How to cite this article: Borges I, Añez R, Chávez-Castillo M, Salazar J. Late-onset type 1 diabetes mellitus or latent
autoimmune diabetes in adults: a teachable moment. Ciencia e Innovación en Salud. 2020. e93: 351-356 DOI
10.17081/innosa.93
Late-onset type 1 diabetes mellitus or latent autoimmune diabetes in
adults: a teachable moment
Diabetes mellitus tipo 1 de inicio tardío o diabetes autoinmune latente del
adulto: un momento educable
Isabel Borges
1
, Roberto Añez
2
, Mervin Chavez-Castillo
3
y Juan Salazar
3
*
1
Centro Clínico Materno Pediátrico Zulia. Maracaibo, Venezuela
2
Hospital General Universitario Gregorio Marañón. Madrid, España
3
Centro de Investigaciones Endocrino-Metabólicas Dr. Félix Gómez. Universidad de Zulia. Maracaibo, Venezuela
* Dirigir correspondencia a: juanjsv18@hotmail.com
ABSTRACT
Adult-onset autoimmune diabetes (AOAD) is clinical form of diabetes with a wide spectrum of
genotypical and phenotypical manifestations, which has risen in prominence in recent decades,
probably due to greater interest in its pathogenic mechanisms, and increased identification of
autoimmune markers. The clinical presentation may vary from type 1 diabetes mellitus to latent
autoimmune diabetes in adults, which although clearly distinct from a theoretical viewpoint, may
pose various clinical pitfalls in practice. We present the case of a patient with AOAD which
featured several diagnostic challenges during follow-up
Keywords: Diabetes; adults; autoimmunity; diagnosis; insulin therapy.
History Article
Recieved: 09 01 20
Aceppted: 10 09 20
Published: 09 10 20
I. INTRODUCTION
Adult-onset autoimmune diabetes (AOAD) is clinical form of diabetes with
a wide spectrum of genotypical and phenotypical manifestations, which
has risen in prominence in recent decades, probably due to greater
interest in its pathogenic mechanisms, and increased identification of
autoimmune markers. The clinical presentation may vary from type 1
diabetes mellitus (DM1) to latent autoimmune diabetes in adults (LADA).
Although the latter is more frequent according to several reports, they
share various pathophysiological autoimmune components, as well as the
presence of insulitis (1, 2). However, the classification of these disorders
is still controversial and a widely debated topic in the field of endocrinology.
The low prevalence and notable heterogeneity of AOAD in comparison
with type 2 diabetes mellitus (DM2) demands a high degree of clinical
suspicion to achieve early diagnosis and differentiation of the distinct
forms (3). This is particularly relevant in Venezuela, in light of the severe
difficulties for complementary testing and management in our region. We
present the case of a patient with AOAD which featured several diagnostic
challenges during follow-up.
DOI 10.17081/innosa.93
©Copyright2020.
Borges
1
et al.
352
II. CASE REPORT
A 26-year-old woman with family history of DM2 (second degree relative), consults after 5 days of
dysuria with strong-smelling urine, referring generalized weakness, a burning, moderate-intensity
epigastric pain with no apparent triggers or periods of remission, and dyspnea at rest of insidious onset.
On the physical examination, the patient was on bad general conditions, with tachypnea (respiratory
rate: 25 bpm), fever (temperature: 39 °C), tachycardia (heart rate: 105 bpm), blood pressure of 100/65
mmHg, and body mass index of 28.5 Kg/m
2
. The patient had marked dehydration, slight pallor, and
ketotic breath; the cardiopulmonary examination found a Kussmaul breathing pattern, with a normal
vesicular murmur in all lung fields, rhythmic heart sounds without murmurs. The abdomen was
depressible and painful upon deep palpation in the epigastrium and hypogastrium, with 4 bowel sounds
per minute, without signs of peritoneal irritation or visceromegaly. No neurological alterations were
found.
Laboratory testing found White blood cell count 18,800 per mm
3
(neutrophils 86% / lymphocytes 13%),
hemoglobin: 11.9 g/dL, hematocrit: 39%, platelets 319,000 per mm
3
, random blood glucose: 390
mg/dL, urea: 21 mg/dL, creatinine: 1 mg/dL, serum sodium: 129 mmol/L, potassium: 3.4 mmol/L,
chlorine: 92.8 mmol/L, calcium: 9 mg/dL, magnesium: 2.2 mg/dL, pH: 7.18; PCO2: 26.3 mmHg; PO2:
99 mmHg; HCO
3
: 9.8 mmol/L, O
2
saturation: 98%. The urinalysis reported fetid and turbid general
conditions, density: 1030, pH: 5, proteins: +/++++, nitrites: +/++++, ketones: +++/++++, glucose:
+++/++++, bilirubin: absent, epithelial cells: 2-4 per field, leukocytes >30 per field, bacteria: abundant,
pyocytes: 2-4 per field, erythrocytes: 1-2 per field.
