A 24-year-old woman comes to the office due to episodic sweating, palpitation, and tremor for the past 3 weeks. The symptoms typically occur after she skips meals and are relieved by eating carbohydrate-containing foods. The patient has had no abdominal pain, weight change, or excessive urination. Three months ago, she was diagnosed with diabetes mellitus, and treatment with insulin degludec was started. She refuses to monitor glucose levels at home. Medical history is notable for chronic pancreatitis resulting from adult-onset cystic fibrosis; the patient has no other organ involvement from this disease. Her only other medication is oral lipase for pancreatic exocrine insufficiency. Examination shows no abnormalities. BMI is 24 kg/m². Laboratory results show a hemoglobin A1c of 7.5% and serum creatinine of 0.75 mg/dL. Which of the following is the primary contributor to this patient's symptoms?

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11ec25c8_d2f7_451b_bc81_f5ac966fdd61_MD0003_00 Abnormalities of the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause formation of viscous mucus, which can lead to obstruction of the pancreatic duct with inflammation and fibrosis of the surrounding gland. In addition to exocrine pancreatic insufficiency, destruction of the insulin-secreting beta cells in the pancreatic islets can develop, resulting in pancreatogenic diabetes. In such cases, exogenous insulin is required. Pancreatogenic diabetes is also common in patients with pancreatectomy or chronic pancreatitis of other causes (eg, alcohol). Patients with pancreatogenic diabetes typically also lose glucagon-secreting alpha cells. Because glucagon is the primary counterregulatory hormone to insulin, these patients are at risk for insulin-induced hypoglycemia, which may be rapid and severe. Loss of alpha cell reserve is also seen in patients with long-standing type 1 (idiopathic) diabetes. This patient is likely experiencing recurrent hypoglycemia due to unopposed insulin analogue therapy. Management requires a conservative insulin regimen, and she should be advised that careful monitoring of home glucose is necessary. In addition, she should be issued an emergency glucagon kit for use in severe hypoglycemia. (Choice A) Insulin degludec is an insulin analogue that forms polymers at the injection site, causing delayed uptake from the site and a prolonged duration of action. The insulin is cleared primarily by the kidneys; this patient has normal renal function and clearance is likely normal. (Choices B and D) Malabsorption in patients with cystic fibrosis primarily affects fats and proteins, not carbohydrates. At least 24-48 hours of fasting is typically required to deplete hepatic glycogen stores, and this patient has no other indication of reduced carbohydrate reserve. In patients with intact counterregulatory systems (ie, glucagon, epinephrine), as glycogen stores are depleted, hepatic glucose production continues via gluconeogenesis. However, this effect is inadequate in this patient due to loss of glucagon. (Choice E) Excessive circulating insulin can cause hypoglycemia and leads to down-regulation, not upregulation, of insulin receptor expression. Educational objective: Chronic pancreatitis or pancreatic resection can cause loss of insulin-producing beta cells, leading to pancreatogenic diabetes; exogenous insulin is required. Patients typically also lose glucagon-secreting alpha cells and are at risk for rapid and severe hypoglycemia.

A 24-Year-Old Woman Comes to the Office Due to Episodic