Insulinoma

　　1. Causes of Onset

　　It usually occurs during stress such as fasting, drinking, infection, excessive activity, etc. Most cases progress from occasional to frequent episodes, gradually worsening, even occurring several times a day. The duration of the episode can be as short as a few minutes, as long as several days, or even more than a week, and may be accompanied by other complications such as fever. If glucose is ingested or injected intravenously promptly, symptoms can be relieved within a few minutes. In initial cases or diabetic patients with this condition, hypoglycemic symptoms can occur if blood glucose levels do not drop below 3.33 mmol/L (60 mg/dl). However, clinical symptoms and blood glucose levels are not always proportional, and some may never experience symptoms before breakfast; blood glucose levels may not necessarily be low during an episode, and symptoms can also resolve without glucose supplementation; if the condition is severe or the episode lasts a long time, symptoms may not disappear until several hours after eating. These atypical clinical manifestations may be related to the intermittent secretion of insulin by the tumor, as well as the degree, speed, duration, course of the disease, and individual differences in sensitivity to hypoglycemia. This complex clinical presentation poses certain difficulties for diagnosis. It is often misdiagnosed as epilepsy, hysteria, mental illness, transient cerebral ischemia, but there are also neurologic symptoms due to long-term use of sedatives and anticonvulsants, causing brain tissue damage, etc. The main reason is the insufficient understanding of the clinical characteristics of the disease under different conditions.

　　Most insulinomas are solitary, accounting for about 91.4%, while a few are multiple. The tumor size is generally small, with about 82% having a diameter of 1-2.5 cm. The incidence in the head of the pancreas is 17.7%, in the body 35%, and in the tail 36%; the incidence of ectopic insulinoma is less than 1%.

　　Insulinoma has a smooth surface observed with the naked eye, often circular or elliptical, occasionally irregular. Generally, it appears pink or dark red with clear boundaries and slightly hard texture. Tumor cells contain insulin, with approximately 10-30 IU per gram of tumor tissue, with some reaching up to 100 IU (normal pancreatic tissue contains 1.7 IU of insulin per gram). Under microscopic examination, tumor cells are polygonal with blurred cell boundaries and sparse, translucent cytoplasm; the nuclei are round or elliptical, of uniform size, with finely detailed chromatin and nuclei are usually not easily seen; tumor cells are arranged in clusters closely associated with capillaries, forming small nodules or islets; tumor cells can also be arranged in an acinar pattern, forming daisy-like clusters, with red-stained secretions sometimes visible in the acinar cavities, cells are mostly columnar with the nucleus at the base; tumor cells can also be distributed in a sheet-like manner. Under electron microscopy, the secretory granules of tumor cells can be seen to have B-granule characteristics. Insulinoma can be benign or malignant, and it is sometimes difficult to confirm solely based on cell morphology, with the most reliable indicator being the presence or absence of metastasis.

　　The clinical symptoms caused by insulinoma are related to the elevated level of insulin in the blood, but more importantly, it is the lack of normal physiological feedback regulation of insulin secretion, not simply excessive insulin secretion. Under physiological conditions, normal blood glucose levels are regulated and maintained by insulin and glucagon. When blood glucose levels drop, the secretion of glucagon increases, and the secretion of insulin is inhibited. When blood glucose drops to 1.94mmol/L, insulin secretion is almost completely stopped. However, in patients with insulinoma, this normal physiological feedback mechanism is completely lost, and tumor cells continue to secrete insulin, leading to hypoglycemia. The metabolic activity of human brain cells can almost only use glucose and cannot utilize glycogen to supply heat. Therefore, when blood glucose levels drop, it first affects the metabolism of brain cells, leading to central nervous system symptoms such as drowsiness, confusion, and even coma.

　　2. Pathogenesis

　　1. Pathogenesis The islets are mainly composed of endocrine cells and are part of the gastro-entero-pancreatic endocrine system. According to the ultrastructure and immunocytochemical characteristics of islet cells, human islet cells are divided into A, B, D, Dl, and EC cells, and there may also be F cells. Islet B cells are mostly distributed in the center of the islets, accounting for about 3/4 of the total number of islet cells, and they secrete insulin and a small amount of proinsulin.

　　The main defect of insulinoma is the decreased ability to store insulin. Insulinoma cells can synthesize insulin and also respond to various stimuli, but they have partially or completely lost the ability to store insulin. Under normal physiological conditions, the maintenance of normal blood glucose levels mainly relies on the regulation of insulin and glucagon secretion, and blood glucose levels are an important factor in controlling insulin release. When blood glucose levels drop, it can directly promote the secretion of glucagon and inhibit the secretion of insulin. When blood glucose drops to 1.96mmol/L (35mg%), insulin secretion is almost completely stopped. However, this normal physiological feedback phenomenon is lost in patients with insulinoma, leading to a continuous release of insulin from islet cells and an inhibition of glycogenolysis in the liver that exceeds the requirements of blood glucose levels, thus causing hypoglycemia syndrome.

