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From the Clinical Research Centers |
Division of Endocrinology and Metabolism (F.J.S., N.N.), Department of Surgery (G.B.T., C.S.G., J.A.v.H.), Department of Radiology (J.C.A.), Division of Cardiovascular Diseases (E.L., A.T.), and Department of Pathology (R.V.L.), Mayo Clinic and Foundation, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: F. John Service, M.D., Division of Endocrinology and Metabolism, Mayo Clinic and Foundation, 200 First Street SW, Rochester, Minnesota 55905.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In infancy, persistent hyperinsulinemic hypoglycemia is caused by generalized pancreatic ß-cell dysfunction characterized histologically by nesidioblastosis and islet hypertrophy (6). In some familial forms of persistent hyperinsulinemic hypoglycemia of infancy, mutations in the ß-cell sulfonylurea receptor (SUR1) gene or inwardly rectifying potassium channel (Kir6.2) gene have been found (7, 8, 9, 10). Kir6.2 and SUR1 physically associate to form a functional ATP-sensitive potassium channel responsible for glucose-induced insulin secretion by the pancreatic ß-cell (11, 12, 13)
Islet hypertrophy and nesidioblastosis are rarely encountered in adults with hyperinsulinemic hypoglycemia (3, 14). Furthermore, mutations in the Kir6.2 and SUR1 genes have not been examined in adults with nesidioblastosis and islet hypertrophy.
We report five adults with hyperinsulinemic hypoglycemia not due to insulinoma who had episodes of neuroglycopenia that were exclusively postprandial, negative 72-h fast, positive selective arterial calcium stimulation test, islet hypertrophy/nesidioblastosis, and no disease-causing mutation in Kir6.2 and SUR1 genes. Their unique clinical features and responses to diagnostic testing establish a clinical syndrome that predicts the presence of diffuse islet cell hyperfunction and determines an appropriate surgical procedure.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From 1995–1998 the following five patients were evaluated and treated at the Mayo Clinic (Rochester, MN).
Patient A. A 37-yr-old man had recent onset of generalized tonic-clonic seizures that resulted in a fracture dislocation of a shoulder. Each seizure occurred within 2 h of eating, especially after consuming regular soda and fast foods. The seizures were heralded by a queasy feeling, shakiness, diaphoresis, and blurred vision. The nonseizure symptoms were often associated with low capillary blood glucose levels and could be relieved by food ingestion. He had autoimmune polyglandular failure type 1: hypoparathyroidism and Addison’s disease since childhood on full replacement therapy. He was 168 cm tall and weighed 65.6 kg with a blood pressure of 122/90 mm Hg and a pulse of 88 beats/min. He had alopecia totalis and melanosis with lentigines, but no other abnormalities. Initial laboratory evaluations were normal, except for serum calcium of 11 mg/dL, urinary calcium of 367 mg/24 h, and PTH of less than 0.2 pmol/L. Insulin antibodies were absent. Magnetic resonance imaging of the head and awake/sleep electroencephalography were negative. Comprehensive neurological assessment concluded that he did not have a primary seizure disorder.
While in the Mayo Clinic General Clinical Research Center (GCRC) 4
h after a large meal of fast foods, he developed symptoms with plasma
glucose of 50 mg/dL, plasma insulin of 288 pmol/L, plasma C peptide of
1400 pmol/L, plasma proinsulin of 84 pmol/L, and negative plasma
sulfonylurea screen (Table 1
). He had
relief of symptoms after iv glucagon.
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Patient C. A 72-yr-old man had recurrent episodes of blurred
vision, disorientation, dysarthria, and diaphoresis relieved by orange
juice. Medications were verapamil (80 mg, three times per day), calcium
carbonate (500 mg, twice daily), and one multivitamin tablet daily. He
was 177 cm tall and weighed 68.9 kg with a blood pressure of 160/100 mm
Hg and a pulse of 76 beats/min. The physical examination was normal.
Routine laboratory tests were also normal. Insulin antibodies were
absent. During a spontaneously occurring spell at the Mayo Clinic
3.5 h postprandially, plasma glucose was 40 mg/dL, plasma insulin
was 42 pmol/L, plasma C peptide was 1100 pmol/L, and a plasma
sulfonylurea screen was negative (Table 1
).
