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Electrical short-circuit in β-cells from a patient with non-insulinoma pancreatogenous hypoglycemic syndrome (NIPHS): a case report
© Bränström et al; licensee BioMed Central Ltd. 2010
Received: 22 October 2009
Accepted: 23 September 2010
Published: 23 September 2010
Non-insulinoma pancreatogenous hypoglycemic syndrome is a rare disorder among adults, and, to our knowledge, only about 40 cases have been reported in the literature.
The patient is a previously healthy 35-year-old Caucasian man. His symptoms began four years ago when he suddenly felt weakness in his legs and started sweating for unknown reasons. The symptoms worsened, and laboratory tests revealed hypoglycemia and hyperinsulinemia at the time of the symptoms. All diagnostics attempts using magnetic resonance imaging, computed tomography, and endoscopic ultrasound did not reveal any abnormalities. At this stage, surgical intervention was planned, and a distal 80% pancreatectomy was performed. The histopathologic and immunohistochemical investigations of the pancreas showed an increased number of islets of different sizes, more or less evenly distributed in the gland, but no insulinoma. Patch-clamp recordings from isolated pancreatic β-cells showed that, even at a low glucose concentration (3 mmol/L), the β-cell membrane was depolarized, and action potentials were seen. Surprisingly, in patch-clamp experiments, the addition of diazoxide had a marked effect on K-ATP channel activity and membrane potential, but no effect on insulin levels in vivo before surgery.
This case report adds new information on the pathogenesis of non-insulinoma pancreatogenous hypoglycemic syndrome, as we performed an electrophysiologic characterization of isolated islet cells. We show, for the first time, that β-cells isolated from a non-insulinoma pancreatogenous hypoglycemic syndrome patient are constantly depolarized, even at low glucose levels, but display normal K-ATP channel physiology.
Nesidioblastosis is a rare, but well-recognized disorder of persistent hyperinsulinemic hypoglycemia in infancy. Nesideroblastosis is associated with mutations in adenosine triphosphate (ATP)-sensitive K+ (K-ATP) channel subunits Kir6.2 and sulphonylurea receptor type 2 (SUR2). In adults, the most common cause of hyperinsulinemic hypoglycemia is solitary or multiple insulinoma(s). Recently, non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) was described in adults as a novel cause of hyperinsulinism. NIPHS is often referred to as nesidioblastosis, even though NIPHS originates independent of mutations in K-ATP channel genes (Kir6.2 and SUR2) . NIPHS is a very rare disorder among adults, to our knowledge, and only about 40 cases have been reported in the literature. Clinical presentation is heterogeneous, and here we describe a case of NIPHS in a 35-year-old man. In addition, this case report adds new information on the pathogenesis of NIPHS, as we performed an electrophysiologic characterization of isolated islet cells. We show, for the first time, that β-cells isolated from an NIPHS patient are constantly depolarized, even at low glucose levels, but display normal K-ATP channel physiology. Furthermore, we demonstrated that, although diazoxide had an effect on K-ATP channel activity in vitro in isolated β-cells, no effect of the drug was noted in vivo.
The patient is a 35-year-old previously healthy Caucasian man. His symptoms began four years ago when he suddenly felt weakness in his legs and started sweating for unknown reasons. He noticed that if he lay down and consumed food, the symptoms disappeared. In the beginning, he had similar episodes with intervals of one to several months. These episodes were related to mental or physical stress or both. Later the attacks were more frequent, which eventually made him seek medical attention. Laboratory tests revealed hypoglycemia and hyperinsulinemia at the time of the symptoms. However, magnetic resonance imaging (MRI), computed tomography (CT), abdominal ultrasound, gastroscopy, and octreotide scintigraphy did not reveal any abnormalities, and he received the diagnose "hypoglycemia of unknown cause."
Non-insulinoma pancreatogenous hypoglycemic syndrome (NIPHS) is a rare disorder among adults and, to our knowledge, only about 40 cases have been reported in the literature [1, 3–5]. This case report adds new information, as we performed an electrophysiologic characterization of isolated islet cells. As the time window for experiments was limited (two to three days after isolation), we were able to estimate KATP channel activity in response to only one concentration of ATP (100 μmol/L). Comparison of the blocking effect of 100 μmol/L ATP in these cells with that found in wild-type pancreatic β-cells  demonstrated a slightly decreased effect of ATP. Surprisingly, in patch-clamp experiments, addition of diazoxide had a marked effect on KATP channel activity and membrane potential, but no effect on insulin levels in vivo before surgery.
One plausible reason for this discrepancy could be that the concentration of diazoxide was not high enough in the β-cells in the hyperplastic islets. Another possibility is that isolated β-cells, directly exposed to the drug, respond differently compared with cells in the natural milieu within the islets surrounded by other endocrine cells, as well as vessels and nerves.
Preoperative management of patients with hypoglycemia has been debated repeatedly . Because of improvements in various imaging methods, the previous recommendations for using the surgeon's hand and intraoperative ultrasound as the most sensitive methods are abandoned more frequently now. Thus, even though they were not successful in the present patient, we recommend CT or MRI as well as endoscopic ultrasound as initial imaging procedures. If these are negative, we advocate intra-arterial calcium-stimulation testing, which is a sensitive technique . However, in our patient, no specific area of the pancreas showed hypersecretion of insulin, which led to the decision to remove 80% of the pancreas. The histopathologic investigation, showing an increase number of islets evenly distributed within the resected part of the pancreas, was in agreement with the results from the intra-arterial calcium-stimulation tests. NIPHS may be surgically cured by a subtotal pancreatic resection if no intraoperative insulinomas are found. Surgery in the present patient was delayed because of diagnostic difficulties but also by emigration and immigration to Sweden. The resulting memory dysfunction in our patient underscores the importance of the fast handling of patients with hypoglycemic symptoms.
This case report adds new information on the pathogenesis of NIPHS, as we performed an electrophysiologic characterization of isolated islet cells. We show, for the first time, that β-cells isolated from an NIPHS patient are constantly depolarized, even at low glucose levels, but display normal K-ATP channel physiology.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
This work was supported by grants from the Swedish Research Council, the Novo Nordisk Foundation, Funds of the Karolinska Institute, the Tore Nilsson Foundation, the Thuring Foundation, the Jeansson Foundations, the Åke Wiberg Foundation, Magn. Bergwall Foundations, the Stockholm County Council, and the Family Erling-Persson Foundation.
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