　　In the cells of the whole body tissue, the energy source of brain, kidney cells, small intestinal mucosal epithelial cells, and others is glucose, especially in the brain tissue, the energy supply from glucose oxidation is almost the only energy source, and the utilization of fat and protein in brain tissue is far less than that of other tissues. On the other hand, the glycogen storage in brain tissue is extremely low, with a total amount of only 1g, and the brain tissue requires about 60mg of glucose per minute under normal conditions. Once blood glucose levels drop, it causes a reduction in glucose supply to brain cells and cell metabolic disorders. During hypoglycemia, the cerebral cortex is usually affected first, and if hypoglycemia persists, the mesencephalon, pons, and medulla oblongata will be affected sequentially. The early damage to brain cells during hypoglycemia is transient and reversible, but if repeated episodes last too long, it can lead to severe damage to brain cells and irreversible pathological changes. Degenerative changes and necrosis can be seen in the basal ganglia of the cerebral cortex, chromatin dissolution, cell atrophy, and proliferation and swelling of the endothelial cells of central small blood vessels, leading to local tissue ischemia. This thus produces a series of neurological and psychiatric symptoms.

　　After the onset of hypoglycemia, the body needs to maintain blood glucose levels, compensatorily accelerate the secretion of adrenaline, increase the activity of phosphatase, and promote the conversion of glycogen to glucose. Therefore, the content of adrenaline in the blood and urine of patients can increase. In the early stage of hypoglycemia and before coma, clinical symptoms of sympathetic nervous system excitement, such as rapid pulse, increased blood pressure, palpitations, and sweating, can be seen.

　　Therefore, the main metabolic change of insulinoma is hypoglycemia, which leads to central nervous system disorders, even coma, and clinical symptoms of sympathetic-adrenal medullary excitement due to hypoglycemia.

　　2, Pathological changes Insulinomas can occur at any part of the pancreas, with the incidence of the head, body, and tail of the pancreas being basically the same. The incidence of those occurring in the tail is slightly higher, but the head and hook-like parts are not easy to detect. The tumor volume is generally small, with the diameter of the tumor usually between 0.5-5cm, but more than 80% of the tumors have a diameter less than 2cm, which causes great difficulty in localization diagnosis. Most are spherical, and most of the tumors have clear boundaries, but no obvious capsule; some tumors have a capsule or pseudocapsule. The texture is softer than that of normal tissue, and it is rich in blood supply. The living tumor seen during surgery is reddish-brown or bluish-purple, while the tumor section after surgery is dark red or light red. Insulinoma is the most common type among various islet cell tumors, with about 50% of the tumors being pure β-cell tumors, but some are mixed tumors containing α-, δ-, PP, and G cells. β-cell hyperplasia has diffuse and nodular types, and sometimes it can be accompanied by microadenoma. At present, it is still very difficult to distinguish the specific type of tumor cells, whether under light microscopy or electron microscopy. Insulinoma is composed of tumor cells, connective tissue, and amyloid material deposited between tumor cells and capillaries. Under light microscopy, it appears as an increase in the size or number of local islets, and the tumor cells under the microscope are quite similar to normal β-cells, showing that the tumor cells are arranged in string-like or mass-like, being islet B cells of unequal size, with pale cytoplasm containing granules. They are polygonal, cuboidal, or columnar, and the nuclei are round or oval, with rare nuclear division. Under electron microscopy, the tumor cells contain abundant functional organelles, with rich mitochondria in the cytoplasm. In some tumor cells, typical β-cell secretory granules are also present, but since not all insulinoma cells contain secretory granules internally, and high-density secretory granules can also appear in other types of islet cells, it is still very difficult to judge the specific type of tumor cells under electron microscopy.

　　Under electron microscopy or immunohistochemical examination, the tumor cells show several different morphologies.

　　Type Ⅰ: The adenoma is completely composed of typical β-granule cells, accounting for more than 50%;

　　Type Ⅱ: The adenoma is mainly composed of typical β-granule cells, with a small number composed of a mixture of atypical β-granule cells;

　　Type Ⅲ: The adenoma is completely composed of atypical β-granule cells;

　　Type Ⅳ: It is almost entirely composed of acellular cells. In typical β-granule cells, insulin content is the highest, while atypical β-granule cells contain proinsulin or proinsulin-like components (PLC); acellular cells may be malignant.

　　Immunohistochemistry fills the gap of light microscopy and electron microscopy and is the best technique for diagnosing and differentiating islet tumors so far. This method uses specific anti-insulin antibodies, which can cause the vast majority of β-cell tumors to show immunopositive reactions and is currently the main basis for the pathological diagnosis of insulinoma.

　　The disease often has liver and nearby lymph node metastasis. Malignant insulinoma (islet B-cell carcinoma) is rare and it is not easy to distinguish from the benign one just by morphology. Generally, the tumor mass is larger, mostly occurring in the tail of the pancreas, and appears gray or dark red. Under the microscope, the arrangement of cancer cells also shows a fibrous pattern, but the cell morphology is not uniform, the cytoplasm is transparent, the nucleus is deeply stained, showing square or polygonal shape, and nuclear division is common. However, the reliable basis for diagnosing malignant insulinoma at present is tumor metastasis or obvious infiltration of surrounding tissues.

　　Most tumors grow within the pancreas, with ectopic tumors being rare, with an incidence rate of less than 1%, mostly located in the duodenum, porta hepatis, and adjacent to the pancreas. This often brings difficulties to preoperative localization and is not easy to be discovered during surgery.

　　When patients have multiple endocrine adenomas (insulin-dependent type), pituitary adenoma, thyroid adenoma, adrenal adenoma, and hyperparathyroidism may coexist. In clinical practice, in addition to hypoglycemia symptoms, there may also be symptoms such as headache, bone pain, polyuria, etc.

　　Insulinoma can cause paroxysmal hypoglycemia or hypoglycemic coma, manifested as cold sweat, palpitations, tremors in hands and feet, thirst, tachycardia, etc.

