Insulinoma accompanied by diabetes mellitus

A 53-year-old type 2 diabetic man was admitted due to spontaneous relatively hyperinsulinemic hypoglycemia. Oral glucose ingestion and arginine tolerance test showed hyperinsulinemic response. Arterial stimulation and venous sampling (ASVS) showed hyperinsulinemic response measured from the splenic artery after calcium gluconate stimulation. Diagnosis was insulinoma in the pancreas feeding from the artery. He has not suffered from spontaneous hypoglycemia since removal of the pancreatic body, tail and spleen. The specimen showed a solitary islet cell tumor. The high homeostasis model assessment of insulin resistance (HOMA-R) levels reflecting insulin resistance and hyperinsulinemic response after operation remained almost unchanged, indicating high insulin resistance and an insulin hypersecreting diabetic patient.     

A rare case of adult-onset nesidioblastosis treated successfully with diazoxide

A 54-year-old man was admitted to our hospital for evaluation of hypoglycemia. He had frequent episodes of loss of concentration before dinner. The ratio of IRI to plasma glucose (PG) was 0.8-1.0. Abdominal CT revealed no pancreatic tumor, and angiography of splenic artery showed no definite tumor stain within the pancreas. Based on the results of selective arterial calcium stimulation and hepatic venous sampling (ASVS), the provisional diagnosis was a small insulinoma in the pancreatic body. The patient underwent subtotal distal pancreatectomy. However, histopathological and immunohistochemical examinations of the resected tissue showed hypertrophy of islets of Langerhans islands and beta cells around pancreatic ducts. The final diagnosis was adult-onset nesidioblastosis. Postoperatively, the patient continued to exhibit hyperinsulinemia and nighttime hypoglycemia. Octreotide, voglibose and diet therapies failed to improve the nocturnal hypoglycemia. However, treatment with diazoxide at a starting dose of 200 mg/day resulted in immediate amelioration of nocturnal hypoglycemia. This is the first Japanese adult case of nesidioblastosis treated successfully with diazoxide. This case report suggests that diazoxide may be effective for adult-onset nesidioblastosis in a manner similar to that described for pediatric cases.     

Adult-onset diffuse nesidioblastosis causing hypoglycemia

We report the case of a 32-year-old male with adult-onset diffuse nesidioblastosis causing hypoglycemia. Under the tentative diagnosis of insulinoma, localization procedures were carried out but no tumor was found. The presence of an insulinoma in the tail of the pancreas was suggested by selective intra-arterial calcium stimulation with hepatic venous sampling (ASVS). A distal pancreatectomy was performed under the assumed diagnosis of insulinoma in the tail based upon the ASVS. Diffuse nesidioblastosis was diagnosed by histopathological evaluation. During the post-operative course, the patient’s glucose and insulin levels were well controlled and uneventful without any medications or insulin for 7 months.     

Hyperinsulinemic hypoglycemia due to diffuse nesidioblastosis in adults： A case report

Persistent hyperinsulinemic hypoglycemia is caused most commonly by an insulinoma in adults or by nesidioblastosis in neonates. In adults, nesidioblastosis is a rare disorder characterized by diffuse or disseminated proliferation of islet cells. We recently encountered a case of nesidioblastosis in an adult. A 71-year-old man was admitted due to intermittent general weakness, abdominal pain, and mild dyspnea. The patient underwent a subtotal gastrectomy for a gastric adenocarcinoma two years ago. After 5 d of admission, the patient showed symptoms of cold sweating, chilling, and hypotension 30 min after eating. Thereafter, he frequently showed similar symptoms accounting for hypoglycemia regardless of food consumption. Laboratory findings revealed a low fasting blood glucose level （25 mg/dL）, and a high insulin level （47 μIU/mL）. Selective intra-arterial calcium stimulation with hepatic venous sampling （ASVS） was performed to localize a mass and revealed an increased insulin level about fourfold that of the normal fasting level at 60 s in the splenic artery, which suggested the presence of an insulinoma in the tail of pancreas. A distal pancreatectomy was performed. Neither intraoperative exploration nor a frozen biopsy specimen detected any mass-forming lesion. On the histological examination, many of the islets were enlarged and irregularly shaped in all specimens, the arrangement of which was a Iobulated islet pattern. Cytologically, a considerable subpopulation of endocrine cells showed enlarged and hyperchromatic nuclei. By immunohistochemistry, the cells were identified as p-cells. These clinical, radiological, microscopic and immuno-histochemical findings are consistent with diffuse nesidioblastosis in adults.     

