Natural History of a Proinsulin-Secreting Insulinoma: From Symptomatic Hypoglycemia to Clinical Diabetes
Elif Arioglu,
Nicole A. Gottlieb,
Christian A. Koch,
John L. Doppman,
Neil J. Grey and
Phillip Gorden
Diabetes Branch, Division of Intramural Research, National
Institute of Diabetes and Digestive and Kidney Diseases (E.A., N.A.G.,
P.G.), National Institute of Child Health and Human Development
(C.A.K.), Diagnostic Radiology Department (J.L.D.), Clinical Center,
National Institutes of Health, Bethesda, Maryland 20892; and Medical
Director of Diabetes Life Care, School of Medicine, University of
Connecticut (N.J.G.), Hartford, Connecticut 06105
Address correspondence and requests for reprints to: Phillip Gorden, M.D., National Institutes of Health, NIDDK Director, Building 10, Room 8S235, Bethesda, Maryland 20892. E-mail: phillip_gorden{at}nih.gov
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Introduction
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Insulinoma, an islet cell tumor of the pancreas,
is clinically characterized by symptomatic hypoglycemia, an
inappropriately increased plasma insulin level, and an increased
proinsulin concentration. Current imaging and surgical techniques
usually permit localization and resection of these mostly benign islet
cell tumors with resolution of hypoglycemic symptoms.
The association of diabetes mellitus and insulinoma is extremely rare.
It has been reported in diabetic patients whose hypoglycemic symptoms
or high circulating insulin levels were ultimately explained by the
discovery of an insulinoma (1, 2, 3, 4). Here, we describe a
patient with a most unusual 24-yr history of a benign
proinsulin-secreting insulinoma that initially caused classical
hypoglycemic symptoms and then changed over time to the development of
clinical diabetes.
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Case Report
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In 1976, a 47-yr-old white man without a prior history of
endocrinopathy presented to the Clinical Center of the NIH for
evaluation of a presumed insulinoma. He had no family history of
endocrinopathy or diabetes. Eighteen months previously the patient had
experienced an episode of hunger, diaphoresis, nervousness, and
palpitations during a religious fast. These symptoms became more
frequent over time and were typically relieved with food. Insulinoma
was suspected on the basis of fasting hypoglycemia and inappropriately
high insulin levels. In 1975, the patient underwent an exploratory
laparotomy. However, the tumor could not be found, and a distal
pancreatectomy and splenectomy were performed. Postoperatively,
hyperinsulinemia and symptomatic hypoglycemia persisted. The patient
was subsequently referred to the NIH.
On presentation to the NIH in 1976, his physical examination was
unremarkable. An overnight fasting plasma glucose was 4.3 mmol/L
(4.26.1 mmol/L), and insulin was 754 pmol/L (normal, 29172 pmol/L).
The insulin levels were measured with RIA, and the total immunoreactive
insulin comprised of both insulin and proinsulin-like activity
(5). The specific proinsulin-like activity was markedly
elevated at 74% (normal, <20%) (5). Anti-insulin
antibodies were negative. At the time, it was not possible to obtain a
C-peptide level or a sulfonylurea screen. After 18 h of fasting,
the patients plasma glucose decreased to 2.2 mmol/L with marked
neuroglycopenic symptoms, whereas insulin levels ranged between 754 and
825 pmol/L (Table 1
). A gastroduodenal
arteriogram revealed an approximately 15-mm oval homogeneously staining
density in the head of the pancreas (Fig. 1A
). Right hepatic artery injection
showed no evidence of hypervascular metastases.

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Figure 1. A selective gastroduodenal arteriogram (1975)
showing a 15-mm diffusely enhancing islet cell tumor (A,
arrows) in the inferior portion of the head of the pancreas.
T-1 weighted (B) and gradient echo (C) magnetic resonance imaging scans
(1998) show a 15-mm tumor (B and C, arrows) in the inferior
portion of the pancreatic head, with imaging characteristics typical
for a neuroendocrine tumor (low signal intensity on T-1-weighted images
and bright signal on gradient echo images). Contrast-enhanced
computerized tomography demonstrated a hypervascular tumor at the same
site. A, Superior mesenteric artery; V, superior mesenteric vein; D,
second duodenum.
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The patient was advised to undergo a second laparotomy for the removal
of the insulinoma. However, he refused this operation because he could
not be assured that a total pancreatectomy could be avoided. He was
well informed and intelligent and elected medical therapy. Accordingly,
he received diazoxide 100300 mg per day, from 1976 to 1995. In 1995,
symptomatic hyperglycemia developed (Fig. 2
). The diazoxide was discontinued.
Although his diet and weight remained stable over the following 3 yr
(body mass index, 25.4 kg/m2), his fasting plasma glucose
values ranged between 8.3 and 13.9 mmol/L off diazoxide.
HbA1c was 9.3% (normal, <6.2%) in March 1998.

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Figure 2. Change of plasma glucose concentrations between
1975 and 1999. The diagnosis of insulinoma was made in 1975, and the
patient was treated with diazoxide (D) after he refused surgery. Plasma
glucose levels were markedly increased after 1991, and the diagnosis of
type 2 diabetes was made in 1998. Treatment with metformin (M) was
initiated.