The patient was admitted into the intensive care unit (ICU) with the following diagnoses: 1)
Hyperglycemic crisis: Severe diabetic ketoacidosis (DKA), 2) Upper urinary tract infection: Acute
pyelonephritis, 3) DM1. Management was based on parenteral rehydration, electrolytic correction,
insulin therapy, antibiotic therapy, achieving a satisfactory evolution. She was discharged from the ICU
after 3 days, and from the medical center after 7 days. Treatment was adjusted during this time, and
the patient was discharged with insulin glargine only, as she presented frequent symptomatic episodes
of hypoglycemia when using preprandial rapid insulin, with glucose levels of 50-90 mg/dL. A follow-up
consultation was programmed for one week after discharge; however, the patient did not attend.
Approximately 12 months later, the patient returns to the emergency department with a similar history
of 3 days with dysuria and fever, and the generalized weakness with dyspnea at rest of insidious onset.
The patient and her family commented she had not taken any treatment for diabetes since the previous
hospitalization, as she did not agree with the diagnosis.
The clinical assessment found tachypnea (respiratory rate: 28 bpm), fever (temperature: 38 °C),
tachycardia (heart rate: 115 bpm), blood pressure: 105/70 mmHg, body mass index: 27 Kg/m
2
; with
marked dehydration and Kussmaul breathing. The abdominal examination found hypogastric pain
upon deep palpation, without peritoneal irritation. The significant findings in laboratory testing included
white blood cell count: 19.800 per mm
3
(neutrophils: 84% / lymphocytes: 15%), hemoglobin: 12 g/dL,
hematocrit: 40%, platelets 450,000 per mm
3
, random blood glucose: 398 mg/dL, urea: 25 mg/dL,
creatinine: 1.1 mg/dL, serum sodium: 133 mmol/L, potassium: 3.6 mmol/L, chlorine: 94 mmol/L, pH:
353
7.22; PCO
2
: 28.1 mmHg; PO
2
: 97 mmHg; HCO3: 9.1 mmol/L, O
2
saturation: 97%. The urinalysis
reported fetid and turbid general conditions, density: 1025, pH: 5.2, proteins: +/++++, nitrites: +/++++,
ketones: +++/++++, glucose: +++/++++, bilirubin: absent, epithelial cells: absent, leukocytes:
uncountable, bacteria: abundant, pyocites: 4-6 per field, erythrocytes: 1-2 per field.
Therefore, the patient was admitted into the ICU again, with the same diagnoses as before, and a
similar management and evolution. She was discharged with a basal insulin glargine scheme, along
with occasional doses of ultra-rapid insulin (Aspart) for fasting blood glucose levels (FBG) >120 mg/dL;
as its regular use during hospitalization was associated with frequent symptomatic episodes of
hypoglycemia. Again, a follow-up consultation was programmed for one week after discharge.
During follow-up, the patient achieved adequate metabolic control, with FBG levels between 85-115
mg/dL and post-prandial blood glucose levels between 102-151 mg/dL; in spite of performing low levels
of physical activity (<100 METS/min/week) and displaying low adherence to nutritional changes. While
in treatment with 20 UI of insulin glargine, laboratory testing revealed: HbA1c: 6.9%; basal insulin: 8
UI/mL (reference values: 5 – 25), FBG: 105 mg/dL; HOMA-IR: 2.1; C-peptide: 0.66 ng/mL (reference
values 0.70 – 5.2); anti-glutamic acid decarboxylase antibodies (GADAb; ELISA): 16 UI/mL (positive:
>10 UI/mL), anti-insulin antibodies (ELISA): 0,21 UI/mL (positive: >1.1 UI/mL), anti-islet cell antibodies
(ICA; indirect immunofluorescence): negative.
Upon these clinical and laboratory findings, we diagnosed late-onset DM1. Treatment was maintained
with basal insulin glargine and occasional mealtime aspart doses. An interconsultation was also issued
with department of Psychology to improve the psychosocial management, with emphasis on lifestyle
changes and treatment adherence. After 2 years of follow-up, no further acute complications have
occurred, and in recent weeks, the patient has begun to require lower doses of fixed mealtime aspart.
Several clinicians evaluated the case and considered the diagnosis of LADA after the second
hospitalization, which has motivated this report.