Patient D. A 72-yr-old man experienced a sudden episode at
the Mayo Clinic of diaphoresis, light-headedness, tremulousness,
perioral numbness, and diplopia 2.5 h after a light noon meal. His
plasma glucose was 40 mg/dL. During a subsequent episode 4 h after
breakfast, plasma glucose was 36 mg/dL, plasma insulin was 960 pmol/L,
plasma C peptide was 5600 pmol/L, plasma proinsulin was 190 pmol/L, and
a plasma sulfonylurea screen was negative (Table 1). He recovered after
the administration of oral carbohydrate. He was 194 cm tall and weighed
92.2 kg with a blood pressure of 128/80 mm Hg and a pulse of 72
beats/min. Physical examination disclosed flat prostate from prior
transurethral prostatic resection. Routine laboratory tests were
normal. Insulin antibodies were absent.
Patient E. A 78-yr-old woman had recurrent episodes of
flushing, tremulousness, blurred vision, and confusion 2 h
postprandially, relieved by oral carbohydrate. During one episode,
plasma glucose was 40 mg/dL, insulin was 810 pmol/L, and C peptide was
4237 pmol/L (Table 1). During subsequent hypoglycemic episodes, plasma
sulfonylurea screen was negative. Her medication was
Synthroid (Knoll Pharmaceutical Co., Mount Olive,
NJ; 0.1 mg daily). She was 161 cm tall and weighed 64.8 kg with a blood
pressure of 140/88 mm Hg and a pulse of 85 beats/min. Physical
examination disclosed surgical scars from remote appendectomy, cervical
laminectomy, and right nephrectomy for hypernephroma. Routine
laboratory tests were normal. Insulin antibodies were absent.
Analytic methods
First and second generation sulfonylureas were measured in plasma by gas chromatographic mass spectroscopy and liquid chromatographic mass spectroscopy, respectively, with lower limits of detection of 100 and 25 ng/mL, respectively. Plasma glucose was measured with a Beckman Coulter, Inc., Synchron CX3 chemistry analyzer (Beckman Coulter, Inc., Brea, CA) (15). Plasma ß-hydroxybutyrate was measured by an automated kinetic method (16).
Plasma insulin was measured by RIA (17), and plasma C peptide (18) and plasma proinsulin (19) were determined by immunochemiluminometric assays. The lower limits of detection were: insulin, 30 pmol/L; C peptide, 33 pmol/L; and proinsulin, 0.2 pmol/L. Antibodies to human, pork, and beef insulin were measured in each patient (20).
Procedures
72-h fast. The procedure for the 72-h fast has been
described previously (21). Our recommended diagnostic criteria for
hyperinsulinemia at the time of hypoglycemia, whether induced by the
fast or occurring spontaneously, are: plasma insulin, 36 pmol/L or
higher; plasma C peptide, 200 pmol/L or higher; and plasma proinsulin,
5 pmol/L or higher (21). For a fast to be considered positive, both
symptoms and/or signs of hypoglycemia and biochemically confirmed
hypoglycemia (plasma glucose 
45 mg/dL preferably, although some
insulinomas have had values as high as 57 mg/dL) must be present,
because plasma glucose alone is not a discriminate between insulinoma
patients and normal subjects (21).
C Peptide suppression test. This test is interpreted on the basis of percent suppression of C peptide from the baseline after 60 min of insulin infusion (0.125 U/kg) in contrast to normative data adjusted for body mass index and age (22).
Selective arterial calcium stimulation test. When performed as originally described (23) and later modified (Doppman, J., personal communication), a 2-fold or higher increase in insulin concentration (in contrast to no response from normal ß-cells) in the right hepatic vein in response to the injection of 0.025 mEq Ca2+/kg BW into the splenic, superior mesenteric, and gastroduodenal arteries is considered to indicate an insulinoma in the vascular territory of the artery studied. Although overlap across vascular territories can occur, these can be identified from the angiographic findings. In general, the body and tail of the pancreas are within the splenic distribution, the head and secondarily the uncinate are within the gastroduodenal distribution, and the uncinate and secondarily the head are within the superior mesenteric artery distribution.
Pathology
The resected pancreatic tissues were sectioned into 1-mm slices, fixed in buffered formalin, and embedded in paraffin. Histological criteria for nesidioblastosis in adults (24) were used to evaluate the hematoxylin- and eosin-stained sections.
