Distinct mechanisms of hypoglycaemia in patients with somatostatin‐secreting neuroendocrine tumours

Abstract Introduction Somatostatin‐secreting neuroendocrine tumours may present with diabetes, cholelithiasis and steatorrhoea. In addition, hypoglycaemia has been associated with somatostatinomas. However, the mechanism of hypoglycaemia in patients with somatostatinomas has not been well characterized. Methods We describe two patients with recurrent neuroglycopenic episodes caused by somatostatin‐secreting neuroendocrine tumours in the liver, detected by abdominal CTs and whole‐body octreotide scintigraphy scans and confirmed by biopsy. Results Pancreatic islet hyperplasia and co‐secretion of insulin (in addition to somatostatin) from tumour cells, respectively, have been characterized as completely distinct mechanisms of hypoglycaemia at both the functional and morphological levels in these two patients. Conclusions Hypoglycaemia may be caused by different mechanisms in patients with somatostatinomas.

Somatostatinomas are rare neuroendocrine tumours usually located in the pancreas or in the periampullary region of the duodenum, rarely in the jejunum, the ovaries or elsewhere. Patients with somatostatinomas most often present with nonspecific symptoms such as abdominal pain or weight loss. A more specific clinical manifestation is the somatostatinoma syndrome characterized by diabetes, cholelithiasis and steatorrhoea. 1 Moreover, hypoglycaemia has been associated with somatostatin-secreting neuroendocrine tumours. [2][3][4] The pathogenesis of hypoglycaemia in patients with somatostatinoma has not been well characterized. We describe two patients with malignant somatostatinomas who presented with hypoglycaemia. In both patients, the pattern of hypoglycaemia was well characterized and documented at a functional and morphological level. Patient 1, a 76-year-old man, presented at his local hospital with hypoglycaemic episodes occurring exclusively in the late postprandial period, often preceded by a short episode of diarrhoea following carbohydrate-rich meals. On abdominal CT, he was found to have multiple liver tumour masses, and he was then referred to our clinic for further investigations. Fasting plasma glucose was 7.7 mmol/L. No hypoglycaemic symptoms occurred during a 72-hour fast (plasma glucose concentration 4.8 mmol/L at the end of the fast). In contrast, venous plasma glucose concentration dropped to 1.5 mmol/L and the patient developed severe neuroglycopenic symptoms 240 minutes after intake of 75 g glucose during an oral glucose tolerance test (oGTT). Insulin concentrations during the oGTT showed an excessive increase from 44 pmol/L at baseline up to 6998 pmol/L within 120 minutes following the oral glucose challenge. An intravenous GTT, however, did not provoke hypoglycaemia. A tumour-produced incretin could not be identified (we checked for GLP-1, CCK, pro CCK and GIP), but somatostatin levels were markedly increased in the basal state ASVS was performed as previously described (5). Insulin (and somatostatin for patient 2) levels in the left hepatic vein are shown as a multiple of basal 30, 60 and 120 s after the intraarterial injection of calcium (0.025 mEq Ca ++ per kg body weight) into arteries supplying the pancreas and the liver (shown in the sequence of injections): in the first patient, the superior mesenteric artery (SMA), the splenic artery (SA), the proper hepatic artery and the (inferior) gastroduodenal artery (GDA); in the second patient, the SA, the SMA, right hepatic artery, the GDA and the left hepatic artery (LHA). A more than twofold rise in the insulin level in the hepatic vein indicates pathological β-cells in the arterial distribution of the artery stimulated. In patient 1, the pathological increase in insulin levels in the hepatic vein after calcium stimulation of all pancreatic arteries is suggestive for islet cell hyperplasia. In patient 2, the pathological increase in insulin levels following calcium injection into the LHA indicates an insulin-secreting tumour in the left hepatic lobe Co-secretion of insulin (in addition to somatostatin) by the hepatic somatostatinoma was well characterized as mechanism of hypoglycaemia in this patient.
In conclusion, pancreatic islet cell hyperplasia and co-secretion of insulin (in addition to somatostatin) from tumour cells, respectively, have been characterized as completely distinct mechanisms of hypoglycaemia at the functional and morphological level in these two patients with malignant somatostatinomas.

ACK N OWLED G EM ENTS
We thank Heidi Seiler for the determination of insulin and Cornelia Zwimpfer for the determination of somatostatin.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest in relation to this work.

AUTH O R S' CO NTR I B UTI O N S
PW, VP, MB and CS were directly involved in the management of the patients and contributed to the final manuscript. TP performed the ASVS tests, and AP performed the pathological examinations.

E TH I C S S TATEM ENT
Both patients gave informed consent to publish their data.

DATA AVA I L A B I L I T Y
Data sharing is not applicable to this article as no new data are shown. Data to support the findings are available from the corresponding author (PW), upon reasonable request.