycemic control, as well as the levels of glycated
hemoglobin A1c (HbA1c) and other indicators.

β-Cell Function: C-Peptide. The additional effects of DPP- 4 inhibitors on the C-peptide level
remain controversial. One study [18] reported a positive effect and concluded that sitagliptin
at least attenuated the progressive decrease in the C peptide levels. Three studies [8, 19,
20] did not observe a notable effect, and one study [13] did not address this subject. In
conclusion, 120 patients with T1DM included in this systematic review were C-peptide-
positive, and the increase in the fasting C-peptide level, which was measured as an indicator
of β-cell function, could not be confirmed in the group treated with DPP-4 inhibitors.
Therefore, whether patients with a higher baseline C-peptide level, a shorter duration, and
differential insulin usage will benefit more from combination therapy with any DPP-4 inhibitor
remains unknown.

Glycemic Control: HbA1c. As a main outcome indicator, specific data on the HbA1c levels
were available in four RCTs. Individually, three RCTs did not observe a significant
improvement in the HbA1c levels when the patients were treated with sitagliptin [19, 20] or
vildagliptin [13] in addition to insulin therapy.

In clinical studies, DPP-4 inhibitors reduced the prandial insulin dose and its daily dosage
[13, 37], inhibited glucagon secretion [13, 15], and decreased the blood glucose levels in
patients with T1DM (2-hour postprandial and 24-hour AUCs) [37]. However, some clinical
studies did not show any obvious improvement in the blood glucose levels, AUCs of the C-
peptide levels, or HbA1c levels [18, 20]. Therefore, the therapeutic effects of DPP-4
inhibitors on T1DM remain controversial, and a comprehensive conclusion must be drawn
after summarizing the currently available evidence.
Qixian Wang, et al. DPP-4 Inhibitors as Treatments for Type 1 Diabetes Mellitus: A
Systematic Review and Meta-Analysis. Journal of Diabetes Research. Volume 2018, Article
ID 5308582, 10 pages. https://doi.org/10.1155/2018/5308582

In this double-blind, treat-to-target, crossover trial, insulin degludec compared with insulin
glargine U100 resulted in lower rates of overall symptomatic hypoglycemic episodes and
nocturnal symptomatic hypoglycemia in the 16-week maintenance period and a lower
proportion of patients with severe episodes in the 16-week maintenance period. These
findings were consistent when analyzed over the full 32-week treatment period. The
reduction of hypoglycemia in this trial, reflected in both the rates and the proportions of
severe hypoglycemia, were similar in size to those observed in a meta-analysis of patients
with type 1 diabetes comparing long-acting analogs (insulin glargine and detemir) with
neutral protamine Hagedorn (severe hypoglycemia odds ratio, 0.73; 95% CI, 0.60-0.89) and
in a recently conducted randomized trial (severe hypoglycemia odds ratio, 0.51; 95% CI,
0.19-0.84).

Severe hypoglycemia has been associated with an increased risk of subsequent mortality,
morbidity, and cardiovascular events and, for patients with diabetes, is the most serious
adverse effect of insulin therapy, and can result in costly hospitalization. Therefore, reducing
the risk of severe hypoglycemia could represent a clinically important improvement. Less
hypoglycemia was observed in the context of achieving an HbA1c level lower than 7% during
treatment with both insulin degludec and with insulin glargine U100, a target recommended
by the ADA. In addition, several mechanisms were established to confirm the validity of
reported hypoglycemic episodes. The trial was designed as a double-blinded, crossover,
treat-to-target design that supported the objective of capturing all episodes, and all episodes
of severe hypoglycemia were evaluated by an external blinded adjudication committee.

This trial has several limitations. First, intensive patient monitoring occurred in the trial
setting and may have affected the frequency with which hypoglycemia was collected and
reported compared with the actual clinical setting. However, this type of intensive monitoring
may have provided a more accurate representation of hypoglycemia rates in a population
including patients with recurrent hypoglycemia than would be derived from observational
studies or randomized clinical trials from which such patients are typically excluded. Second,
the crossover design has an inherent potential for carryover; however, specifying the primary
and secondary end points during the maintenance period aimed to eliminate the carryover
effect following a 16-week wash-out and titration period. Third, the higher-than-expected
withdrawal rate may have been a result of the demanding nature of the trial, including its 64-
week duration, 2 different treatments, and the use of vial and syringe.

