The Case of the Mixed Meal and the Insulinoma FA Mahomed Division of Endocrinology Department of Internal Medicine Universitas Hospital   L Bezuidenhout Department of Human Nutrition University of the Free State Bloemfontein JB Fichardt and A Truter Department of Surgery University of the Free State

Abstract The Case of the Mixed Meal and the Insulinoma FA Mahomed and L Bezuidenhout Division of Endocrinology, Department of Internal Medicine, Universitas Hospital and Department of Human Nutrition, University of the Free State, Bloemfontein Introduction and Aim: An insulinoma is an endocrine tumour that produces an excess of insulin. It causes hypoglycaemic episodes and is usually found in the pancreas. Some patients have a genetic tendency to develop these tumours, as in our case, who has the MEN I syndrome [Multiple Endocrine Neoplasia Syndrome Type 1]. It can be controlled by medication, however the definitive treatment is surgical removal. The traditional diagnostic test for insulinoma is the 72 hour fast. This requires admission to hospital for supervision for 72 hours. When hypoglycaemia occurs, blood is taken to establish if the insulin level is inappropriately elevated [The insulin level should be suppressed in hypoglycaemia]. This test is time consuming and labour intensive.The mixed meal test, detailed below, is a shorter and easier test to administer and can be done in an outpatient setting over 5 hours. Methodology: A case study will be presented. A patient with MEN1 syndrome presents with with hypoglycaemic episodes. A mixed meal test is arranged and a CT scan of the abdomen is performed. Results: Basal and half hourly values (1) Insulin [mU/l] : 4.7, >300, 293, 127, 40, 17.7, 9.4, 6.9, 5.0, 5.6, 6.4 (2) Glucose [mmol/l] : 4.0, 6.3, 2.6, 3.0, 2.3, 1.1, 1.6, 1.7, 1.7, 1.8, 2.1 The mixed meal result is abnormal and will be shown in the form of a graph. Prolonged, inappropriate insulin release after the mixed meal is quite evident. The CT scan of the abdomen shows 2 tumours in the tail of the pancreas. This will also be shown. The tumour was removed and the diagnosis is confirmed histologically. Conclusion: This case demonstrates that the mixed meal response may be abnormal in patients with insulinoma. The mixed meal test is much easier to perform than the traditional 72 hour fast and we propose that the mixed meal may be a better diagnostic test for insulinoma and may have some use as a screening test. This is important in a resource poor setting such as exists in South Africa and this needs further study and confirmation.

Introduction An insulinoma is an endocrine tumour that produces an excess of insulin. It causes hypoglycaemic episodes and is usually found in the pancreas. Some patients have a genetic tendency to develop these tumours, as in our case, who has the MEN I syndrome [Multiple Endocrine Neoplasia Syndrome Type 1]. It can be controlled by medication, however the definitive treatment is surgical removal. [1]   The traditional diagnostic test for insulinoma is the 72 hour fast. This requires admission to hospital for supervision for 72 hours. When hypoglycaemia occurs, blood is taken to establish if the insulin level is inappropriately elevated [The insulin level should be suppressed in hypoglycaemia]. This test is time consuming and labour intensive. The mixed meal test, detailed below, is a shorter and easier test to administer and can be done in an outpatient setting over 5 hours. We demonstrate the abnormal mixed meal test response of a patient with a confirmed insulinoma and propose that the mixed meal test may be an acceptable alternative diagnostic test and warrants further research.

The mixed meal test Definition of a mixed meal tolerance test: The mixed meal test entails measurement of blood glucose and insulin levels at specific times after consumption of a meal containing carbohydrate combined with fat and protein that would be present in a normal meal during ordinary life activities [2]. The test is performed after an overnight fast (12 – 16 hours) and blood samples are collected 15 minutes before, at zero time and at 30 minutes intervals for 5 hours after the ingestion of the mixed meal. Although the test is not well standardized, the following is used as the standard: [3] 1g/kg carbohydrate 8.6 kcal/ kg 50 % carbohydrates 15% protein 35% fat Physiological response to a mixed meal: A normal physiological response to a mixed meal is characterized by a peak response in serum insulin occurring between 30 and 60 minutes after a meal and usually concide with the peak response for serum glucose. By the end of the absorptive period (180 minutes), serum insulin and glucose levels return to basal levels [2][4]. Pathophysiological response to a mixed meal: A Mayo Clinic Proceedings study found that the mixed meal can stimulate a supraphysiological increase in insulin with attendant hypoglycaemia in patients with insulinomas. They concluded that the meal test seems reliable because pathological hypoglycaemia of patients with insulinoma was readily detected [3].