Immunohistochemical staining was performed on 5-µm thick paraffin sections using the avidin-biotin-peroxidase complex system as previously reported (25). The antibodies used, sources, and dilutions included: chromogranin A (Boehringer Mannheim, Indianapolis IN), 1:100; insulin (DAKO Corp., Carpinteria CA), 1:750; glucagon (DAKO Corp.), 1:3000; somatostatin (DAKO Corp.), 1:1000; and gastrin (DAKO Corp.), 1:1000. Positive controls for immunostaining consisted of normal pancreatic tissues. Negative control consisted of omitting the primary antibody during the immunostaining procedure.
The immunostained slides were analyzed for staining in the islets, ducts, and in between acinar cells in the pancreas.
The sizes of the islets were estimated by randomly measuring 20 islets/case with a micrometer in the ocular of the microscope, and a mean islet diameter was obtained. Pancreatic tissue from five age-matched patients without endocrine disease was also analyzed as a control.
Kir6.2 and SUR1 mutant screening
Genomic DNA was extracted for all five patients from whole cell blood using the Puregene extraction procedure (Gentra Systems, Inc., Research Triangle Park, NC). DNA was run on agarose gels to assure intactness, and optical density measurements were taken to assure purity. The DNA was stored at a final concentration of 0.3 µg/µL at 4 C. PCR amplifications using appropriate primers were performed with the Taq polymerase kit (Boehringer Mannheim). For the Kir6.2 gene, the following primers were used: U, 5'-CTGAGGCTGGTATTAAGAAGTGAAGT-3'; and D, 5'-AGGGGTGAGCCAGTCCTAAAT-3'. For the SUR1 gene, the primers employed were described previously (8, 26). Reaction conditions were optimized for primer concentrations and temperature profile for each amplification reaction. In general, for a 25-µL reaction conditions were as follows: 2.5 µL of 10 x PCR buffer, 1 µL genomic DNA target, 0.1 µL Taq polymerase, 0.125 µmol/L of each dNTP, 1.25–6.25 pmol/L of each primer, and 1.5–2.5 mmol/L MgCl2. The temperature profile was optimized for a Perkin Elmer 9600 machine (Norwalk, CT) with denaturation at 95 C for 30 s, annealing at 53 to 58 C for 30 s, and extension times from 1–3 min at 68–72 C according to the amplimer requirements. Sequencing was performed using the ABI fluorescent-labeled sequencing at the Mayo Molecular Biology Core facility. Polymorphisms in the patient population were compared to previously published results for control, diabetic, and hyperinsulinemic populations (27).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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)Each patient had a negative 72-h fast conducted in the Mayo Clinic GCRC according to protocol. Each patient was entirely asymptomatic. Only one patient (B) had a plasma glucose concentration (48 mg/dL) that overlapped the range (14–57 mg/dL; n = 100) we have observed for patients with insulinoma. However, such a plasma glucose level (48 mg/dL) was also within the range (44–99 mg/dL; n = 100) we have observed for normal subjects fasted for 72 h. Seven percent of normal subjects in our experience have plasma glucose concentrations of 50 mg/dL or less after 72 h of fasting.
Each patient had evidence of endogenous hyperinsulinemia during spontaneous episodes of hypoglycemia or as in the case of patient B, at the end of the 72-h fast. In our experience, all normal subjects who have plasma glucose of 55 mg/dL or less at the end of the 72-h fast (14%) have completely suppressed ß-cell polypeptide concentrations; those in patient B were uniformly and distinctly elevated. The absence of sulfonylurea in the circulation in each patient confirms the endogenous nature of the hyperinsulinemia.
C Peptide suppression testing showed variable results: positive in patients A, B, and C, and negative in patient E. The test was technically uninterpretable in patient D.
Spiral computed tomography, transabdominal ultrasound, and celiac axis
arteriography were negative in each patient. In contrast, the selective
arterial calcium stimulation test was positive in each patient (Fig. 1), showing ß-cell hyperfunction in the
distribution of the splenic, gastroduodenal, and superior mesenteric
arteries for patient A; splenic artery for patient B; and splenic and,
to a lesser degree, gastroduodenal arteries in patients C and D.