Among patients with type 1 diabetes and at least 1 risk factor for hypoglycemia, treatment
for 32 weeks with insulin degludec compared with insulin glargine U100 resulted in a
reduced rate of overall symptomatic hypoglycemic episodes.

The SWITCH 1 trial was conducted in accordance with the Declaration of Helsinki and
International Conference of Harmonisation Good Clinical Practice.Prior to trial initiation, the
study design, protocol, consent form, and patient information sheet were reviewed and
approved by appropriate health authorities, and an independent ethics committee and
institutional review board at each site (trial protocol in Supplement 1). The review panel,
which operated independently from the investigators and study sponsor, was responsible
for ensuring the protection of the rights, safety, and well-being of trial participants. All
protocol amendments were reviewed and approved as required according to local
regulations, prior to implementation. Informed written consent was obtained from all
participating patients before they entered the trial. This randomized, double-blind, 2-period
crossover, multicenter, treat-to-target clinical trial involved patients with type 1 diabetes and
who had at least 1 hypoglycemia risk factor (eFigure 1 in Supplement 2), across 84 sites in
the United States and 6 sites in Poland between January 2014 and January 12, 2016. The
trial spanned 65 weeks, consisting of treatment with once-daily insulin degludec or insulin
glargine U100, both with insulin aspart 2- to 4-times daily for 2 consecutive 32-week periods
and 1 week of follow-up (eFigure 1 in Supplement 2). Each 32-week treatment period
consisted of a 16-week titration period (to reduce potential carry-over effects and to obtain
stable glycemic control) and a 16-week maintenance period (to compare the difference in
hypoglycemia when glycemic control and dose are stable).

Lane, W., et al. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia
in Patients With Type 1 Diabetes. The SWITCH 1 Randomized Clinical Trial. JAMA.
2017 Jul 4; 318(1): 33-44.

Current approaches for the prediction of type 1 diabetes take advantage of the major genetic
risk factors, genotyping for HLA-DR and HLA-DQ loci (which is then combined with family
history), and screening for autoantibodies directed against islet- cell antigens.43,44 The
individual distribution of specific risk alleles correlates with gradations in disease
penetrance, enabling a tiered staging strategy for the prediction of type 1 diabetes. For
example, children who carry both of the highestrisk HLA haplotypes (DR3–DQ2 and DR4–
DQ8) have a risk of approximately 1 in 20 for a diagnosis of type 1 diabetes by the age of
15 years.45 If the child has a sibling who has diabetes and the same haplotypes, the risk is
even higher (approximately 55%).46 Since this haplotype combination occurs in only 2.3%
of the white population, it is possible to envision universal screening strategies that pinpoint
this highest-risk group. Inclusion of additional moderate HLA risk haplotypes and screening
for autoantibodies would add cost and complexity to a population-screening approach but
have the potential to identify the majority of all children with diabetes before the onset of the
disease.
If this were possible, then tests of potential preventive strategies could be performed, as
outlined later in this article. The large number of new risk loci for type 1 diabetes that were
recently identified from genomewide association studies could be added to these prediction
schemes. These genetic factors are relatively easy, inexpensive, and noninvasive to
measure and can be detected well before other features, such as autoantibodies, would
typically develop.
As true risk variants for type 1 diabetes are fine mapped, identified, and characterized, their
functional use for prediction and prevention should become clearer. Even based on the
current collection of implicated risk loci, it is obvious that multiple distinct biochemical
pathways are involved.
Not all pathways are likely to influence the risk of type 1 diabetes in the same way (Fig. 3).
Some may be associated with an earlier (or a later) age of onset, a slower or faster rate of
loss of beta cells, or a different pattern of epitope spreading in the autoimmune destruction
of islets. Although some variants make small individual contributions to risk, they may cluster
in pathways so that functional assays targeting these processes may have useful predictive
value.
Genetics of Type 1A Diabetes. Concannon, P., et al. N Engl J Med
2009;360:1646-54

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