The new PMC design is here!

Learn more
about navigating our updated article
layout. The PMC legacy view will also be
available for a limited time.

Skip to main content

NIH NLM LogoLog in
Access keysNCBI HomepageMyNCBI
HomepageMain ContentMain Navigation

Logo of aaceccr
AACE Clin Case Rep. 2020 Jan-Feb; 6(1):
e30–e32. Published online 2020 Sep 26.
doi: 10.4158/ACCR-2019-0227
PMCID: PMC7279769PMID: 32984519
A UNIQUE CASE OF ATEZOLIZUMAB-INDUCED
AUTOIMMUNE DIABETES
Mimi Wong, MBBS,corresponding author1,2
Nirjhar Nandi, FRACP,1 and Ashim Sinha,
MD, FRACP, FACE1,3
Author information Article notes
Copyright and License information
Disclaimer
This article has been cited by other
articles in PMC.
Go to:
Abstract
Objective:
Immunotherapy is a novel treatment that
can cause autoimmune diabetes in rare
cases. More cases occur following use of
the inhibitor to the protein programmed
cell death-1 rather than the inhibitor to
programmed cell death-ligand 1.

Methods:
We report a unique case of autoimmune
diabetes following atezolizumab use.

Results:
A 55-year-old, Aboriginal Australian
female with no prior history of diabetes
was commenced on atezolizumab for
recurrent squamous cell lung carcinoma.
Two months following its commencement,
there was the onset of fatigue, polyuria,
polydipsia, and new hyperglycemia.
Subsequently she was found to have a
borderline-low C peptide level of 0.6
nmol/L (reference range is 0.5 to 1.0
nmol/L), and positive zinc transporter-8
antibodies. Following the diagnosis of
autoimmune diabetes, 5 units of glargine
insulin was commenced which maintained
euglycemia and resolved her symptoms of
hyperglycemia.

Conclusion:
There are few case reports of
atezolizumab-induced autoimmune diabetes.
We present the first case associated with
zinc transporter-8 antibodies, and a
unique case of autoimmune diabetes in a
patient of Aboriginal Australian
background.

Go to:
INTRODUCTION
Immunotherapy is a novel way of managing
hematological and solid organ cancers.
Neoplastic cells can express programmed
cell death-ligand 1 (PD-L1), which when
it interacts with programmed cell death-1
(PD-1) on T cells, generates an
inhibitory T cell signal and allows
neoplastic cells to evade immune
recognition. Targeted therapies to PD-1
and PD-L1 have been developed to help
prevent immune escape of neoplastic
cells. Atezolizumab is an immunoglobulin
G1 monoclonal antibody which targets
PD-L1 and can be used to treat non-small
cell lung cancer and urothelial carcinoma
(1,2).

Due to increased immune activity with

immunotherapy, its use is associated with
autoimmunity. Typically auto-immunity
occurs in the first few weeks to months
following commencement of therapy and can
affect any organ system (1). The risk of
autoimmune diabetes mellitus (DM) is
quite low, occurring in only 0.2 to 1.0%
of patients (3–5). Furthermore most cases
of autoimmune DM occur following PD-1
inhibition rather than PD-L1 inhibition
(6). Here we present a unique case of
autoimmune DM following PD-L1 inhibitor
use with atezolizumab.
Go to:
CASE REPORT
A 55-year-old, Aboriginal Australian
female with a background remarkable for
smoking, chronic obstructive lung
disease, and hypertension developed
recurrent squamous cell lung carcinoma.
Prior to the commencement of 1,200 mg
atezolizumab taken every 3 weeks starting
in June of 2018, she had no history of
DM, autoimmune conditions, or thyroid
disease. Hemoglobin A1c prior to the
commencement of atezolizumab was 5.1% (32
mmol/mol), with random blood sugar levels
ranging between 4.8 to 7.9 mmol/L.