Insulin and somatostatin releasing islet cell tumor caused hypoglycemia

We report a hypoglycemic case with normal insulin levels, which was caused by an islet cell tumor that was releasing insulin and somatostatin. A fasting test suggested the over secretion of insulin. Moreover, this hypoglycemia was enhanced by the inhibitory effect of somatostatin on the secretion of insulin counter-regulatory hormones, such as glucagon, in addition to the autonomous secretion of insulin from the tumor. In cases of hypoglycemia with apparently normal insulin levels, the measurement of somatostatin and various provocative tests are recommended. Arterial stimulation venous sampling (ASVS) was useful to detect the location of this functioning islet cell tumor.     

Assessment of selective arterial calcium stimulation and hepatic venous sampling to localize insulin-secreting tumours

OBJECTIVE: Non-invasive localization modalities such as ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) often fail to localize insulinomas smaller than 2 cm in diameter. Recent studies have shown that the selective arterial stimulation and hepatic venous sampling (ASVS) technique using intra-arterial calcium as the insulin secretagogue facilitates the regionalization of such occult insulinomas. This study assesses the sensitivity of ASVS in localizing insulin-secreting tumours. SUBJECTS AND METHODS: Eleven consecutive patients (8 women), aged 29-82 years, were studied over the past 4 years at our hospital. Hyperinsulinaemic hypoglycaemia due to an insulin-secreting tumour was proven in all patients. Calcium gluconate (0.025 mEq/kg body weight) was injected directly into the arteries supplying the pancreas and the liver. Insulin levels were measured in samples taken from the right hepatic vein before and 30, 60 and 120 s after each injection. The ASVS technique was performed in all 11 patients; the results were compared with the surgical findings in 10 patients and the autopsy findings in 1 case. The ASVS results were also compared with the findings of other, previously performed imaging modalities. RESULTS: ASVS correctly localized 4 insulin-secreting tumours to the head, 3 to the body, 1 to the tail, 2 to the tail or body of the pancreas and 1 to the liver. Thus, the sensitivity was 100% (11/11) whereas other localization techniques were less sensitive: 7/11 tumours were detected by angiography, 4/8 by endosonography, 3/8 by CT and 1/6 by MRI. Insulinomas (confirmed by histological examination), sized 4-25 mm, were found in 10 patients. All were cured by selective surgery and remained free of hypoglycaemia over the next 1-4 years of follow-up. An insulin-secreting neuroendocrine tumour in the liver was documented in 1 case at autopsy. CONCLUSIONS: Arterial stimulation and hepatic venous sampling is a very sensitive technique for preoperative localization of insulin-producing tumours. It can help to plan minimally invasive surgery and to select an appropriate strategy for patients suffering from malignant tumours in others.     

Clinical pathology of endocrine tumors of the pancreas

A clinicopathological analysis of endocrine tumors of the pancreas, using 800 autopsy cases (422 men, 378 women, mean age 78.7) was accomplished. The results were: (1) Endocrine tumors and similar lesions were found in 3% or 24 cases (25 lesions). Twenty lesions (20 cases) were found to be tumors and five lesions (five cases) were determined to be hyperplasia of Langerhans islets. (2) Incidence of tumor was 10% (6/60) in individuals having histological studies of all sections of the pancreas, and 1.6% (12/738) in individuals having histological studies of three random sections of the pancreas. (3) None of the cases with tumors and hyperplastic lesions showed symptoms of hormone production. (4) Immunohistochemical analysis revealed hormone production in all 20 tumor cases and multiple hormone production was found in 14 of these (70%). (5) Ductular or tubular structures were found in or adjacent to the tumors in 12 cases (60%) and hyperplasia in one case (20%). Langerhans islets, 500 m or larger in size, were found in three lesions of the tumor (15%). Langerhans islets with the mean diameter of normal islets +2sd or larger also were found around five tumors (25%) and three hyperplasias (60%). The above findings suggest that endocrine tumors of the pancreas are prevalent and that they do not produce symptoms of excessive hormone production even though they do continue to produce hormones. Some of the endocrine tumors or hyperplasias develop from totipotent stem cells of the duct epithelia, and factors promoting the growth of Langerhans islets might exist.     

