Hypoglycemia in cystic fibrosis during an extended oral glucose tolerance test

Abstract

Background Hypoglycemia in cystic fibrosis (CF), in the absence of glucose‐lowering therapies, has long been identified as an important issue in the management of CF. There is currently still no unifying hypothesis for its etiology. Aim The aims of this study were to perform a 3‐h oral glucose tolerance test (OGTT) in participants with CF and (1) document glucose, insulin, glucagon, glucagon‐like‐peptide‐1 (GLP‐1), and glucose‐dependent insulinotropic peptide (GIP) release patterns within varying glucose tolerance groups during the OGTT; (2) determine the prevalence of hypoglycemic during the OGTT; and (3) define any association between hypoglycemia and patterns of insulin, glucagon, GLP‐1, and GIP release. Methods Eligible participants attending an adult CF clinic completed a 3‐h OGTT. Hypoglycemia on OGTT was defined as mild (glucose 3.4–3.9 mmol/L), moderate (glucose 3.1–3.3 mmol/L), and severe (glucose ≤ 3 mmol/L). Hormones were measured at fasting, 30, 60, 120, and 180 min. Results Twenty‐four participants completed the study, of which 7 had normal glucose tolerance, 12 had abnormal glucose tolerance, and 5 had cystic fibrosis related diabetes (CFRD). All participants had a delayed insulin response compared with normative data. All glucose tolerance groups showed appropriate and similar suppression of fasting glucagon. Four participants (17%) had mild hypoglycemic, three (13%) had moderate hypoglycemic, and eight (33%) had severe hypoglycemic. No participant with CFRD demonstrated hypoglycemic. Of the 19 participants without CFRD, 15 (79%) experienced hypoglycemic. Participants with hypoglycemic had greater peak glucose and insulin responses than those that did not have hypoglycemic, and this approached significance (p = .0625 for glucose and p = .0862 for insulin). No significant mean differences between GLP‐1 and GIP release were found. There was no relationship between hypoglycemic and modulator therapy. Conclusion Postprandial hypoglycemic was unmasked by the extension of an OGTT to 3 h. Delayed and abnormal insulin release, and ineffective counter‐regulatory action of glucagon may have a role in its etiology.

Year in Review 2020: Multisystemic Impact of Cystic Fibrosis

“…None of the patients with CFRD had hypoglycemia, while 79% (15/19) of the remaining subjects showed hypoglycemia at the 3-hour time point, with 5 being symptomatic (sweaty, clammy hands and dizzy). Similar to the study by Kilberg et al 24 , those with hypoglycemia had a higher peak glucose and delayed and higher insulin release 25 . Incretins, hormones produced by the intestines that signal insulin secretion after eating, were not different between groups, and there was no change in the counter regulatory glucagon response.…”

“…Another outcome of screening for CFRD, can be the appearance of post-prandial or OGTT-related hypoglycemia. While the mechanism remains unclear, it is speculated to be related to derangement in glucose homeostasis involving both insulin and glucagon 24,25 . Kilberg et al 24 used a mixed meal tolerance test (MMTT) in 34 nondiabetic adolescents and young adults with pancreatic insufficiency, finding 26% (9/34) with hypoglycemia.…”

“…Further study of hypoglycemia was done by Armaghanian et al 25 using a 3-hour glucose tolerance test in 24 patients (7 normal glucose tolerance, 12 abnormal glucose tolerance and 5 CFRD). None of the patients with CFRD had hypoglycemia, while 79% (15/19) of the remaining subjects showed hypoglycemia at the 3-hour time point, with 5 being symptomatic (sweaty, clammy hands and dizzy).…”

Islet Function in the Pathogenesis of Cystic Fibrosis-Related Diabetes Mellitus

“… 29 Along the same lines, Kilberg et al 21 showed that reduced glucagon secretion hours after a meal can lead to hypoglycemic events in CF patients diagnosed with pancreatic insufficiency. The dysregulation of glucagon secretion, with impaired high secretion in the early post-prandial phase 20 , 24 followed by a failed counter-regulatory response in the later phase 20 , 30 is not well understood.…”

“… 26 Rather, the only established secretion abnormality is failed counter-regulatory secretion of glucagon in late phases of OGTT trials, even though there may be some aberrant increased secretion in the early phase. 20 , 21 , 30 …”