　　Some cases present with chronic hypoglycemia, with unconscious changes in personality, decreased memory, loss of reason, unsteady gait, blurred vision, mania, hallucinations, and abnormal behavior, leading to misdiagnosis as mental illness.

　　The typical clinical manifestation of insulinoma is the Whipple 'triad' or insulinoma triad, namely:

　　Paroxysmal hypoglycemia or coma often occurs during hunger or fatigue.

　　During an acute attack, blood sugar is usually below 2.8 mmol/L (50 mg％).

　　After oral or intravenous administration of glucose, symptoms are relieved.

　　Hypoglycemia is the basic cause of various clinical manifestations. Hypoglycemia or hypoglycemic coma is caused by elevated insulin concentration in the blood, which usually occurs in the morning, after fasting, fatigue, and emotional tension. Initially, it may occur every few days, weeks, or months, but over time, the frequency and severity of attacks increase. When blood sugar rapidly decreases, the body's compensatory mechanism, to promote glycogenolysis in the liver, increases adrenaline secretion, leading to symptoms of sympathetic overexcitation: weakness, fatigue, cold sweat, palpitations, tremors in hands and feet, pale skin, thirst, tachycardia, hunger, nausea, and vomiting, etc. When blood sugar continues to decrease and the body loses compensatory response, brain cells are insufficiently supplied with glucose, usually affecting the cerebral cortex first, leading to neurological and psychiatric symptoms, accompanied by mental disorder, drowsiness, convulsions, facial twitching, opisthotonos, frothing at the mouth, locked jaw, incontinence of urine and feces, delayed response, disorientation, blurred vision, diplopia or fixed gaze, transient hemiplegia, positive pyramidal tract sign, disappearance of reflexes, and coma, etc. Mild cases may manifest as staring eyes, dementia, and delayed response; severe cases may have symptoms such as restlessness, incoherent speech, personality changes, and even auditory and visual hallucinations and delusions, etc. Subsequently, it may affect the diencephalon, mesencephalon, pons, and medulla oblongata. When the mesencephalon, pons, and medulla oblongata are affected, coma may occur. Multiple episodes of hypoglycemia can lead to malnutrition and degenerative changes in the brain, resulting in chronic symptoms such as mania, depression, dementia, and muscle atrophy, etc.

　　Some cases present with chronic hypoglycemia, with atypical symptoms, such as unconscious changes in personality, decreased memory, loss of reason, unsteady gait, blurred vision, and sometimes mania, hallucinations, and abnormal behavior, leading to misdiagnosis as mental illness. Less common symptoms include peripheral neuropathy and progressive muscle atrophy; some may frequently eat to avoid hunger or alleviate symptoms, resulting in 'obesity'.

　　The course of insulinoma is long, with slow progression. Initially, the symptoms are mild and short-lived, occurring once or twice a year, seemingly偶然. Later, the frequency of attacks increases and the symptoms become more severe, even several times a day. Prolonged and repeated attacks of hypoglycemia in the brain can lead to irreversible damage to the nervous system, causing intellectual impairment and abnormal behavior in the remission period, leading to dementia and the loss of working capacity.

　　Some cases are accompanied by Zollinger-Ellison syndrome, and about 10% of patients have peptic ulcers. However, it must be pointed out that various symptoms can appear in any type of hypoglycemia. Many patients eat more to prevent hypoglycemic attacks, only to become overweight due to excessive calorie intake. Cancer patients have a rapid progression of the disease, liver enlargement, hard texture, weight loss, abdominal pain, diarrhea, and other severe symptoms of hypoglycemia.

　　There are no effective preventive measures for this disease. Early detection and early diagnosis are the key to the prevention and treatment of the disease. Hypoglycemia is the basic cause of various clinical manifestations. Hypoglycemia or hypoglycemic coma is caused by an increase in insulin concentration in the blood. It often occurs in the morning, after fasting, after exertion, and during emotional tension. In the early stages, it may occur every few days, weeks, or months, and as it progresses, the frequency and severity of attacks increase. Therefore, it is necessary to actively prevent the occurrence of hypoglycemia.

　　1. Blood Glucose Measurement:When clinical symptoms occur, blood glucose should be measured immediately. If the blood glucose level is below 40 mg/dl, it can be considered an important diagnostic basis. However, if blood is drawn slightly later in the attack, it may sometimes not reflect a severe hypoglycemic state due to fluid regulation and compensatory action.

　　2. Qualitative Diagnosis

　　1. Fasting Test:The method is simple and easy to perform, with a positive rate of 80% to 95%. The clinical symptoms are atypical, and fasting blood glucose should be greater than 2.8 mmol/L (50 mg/dl) before the test can be conducted. Generally, hypoglycemia can be induced after 12 to 18 hours of fasting (water excluded); the positive rate after 24 hours of fasting is 85%; after 48 hours of fasting, the positive rate is above 95%, and after 72 hours, it is 98%. Increasing exercise can induce hypoglycemia, especially when blood glucose levels decrease while plasma insulin levels do not decrease, which has diagnostic significance. If hypoglycemia is not induced after 72 hours of fasting, the disease can be ruled out. This test must be conducted under strict observation and with emergency measures in place to prevent accidents. Three consecutive checks are required, and fasting blood glucose below 2.8 mmol/L (50 mg/dl) can be diagnosed as an insulinoma. In mild cases, fasting can be extended to more than 24 to 48 hours. Each episode of hypoglycemic coma and convulsions may exacerbate the damage to brain nerve cells. Therefore, in patients with typical symptoms, it is not advisable to perform this provocative test again. During the examination, if symptoms appear, 50% glucose solution should be administered intravenously immediately to relieve the symptoms.