Insulin responses to selective arterial calcium infusion under hyperinsulinemic euglycemic glucose clamps: case studies in adult nesidioblastosis and childhood insulinoma

Selective arterial calcium stimulation and hepatic venous sampling (ASVS) for insulin secretion is used as a diagnostic procedure in patients with insulinomas or adult nesidioblastosis. In some of those patients, severe hypoglycemia requiring urgent glucose administration occurs during the procedure. Such glucose administration, however, may affect the results and damage the validity of the test. We report two cases of hyperinsulinemic hypoglycemia, in which ASVS tests were successfully performed under hyperinsulinemic euglycemic glucose clamps. A 40-year-old male with nesidioblastosis developed continual severe hypoglycemia several years after a Billroth II-Braun gastrectomy, and continuous glucose infusion could not be stopped even during ASVS tests. A 9-year-old girl with an insulinoma that showed atypical hypovascularity on imaging examinations had ASVS tests under a glucose clamp for safety. Hyperinsulinemic (approximately 100 microU/ml) euglycemic (approximately 90 mg/dl) clamps were achieved by an artificial endocrine pancreas. The insulin analogue lispro was utilized for clamps and endogenous insulin was measured with an assay that does not cross-react with the analogue. Diagnostically significant responses (more than twofold) of insulin secretion were observed under hyperinsulinemic clamps in both cases. The use of the hyperinsulinemic glucose clamp technique during the ASVS test should be considered for maintaining the safety of some hypoglycemic patients.     

A case with insulinoma diagnosed and localized preoperatively using contrast-enhanced ultrasonography (CEUS) and arterial stimulation and venous sampling (ASVS)

We report a case with insulinoma diagnosed and localized preoperatively using a combination of contrast-enhanced ultrasonography (CEUS) and arterial stimulation and venous sampling (ASVS). A 76-year-old woman was admitted to our hospital because of hypoglycemic attacks, delirium, and dementia. Fajans' ratio, Grunt's ratio, and Turner's ratio, which are reported to be indexes for endogenous hyperinsulinemia in insulinoma, were all negative. Imaging tests, including computed tomography, magnetic resonance imaging and angiography, failed to detect any abnormalities. CEUS showed a small low echoic lesion in the pancreatic body with blood flow and ASVS showed that the insulin levels in the hepatic vein were extremely increased by calcium injection to the splenic artery, indicating an insulinoma in the pancreatic body preoperatively. An open intra-abdominal operation was performed and an insulinoma was confirmed in the pancreatic body. Enucleation of tumor was undertaken and symptomatic hypoglycemia improved.     

Gastrointestinal/pancreatic hormone concentrations in the portal venous system of nine patients with organic hyperinsulinism

Percutaneous transhepatic sampling of blood in the portal venous system (TPVS) was used to; (1) localize hormone secreting tumors and help in differentiating tumors from diffuse disease (nesideoblastosis and hyperplasia with adenomata) in 9 patients with fasting hypoglycemia and hyperinsulinism, and (2) study the concentration an distribution of the immunoreactive peptides: insulin (IRI), gastrin (IG), glucagon (IRG), pancreatic polypeptide (hPP), and somatostatin (SRIF-LI), in the venous drainage of the uninvolved portion of the pancreas and GI tract. Localized elevations of IRI (64-920 microunits/ml) predicted tumor localization in 6 patients with single tumors that were not demonstrable angiographically. In one patient with nesideoblastosis and another with islet cell hyperplasia with adenoma, elevated IRI concentrations at multiple locations suggested a diffuse or multicentric process. Elevations of SRIF-LI in the same region as IRI elevations in one patient and of IRG in another patient suggested that these tumor produced two hormones. Some problems in the interpretation of portal venous insulin concentrations are discussed. The locations of maximum portal venous system plasma concentrations and portal-arterial gradients (mean +/- SE pg/ml) in five patients with small single insulinomas were: IG, gastrocolic trunk (126 +/- 27, 46 +/- 22); IRG, proximal splenic vein (130 +/- 30, 47 +/- 13) and gastrocolic trunk (131 +/- 23, 60 +/- 13); hPP, portal vein (164 +/- 48, 49 +/- 22); SRIF-LI, superior mesenteric vein (186 +/- 50, 57 +/- 20) and gastrocolic trunk (178 +/- 59, 55 +/- 21). It is concluded; (1) TPVS can be used successfully to localize single insulin-secreting tumors of the pancreas and to help distinguish them from diffuse disease but problems in such differentiation do occur, (2) circulating SRIF-LI and IRG are derived from both the pancreas and the gut, IG predominantly from the proximal gut and hPP from the head of the pancreas, and (3) The data provide new information for the interpretation of portal insulin concentrations in patients with organic hyperinsulinism and of hormone concentrations for localization of peptide-producing tumors of the pancreas other than insulinomas.     

