O-08 Mutation in insulin receptor gene with hypoglycemia symptoms

Abstract

Abstract Introduction Monoallelic/heterozygous mutations in the insulin receptor INSR gene are typically associated with type A insulin resistance syndrome, but less is known about INSR-related hyperinsulinemic hypoglycaemia (HH) characterized by fasting hyperinsulinemia and postprandial hypoglycemia. Clinical Case A 38-year-old woman with a history of migraines not needing preventive medication was admitted to an endocrinology outpatient clinic because of general malaise, weakness, and reduced exercise tolerance. For several years, she has had to eat small snacks during the workday to avoid sudden hypoglycemic symptoms. As a result, she gained nearly 30 kilograms in a few years. The symptoms started after she lost 23 kg and weighed 55 kg after following a ketogenic diet in 2016. The symptoms worsened despite weight regain and dietary changes to attempt to avoid hypoglycemia. Diagnostic evaluation: Initial BMI was 31.5 kg/m2. Continuous glucose monitoring (CGM) showed low blood glucose levels during extended fasting, such as during the night or prolonged meal intervals during the workdays (Figure 1). Hypoglycemia also occurred during and after exercise. She underwent a 2-hour glucose tolerance test, a mixed-meal test and a 72-hour fasting test (Tables 1 and 2), abdominal CT, and endoscopic ultrasonography, none of which led to a specific diagnosis. The glucose profile of this patient had hypoglycemias <3.0 mmol/L only a few times, and normal findings on imaging suggest that insulinoma is unlikely. Blood samples were taken during a postprandial hypoglycemic episode at work, but the plasma glucose (3.2 mmol/L) did not meet the criteria for Whipple's triad (<2.7 mmol/L), despite pronounced symptoms that were relieved by consuming carbohydrates. Finally, gene panel for monogenic causes of hypoglycemia identified a likely pathogenic INSR mutation c.2106T>G, p. (Tyr702*), which turned out to have been found in a symptomatic third-degree relative several years ago. Isolated case reports have found a beneficial effect of metformin in decreasing hypoglycemic symptoms, although the exact mechanisms by which it may decrease symptoms are unclear. We conducted a treatment trial with increasing doses of metformin to manage the patient's symptoms and to decrease the insulin resistance that had developed as a result of the INSR mutation and pronounced weight gain. Before the treatment trial, BMI was 34.4 kg / m2. Patient responded positively to metformin and weight started to decrease. Her quality of health increased subjectively and hypoglycemic episodes decreased during work and exercise. Conclusion The differential diagnostics of hypoglycemia may be challenging. Monogenic causes for adulthood-onset hypoglycemia are very rare but should be considered in cases of prolonged hypoglycemia susceptibility impairing daily activities. Genetic testing is also warranted in cases of family history of hypoglycemia symptoms.Figure 1.Continuous glucose monitor (CGM)Patient had low blood glucose levels (2.9-3.6 mmol/L) during extended fasting, such as during the night or prolonged meal intervals during the workdays. Hypoglycemiasymptoms also occurred during and after exercise. Table 1.Laboratory Values Table 2.72-hour fasting test and 5-hour Mixed-Meal test