Keywords
Clopidogrel - hyperinsulinemic hypoglycemia - insulin autoimmune syndrome - severe
hypoglycemia - type 2 diabetes mellitus
Introduction
Hyperinsulinemic hypoglycemia in patients with diabetes, and no history of bariatric
surgery, is likely related to treatment, insulinoma, extrapancreatic tumors, and autoimmune
hypoglycemia.[[1]],[[2]],[[3]] We report an interesting patient with hypoglycemia in a diet-treated type 2 diabetes
(T2D).
Case Report
A 67-year-old Emirati woman with diet-controlled T2D, hypertension, hyperlipidemia,
gastroesophageal reflux disease, idiopathic hypercalciuria, and kidney stones developed
episodes of recurrent symptomatic hypoglycemia mainly 2–4 h after meals, in addition
to few incidents of fasting hypoglycemia. Baseline laboratory assessment confirmed
normal thyroid, renal, and liver function tests with glycated hemoglobin of 6.1% (43.2
mmol/mol).
During 60 h of supervised fast, the patient's blood glucose failed to drop below 4.8
mmol/L (88 mg/dl). However, 4 h after a mixed meal, she developed symptomatic hypoglycemia
with serum glucose of 2.7 mmol/L (48 mg/dL) [[Figure 1]]. Insulin level was 2000 uU/mL (2.6 − 24.9 uIU/mL), and C-peptide levels 1.7 ng/mL
(0–1.2 nmol/L). Additional testing confirmed no intake of insulin secretagogues and
negative ketones.
Figure 1: Blood glucose changes during prolonged fasting and after a mixed meal
Repeated testing 2 h after breakfast on the following day demonstrated a blood glucose
level of 196 mg/dl. Total and free insulin measured by chemiluminescent immunometric
assay at LabCorp, USA, were 2976 uIU/mL and 57 mIU/mL, respectively (normal total
insulin for fasting adults is 0–17 uU/ml, and normal 2-h total insulin after the meal
is 16–166 uIU/mL); C-peptide level was 3.61 nmol/L (<1.2). Proinsulin level was 77.3
pmol/L (0–10) and anti-insulin antibody titer was >625uU/mL (normal <5) [[Figure 2]].
Figure 2: Temporal changes in insulin, insulin antibodies, and C-peptide levels
The patient's medications included: indapamide SRFNx011.5 mg daily, losartan 50 mg
daily, and atorvastatin 20 mg daily, in addition to clopidogrel that was started 7
days before the incidence of hypoglycemia. The patient was not exposed to insulin
or insulin secretagogues previously.
Clopidogrel was switched to aspirin, and the patient was treated with acarbose, an
alpha-glucosidase inhibitor, to slow the absorption of carbohydrates and minimize
postprandial glucose spikes, in addition to prednisone 40 mg daily. The patient reported
a rapid resolution of her hypoglycemia within 2 days [[Figure 2]].
Monitoring total insulin level, free insulin and anti-insulin antibody titers revealed
a steady decline over the next few months [[Figure 2]]. Glucocorticoid dose was tapered off over 7 months. Two months after discontinuing
prednisone, the patient did not have any further hypoglycemic episodes. Total insulin
and insulin antibody levels remained in the normal range.
Discussion
To our knowledge, this is the first case report of insulin autoimmune syndrome (IAS),
also known as Hirata disease, causing hypoglycemia in an Emirati patient following
clopidogrel exposure.
In our patient, Whipple's triad of symptomatic hypoglycemia and resolution following
glucose/food intake were documented before the initiation of medical evaluation.[[2]],[[3]],[[4]] The occurrence of fasting and postprandial hypoglycemia was confirmed by continuous
glucose monitoring. The diagnosis of hyperinsulinemic hypoglycemia was confirmed by
simultaneous low blood glucose, elevated insulin, proinsulin, and C-peptide levels.
The mismatch between the insulin and C-peptide pointed to the likelihood of the existence
of insulin antibodies. The finding of high insulin antibodies clinched the diagnosis
of IAS.
Although patients with IAS typically experience symptoms of mild and transient hypoglycemia
a few weeks after exposure to medications containing a sulfhydryl group,[[5]] our patient had recurrent severe incapacitating hypoglycemic attacks after her
sixth dose of clopidogrel.
There have been few case reports of IAS during clopidogrel therapy.[[5]],[[6]],[[7]],[[8]] The proposed explanation for hypoglycemia is that the clopidogrel sulfhydryl group
interacts with the insulin molecule's disulfide bond, rendering it immunogenic. Consequently,
insulin autoimmune antibodies (IAAs) produced circulate in the blood.[[9]] Another Interesting case was reported recently in this journal. Spontaneous hypoglycemia
after starting carbimazole due to insulin autoimmune syndrome, characterized by high
levels of insulinemia and circulating autoantibodies to insulin without prior insulin
administration was described from Saudi Arabia.[[10]]
During fasting, IAAs are not fully occupied, and free insulin concentrations are low.
Insulin secreted after meals typically binds to the available IAAs and is metabolically
ineffective, leading to postprandial hyperglycemia. Insulin will, however, be released
from the IAA-insulin complexes when all sites are occupied, causing hypoglycemia.[[11]] An alternative mechanism for hypoglycemia is developing antibodies to the insulin
antibody resulting in the direct activation of insulin receptors.[[12]]
Management of IAS requires discontinuation of the offending agent, a low-carbohydrate
diet, and often the use of glucocorticoids. Acarbose, an α-glucosidase inhibitor,
was used to treat reactive hypoglycemia but was minimally effective. In our patient,
treatment with glucocorticoids was indicated because of severe hypoglycemia. Prednisone
was quite effective in controlling glycemic levels and in reducing IAA titers.
Conclusions
This is the first case report of IAS in an Emirati patient caused by the use of clopidogrel.
IAS should be considered in the differential diagnosis of patients with hyperinsulinemic
hypoglycemia. Clinical suspicion of IAS in affected patients can prevent costly imaging
and unnecessary surgery.
Declaration of patient's consent
The authors certify that they have obtained the appropriate patient consent. The patient
has given the consent for images and other clinical information to be reported in
the journal. The patient understands that no names and initials will be published
and all due efforts will be made to conceal his identity, but anonymity cannot be
guaranteed.
Authors' Contribution
All authors were involved in the care of the reported case and the drafting and revising
of the manuscript. They all approved the final version of the manuscript.
Compliance with ethical principles
No prior ethical approval is required at our institution for single case reports and
small case series. However, the patient provided consent for anonymous reporting.
Data availability
Not available
