(2021) 15:479
Singbo et al. J Med Case Reports
https://doi.org/10.1186/s13256-021-03047-2
Open Access
CASE REPORT
Challenge of coexisting type 2 diabetes
mellitus and insulinoma: a case report
Joseph Singbo1, Michael Locketz2 and Ian Louis Ross1*
Abstract
Background: Insulinomas are rare clinical entities, but concurrent diabetes mellitus is even more uncommon, and
the combination is easily missed. Recurrent hypoglycemia could be misconstrued as improved glycemic control. We
present an unusual patient with type 2 diabetes and neuroglycopenia, with apparent improved glycemic control due
to an insulinoma.
Case presentation: A 54-year-old mixed ancestry man with a positive family history of type 2 diabetes mellitus was
diagnosed with type 2 diabetes mellitus and hypertension 8 years prior to admission. He presented with episodes of
abnormal behavior and hypoglycemia. Inappropriately high insulin and C-peptide concentrations were identified at
the time of hypoglycemia. Despite poor adherence to his diabetic treatment, he had no target organ damage relating
to diabetes, and his hemoglobin A1c (HbA1c) was 5.3%. A diagnosis of insulinoma was made, and he was started on
diazoxide, with endoscopic ultrasound revealing a possible lesion in the pancreatic tail measuring 12 mm × 12 mm.
A fine-needle aspiration biopsy could not be performed due to overlying splenic arteries and the risk of vascular
perforation. An intraoperative ultrasound confirmed a 15 mm × 10 mm tumor in the pancreatic tail, necessitating a
partial pancreatectomy and splenectomy, which were curative. A well-differentiated intermediate grade 2 pancreatic
neuroendocrine tumor producing insulin was confirmed on histopathology.
Conclusions: Recurrent, progressive hypoglycemia and improved glycemic control in a diabetic, without an alternative explanation, may suggest an insulinoma. Insulinomas that exist with type 1 diabetes mellitus, particularly
malignant insulinomas, must have escaped autoimmune attack through lack of autoantigen expression. Computed
tomography on its own may be insufficiently sensitive for diagnosis of insulinomas, whereas endoscopic and intraoperative ultrasonography may improve the identification of the culprit lesion.
Keywords: Recurrent hypoglycemia, Diabetes mellitus, Insulinoma, Endoscopic ultrasound
Background
Hypoglycemia accounts for significantly increased mortality rates in diabetes. The coexistence of insulinoma and
diabetes is so rare that there are only a few published case
reports. In addition, there has been a case of insulinoma
in which, despite stopping sulfonylureas, hypoglycemic
*Correspondence: ian.ross@uct.ac.za
1
Department of Medicine J47 Old Main Building Division
of Endocrinology and Diabetes, Groote Schuur Hospital, University
of Cape Town, Observatory, Cape Town 7945, South Africa
Full list of author information is available at the end of the article
episodes persisted [1]. We report a rare case of insulinoma in a 54-year-old man with pre-existing type 2 diabetes mellitus and a significant family history of diabetes.
Despite poor adherence to therapy, he had unexplained
well-controlled diabetes, hemoglobin A1c ( HbA1c) of
5.3 %, and recurrent hypoglycemic episodes, predominantly in the fasting state. As the diagnosis remains
challenging, especially among diabetics, insulinoma is
frequently diagnosed postmortem, due to the apparent
optimal glucose control [2]. When hypoglycemic unawareness is present, it may be life-threatening, since it
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Singbo et al. J Med Case Reports
(2021) 15:479
can induce irreversible brain damage, subsequent cardiac
arrhythmias, and death.
Hypoglycemia is common, with potentially fatal consequences. The estimated rate of severe hypoglycemia
events (needing emergency services) per patient per year
ranges from 0.90 to 1.50 in patients with type 1 diabetes,
but much lower in type 2 diabetes (from 0.30 to 0.63 per
year) [3], where it is associated with an advanced clinical
course and endogenous insulin deficiency. Hypoglycemia
is associated with poorer quality of life and has significant financial implications. Complications of diabetes,
malabsorption, associated endocrinopathies (for example, primary hypoadrenalism), factitious use of insulin,
and psychological factors can predispose to hypoglycemia. The treating physician should always consider overly
tight glycemic control, renal insufficiency, and pregnancy, and that previous hypoglycemia begets a future of
hypoglycemia.