Regionalization of occult pancreatic insulinomas with the arterial stimulation venous sampling (ASVS) technique

Non-invasive modalities (ultrasound, computerized tomography, MRI and somatostatin receptor scintigraphy) often fail to localize insulinomas smaller than 1.5 cm in diameter. Recently, regionalization of such occult insulinomas was facilitated by the arterial stimulation and venous sampling (ASVS) technique, using calcium as the insulin secretagogue. However, so far experience with this technique has been limited to a few tertiary referrals centres worldwide. In these case studies we report our experience in three consecutive patients with occult insulinomas.
Three consecutive patients (all men 34, 51 and 56 years of age) with insulin-mediated hypoglycaemia were studied. Diagnosis of insulin hypersection was established by the finding of a high amended insulin : blood sugar ratio during fasting. Localization of a pancreatic mass lesion was unsuccessful by ultrasound, CT and/or MRI in all patients. Two patients had negative octreotide scans. In all patients after the infusion of calcium sequentially into the gastroduodenal, splenic and the superior mesenteric arteries, insulin levels rose significantly in right hepatic vein samples giving rise to diagnostic gradients from the splenic artery (in 2 patients) and gastroduodenal artery (in 1 patient), regionalizing insulinomas in the tail and head or neck of the pancreas respectively. The simultaneously obtained angiogram was positive in only 1 patient, in whom it corresponded to the insulin gradient. Regionalization of these occult tumours was subsequently confirmed at laparoscopy in the 2 patients operated.
It is concluded, that the arterial stimulation venous sampling technique is an effective method in regionalizing occult insulinomas and should complement invasive angiography whenever the latter procedure is performed.     

Insulinoma: Selective arterial calcium injection performed to confirm localization and complete resection

A case of insulinoma is reported in a patient in whom selective arterial calcium injection (SACI) tests were performed both to confirm tumor localization before surgery and to confirm complete tumor removal during surgery. An 18-year-old woman with hypoglycemic episodes was diagnosed with an insulinoma in the pancreatic body demonstrated by celiac arteriography. In a preoperative SACI test, calcium was injected into the splenic artery (SpA), gastroduodenal artery (GDA), and superior mesenteric artery (SMA). Serum immunoreactive insulin (IRI) and proinsulin levels were measured in hepatic venous samples. IRI was markedly increased after the injection of calcium into the GDA and SMA, while there was no response in IRI levels when calcium was injected into the SpA. Therefore, no occult insulinoma was revealed in the distal area fed by the SpA, although the presence of insulinoma was uncertain in the proximal pancreas. In the intraoperative SACI test, calcium was injected into the celiac artery. Insulin (determined by enzyme immunoassay) and proinsulin levels were measured in portal venous samples before and after resection of the tumor. After resection, these levels decreased in response to the calcium stimuli, confirming complete removal of the insulinoma. The SACI test was helpful to localize the insulinoma and was useful to confirm the complete removal of the tumor.     

Islet cell hyperplasia: an unusual cause of hypoglycemia in an adult

This is a case presentation of a 32-year-old man with a one year history of symptomatic hypoglycemia and documented elevations of his fasting plasma insulin to glucose ratio, caused by islet cell hyperplasia. Islet cell hyperplasia is a common cause of hypoglycemia in the pediatric population, but is very rare in adults. As in the pediatric group, adults should be treated with subtotal (75-85%) resection of the pancreas and with diazoxide for symptomatic recurrence of hypoglycemia. We suggest that the term islet cell hyperplasia is preferred to designate a diffuse proliferation of endocrine cells that may express itself with different morphologic patterns, varying from case to case. Islet cell hyperplasia, therefore, comprises nesidioblastosis, endocrine cell budding from ductal structures, as well as islet and islet cell hypertrophy, septal islets, islet dysplasia, and adenomatosis. Immunohistochemistry is a valuable method for the demonstration of the polymorphic hormonal content of the proliferated islet cells. We propose that the term nesidioblastosis, previously used to describe some similar cases, should be avoided because of confusion about its definition.     