Case report Mrs X, a 48 year old patient from a family known to have MEN I syndrome [Multiple Endocrine Neoplasia Syndrome Type 1] presented to Universitas Hospital with the problem of hypoglycaemic episodes. She had a history of parathyroidectomy 1991, performed for hypercalcaemia due to a parathyroid tumour. She was admitted to Universitas Hospital for a mixed meal tolerance test and a 72 hour fast. Her Baseline blood tests were as follows:   Electrolytes - normal Prolactin - 19 ug/l [1.8-20.3] Corrected Calcium - 2.74 mmol/l [2.0-2.6] PTH - 15.0 pmol/l [elevated] Thyroid Function tests -normal Growth Hormone - 10.8 mU/l [0-9.5] Somatomedin C - normal ACTH - 41pg/ml [0-71]

Results Time minutes Glucose mmol/L Insulin mU/L Mixed Meal Result [Figure 1]: Note basal insulin and glucose level are normal and the initial rise in insulin is massive, but also, once the glucose level drops below 3.0 mmol/l, the insulin level remains pathologically elevated and fails to suppress.   MRI brain: normal MIBI scan of the neck: normal CT abdomen [Figure 2]: The scan showed 2 lesions in the tail of the pancreas, compatible with insulinoma and a small nodule in the left adrenal gland. Surgery [Figure 3]: During surgery, the tail of the pancreas was resected and the left adrenal removed. Histological examination confirmed the diagnosis of insulinoma in the pancreas and benign nodular disease in the left adrenal. The patient has recovered and is doing well. Time minutes 30 60 90 120 150 180 210 240 270 300 Glucose mmol/L 4.0 6.3 2.6 3.0 2.3 1.1 1.6 1.7 1.8 2.1 Insulin mU/L 4.7 >300 293.1 127.7 40.4 17.7 9.4 6.9 5.0 5.6 6.4

Figure 1 Mixed Meal results Abnormal

Figure 2 CT scan of Abdomen

Surgical view of the insulinoma in the tail of pancreas Figure 3 Surgical view of the insulinoma in the tail of pancreas Both tumours bisected- cut surface 2 tumours in situ in the tail of pancreas

Discussion and conclusions MEN I syndrome [ Multiple Endocrine Neoplasia Syndrome Type 1] is inherited in an autosomal dominant way. The gene has been described- it is found on chromosome 11Q13. The gene product is Menin, a proto-ongogene [1]. Tumours can arise in the pituitary, pancreas or parathyroid glands. In identified families, surveillance for the occurrence of new tumours is a vital part of management. In the UK [1], screening includes an MRI of the abdomen every 3 years. There is some debate about the use of the 72 hour fast or mixed meal test as screening tests. The 72 hour fast is used as a diagnostic test. This patient had prolonged insulin response to a mixed meal test, despite having normal basal levels of insulin and glucose. This case demonstrates that the mixed meal response may be abnormal in patients with insulinoma. The mixed meal test is much easier to perform than the traditional 72 hour fast and we propose that the mixed meal may be a better diagnostic test for insulinoma and may have some use as a screening test. This is important in a resource poor setting such as exist in South Africa and this needs further study and confirmation.

References:   Turner HE, Wass JAH. Oxford Handbook of Endocrinology and Diabetes 2002. Oxford University Press. Mahan LK & Escott-Stump S. Krause’s Food, Nutrition and Diet Therapy. 10th Edition. 2000. WB Saunders Company. Hogan MJ, Service FJ, Sharbrough FW, Gerich JE. Oral Glucose Tolerance Test compared with a mixed meal in the diagnosis of reactive hypoglycaemia. Mayo Clinic Proceedings, 1983 58: 491-496. Porte D & Sherwin RS. Ellenberg and Rifkin’s Diabetes Mellitus: theory and practice. 5th Edition. 1997. USA: Appleton and Lange, Stamford, Connecticut.