Dysregulated insulin in pancreatic insufficient cystic fibrosis with post-prandial hypoglycemia

Abstract

Background: Post-prandial and oral glucose tolerance test-related hypoglycemia is common in cystic fibrosis (CF); however, the underlying mechanisms are unclear.

Methods: To understand the relationship of hypoglycemia with meal-related glucose excursion and insulin secretion, we analyzed plasma glucose, insulin, C-peptide, glucagon and incretins obtained during standardized mixed-meal tolerance tests (MMTT) in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF).

Results: Hypoglycemia, defined as glucose <70 mg/dL, occurred in 9/34 subjects at 150 (range:120-210) minutes following initial meal ingestion. Hypoglycemia[+] and hypoglycemia[-] groups did not differ in gender, age, lung function, HbA1c, or BMI. While 11/14 hypoglycemia[-] individuals displayed normal glucose tolerance (NGT), only 2/9 hypoglycemia[+] had NGT. Peak glucose was higher in hypoglycemia[+] vs hypoglycemia[-]. Compared to hypoglycemia[-] NGT, hypoglycemia[+] exhibited lower early-phase insulin secretion (ISR-AUC0-30min). ISR-AUC120-180min was not different in hypoglycemia[+] vs hypoglycemia[-] with abnormal glucose tolerance (AGT); however, glucose-AUC120-180min was lower in hypoglycemia[+] vs hypoglycemia[-] AGT. After adjusting for glucose-AUC, hypoglycemia[+] subjects tended to have higher ISR-AUC120-180min than hypoglycemia[-] AGT. Glucagon concentration did not differ between groups. Lower GLP-1-AUC30min and AUC180min and higher GIP-AUC30min were present in hypoglycemia[+] individuals.

Conclusion: Hypoglycemia is common in PI-CF following MMTT and is associated with early glucose dysregulation (higher peak glucose), more impaired early-phase insulin secretion (lower ISR-AUC30min), and possibly late compensatory hyperinsulinemia. Further study is required to understand whether absence of glucagon difference in the hypoglycemia[+] individuals signals counterregulatory impairment, to delineate the role of incretins in hypoglycemia, and to determine the relationship of hypoglycemia to emergence of CFRD.

Keywords: Cystic fibrosis; Glucose tolerance; Hypoglycemia; Insulin secretion; Pancreatic insufficiency.

Conflict of interest statement

CONFLICTS OF INTEREST: The authors have no conflicts of interest directly related to this study. Dr. De Leon has a patent issued for exendin-(9–39) as a method for treating post-prandial hypoglycemia.

Copyright © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Figures

Figure 1:

(Left) Peak plasma glucose and glucose nadir for hypoglycemia [−] subjects. (Right) Peak plasma glucose and glucose nadir for hypoglycemia [+] subjects. Peak plasma glucose was higher in the hypoglycemia [+] group (215±21 vs 168±33 mg/dL, pRed dashed line represents plasma glucose of 180mg/dL and blue dashed line represents plasma glucose of 70mg/dL.

Figure 2:

A) Plasma glucose (mg/dL) following MMTT in hypoglycemia [+] vs hypoglycemia [−] groups. B) Insulin secretory rate (μU/mL per min) in response to MMTT. Early phase insulin secretion is blunted in hypoglycemia [+] vs hypoglycemia [−](p=0.03). C) Plasma glucose (mg/dL) following MMTT. Hypoglycemia [+] subjects have higher plasma glucose at 60 minutes (p=0.004). but declines in glucose through 120 to 180 minutes of testing unlike NGT subjects whose blood glucose values stabilize at 120 minutes. Accordingly, glucose AUC120–180 min was lower in the hypoglycemia [+] group (p= 0.015). D) Insulin secretory rate (μU/mL per min) in response to MMTT. Significant blunting of early phase insulin secretion is demonstrated in both hypoglycemia [−] AGT (purple) and hypoglycemia [+] (green) groups. Black dashed lines represent the Insulin secretory rates (μU/mL per min) for the 2 NGT-hypoglycemia [+] subjects. These subjects demonstrate loss of early phase insulin secretion despite normal glucose tolerance. After adjusting for glucose AUC over this interval, hypoglycemia [+] tended to have higher late insulin secretion than hypoglycemia [−] AGT (p=0.1). Markers indicate mean value at that time point while bars indicate standard error of the mean. Black dashed lines are absolute insulin secretory rate for each of the two NGT-hypoglycemia [+] subjects. Red dashed line represents plasma glucose of 180mg/dL and blue dashed line represents plasma glucose of 70mg/dL. * indicates p-value

Figure 3:

Glucagon concentration over time by group. No difference in glucagon between hypoglycemia [+] and hypoglycemia [−] NGT were found (p> 0.18 for all times), despite differences in plasma glucose.

Figure 4:

GLP-1 concentration over time by group: significantly lower GLP-1 AUC 30 min and GLP-1 AUC 180 min in hypoglycemia [+] compared to either hypoglycemia [−] group (supplemental table).

Figure 5:

GIP concentration over time by group: significantly higher in the hypoglycemia [+] group; however, GIP AUC 180 min was not different between group (supplemental table).