Severe hypoglycemia after gastric bypass surgery for morbid obesity

Recently, hypoglycemia with endogenous hyperinsulinemia has been described after undergoing bariatric surgery because of morbid obesity. It has been theorized that after a gastric bypass surgery, some trophic factors affecting pancreatic beta cells could emerge. The authors present a case of morbidly obese patient with severe hypoglycemia 3 months after bariatric surgery. An abdominal helicoidally computed tomography scan showed a 1.7 cm tumor in the tail of the pancreas. Histopathology revealed an insulinoma with well-defined contours surrounded by pancreatic tissue with atrophic signs and with hyperplasia and hypertrophic phenomena compatible with nesidioblastosis in adjacent islets of the pancreatic duct. Authors hypothesize that maintenance of the stimulus produces hyperplasia/hypertrophy of the pancreatic islets and reemphasizes the dynamic qualities of pancreatic beta cells and the possibility of producing hyperplasia from the extreme resistance to insulin present in morbidly obese patients.     

Localization of a Vasoactive Intestinal Peptide-producing Tumor with Selective Venous Sampling

A case of vasoactive intestinal peptide-producing adenoma of the tail of the pancreas (VIP) successfully managed by surgical resection is presented. Peripheral venous VIP levels correlated with the severity of the diarrhea. Intraoperatively, the VIP levels in the splenic and portal veins were 485 and 100 pg./ml, respectively. These data suggest that preoperative selective transhepatic venous catheterization for VIP sampling might be used to establish the site of VIP production and, thereby, direct surgical management. This technic requires further evaluation regarding its role in this clinical setting.     

Clinical case seminar: hypoglycemia after pancreas transplantation: association with allograft nesidiodysplasia and expression of islet neogenesis-associated peptide

We report a case of severe hypoglycemia occurring in a 35-yr-old woman, 6 yr after pancreas transplantation for type 1 diabetes mellitus. Extensive preoperative and intraoperative exploration failed to disclose the presence of a focal adenomatous lesion. Partial allograft pancreatectomy was performed initially, but it failed to control the hypoglycemic symptoms, leading to complete removal of the pancreas allograft. Histopathological examination of the resected pancreas allograft showed the presence of nesidioblastosis, characterized by foci of islet cells budding off ducts, accompanied by an increase in the number of islets, numerous small intralobular islet cell aggregates, and nesidiodysplasia (large, hyperchromatic islet cell nuclei). Islet neogenesis-associated protein-positive islets and ducts were seen by immunofluorescence. Insulin-positive islets ranged from very small to large, with isolated insulin-positive cells diffusely scattered, consistent with islet neogenesis. Very little glucagon staining was identified. Reported cases of adult nesidioblastosis are reviewed. The significance of nesidioblastosis in the context of pancreas transplantation and possible mechanisms of posttransplant hypoglycemia are discussed.     

Congenital hyperinsulinism: pancreatic [18F]fluoro-L-dihydroxyphenylalanine (DOPA) positron emission tomography and immunohistochemistry study of DOPA decarboxylase and insulin secretion

CONTEXT: Congenital hyperinsulinism (HI) is characterized by hypoglycemia related to inappropriate insulin secretion. Focal and diffuse forms of hyperinsulinism share a similar clinical presentation, but their treatment is dramatically different. Preoperative differential diagnosis was based on pancreatic venous sampling, a technically demanding technique. OBJECTIVE: Positron emission tomography (PET) after injection of [18F]fluoro-L-DOPA (L-dihydroxyphenylalanine) has been evaluated for the preoperative differentiation between focal and diffuse HI, by imaging uptake of radiotracer and the conversion of [18F]fluoro-L-dopa into dopamine by DOPA decarboxylase. We propose to validate this test by immunohistochemical approach. PATIENTS AND METHODS: Pancreatic surgical specimens of four focal and three diffuse HI were studied, using anti-DOPA decarboxylase and proinsulin antibodies. The effect of an inhibitor of DOPA decarboxylase (carbidopa) on insulin secretion was evaluated in vivo and in cultured INS-1 cells. RESULTS: Immunohistochemical detection of DOPA decarboxylase showed diffuse staining of Langerhans islets in the whole pancreas in all diffuse cases, in contrast with dense focal staining in all focal cases. Staining of Langerhans islets outside the focal lesion was diffusely but weakly positive. We correlated the localization of DOPA decarboxylase and proinsulin in normal pancreas and in both diffuse and focal HI tissues. The diffuse PET uptake found before treatment in one child with diffuse HI disappeared completely after carbidopa administration, suggesting in vivo that pancreatic cells can take up amine precursors and contain DOPA decarboxylase. The insulin secretion measured in the supernatant was the same whether INS-1 cells were treated by dopamine or Lodosyn or untreated. CONCLUSION: We validate PET with as a consistent test to differentiate diffuse and focal HI.     

