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

Abstract

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 Δglucagon120-180min and Δfree 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-AUC0-30 min results were lower and insulin and C-peptide, and AUC120-180min results were higher (P < 0.05). Individuals with CF-Hypo[+] had lower Δglucagon120-180min and ΔFFA120-180min 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.

Keywords: cystic fibrosis; glucose counterregulation; glucose tolerance; hypoglycemia; insulin secretion; pancreatic insufficiency.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

(A) Plasma glucose in response to ingestion of 1.75 g/kg of glucose solution (max 75 g) over a 5-minute period starting at t = 0 during the oral glucose tolerance test (OGTT). Data are expressed as mean ± standard error of the mean. Average glucose at 90 to 180 minutes is higher in the CF-Hypo[–] group versus the CF-Hypo[+] group. Average glucose concentration at 90 to 180 minutes and glucose area under the curve120-180min were lower in the CF-Hypo[+] group versus CF-Hypo[–] group. (B) Left: Nadir plasma glucose for control-Hypo[+] group and CF-Hypo[+] group. Right: Peak plasma glucose for control-Hypo[+] and CF-Hypo[+] groups. The 1-hour glucose was higher (197 ± 49 vs 139 ± 53 mg/dL; P = 0.05), and the nadir glucose was lower (48 ± 7 vs 59 ± 4 mg/dL; P < 0.01) in the CF-Hypo[+] group compared with the control-Hypo[+] group. CF, cystic fibrosis; Hypo, hypoglycemia.

Figure 2.

(A) Insulin secretory rate (ISR), (C) plasma insulin, and (E) C-peptide in response to the OGTT. (B) ISR AUC0-30min, (D) insulin AUC0-30min & 120-180min, and (F) C-peptide AUC0-30min & 120-180min as measures of early responses and late effects during the OGTT. Data are means ± SE (A, C, E), and box plots represent the median, upper and lower quartiles, minimum and maximum except outliers (whiskers), and outliers (dots). Note that apparent discrepancy in median insulin AUC120-180min, for the CF-Hypo[+] group compared with the control-Hypo[+] group in the line graph versus box plot is related to the termination time for individuals with CF. AUC, area under the curve; CF, cystic fibrosis; Hypo, hypoglycemia; OGTT, oral glucose tolerance test; SE, standard error.

Figure 3.

(A) Glucagon and (C) free fatty acids (FFA) in response to the OGTT. (B) ΔGlucagon120-180min and (D) FFA rebound slope as measures of the counterregulatory response during OGTT-related hypoglycemia. Hypo, hypoglycemia; OGTT, oral glucose tolerance test.