Case presentation
A 54-year-old married mixed ancestry man and father
of four children, working in the construction industry,
was diagnosed simultaneously with type 2 diabetes mellitus and hypertension 8 years prior to admission. He also
had a significant family history of type 2 diabetes mellitus, with his father and two of his brothers affected, all
of whom are deceased, having suffered complications of
ischemic cardiac failure and renal failure, respectively.
However, none of the siblings had a history of admission for recurrent hypoglycemia. The father of the index
subject died at 70 years of age, having had ischemic cardiomyopathy, which necessitated coronary artery bypass
graft surgery prior to this event, whereas his two brothers
died from diabetic nephropathy at age 48 and 50 years. In
addition, there was no family history suggestive of pituitary disease or hyperparathyroidism. Between 2010 and
2017, our patient presented several times to his primary
care physician with blood glucose measurements greater
than 26 mmol/L. At each of these visits, he received
short-acting human insulin and intravenous fluid. His
final presentation to the primary health care facility with
hyperglycemia occurred 12 months prior to admission.
His current presentation on June 27, 2018, involved
a referral to his secondary care hospital, having been
asymptomatic for a year, with no episodes of hyperglycemia except for weight gain of 14 kg in the preceding
3 months. According to his family, he suffered from confusion and sleepwalking, particularly in the early hours of
the morning between 03:00 and 08:00. These symptoms
occurred almost every day, associated with generalized
body weakness and sweating, which were noticeable after
each episode. His family reported physical and verbal
aggression and confusion. During additional episodes in
Page 2 of 7
hospital, he was noted to be combative with the nursing staff and fellow patients and was found to be hypoglycemic on several occasions. Our patient appeared to
develop symptoms indicative of hypoglycemic unawareness, as he manifested with no sympathetic symptoms,
despite glucose concentrations below 1.8 mmol/L (3.8–
5.5 mmol/L). During this admission, he exhibited recurrent episodes of fasting and post-prandial hypoglycemia,
which measured between 1.2 and 3.0 mmol/L.
The possibility of nonconvulsive seizures was entertained; thus a computed tomography (CT) brain scan
was ordered and found to be normal, whereas an electroencephalogram was not available at the secondary care
facility. He was transferred to a tertiary hospital for evaluation by the endocrine service.
At admission, his chronic medications were metformin,
enalapril, hydrochlorothiazide, and simvastatin. Aside
from metformin, he was not taking any oral hypoglycemic agent or insulin and denied using any other agents.
Pharmacy records failed to identify that he had received
either a sulfonylurea or insulin. The two-hourly ward
glucose measurements showed recurrent hypoglycemic episodes ranging from 1.2 to 3.4 mmol/L, occurring
between 03:00 and 08:00.
Clinical examination failed to identify insulin injection
sites or evidence of target organ damage relating to diabetes, hypertension, or any other chronic disease. In particular, he had no indication of melanoderma.
Investigations
In view of the fasting hypoglycemia, the results of the
investigations are shown in Table 1. In summary, the biochemical tests showed episodes of hypoglycemia with
inappropriately high insulin and C-peptide levels, suggesting that the cause may be endogenous insulin secretion. The sulfonylurea screening was negative.
His HbA1c was 5.3%; the renal and hepatic function,
serum calcium and phosphate levels, serum cortisol level
(8:00 am), parathyroid hormone (PTH), pituitary function tests, and metanephrines were normal. His cortisol rose from 109 to 556 nmol/l within 30 minutes of
a 250-microgram Synacthen® test, excluding primary
hypoadrenalism. The serum potassium and sodium were
3.2 and 138 mmol/L, respectively Insulin-like growth
factor 1 (IGF-1) was 215.1 mU/L (55–248 mU/L). Liquid chromatography–tandem mass spectrometry of
plasma and urine were negative for the following sulfonylureas: glimepiride, gliclazide, glyburide, glipizide, and
gliquidone.
Given the prior history of type 2 diabetes, recent onset
of symptomatic fasting hypoglycemia, and the inappropriately elevated serum insulin and C-peptide concentrations, a diagnosis of insulinoma was considered.