After the commencement of atezolizumab

therapy, in August of 2018 she developed
symptoms of fatigue, polyuria,
polydipsia, and new-onset hyperglycemia,
with random blood sugar levels peaking up
to 10.9 mmol/L. Investigations showed a
borderline-low C peptide level of 0.6
nmol/L (reference range is 0.5 to 1.0
nmol/L), zinc transporter-8 (ZnT8)
antibodies were 30 U/mL (reference range
is <15 U/mL), and glutamic acid
decarboxylase (GAD) and islet tyrosine
phosphatase-2 (IA2) antibodies were
undetectable.

Following a diagnosis of autoimmune DM, 5

U daily of glargine insulin were
commenced which maintained fasting blood
sugar levels between 5 to 7 mmol/L and
resolved her hyperglycemia. Although
atezolizumab was thought to have led to
the development of her autoimmune DM,
treatment was initially continued with
close oncology and endocrinology follow
up. However, after receiving 11 cycles of
atezolizumab treatment, she developed
progressive disease and therefore
atezolizumab treatment was ceased.

Go to:
DISCUSSION
We have described a case of autoimmune DM
following atezolizumab use in a patient
with no prior history of DM. Two months
following atezolizumab commencement, the
patient experienced the onset of fatigue,
polyuria, polydipsia, and hyperglycemia.
Her low basal insulin requirement,
borderline-low C peptide level, and
positive ZnT8 antibodies are in keeping
with autoimmune DM.

Based on our literature review of

atezolizumab-induced autoimmune DM, we
found only 5 prior reported cases (Table
1) (4,7–10). Two cases were associated
with GAD antibodies (8,9). Lanzolla et al
(7) reported a case in the setting of
atezolizumab-induced polyglandular
syndrome type 2, though both IA2 and GAD
antibodies were negative. Two other
reports presented cases of diabetic
ketoacidosis following atezolizumab use,
with the absence of antibodies (4,10).
Our case is unique, as it is the first
report of atezolizumab-induced autoimmune
DM with ZnT8 antibodies.
Table 1
Prior Case Reports of Autoimmune Diabetes
Mellitus Following Atezolizumab Use

Year of publication Age in years, sex

Primary diagnosis Presentation
Autoantibodies
Lanzolla et al (7) 2019 60, male
NSCLC Hyperglycemia GAD negative, IA2
negative
Patti et al (4) 2018 70, female
NSCLC Diabetic ketoacidosis GAD
negative
Way et al (8) 2017 Unknown age, male
Urothelial carcinoma Hyperglycemia
GAD positive
Kapke et al (9) 2017 63, female
Urothelial carcinoma Diabetic
ketoacidosis GAD positive
Hickmott et al (10) 2017 57, male
Urothelial carcinoma Hyperglycemia
GAD negative, islet cell antibody
negative
Open in a separate window
Abbreviations: GAD = glutamic acid
decarboxylase; IA2 = islet tyrosine
phosphatase-2; NSCLC = non-small cell
lung carcinoma.

ZnT8 antibody levels (especially the

arginine variant), in contrast to GAD and
IA2 antibodies, are positively associated
with C peptide levels and β-cell function
(11,12), which is consistent with our
case where mild hyperglycemia was
observed. It is possible that prior cases
may have been underrecognized, and
therefore we suggest testing for ZnT8
antibodies if there is clinical suspicion
of autoimmune DM and GAD and IA2
antibodies are negative.

The assessment of ZnT8 antibodies has

been shown to improve sensitivity for
β-cell autoimmunity from 67 to 76% (13),
and has been detected in 60 to 80% of
Caucasian patients with type 1 DM (14).
As ZnT8 antibodies can appear years
before clinical diagnosis of DM, their
measurement can improve accuracy of
disease risk prediction (15,16). There
may also be limited reports of
atezolizumab-induced autoimmune DM due to
the clinical application of atezolizumab,
as it is indicated in patients with
metastatic lung and urothelial cancer
whom have previously trailed chemotherapy
(2,10).