　　Blood glucose, insulin, and C-peptide levels are measured every 4 to 6 hours. If hypoglycemic episodes are severe, the test should be immediately terminated and 50% glucose 60 to 80ml should be administered intravenously when blood glucose ≤2.5 mmol/L (45 mg/dl). Patients with liver disease and hypopituitarism-adrenal insufficiency may also develop severe hypoglycemia, so caution is necessary.

　　2. Oral glucose tolerance test (OGTT):Multiple measurements of fasting blood glucose, and

　　3. Measurement of insulin and proinsulin:In addition to fasting and episodes when blood glucose is below 2.2 mmol/L (40 mg/dl), the following tests can be used:

　　(1) Measurement of plasma insulin during fasting attacks: In normal individuals, the concentration of plasma insulin during fasting is generally within the range of 5 to 20 mU/L, rarely exceeding 30 mU/L. However, this disease often has autonomous secretion of hyperinsulinemia. When patients fast for 12 to 14 hours in the morning, about 80% of them can develop hypoglycemia and have relatively high plasma insulin levels. For patients with both hypoglycemia and hyperinsulinemia, measurement of plasma C-peptide can help distinguish between iatrogenic hypoglycemia caused by exogenous insulin and spontaneous hypoglycemia. In 95% of insulinoma patients, the C-peptide level is ≥300 pmol/L. However, hypoglycemia caused by sulfonylurea drugs cannot be excluded by C-peptide measurement, and detection of these drugs in urine is necessary. However, obesity, acromegaly, Cushing's syndrome, late pregnancy, oral contraceptives, and other factors can lead to hyperinsulinemia. In insulinoma-induced hypoglycemia, most insulin levels are elevated, especially when insulin and C-peptide levels are inconsistent in patients with hypoglycemia. Measurement of proinsulin is very necessary in this case, as it is of diagnostic value in distinguishing between hypoglycemia caused by endogenous and exogenous insulin. However, the diagnosis of hypoglycemia cannot be made solely based on elevated proinsulin levels. C-peptide and insulin are secreted simultaneously, and C-peptide has antigenicity. Therefore, the use of radioimmunoassay to measure C-peptide can reflect the secretory function of islet cells. When serum and urine C-peptide levels increase in insulinoma or islet B-cell hyperplasia, since exogenous insulin does not contain C-peptide, it will not interfere with C-peptide measurement. Therefore, in diabetic patients treated with insulin who also have an insulinoma, this test is of great value.

　　(2) Insulin release test: The tolbutamide (D860) test can stimulate the pancreas to release insulin, causing a marked hypoglycemia that lasts for 3 to 5 hours. In normal individuals, intravenous injection of 1g of D860 (or 20 to 25mg/kg dissolved in 20ml of physiological saline) at 5 minutes causes a transient plasma insulin increase to 60 to 130 μu/ml. After 20 to 30 minutes, blood glucose levels gradually decrease, and they can return to normal within 1.5 to 2 hours. However, in patients with insulinoma, the reaction is intensified within 5 to 15 minutes after injection, and hypoglycemia does not recover 2 to 3 hours later. After tumor resection, this abnormal reaction disappears, and it can be used to judge the functional status of beta cells in the islets. Since insulinoma can secrete insulin intermittently, suspicious patients need to be re-examined regularly. The glucose tolerance curves of patients with various diseases can be significantly different.

　　A. Its specific methods include:

　　a. Intravenous method: You can use the 25g glucose intravenous injection method for glucose tolerance test. If the curve shows that the peak of insulin level at one point at any time point exceeds 150mU/L, it also supports the diagnosis of this disease. Inject 1g of D860 intravenously, and draw blood every 2.5, 5, 10, 30, and 60 minutes after injection. Insulinoma patients may experience acute hypoglycemia, often with blood glucose levels dropping below 1.6mmol/L within 30 to 60 minutes after injection, and hypoglycemia can last for more than 180 minutes. Normal individuals show no spontaneous hypoglycemia reactions, and the plasma IRI level is significantly increased.

　　b. Oral method: After taking 75g of glucose, perform a glucose tolerance test. At the same time as measuring blood glucose levels, measure insulin levels. The glucose tolerance curve of this disease is mostly flat, but the insulin curve is relatively high. If the peak of one point at any time point exceeds 150mU/L, it is helpful for the diagnosis of the disease. After drawing blood to test blood glucose in the morning, take 2g of D860 orally, and then draw blood every 1/2 hour thereafter. Insulinoma patients often show significant hypoglycemia within 3 to 4 hours, and the blood glucose curve shows hypoglycemia after taking the medicine, with a significant degree of hypoglycemia and a long duration that is difficult to recover, and it can also induce hypoglycemic coma.

　　B. Points to note for the D860 test:

　　a. Fasting blood glucose level of the patient

　　b. If loss of consciousness or symptoms of hypoglycemia occur during the test, stop the test immediately and administer glucose orally or intravenously.

　　c. The D860 injection test is relatively dangerous. After injecting D860, connect normal saline to maintain the patency of the infusion, and be able to promptly inject glucose or glucagon if a hypoglycemic episode occurs.

　　III. L-leucine test:After taking an oral solution of L-leucine at a concentration of 2% for 150mg/kg for about half an hour, the patient's blood glucose level decreases to below 60% of the fasting blood glucose level, and then gradually recovers. The plasma insulin content increases. Normal individuals show no decrease in blood glucose after taking it, with a positivity rate of 50% to 60%.