Singbo et al. J Med Case Reports
(2021) 15:479
Page 3 of 7
Table 1 Results of appropriate investigations directed at determining the cause of hypoglycemia
Plasma glucose (4–7
mmol/L)
C-peptide (1.1–2.4 ug/L) Insulin levels (2.6–24.9
mIU/L)
Sulfonylurea screening
Ketones
27/06/18
–
8.6
–
Rejected
–
28/06/18
2.6
5.5
40.7
Rejected
–
30/06/18
1.3
–
20.3
–
–
07/04/18
–
3.6
14.3
–
–
07/09/18
2.3
–
–
–
Negative
07/10/18
2.4
3.6
14.8
–
–
A CT scan of the abdomen revealed a lesion measuring
12 mm × 10 mm in the tail of the pancreas (see Fig. 1A).
Magnetic resonance cholangiopancreatography (MRCP)
revealed a lesion measuring 10 mm × 12 mm which
suggested an accessory spleen in the pancreatic tail (see
Fig. 1B).
In view of the discordant reports on abdominal CT and
MRCP, an endoscopic ultrasound was performed, which
suggested a 12 mm × 12 mm lesion in the pancreatic tail
(see Fig. 2A). A fine-needle aspiration biopsy was not
performed due to overlying splenic arteries and the risk
of vascular perforation (see Fig. 2B).
In view of the increasing number of hypoglycemic episodes and unawareness, diazoxide 75 mg was
initiated and titrated up to 100 mg every 8 hours.
An intraoperative ultrasound confirmed a 15 mm ×
10 mm tumor in the pancreatic tail, necessitating a
partial pancreatectomy and splenectomy (see Fig. 3).
The histopathologic findings were in keeping with a
well-differentiated pancreatic neuroendocrine tumour,
grade 2, producing insulin (see Fig. 4). The well-circumscribed, 12-mm-diameter tumor was composed of
nests and ribbons of cuboidal epithelial cells with small
round central nuclei, speckled chromatin, and moderate amounts of granular eosinophilic cytoplasm, in a
fibrous stromal background. There was no necrosis. The
tumor was confined to the pancreas, with no lymphovascular or perineural invasion seen. There were zero
mitotic figures per 10 high power fields, but the Ki67
proliferation index was 3%, corresponding to grade 2 of
the World Health Organization (WHO) 2017 classification. Immunohistochemistry showed strong positive
staining for synaptophysin, and weak positive staining
for chromogranin A and insulin.
Postoperatively, our patient exhibited no further hypoglycemic episodes, and fasting and random blood glucose
concentrations on metformin varied between 6.0 and
8.0 mmol/L. A pneumococcal vaccine was administered
as prophylaxis for overwhelming postoperative streptococcal infection (OPSI).
Fig. 1 Contrast-enhanced computed tomography (CT) of the abdomen and magnetic resonance cholangiopancreatography (MRCP) of our
patient. A CT of the abdomen showing a 12 × 10 mm mass lesion of the tail of the pancreas. B MRCP showing 10 × 12 mm mass in the pancreatic
tail in keeping with an accessory spleen (arrow is indicating the lesion)
Singbo et al. J Med Case Reports
(2021) 15:479
Page 4 of 7
Fig. 2 A Endoscopic ultrasound of our patient showing a 12 × 12 mm mass lesion of the pancreatic tail; B endoscopic ultrasound showing a mass
lesion of the pancreatic tail with overlying splenic arteries (risk of perforation on fine-needle biopsy)
Fig. 3 Intraoperative ultrasonography, searching for the tumor in our
patient. (Dr. Sean Burmiester). Histopathological diagnosis.
Discussion
We present our patient with type 2 diabetes mellitus,
significant family history of type 2 diabetes, and recent
onset of recurrent symptomatic hypoglycemia due to
an insulinoma. The insulinoma most certainly modified
his diabetic control, such that he did not need either
oral hypoglycemic agents or insulin.
The association between diabetes and insulinoma
is rare. In a retrospective study from the Mayo Clinic
comprising 313 cases of confirmed insulinoma between
1927 and 1992, there was only one patient with preexisting diabetes [4]. A Japanese review of 443 cases of
insulinoma between 1976 and 1990 identified only one
patient who had concurrent diabetes and insulinoma
[5]. In a review from Taiwan of 23 cases of insulinoma
spanning 22 years, only one patient had type 2 diabetes [5]. There are a few case reports of insulinoma in
patients with type 1 diabetes. Insulinoma may mask
the existence of type 1 diabetes or cause recurrent
hypoglycemia and decreased insulin requirement in a
type 1 diabetic patient [6, 7].