Furthermore, this case is also unique in

that it occurred in an Aboriginal
Australian patient. Wright et al (3)
retrospectively investigated cases of DM
that had been reported following
checkpoint inhibitor use between 2014 to
2018, and they found that 45.2% of cases
were from America, 26.2% from Europe,
25.1% from Asia, and only 3.5% of cases
were from Oceania. Based on our
literature search there appears to be no
prior case of an Aboriginal Australian
developing autoimmune DM from
immunotherapy.

Among Aboriginal Australians, there is a

high prevalence of metabolic syndrome and
type 2 DM. Compared to non-Aboriginal
Australians, autoimmune disease is
infrequent, with the exception of
increased risk for rheumatic fever,
post-streptococcal glomerulonephritis,
and systemic lupus erythematosus (17).
Aboriginal Australians have restricted
and unique polymorphisms of the major
histo-compatibility complex, and it is
unclear if this contributes to their
reduced susceptibility to autoimmune
disease. They also have lower lymphocyte
counts (17), which may contribute to
their lower rates of autoimmune disease.

There is currently a paucity of

literature regarding the underlying
pathophysiology of autoimmune DM
following targeted therapy. Autoreactive
T cells appear to play a role. It is
thought that PD-L1 expression on
pancreatic islet cells is protective
against autoreactive T lymphocytes, and
with immunotherapy this inhibitory signal
is lost (18). Mouse models have confirmed
the importance of the interaction of PD-1
and PD-L1 in pancreatic islet cells, with
PD-1 and PD-L1 blockade precipitating the
onset of DM (19).

Go to:
CONCLUSION
Autoimmune DM is a rare complication of
immunotherapy, and most cases have been
reported following inhibition of PD-1
rather than PD-L1. There are few case
reports following atezolizumab use, and
we report a unique case occurring in an
Aboriginal Australian patient. Assessment
of ZnT8 antibodies may be important for
the diagnosis of autoimmune DM in these
cases.

Go to:
Abbreviations
DM diabetes mellitus
GAD glutamic acid decarboxylase
IA2 islet tyrosine phosphatase-2
PD-1 programmed cell death-1
PD-L1 programmed cell death-ligand 1
ZnT8 zinc transporter-8
Go to:
Footnotes
DISCLOSURE

The authors have no multiplicity of

interest to disclose.

