Hypoglycemia and Islet Dysfunction Following Oral Glucose Tolerance Testing in Pancreatic-Insufficient Cystic Fibrosis

Context: Oral glucose tolerance test (OGTT)-related hypoglycemia is common in pancreatic-insufficient cystic fibrosis (PI-CF), but its mechanistic underpinnings are yet to be established. Objective: To delineate the mechanism(s) underlying OGTT-related hypoglycemia. Design and Setting: We performed 180-minute OGTTs with frequent blood sampling in adolescents and young adults with PI-CF and compared results with those from a historical healthy control group. Hypoglycemia (Hypo[+]) was defined as plasma glucose <65 mg/dL. We hypothesized that CF-Hypo[+] would demonstrate impaired early phase insulin secretion and persistent late insulin effect compared with control-Hypo[+], and explored the contextual counterregulatory response. Main Outcome Measure: OGTT 1-hour and nadir glucose, insulin, C-peptide, and insulin secretory rate (ISR) incremental areas under the curve (AUC) between 0 and 30 minutes (early) and between 120 and 180 minutes (late), and Delta glucagon(120-180min) and Delta free fatty acids (FFAs)(120-180min) were compared between individuals with CF and control participants with Hypo[+]. Results: Hypoglycemia occurred in 15/23 (65%) patients with CF (43% female, aged 24.8 [14.6-30.6] years) and 8/15 (55%) control participants (33% female, aged 26 [21-38] years). The CF-Hypo[+] group versus the control-Hypo[+] group had higher 1-hour glucose (197 +/- 49 vs 139 +/- 53 mg/dL; P = 0.05) and lower nadir glucose levels (48 +/- 7 vs 59 +/- 4 mg/dL; P < 0.01), while insulin, C-peptide, and ISR-AUC(0-30min) results were lower and insulin and C-peptide, and AUC(120-180min) results were higher (P < 0.05). Individuals with CF-Hypo[+] had lower Delta glucagon(120-180min) and Delta FFA(120-180min) compared with the control-Hypo[+] group (P < 0.01). Conclusions: OGTT-related hypoglycemia in PI-CF is associated with elevated 1-hour glucose, impaired early phase insulin secretion, higher late insulin exposure, and less increase in glucagon and FFAs. These data suggest that hypoglycemia in CF is a manifestation of islet dysfunction including an impaired counterregulatory response.