　　IV. Glucagon test:Intravenous injection of glucagon 1mg (completed within 2 minutes), followed by the measurement of plasma insulin and blood glucose levels within 30 minutes. Blood glucose can rapidly increase, while the plasma insulin concentration can decrease. However, the blood glucose level returns to normal within 1 to 1.5 hours after the injection of glucagon. 2 hours later, it shows hypoglycemia of 2.52mmol/L to 2.8mmol/L (45mg% to 50mg%), with an increase in insulin content. If the blood glucose level is below 2.52mmol/L (45mg%), and the plasma insulin level is greater than 100μu/ml, a definite diagnosis can be made. The positivity rate of this test can reach 80%, therefore, this test has diagnostic value for insulinoma-induced hyperinsulinism. This test is safer than sodium metformin and has higher accuracy. Normal individuals show no symptoms of hypoglycemia.

　　V. Calcium stimulation test:Intravenous administration of calcium gluconate at 5mg/kg·h for a total of 2h, the blood glucose level gradually decreases 15 to 30 minutes after administration, and the plasma insulin content increases. In normal individuals or patients with functional hypoglycemia, there is no significant change.

　　The ratio of plasma proinsulin (or pre-insulin) to insulin:When B cells secrete insulin, it contains insulin, C-peptide, and proinsulin. The ratio of proinsulin to insulin in normal plasma does not exceed 25%. In the plasma of insulinoma patients, the content of proinsulin is almost always increased, and some can be more than 10 times higher (normal value below 0.25ng/ml). An increased ratio of proinsulin to insulin is more obvious in cases with malignant transformation.

　　Seven, plasma IRI measurement and IRI/G ratio:The concentration of fasting plasma immunoreactive insulin (IRI) in normal people is less than 24μu/ml, and the concentration in insulinoma patients is moderately elevated. However, due to the periodic nature of insulin secretion, the peak and minimum values in peripheral blood can differ by a factor of 5. In addition, obesity, acromegaly, Cushing's syndrome, and late pregnancy can all cause hyperinsulinemia. Therefore, insulinoma cannot be diagnosed solely based on IRI. The calculation of the IRI/glucose concentration ratio (IRI/G) has greater diagnostic value, with a normal IRI/G value less than 0.3. 95% of insulinoma patients have a fasting IRI/G > 0.3 for 24 hours. If fasting is extended to 72 hours, all cases are positive. Tarrer et al. proposed the 'modified IRI/G' calculation method: IRI × 100 / G - 3. The ratio is 50 in the morning of normal people, which almost definitely indicates the diagnosis of insulinoma.

　　Eight, suppression test:Creutzfeldt et al. used a computer-controlled glucose infusion system to determine the amount of glucose needed to maintain a blood glucose level of 4.5mmol/L in patients, which is about 25mg/min in normal people, while insulinoma patients have a significantly higher value. In the second stage, this infusion system was maintained, and somatostatin (SRIH) and diazoxide, which can inhibit insulin release, were injected. Then, the amount of glucose infusion needed to maintain a blood glucose level of 4.5mmol/L was recalculated. Normally, this value is significantly lower than that at rest due to the decrease in insulin secretion, while insulinoma has a certain resistance to the inhibition of these two drugs, so this value remains unchanged or only slightly decreases. In malignant insulinoma, there is no response to drugs that normally inhibit insulin secretion, so this test can serve as a diagnostic test for insulinoma and also help in preoperative judgment of benign or malignant insulinoma, and can help judge the effectiveness of SRIH treatment in clinical practice.

　　Nine, diagnostic imaging:Before localization diagnosis, it should be further confirmed as necessary after the biochemical diagnosis is re-evaluated repeatedly.

　　1. Selective arterial angiography:Selective functional angiography is helpful for localization, but this method has the risk of vascular injury, and abdominal angiography lacks sensitivity. Angiography can be performed separately for the gastric duodenal artery, superior mesenteric artery, splenic artery, and pancreaticoduodenal artery. Observe the tumor capillary phase, as the tumor vessels are rich, the contrast agent can show smaller tumors, and the positive manifestation is tumor filling staining, increased vascular twisting, with a positive rate of 20% to 80% (average 63%). If this method is combined with the determination of insulin levels by segmental blood sampling from the splenic hilum portal vein, it can improve the accuracy of tumor localization during surgery.

　　2, B-ultrasound examination:Although B-ultrasound is safe, due to the small size of the tumor, it cannot locate more than 50%, during surgery, intraoperative ultrasound examination can help further diagnosis. In laparotomy, using an ultrasound probe directly aimed at the pancreas can better distinguish the tumor from normal tissue. On the ultrasound image, the lesion can be seen as a circular or elliptical solid dark area with clear boundaries and smoothness, clearly demarcated from normal pancreatic tissue. In cases of malignant insulinoma, the tumor volume is usually large, with bleeding, necrosis, and local infiltration, but it is difficult to differentiate from pancreatic cancer based solely on its ultrasound image. The sensitivity of B-ultrasound for insulinomas is about 30%, and it is difficult to detect tumors smaller than 1.5 cm in diameter using B-ultrasound.