In 1962, a report suggested an association between
insulinoma and a family history of diabetes [7], and about
30% of patients with insulinoma had a family history of
diabetes in a series of the Mayo Clinic [8]. A possible
explanation for a positive family history of diabetes may
be insulin resistance and, consequently, exuberant elaboration of insulin. The increase in insulin secretion can
theoretically result in hyperplasia of islet of Langerhans
cells, which maintains a relative normoglycemic state.
However, it is conceivable that without appropriate control mechanisms and a degree of autonomy, an insulinsecreting beta cell tumor could develop [9].
An insulinoma may also mask diabetes. In some case
reports of insulinoma with concurrent diabetes mellitus, the diabetes was only diagnosed after the tumor was
resected [5, 9]. There are also case reports where insulinomas were only diagnosed on postmortem examination of diabetes patients [3]. Overall, the coexistence of
diabetes mellitus and insulinoma is rare, and there are no
reported cases in South Africa. We recommend examining patients for primary or secondary hypoadrenalism,
IGF-1, C-peptide, ketones, sulfonylurea concentrations,
and in some instances insulin in cases of unprovoked
hypoglycemia in a diabetic.
The occurrence of persistent hyperglycemia following
surgical removal of the insulinoma suggests underlying
diabetes, bearing in mind the possibility of damage to
the pancreas during the surgical procedure and giving
rise to diabetes, rather than a prior diagnosis of diabetes.
In cases of coexistent type 1 diabetes mellitus, the blood
tests reveal low levels of serum C-peptide and high titers
Singbo et al. J Med Case Reports
(2021) 15:479
Page 5 of 7
Fig. 4 Histology of tail of pancreas excision showing a well-differentiated neuroendocrine tumor (NET) grade 2. A Hematoxylin and eosin
stain, low-power magnification; B hematoxylin and eosin stain, high-power magnification; C immunohistochemical stain for synaptophysin,
medium-power magnification; D immunohistochemical stain for chromogranin, medium-power magnification; E immunohistochemical stain for
Ki67, medium-power magnification; F immunohistochemical stain for insulin, medium-power magnification
Singbo et al. J Med Case Reports
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of anti-glutamic acid decarboxylase antibody; histological examination of the resected specimen may reveal
insulitis in non-tumorous pancreatic tissue in which beta
cells had already disappeared [6]. In addition, there was
infiltration of the insulinoma by inflammatory cells, as if
it were insulitis of type 1 diabetes, suggesting the existence of anti-islet autoimmunity [6]. The absence of both
proven autoimmunity and inflammatory infiltration
together with adequate glycemic control on oral hypoglycemic agents suggests type 2 diabetes mellitus. A prolonged supervised fast is a gold standard test to evoke
hypoglycemic episodes and is also useful in patients with
diabetes mellitus [10]. This was not performed in our
patient, as he manifested with unprovoked hypoglycemia. Considering their relative accuracy, continuous glucose monitoring devices may replace the prolonged fast
in the near future. As expected in benign insulinoma,
we did not encounter local tumor effects (local, regional
organ or vascular compression), as these are described
very rarely.
The majority of insulinomas are benign, whereas
between 5 and 12% are malignant [9]. Only 22 cases have
been published demonstrating the association between
malignant insulinoma and diabetes [11]. There is no difference in the pattern of recurrence of hypoglycemia at
presentation of patients with benign versus malignant
insulinoma. However, we expect hypoglycemia to be
more frequent and severe in the presence of malignant
insulinoma depending on the size of the tumor and presence of metastases. A case report demonstrated paradoxical weight gain in a subject who had both type 2 diabetes
mellitus and malignant insulinoma, and the explanation
for the weight gain lies in recurrent eating to avoid hypoglycemia [10]. Distinction between malignant and benign
tumors can only be made by the presence of metastasis,
as there are no specific morphologic, biochemical, or
genetic features distinguishing them. Histologically, insulinomas are epithelial neoplasms associated with strong
and diffuse immunohistochemical expression of neuroendocrine markers such as synaptophysin and chromogranin. Most patients with malignant insulinoma have
lymph node or liver metastases and, rarely, bone involvement [10].