Go to:
REFERENCES
1. Postow MA, Sidlow R, Hellmann MD.
Immune-related adverse events associated
with immune checkpoint blockade. N Engl J
Med. 2018;378:158–168. [PubMed] [Google
Scholar]
2. Blair HA. Atezolizumab: a review in
previously treated advanced non-small
cell lung cancer. Target Oncol.
2018;13:399–407. [PubMed] [Google
Scholar]
3. Wright JJ, Salem JE, Johnson DB et al.
Increased reporting of immune checkpoint
inhibitor-associated diabetes. Diabetes
Care. 2018;41:e150–e151. [PMC free
article] [PubMed] [Google Scholar]
4. Patti R, Malhotra S, Sinha A, Singh P,
Marcelin M, Saxena A.
Atezolizumab-induced new onset diabetes
mellitus with ketoacidosis. Am J Ther.
2018;25:e565–e568. [PubMed] [Google
Scholar]
5. Tsang VHM, McGrath RT, Clifton-Bligh
RJ et al. Checkpoint inhibitor-associated
autoimmune diabetes is distinct from type
1 diabetes. J Clin Endocrinol Metab.
2019;104:5499–5506. [PubMed] [Google
Scholar]
6. González-Rodríguez E, Rodríguez-Abreu
D, Spanish Group for Cancer
Immuno-Biotherapy Immune checkpoint
inhibitors: review and management of
endocrine adverse events. Oncologist.
2016;21:804–816. [PMC free article]
[PubMed] [Google Scholar]
7. Lanzolla G, Coppelli A, Cosottini M,
Del Prato S, Marcocci C, Lupi I. Immune
checkpoint blockade anti-PD-L1 as a
trigger for autoimmune polyendocrine
syndrome. J Endocr Soc. 2019;3:496–503.
[PMC free article] [PubMed] [Google
Scholar]
8. Way J, Drakaki A, Drexler A, Freeby M.
Anti-PD-L1 therapy and the onset of
diabetes mellitus with positive
pancreatic autoantibodies. BMJ Case Rep.
2017:2017. [PMC free article] [PubMed]
[Google Scholar]
9. Kapke J, Shaheen Z, Kilari D, Knudson
P, Wong S. Immune checkpoint
inhibitor-associated type 1 diabetes
mellitus: case series, review of the
literature, and optimal management. Case
Rep Oncol. 2017;10:897–909. [PMC free
article] [PubMed] [Google Scholar]
10. Hickmott L, De La Peña H, Turner H et
al. Anti-PD-L1 atezolizumab-induced
autoimmune diabetes: a case report and
review of the literature. Target Oncol.
2017;12:235–241. [PubMed] [Google
Scholar]
11. Andersen ML, Vaziri-Sani F, Delli A
et al. Association between autoantibodies
to the arginine variant of the zinc
transporter 8 (ZnT8) and stimulated
C-peptide levels in Danish children and
adolescents with newly diagnosed type 1
diabetes. Pediatr Diabetes. 2012;13:454–
462. [PubMed] [Google Scholar]
12. Yi B, Huang G, Zhou ZG. Current and
future clinical applications of zinc
transporter-8 in type 1 diabetes
mellitus. Chin Med J (Engl)
2015;128:2387–2394. [PMC free article]
[PubMed] [Google Scholar]
13. Gomes KF, Semzezem C, Batista R et
al. Importance of zinc transporter 8
autoantibody in the diagnosis of type 1
diabetes in Latin Americans. Sci Rep.
2017;7:207. [PMC free article] [PubMed]
[Google Scholar]
14. Kawasaki E. ZnT8 and type 1 diabetes.
Endocr J. 2012;59:531–537. [PubMed]
[Google Scholar]
15. Barker JM, Barriga KJ, Yu L et al.
Prediction of autoanti-body positivity
and progression to type 1 diabetes:
Diabetes Autoimmunity Study in the Young
(DAISY) J Clin Endocrinol Metab.
2004;89:3896–3902. [PubMed] [Google
Scholar]
16. Zhang L, Eisenbarth GS. Prediction
and prevention of type 1 diabetes
mellitus. J Diabetes. 2011;3:48–57.
[PubMed] [Google Scholar]
17. Roberts-Thomson PJ, Roberts-Thomson
RA, Nikoloutsopoulos T, Gillis D. Immune
dysfunction in Australian Aborigines.
Asian Pac J Allergy Immunol. 2005;23:235–
244. [PubMed] [Google Scholar]
18. Smati S, Buffier P, Bouillet B,
Archambeaud F, Vergès B, Cariou B. Expert
opinion on immunotherapy induced
diabetes. Ann Endocrinol (Paris)
2018;79:545–549. [PubMed] [Google
Scholar]
19. Ansari MJ, Salama AD, Chitnis T et
al. The programmed death-1 (PD-1) pathway
regulates autoimmune diabetes in nonobese
diabetic (NOD) mice. J Exp Med.
2003;198:63–69. [PMC free article]
[PubMed] [Google Scholar]
Articles from AACE Clinical Case Reports
are provided here courtesy of American
Association of Clinical Endocrinology
FOLLOW NCBI
Connect with NLM

National Library of Medicine

8600 Rockville Pike
Bethesda, MD 20894

Web Policies
FOIA
HHS Vulnerability Disclosure

Help
Accessibility
Careers

NLM
NIH
HHS
USA.gov
Feedback