　　3, CT examination:For insulinomas with a diameter greater than 2 cm, the detection rate of CT can reach more than 60%, for tumors with a diameter less than 2 cm, although CT's localization ability is slightly stronger than that of B-ultrasound, its sensitivity is still only 7% to 25%; the sensitivity is related to the type of machine and the examination method. It is necessary to perform an enhanced scan when using CT to examine insulinomas, and it is as good as possible to use dynamic scanning after enhancement. Only in this way can some small insulinomas be detected due to obvious enhancement, although the detection rate of CT is not high, as it is a non-invasive examination and can simultaneously detect multiple lesions and liver metastases, it is currently one of the most commonly used methods for preoperative localization of insulinoma surgery. Enhanced CT scanning can improve the visibility of insulinomas, as insulinomas are highly vascular tumors, when using iodinated agents, a bright area can appear in the normal pancreatic tissue, with a positive rate of about 40%.

　　4, MRI:As compared with current clinical practice, MRI is not as good as CT in localizing insulinomas, with a sensitivity of 20% to 50%; the detection rate of liver metastasis is also not as good as CT, so MRI is generally not used for preoperative localization examination.

　　Ten, Selective percutaneous liver venous blood sampling:The combination of selective percutaneous liver venous blood sampling with plasma insulin measurement has been clinically applied to clarify hyperinsulinemia locally in the head, body, and tail of the pancreas, ①it is necessary to have experience in selective venous catheter insertion surgery, ②the incidence of intra-abdominal hemorrhage, infection, and bile leakage after surgery is high, ③for some rare cases, such as multiple adenomas with hyperplasia, this method cannot accurately locate, when sampling from the spleen and portal vein system, due to the fast blood flow speed, the blood sample is diluted, causing a negative result of low plasma insulin, ④the drug used to inhibit insulin secretion must be discontinued for at least 24 hours before sampling to allow the recurrence of hypoglycemia in the patient.

　　Eleven, Endoscopic ultrasonography (endoscopicultrasonography):This technique can be the best imaging technique before surgery, with a diagnosis rate of about 95% for intrapancreatic islet cell tumors. However, it requires a skilled operation technician. Techniques such as pancreatic radionuclide scanning, endoscopic retrograde cholangiopancreatography, and digital subtraction angiography are helpful for the diagnosis of this tumor.

　　Twelfth, labeled scanning drugs:Recently, the use of 125I-tyrosine complex 8-peptide as a scanning drug has been used to locate pancreatic islet cell tumors and their metastases, finding that they have special somatostatin receptors. This method may be helpful for tumor localization before surgery.

　　1. Foods that are good for insulinoma patients to eat

　　(1) Consume fresh fruits rich in vitamins, such as rapeseed, spinach, Chinese cabbage, tomatoes, oranges, hawthorn, fresh jujube, and kiwi.

　　(2) Selenium, a trace element, is a strong antioxidant that can also resist mutation, inhibit cell proliferation, promote the natural inactivation of carcinogens, and enhance immunity. Foods rich in selenium include garlic, pork kidneys, chicken livers, shrimp, fish, egg yolks, mushrooms, asparagus, cabbage, and broccoli.

　　(3) Molybdenum can block the synthesis of nitrosamines in the body, especially reducing the incidence of intestinal cancer. Foods rich in molybdenum include radishes, cabbage, beans, and sprouts.

　　2. Foods that insulinoma patients should avoid eating

　　Both iodine deficiency and excess can cause thyroid or parathyroid cancer, so it is necessary to consume foods rich in iodine such as kelp, nori, and hair grass in moderation.

　　(The above information is for reference only, please consult a doctor for details)

　　First, treatment

　　1. General treatment:The combined use of medication and dietary methods in the early stage is effective for alleviating the symptoms of some patients. To alleviate symptoms, it is recommended to consume more carbohydrates, increase the frequency and quantity of meals, and take oral or intravenous glucose injections before the expected onset time. Especially in the evening, it is not advisable to restrict the intake of slow-absorbing foods such as bread, potatoes, and rice. When hypoglycemia occurs, use rapidly absorbed sugars such as fruit juice or sucrose. For patients with severe, refractory hypoglycemia, continuous intravenous glucose infusion is a treatment method.

　　2. Surgical treatment of pancreatic islet cell tumors:Surgical resection is the only effective method for the treatment of insulinoma. Once the diagnosis is confirmed, early surgical treatment should be performed. Due to the repeated occurrence of hypoglycemic coma, brain cells can undergo irreversible changes, so in the late stage, even if the tumor is resected, it can only alleviate the symptoms of hypoglycemia, and the symptoms of mental disorders cannot be improved. The Mayo Clinic team performed surgery on 154 patients, with a success rate of 85% and a mortality rate of 5.4%. In patients who have not found a clear tumor, the success rate of pancreatic tail blind resection is significantly reduced, with only 50% of patients showing improvement in their condition. Some patients have not been found to have a primary or metastatic focus, or because the tumor is too small, they are not yet eligible for surgical resection. In cases of successful surgery, it can be observed that plasma glucose levels increase during the surgical process. Although the response to surgery is varied, other factors can also change glucose levels.

