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
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.
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
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
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.
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.
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.
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
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.
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
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.
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
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 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