Because patient E had anomalous vascular supply to the pancreas in
having minimal contribution from the splenic and gastroduodenal
arteries, the positive result from the superior mesenteric artery
injection required further evaluation. When restudied with subselected
injection of calcium into the left and right branches of the superior
mesenteric artery, positive responses occurred with both, indicative of
diffuse ß-cell hyperfunction throughout the pancreas.
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The pancreas of each patient was completely mobilized and carefully palpated without detection of an insulinoma. Intraoperative ultrasonography conducted by experienced radiologists also failed to detect insulinoma. In patients A–D, gradient-guided distal pancreatectomy was performed with the superior mesenteric vein as the distinguishing landmark. When the gradient was confined to the splenic distribution, the distal resection was carried to the superior mesenteric vein. When the gastroduodenal and/or the superior mesenteric distribution were also involved, a safe subtotal distal resection was performed to the right of the superior mesenteric vein. Patient E underwent a limited distal pancreatectomy. Patients A–D had complete resolution of hypoglycemia with up to 3 yr of follow-up. The recurrence of hypoglycemia in patient E during the initial 3 months postoperatively (then none thereafter) may be attributed to the anomalous vascular supply to the pancreas, which led to an underestimation of the optimal extent of the pancreatic resection.
Pathology
There was no gross or microscopic tumor identified in any of the
five patients on the hematoxylin- and eosin-stained sections. The
histologic findings consisted of cells budding off ducts, seen best by
chromogranin A immunohistochemical staining. Chromogranin A stained all
islet cells as well as the endocrine cells budding off ducts. Islets in
apposition to ducts were noted, and there was islet cell hypertrophy.
Analysis of the pancreatic tissues in all five patients showed islets
with a wide range of sizes. The mean islet diameter of controls was
152 ± 16 µm (Fig. 2A), and the
mean diameter of patient A was 228 ± 22 µm, that of patient B
was 229 ± 14 µm (Fig. 2B), that of patient C was 240 ± 18
µm, that of patient D was 234 ± 13 µm, and that of patient E
was 262 ± 19 µm.
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and 4).
Pancreatic polypeptide-positive cells budding off the ducts were also
identified. Additional immunohistochemical staining in patient B showed
small nests and individual islet cells scattered between islets.
Staining for gastrin was negative in the islets as well as in the areas
of nesidioblastosis.
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Kir6.2 and SUR1 genes encode the subunits of the pancreatic
ATP-sensitive K+ channel, responsible for glucose-induced
insulin secretion (11, 12, 13). As such, these genes represent candidates
for possible mutations in the patient described in this study. All
patients had the genomic DNA analyzed for mutations in either the
Kir6.2 open reading frame or the nucleotide binding folds 1 and 2 of
the SUR1 gene (a total of 19 exons). The results of the mutant screen
are summarized in Fig. 5. No definite
disease-causing mutation was detected. Although some of the patients
have mutations in either Kir6.2 or SUR1 that have previously been shown
to predispose to type 2 diabetes (26), no mutation was common to all
patients. In addition, one patient did not show any polymorphisms from
the sequences submitted to GenBank.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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6 min)
permits complete clearance of insulin after suppression of ß-cell
function in response to hypoglycemia within five half-lives (30
min). As suppression of C peptide is chronic in noninsulin-mediated
hypoglycemia and is prolonged in insulin factitial hypoglycemia, its
longer half-life (30 min) is not a factor in assessing the
significance of elevated postprandial C peptide concentrations. In
support of this contention, each of 11 surgically confirmed insulinoma
patients at this institution satisfied criteria for endogenous
hyperinsulinemia when hypoglycemia occurred 4 h or less (3 h,
n = 5; 2 h, n = 2) after food ingestion. Autonomous
ß-cell function demonstrable during hypoglycemia mandated further
evaluation despite negative 72-h fasts. A negative 72-h fast in a
patient with insulinoma is an extraordinarily rare occurrence (28, 29, 30, 31).
Over the past 25 yr, insulinomas have been removed from 216 patients at
the Mayo Clinic. Among these, 178 underwent the 72-h fast. All except
one patient had a positive fast (28). A negative 72-h fast appears to
be a characteristic of nonfocal, i.e. noninsulinoma,
pancreatogenous hypoglycemia. Among 14 case reports of patients
suspected of insulinoma, but with histologically confirmed islet
hypertrophy and/or nesidioblastosis, five had negative 72-h fasts (24, 32, 33, 34, 35, 36, 37, 38, 42). We have previously reported a patient with postprandial
hyperinsulinemic hypoglycemia from islet hypertrophy, who had a
negative 72-h fast, but a positive C peptide suppression test (39).