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In July 1998, the patient was readmitted to the NIH Clinical Center for
follow-up. His physical examination did not reveal hypertension,
exogenous obesity (body mass index, 25.5 kg/m2), or
acanthosis nigricans. His fasting biochemical profile was as follows:
triglycerides, 3.2 mmol/L; total cholesterol, 4.0 mmol/L; fasting
plasma glucose level, 12.7 mmol/L; fasting insulin level, 423 pmol/L;
fasting C-peptide level, 2200 pmol/L (normal, 170900 pmol/L); fasting
proinsulin level, 1000 pmol/L; and HbAlc, 9.7%. During a 5-h oral
glucose tolerance test, levels of 2-h glucose and insulin were 15.1
mmol/L and 373 pmol/L, respectively. There was no significant insulin
release with the oral glucose load, and the patient did not develop
hypoglycemia during the 5-h test. Insulin was determined by an
immunoassay using reagents provided by Abbott Imx Instrument (Abbott
Park, IL; normal range: 35145 pmol/L). The patient fasted for 18
h without symptoms of hypoglycemia (Table 1
). During this fast, his
insulin level decreased to 151 pmol/L; plasma glucose was 4.5 mmol/L,
and proinsulin was 618 pmol/mL (normal, <22 pmol/mL). Plasma C-peptide
levels decreased from 4400 pmol/L to 2200 pmol/L. Computed tomographic
and magnetic resonance imaging studies of the pancreatic head showed a
region of enhancement measuring approximately 15 mm that corresponded
to the vascular tumor in the head of the pancreas, previously seen on
the arteriogram (Fig. 1
, b and c). Following treatment with 500 mg
twice daily metformin therapy for 6 months, HbA1c was still
9.1% (normal, <6.2%) with a fasting plasma glucose level of 7.8
mmol/L and a fasting insulin level of 567 pmol/L. The dose of metformin
was increased to 1 g twice daily.
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Discussion
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At age 45 yr, the patient presented with typical features of
insulinoma, including hypoglycemia associated with marked
neuroglycopenic symptoms, inappropriately high levels of plasma insulin
and proinsulin, and radiographic findings consistent with an islet cell
tumor of the pancreas. Twenty-four yr later, the patient has similar
radiographic and biochemical findings but is now hyperglycemic,
requiring treatment for diabetes. We have considered the possibility
that the patient had a nonfunctional tumor of the pancreas and some
other cause for the hypoglycemia. However, the continued presence of
hyperinsulinemia and hyperproinsulinemia makes this highly
unlikely.
High circulating levels of proinsulin and the net metabolic balance of
hyperglycemia clinically resembles familial hyperproinsulinemia.
Familial hyperproinsulinemia is characterized by normal or elevated
blood glucose concentrations (6). Patients with this
entity do not become hypoglycemic, unless some other process
supervenes. Although circulating proinsulin has only approximately 20%
the bioactivity of insulin, its failure to be suppressed by decreasing
glucose concentrations during fasting results in hypoglycemia in states
of increased metabolic demand or prolonged fasting (6). In
this patient, 25 yr after the diagnosis of the insulinoma, the net
metabolic balance results in hyperglycemia despite clear biochemical
evidence of insulinoma with typical symptoms at the time of initial
diagnosis. The mechanism of this evolution from insulin-induced
hypoglycemia seen 25 yr ago to overt diabetes seen now is not
completely clear.
It is possible that this patient now has two independent conditions
(i.e. insulinoma and type 2 diabetes). A more likely
explanation, however, is that production of proinsulin by the tumor
coupled with suppression of endogenous insulin production by diazoxide
contributes to hyperglycemia. This phenomenon is similar to
hyperglycemia that occurs immediately after successful removal of an
insulinoma and is thought to be due to prolonged suppression of
endogenous insulin by hypoglycemia and/or hyperinsulinemia
(7). In conclusion, this case provided a unique
opportunity to observe the natural history of a proinsulin-secreting
insulinoma without surgical resection. The transition from symptomatic
hypoglycemia to clinical diabetes was unanticipated. We must
reemphasize, again, that the decision made by the patient not to
undergo further surgery is not to be recommended because of the
potential dangers of hypoglycemia and/or malignancy.
Received January 26, 2000.
Revised May 8, 2000.
Revised June 19, 2000.
Accepted June 27, 2000.
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References
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Gittler RD, Zucker R, Eisinger R, Stoller N. 1958 Amelioration of diabetes mellitus by an insulinoma. N Engl
J Med. 258:932935.[Medline]
-
Knight PO. 1967 Insulinoma and generalized islet
cell hyperplasia in a patient with diabetes mellitus. South Med J. 60:119123.[Medline]
-
Kane LA, Grant CS, Nippoldt TB, Service FJ. 1993 Insulinoma in a patient with NIDDM. Diabetes Care. 16:12981300.[Abstract]
-
Wildbrett J, Nagel M, Theissig F, et al. 1999 An
unusual picture of insulinoma in type-2 diabetes mellitus and morbid
obesity. Dtsch Med Wochenschr. 124:248252.[Medline]
-
Gorden P, Skarulis MC, Roach P, et al. 1995 Plasma proinsulin-like component in insulinoma: a 25-year experience. J Clin Endocrinol Metab. 80:28842887.[Medline]
-
Gruppuso PA, Gorden P, Kahn CR, et al. 1984 Familial hyperproinsulinemia due to a proposed defect in conversion of
proinsulin to insulin. N Engl J Med. 311:629634.[Abstract]
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Doherty GM, Doppman JL, Shawker TH, et al. 1991 Results of a prospective strategy to diagnose, localize, and resect
insulinomas. Surgery. 110:989996; discussion 996997.[Medline]