　　Once the diagnosis of insulinoma is confirmed, early surgical treatment should be performed to remove the tumor. Because long-term coexistence and repeated attacks of hypoglycemic coma can cause irreversible damage to the brain tissue, especially the brain.}

　　Anesthesia is general anesthesia or continuous epidural block anesthesia. The incision is chosen as a left upper abdominal midline incision or an upper abdominal curved incision. Qingdao Municipal Hospital uses a Mason incision, which is reported to have good exposure. Whether the tumor location has been determined before the operation or not, the entire pancreas should be explored carefully and thoroughly during the operation to understand the location, size, number, depth of the tumor, and whether there is liver metastasis. For this purpose, a Kocher incision should be made, the duodenum and the head of the pancreas should be freed up; the peritoneum above and below the body and tail of the pancreas should be incised and freed up; the retroperitoneal tissue should be incised and separated along the superior mesenteric artery to explore the hook-shaped part of the pancreas; if necessary, it is also necessary to explore whether there is an ectopic pancreas. Intraoperative ultrasound combined with surgical exploration can make the exploration more accurate. The surgical method should be determined according to the location and number of the tumor:

　　(1) Simple tumor resection: For superficial, small, solitary benign insulinoma, simple tumor resection can be performed.

　　(2) Subtotal pancreatectomy of the body and tail: When the tumor is located in the body and tail of the pancreas, it is large and deep, multiple, or it is difficult to distinguish between benign and malignant, subtotal pancreatectomy of the body and tail can be performed.

　　(3) For benign insulinomas in the head of the pancreas, a wedge resection method can be used, but the margin should be 0.5 to 1 cm away from the tumor. During the operation, it should be avoided to damage the pancreatic duct. Once the pancreatic duct is damaged, a pancreatic jejunum Roux-y anastomosis should be performed; if both the pancreatic duct and the common bile duct are damaged, a pancreaticoduodenectomy should be performed.

　　(4) For those who, after a thorough and careful exploration, still cannot find a tumor, a blind subtotal pancreatectomy can be performed because insulinomas located in the body and tail account for more than 2/3. In recent years, many people have adopted a progressive subtotal pancreatectomy, the method of which is: to start from the tail of the pancreas and cut it section by section, and send the frozen section for examination and measure blood glucose and blood insulin content after each cut. If the frozen section has confirmed the insulinoma, and the blood glucose is still low, and the blood insulin content does not decrease, it may be a malignant tumor, and partial pancreatic tissue should continue to be removed until the blood glucose level rises and the blood insulin content decreases, and then the operation can be stopped. For this hidden insulinoma, it is generally not recommended to perform a total pancreatectomy.

　　(5) If the pathological examination confirms the hyperplasia of pancreatic islet cells, it is often necessary to remove more than 80% of the pancreatic tissue.

　　(6) Matters to be noted during surgery: ① Emphasize the use of non-sugar infusion and continuous monitoring of blood sugar changes during surgery. ② After the complete resection of the tumor tissue, blood sugar can be twice as high as before resection, and those without increase should be considered as not completely resected until 90 minutes after surgery. ③ Sometimes it is difficult to distinguish between benign and malignant insulinoma in pathological sections, and at this time, it should be carefully checked for liver or peripancreatic lymph node metastasis. If there is metastasis, it is considered to be malignant tumor.

　　(7) Postoperative management: ① Measure blood sugar and urine sugar daily for the first 5 days after surgery. Some patients may experience postoperative hyperglycemia and glycosuria, which can be controlled by adjusting the input amount and speed of glucose solution. A few patients may need insulin control. Generally, it can decrease within 15 to 20 days. ② Some patients may experience the recurrence of symptoms after tumor resection, which may be due to the omission of multiple tumors during surgery or the regeneration of tumors after surgery. ③ Common postoperative complications include pancreatic fistula, pseudopancreatic cyst, postoperative pancreatitis, subdiaphragmatic infection, etc.

　　3. Non-surgical treatment of pancreatic islet cell tumors:

　　(1) Non-surgical treatment can be applied in the following situations:

　　① To relieve hypoglycemia symptoms.

　　② As preoperative preparation.

　　③ Patients with malignant insulinoma that has metastasized and cannot be removed.

　　④ Patients who refuse surgical treatment or have contraindications to surgery.

　　⑤ Patients who still have symptoms after surgery have not found an adenoma or the adenoma has not been completely removed.

　　(2) Drugs that inhibit the secretion of insulin by pancreatic B cells: diazoxide (chlorotriazine), chlorpromazine, propranolol (Propranolol), phenytoin sodium, etc.

　　Diazoxide (Chlorotriazine): The most commonly used oral drug in clinical practice is diazoxide (chlorotriazine), which is a non-diuretic thiazide derivative. It directly acts on B cells to inhibit insulin release and increase adrenaline secretion. It can rapidly increase blood sugar in some children with idiopathic hypoglycemia and individual glycogen storage disease type I, and is also used in the treatment of insulinoma. Diazoxide (chlorotriazine) can inhibit the activity of phosphodiesterase in muscle in most insulinoma patients. The therapeutic dose for adults is determined according to individual responsiveness, ranging from 25 to 200mg, taken 2 to 3 times a day. The dose for children is 12mg per kilogram of body weight per day. Side effects include nausea, vomiting, loss of appetite, water and sodium retention, and leukopenia at high doses. Therefore, patients with heart and brain dysfunction should be used with caution, and diuretics may be used in combination when necessary. Occasional side effects include anorexia, arrhythmia, and hirsutism. Overall, this drug is relatively safe and is commonly used in the treatment methods for specific and preoperative patients. It is also used for patients who are not suitable for surgery or with metastatic malignant tumors.

　　Phenytoin sodium: In 1965, Beiten first observed that phenytoin sodium has the effect of increasing blood sugar. Hyperglycemia and hyperosmolar coma often accompany phenytoin sodium poisoning. The increase in blood sugar caused by phenytoin sodium is due to the suppression of insulin secretion by the islets of Langerhans, and the mechanism is not yet clear. The dose is 300-600mg per day, taken in three divided doses. In clinical practice, insulinoma hypoglycemia is easily misdiagnosed as an epilepsy attack, and the use of phenytoin sodium can alleviate some symptoms, leading to further delay in diagnosis, which should be noted.