III. DISCUSSION AND REVIEW OF LITERATURE
This case depicts the presentation of late-onset DM1, debuting as an acute complication in
association with an infection. Because of difficulties accepting the disease, a similar episode
repeated months later, after which treatment adherence significantly improved. It is important
to note the age of onset (26 years), which is older than the average for DM1 cases debuting
with DKA (18 years) (4). This older age, along with the presence of overweight and various
laboratory findings (low levels of C-peptide and GADAb) led several attending clinicians to
consider the diagnosis of LADA. This is another form of diabetes which, although not
recognized by the World Health Organization and the American Diabetes Association,
represents the most common presentation of AOAD in some regions (1). Although LADA is a
key differential diagnosis in this patient, the initial clinical manifestations render this unlikely.
Here, we present various pathophysiological and clinical aspects which allow differentiation of
these entities within the spectrum of AOAD.
From a molecular standpoint, DM1 develops as a result of an immune-mediated process,
chiefly by autoreactive T lymphocytes, leading to the destruction of insulin-secreting cells in
pancreatic islets (5). This triggers the production of ICA which can be detected in serum and
354
establish the underlying autoimmune characteristic of this disease (6). Although not all of the
related mechanisms, epitopes and triggers of this phenomena have been elucidated; the end
result is a reduction in pancreatic beta cell functionality, with decreased insulin secretion which
positively correlates with plasma C-peptide levels (7). In the case we present, the low levels of
GADAb and C-peptide suggest the presence of a low-grade autoimmune response, typical of
AOAD. However, by itself, it does not allow differentiation between late-onset DM1 and LADA
(Figure 1).
Figure 1. Pathophysiological profile of patients with adult-onset autoinmune diabetes.
Fuente: own source
Because of this low degree of immune reactivity, it has been suggested that in AOAD, debuting
with DKA is infrequent (8). However, in our experience, it is common that DM1 debuts with this
complication, independently of age. In this particular case, the concurrent infections were
important triggers for exacerbating the activity of the counterregulatory hormones, favoring
sudden metabolic decompensation (9). The immediate requirement for insulin in 2 occasions
factors against the diagnosis of LADA, considering the reformulated diagnostic criteria of the
Japan Diabetes Society: 1) Presence of GADAb and/or ICA at some time during the disease
course; 2) Absence of ketosis or ketoacidosis at onset (or diagnosis) of diabetes mellitus and
no need for insulin treatment to correct hyperglycemia immediately after diagnosis (10, 11).
Table 1 shows the main differences between late-onset DM1 and LADA.
Regarding the treatment of our case, the requirement of insulin therapy from the beginning—
which characterizes DM1—is notorious. However, the low insulin requirements after resolution
of the DKA episodes and the long time between episodes without any pharmacotherapy should
also be noted. This demonstrates some degree of pancreatic beta cell functionality, known as
355
the “honeymoon” period or partial remission. The duration of this period is variable, depending
of factors such as the concentrations of autoantibodies, initial levels of C-peptide, and the early
age at symptom onset or development of DKA (12, 13).
Table 1. Differences between late-onset type 1 diabetes and latent autoinmune diabetes in
adults.
Late-onset Type 1 Diabetes
Laten Autoinmune Diabetes
in Adults
Body phenotype
Normal to overweight
Variable
Onset
Acute
Rarely acute
Age at diagnosis
<18 years; rare in adulthood
>30 years
Autoimmunity
Very high
High
Antibodies
2 or more positive
At least 1 positive
Pancreatic β cell functionality
Very decreased
Decreased
C-peptide levels
Low or absent
Low
Insulin requirements
Necessary for life (<3 months)
Not during the first 6 months
after diagnosis
Diabetic ketoacidosis
Present
Rare
Fuente: own source
In conclusion, this clinical case depicts a presentation within the AOAD spectrum, whose initial
manifestations (DKA and immediate insulin requirement) permitted the diagnosis of late-onset
DM1, in the presence of low concentrations of only one autoantibody, minimally detectable C-
peptide levels, and low insulin requirements after resolution of the acute complication. The latter
aspects may prompt some clinicians to contemplate the diagnosis of LADA, especially when
assessing the case only after the acute decompensation has passed, and considering this entity
to be more common than late-onset DM1 in various regions.
Author Contributions: "Conceptualization, I.B. y J.S.; preparation of original draft, I.B; J.S.;
writing: review and editing, R.A. y M. Ch. All authors have read and accepted the published
version of the manuscript”.
Conflict of interest: The authors declare that they have no conflicts of interest.
356
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