These five cases extend the experience with that case and establish
that their unique clinical presentation is an indication of diffuse
ß-cell hyperfunction. Positive responses to the selective arterial calcium stimulation test despite negative radiological localizing studies reinforced the impression of abnormal ß-cell function as the basis for the hyperinsulinemic hypoglycemia (23, 40) in these five patients. The major operative finding in each patient was the absence of insulinoma. With the advent of intraoperative ultrasound, the success rate in identification of insulinoma using that modality and complete mobilization and palpation of the pancreas in over 100 cases at our institution is 98%. Islet hypertrophy is an extraordinarily rare cause of hypoglycemia in adults in the experience of others (3, 14) and in our experience (1 in 216 cases of insulinoma).
Nesidioblastosis, the neodifferentiation of islet of Langerhans cells from pancreatic exocrine duct epithelium (41), has been observed in rare cases of adults with hyperinsulinemic hypoglycemia (24, 32, 33, 34, 35, 36, 37, 38, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52), in pancreatic tissue resected from hypoglycemic patients who had concomitant insulinoma (53, 54) or had previously been treated with insulin (45, 55) or a sulfonylurea (56), and in other clinical syndromes, such as Werner Morrison, Zollinger-Ellison (57), and multiple endocrine neoplasia type 1 (58). The histological features of nesidioblastosis in adults include the presence of islet cell enlargement, ß-cells budding off ductular epithelium, and islets in apposition to ducts. All of these features were seen in our five patients. However, attribution to these histological findings of the syndrome of hyperinsulinemic hypoglycemia in adults without insulinoma is controversial. The findings in an autopsy series of subtle histological changes characteristic of nesidioblastosis in 36% of individuals without hypoglycemia (59) and the inability, using morphometric measurements, to quantitatively distinguish pancreatic nesidioblastosis occurring in patients with hypoglycemic hyperinsulinism from those lacking such a clinical association (60) have led some to conclude that the morphological features of nesidioblastosis may be a variant of normal and, therefore, may not be the anatomical basis for hypoglycemia in adults with hyperinsulinism (59, 60). Whether islet hypertrophy and/or nesidioblastosis are pathogenetic in our patients is open to question, just as it is in persistent hyperinsulinemic hypoglycemia of infancy (PHHI). However, a role for some form of diffuse islet cell dysfunction appears well established in our patients and those with PHHI. Whatever pathological process is operative in our patients, it is nonfocal, yet not necessarily with uniform involvement of the whole pancreas. Fortunately, its effects were ameliorated by debulking the pancreas in a gradient-guided fashion even in patients whose disease would appear to have involved the whole pancreas. The mechanism for this effect may be related to the observation of decreased insulin secretion in remnant pancreas after partial pancreatectomy in rats, attributed to reduced glucose transporter GLUT2 (61).
Because of the similar histological findings in our patients and those with PHHI, familial forms of which may be associated with mutations in the Kir6.2 and SUR1 genes (7, 8, 9, 10, 62), we examined these genes in our patients. The mutation analysis suggests that the noninsulinoma pancreatogenous hypoglycemia syndrome in the adult is not linked to mutations in either SUR1 or Kir6.2 genes. Our observations, however, do not rule out that all five patients might have common mutations at another, as yet unspecified disease locus. The small number of patients in the absence of a clear family history precludes a gene-mapping approach based on linkage analysis. Although SUR1 and Kir6.2 are two likely candidate genes for the disease, lately there has been some indication that hyperinsulinism can exist in an autosomal dominant form as well (63). This form of hyperinsulinism is not linked to a gene mapping to chromosome 11p15, the location of both SUR1 and Kir6.2. Thus, it is possible that the patients analyzed in this study do have mutations at other genes, as yet unknown, that are involved in the regulation of insulin secretion.
The unique clinical and diagnostic features in these five adult patients with hyperinsulinemic hypoglycemia have led us to conclude that they represent a newly described clinical entity: the noninsulinoma pancreatogenous hypoglycemia syndrome.
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Acknowledgments |
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Footnotes |
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Received November 4, 1998.
Revised January 4, 1999.
Accepted January 26, 1999.
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