It has been proposed that the insulin-producing cells
in a malignant insulinoma and type 1 diabetes suggest
that the insulin-producing malignant cells must have
escaped autoimmune attack that otherwise had completely destroyed the beta cells of the patient [6]. No
evidence of an inflammatory response in the resected
tumor or normal pancreatic tissue could be identified
[6]. It is speculated that a lack of auto-antigen expression in the insulinoma cells or their ability to escape
Page 6 of 7
immune surveillance in other ways accounts for an
absence of inflammatory response, particularly in coexisting type 1 diabetes mellitus.
In our case and most of the available case reports
of associated insulinoma and diabetes, hypoglycemia
was successfully treated on diazoxide, and the surgical
resection of the tumor was curative [9]. In instances
where malignant insulinomas did not respond to surgical resection, alternative therapies such as peptide
receptor radionuclide therapy (PRRT), after failure
of everolimus and chemotherapy (streptozocin and
capecitabine), have been used to achieve remission. On
the other hand, there are reported cases of malignant
insulinoma refractory to diazoxide and long-acting
somatostatin analog using lanreotide [12]. By contrast,
pasireotide, a multi-receptor-targeted somatostatin
analog, exhibits a strong inhibitory effect of insulin
secretion, and this has been documented to be effective
in medical management of insulinoma [12].
Malignant insulinomas confer a truncated life expectancy after diagnosis, and substantially shorter if there
are metastases. The major sites of metastasis or recurrence are the liver and regional lymph nodes [10]. The
coexistence of diabetes mellitus and malignant insulinoma may result in a delay in diagnosis, but there is
no evidence to suggest that it worsens the prognosis.
Conclusions
We report an unusual association of type 2 diabetes
mellitus and insulinoma. The apparent improvement
in glycemic control and development of hypoglycemia,
despite not using any hypoglycemic therapy, indicated
a sinister underlying cause. Insulinomas are rare, especially among patients with type 2 diabetes mellitus, and
there is a heavy reliance on CT scans of the abdomen
to aid in diagnosis. It is acknowledged that intraoperative ultrasound may not always be available and may
be impractical for smaller lesions. In cases when these
lesions are suspected, they should be referred to a tertiary center for evaluation. Successful resection of the
benign insulinoma eliminated further hypoglycemic
episodes and was curative, whereas malignant insulinomas confer a poor prognosis.
Acknowledgements
Dr. Chris Greyling and Professor Raubenheimer, who co-managed the patient.
Authors’ contributions
JS conceived the case report, initiated the writing, and managed the patient
clinically. ML assisted with the histology and wrote the histological description. ILR supervised the clinical management and supervised the writing of
the case report. All authors read and approved the final manuscript.
Funding
We have received no funding to support this case report.
Singbo et al. J Med Case Reports
(2021) 15:479
Availability of data and materials
The authors grant permission for the use and dissemination of all enclosed
data and material. The case report contains data pertaining to the patient’s
management, but we do not have any data sets other than the repository
housed by the Chemical Pathology Laboratory (National Health Laboratory
Services Observatory Cape Town), which performed routine analyses. Hard
copies and transcripts of the laboratory results can be forwarded to the
Journal if necessary.
Page 7 of 7
2.
3.
4.
5.
Declarations
6.
Ethics approval and consent to participate
The Faculty of Health Sciences Research and Ethics Committee at the University of Cape Town waives ethics submissions for case reports.
7.
Consent for publication
Written informed consent was obtained from the patient for publication of
this case report and any accompanying images. A copy of the written consent
is available for review by the Editor-in-Chief of this journal.
Competing interests
All the authors have no competing interests, whatsoever.
Author details
1
Department of Medicine J47 Old Main Building Division of Endocrinology
and Diabetes, Groote Schuur Hospital, University of Cape Town, Observatory,
Cape Town 7945, South Africa. 2 Department of Histopathology, Groote Schuur
Hospital, University of Cape Town, Anzio Road, Observatory, Cape Town, South
Africa.
Received: 13 May 2020 Accepted: 5 August 2021
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