Successful treatment of insulinoma by a single daily dose of octreotide in two elderly female patients

We report two cases of insulinoma in advanced age patients considered unsuitable for surgery, in whom single daily doses of octreotide successfully improved hypoglycemia and hyperinsulinemia. The biological half-life of octreotide is about 100 min, hence it is customary to use two or three administrations per day to prevent hypoglycemia in insulinoma patients. The first case was a 76-year-old woman who presented with hyperinsulinemic hypoglycemia. Computed tomography (CT) and magnetic resonance imaging did not identify a tumor in the pancreas but a 1.5-cm tumor was found in the pancreatic body on abdominal angiography and selective arterial calcium stimulation and hepatic venous sampling (ASVS) were compatible with insulinoma. The patient refused surgery, but was successfully treated with octreotide at 50 microg subcutaneous injection once daily. Since the treatment was started (1 year), she has not suffered hypoglycemia. Case 2 was an 85-year-old woman who presented with hyperinsulinemic hypoglycemia. CT identified a 1.5-cm tumor in the pancreatic uncus, but she was considered unsuitable for surgery due to advanced age, obesity and cardiopulmonary dysfunction. Octreotide at 100 microg subcutaneous injection once daily prevented further hypoglycemic attacks, but two months later, postprandial plasma glucose was elevated. Octreotide was gradually reduced to 50 microg once daily. Three years have passed since the treatment without any hypoglycemic attack. Successful treatment with octreotide once daily could be due to old-age-related slow metabolism and could be potentially considered as the treatment of choice for elderly patients with insulinoma especially those considered unsuitable for surgery.     

Diagnosis of islet cell tumor by means of endoscopic ultrasonography

A 31-year-old man with recurrent attacks of hypoglycemia was hospitalized with the clinical suspicion of an insulinoma. Computed tomography and conventional (transabdominal) ultrasound were doubtful, showing a small solid low-density mass probably originating from the tail of the pancreas. Selective angiography and transhepatic venous sampling for pancreatic hormone assay were not discriminant. Finally, an endoscopic ultrasonographic examination, allowing a better visualization of the pancreas, established with certainty the origin of the lesion from the tail of the gland. This was subsequently confirmed at operation.     

Abnormalities of proinsulin processing in functioning insulinomas: clinical implications

OBJECTIVE: Abnormal proinsulin processing in insulinomas may result in secretory granules containing both insulin and proinsulin, a finding not encountered in healthy beta-cells. The aim of this study was to test whether such abnormalities in the proinsulin to insulin conversion have clinical implications in patients with hypoglycaemic disorders. DESIGN: Case-series. PATIENTS AND METHODS: Fifteen patients with histologically confirmed insulinoma and two patients with islet cell hyperplasia were included. The immunohistochemical distribution pattern of proinsulin within the tumour cells was classified as Golgi pattern (predominantly perinuclear immunolabelling) or diffuse pattern (immunolabelling in the periphery of the cells, indicating the presence of proinsulin in secretory granules). Data obtained from the 72-h fast and arterial calcium stimulation and hepatic venous sampling (ASVS) test were related to the morphological classification. RESULTS: Six insulinomas exhibited a diffuse proinsulin distribution pattern, while nine insulinomas and two islet cell hyperplasias disclosed a Golgi pattern. Median proinsulin concentrations at the termination of the fast tended to be higher in patients with the diffuse proinsulin distribution pattern than in patients with the Golgi pattern (86.9 vs. 18.8 pmol/l, P = 0.07). Higher insulin (P < 0.005) and proinsulin (P < 0.05) concentrations were significantly correlated with earlier occurrence of hypoglycaemia during the prolonged fast. During the ASVS test, tumours with the diffuse proinsulin distribution pattern exhibited a higher increase in both insulin (median, 37.3- vs. 10.5-fold, P < 0.05) and proinsulin (6.3- vs. 1.6 fold, P < 0.005) concentrations following calcium stimulation than the tumours with the Golgi pattern. CONCLUSIONS: Abnormalities in the proinsulin to insulin conversion in patients with insulinomas and islet cell hyperplasia correlate with impaired regulation of both insulin and proinsulin secretion during the prolonged fast as well as the ASVS test.