　　③ Somatostatin: For cases that are ineffective to diazoxide (chlorobenzothiazine), long-acting somatostatin drugs can be tried. It is a strong inhibitor of insulin secretion, but with a short half-life, it cannot become a clinically effective drug.

　　A. Long-acting somatostatin analog 8 peptide: It has been proven recently that the use of long-acting somatostatin analog 8 peptide has become an effective alternative for the treatment of hormone-producing tumors. Due to the 90 to 120-minute half-life of the 8 peptide, it can be injected subcutaneously several times a day, which has a stable effect on the secretion of hormones. However, it is difficult to use this drug for a long time to inhibit insulin secretion. It can be used in combination with diazoxide to achieve a synergistic therapeutic effect, or as a second-line drug for cases with refractory side effects caused by high doses of diazoxide.

　　B. Octreotide (Sandostatin): Octreotide (Sandostatin) is a gastrointestinal peptide with a wide range of inhibitory effects, which can inhibit the secretion of normal islet cells as well as the secretion of insulinoma. The dose is 3 times a day, with each dose being 50 to 150 μg subcutaneous injection, with a maximum dose of 3 times a day, each time up to 450 μg. Short-term use of this drug can alleviate symptoms in 40% of insulinoma patients.

　　(3) Adrenocorticotropic hormone or corticosteroid drugs: They have a certain effect on alleviating symptoms, but due to the significant side effects they often bring, they are not suitable for routine use.

　　(4) Calcium channel blockers: Including verapamil (isoptin) and diltiazem (thiazolamide) and others.

　　4. Chemotherapy drugs:Malignant insulinoma, due to its low malignancy, has a relatively benign clinical course. Even in cases with metastasis to the liver and local lymph nodes, the disease course can last for 5 to 6 years, so active treatment can still be considered. For patients with malignant islet cell tumors who are elderly or weak and cannot undergo surgery, streptozotocin can be used, which has lytic properties for β cells. This drug can reduce the frequency of hypoglycemia, shrink the tumor, and prolong the survival time of patients. However, this drug has significant toxicity, and when administered systemically, it can produce transient nausea, vomiting, glomerular injury, and hepatotoxic lesions. Secondly, for the treatment of malignant islet cell tumors, fluorouracil, dactinomycin (puromycin), doxorubicin, interferon α, and other drugs can be tried, but none are very ideal.

　　(1) Streptozotozin: It is an antitumor antibiotic isolated from the culture of colorless Streptomyces, which inhibits tumor growth by inhibiting the synthesis of deoxyribonucleic acid (DNA). It has selective damage to pancreatic B cells and good efficacy against metastatic islet cell carcinoma. The dose is 20 to 30 mg/kg body weight, intravenous injection, once a week, for 8 to 10 times in total, with a total dose of 8 to 10 g; or 20 to 30 mg/kg body weight per day, intravenous injection, administered continuously for 5 days as a course of treatment, followed by a rest period of 6 to 8 weeks before repeating. It can also be directly injected into the celiac artery, with a dose of 5 to 10 mg/kg body weight, once every other day, for 5 to 10 times in total, with 50% to 63% of patients experiencing tumor shrinkage and the disappearance of hyperinsulinism after treatment. However, attention should be paid to the damage to the liver, kidneys, and pancreas, and side effects such as nausea and vomiting may occur.

　　(2) Tegafur (Furafur): This drug has inhibitory effects on most solid tumors and can interfere with and block the biological synthesis of DNA, RNA, and proteins in the body, thus producing an antitumor effect. After oral administration, it is absorbed through the gastrointestinal tract, reaching the highest concentration in the blood within 1 to 3 hours, and the duration is longer than that of intravenous administration. The oral dose is 200 to 400 mg per time, 3 times a day, or can start with 100 mg, 3 times a day, and gradually increase the dose. 20 to 35 g is one course. The main side effects are diarrhea, general weakness, and mild nausea and vomiting, rash or hair loss, etc.; it can cause leukopenia, so regular blood tests should be performed, and it should be used with caution in patients with poor liver and kidney function.

　　(3) Fluorouracil (5-Fu): This drug can cause variation in nucleic acids, interfere with the biological synthesis of nucleic acids, and thus inhibit the growth of tumors. The dosage is 500 to 750 mg, intravenous infusion, once a day, for 5 consecutive days, then changed to once every other day, and then used for another 5 times. The dose of one course is 5 to 15 g. Side effects include leukopenia and bone marrow suppression. The above chemotherapy drugs are ineffective for benign insulinoma.

　　Second, Prognosis

　　Single tumor postoperative efficacy is good, but it is difficult to recover from the mental and neurological symptoms caused by long-term hypoglycemia. Surgical treatment of insulinoma is satisfactory, and foreign literature reports that 80% to 90% of patients have disappeared after hypoglycemia symptoms postoperatively, and Chinese scholars report that it is 95%. Possible causes of recurrence after surgery may include incomplete resection, hyperplasia of islet cells, or the occurrence of new tumors. The general recurrence rate is low. The most common complication of surgery is pancreatic fistula, especially with a high incidence rate of up to 50% after pancreatic head tumor surgery. Proper placement of the drainage tube after surgery can reduce its occurrence. The mortality rate after surgery is reported to be 1% to 5% abroad and 4.5% in China.