How low can you go? Chronic hypoglycemia versus normal glucose homeostasis

Background: Set point errors in glucose homeostasis that result in chronic, mild hyperglycemia in the setting of maturity onset diabetes of the young have been described. Similar set point errors may exist that result in chronic, asymptomatic glucopenia. Case: A healthy 39-year-old female was referred for evaluation of chronic, persistent, and asymptomatic glucopenia that persisted over the prior several years with a record of numerous random plasma glucose concentrations between 35 and 45 mg/dL. She denied ethanol intake and family history of hypoglycemia or diabetes. She was not taking any medications known to cause hypoglycemia, and a urine sulfonylurea screen was negative. Fasting insulin and C-peptide levels were not elevated, and pancreatic imaging studies were normal. We hypothesized that this patient possessed an error in glucose metabolism that resulted in chronic, asymptomatic glucopenia. Results: In a series of clinical studies, we demonstrated a nadir plasma glucose concentration of 35 mg/dL in the absence of symptoms during a 60-hour fast. C-peptide secretion was appropriately suppressed during symptomatic hypoglycemia with exogenous insulin infusion, and counterregulatory hormone secretion was intact during insulin-induced symptomatic hypoglycemia. Finally, the patient demonstrated an incremental increase in insulin concentration in response to minimal increases in plasma glucose during a sequential, stepped infusion of 10% dextrose. Conclusions: We conclude that this patient exhibits features of a set point error in glucose homeostasis that manifests as chronic, asymptomatic glucopenia. Although the mechanism for this condition remains to be elucidated, such set point errors do exist and should be considered in the differential diagnosis of chronic hypoglycemia.