Impaired counterregulatory responses to hypoglycaemia following oral glucose in adults with cystic fibrosis

Abstract

Aims/hypothesis The aim of this study was to determine the mechanism(s) for hypoglycaemia occurring late following oral glucose loading in patients with cystic fibrosis (CF). Methods A 3 h 75 g OGTT was performed in 27 non-diabetic adults with CF who were classified based on this test as experiencing hypoglycaemia (glucose <3.3 mmol/l with or without symptoms or glucose <3.9 mmol/l with symptoms, n = 14) or not (n = 13). Beta cell function, incretin (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) and counterregulatory hormone responses (glucagon, catecholamines, growth hormone and cortisol) were assessed. Results The two groups did not differ in age, weight or BMI. There were more male participants and individuals with pancreatic exocrine insufficiency in the hypoglycaemia group. Fasting plasma glucose did not differ between the two groups (5.3 ± 0.16 vs 5.3 ± 0.10 mmol/l). Both fasting insulin (20.7 ± 2.9 vs 36.5 ± 4.8 pmol/l; p = 0.009) and C-peptide (0.38 ± 0.03 vs 0.56 ± 0.05 nmol/l; p = 0.002) were lower in those who experienced hypoglycaemia. Following glucose ingestion, glucose concentrations were significantly lower in the hypoglycaemia group from 135 min onwards, with a nadir of 3.2 ± 0.2 vs 4.8 ± 0.3 mmol/l at 180 min (p < 0.001). The test was terminated early in three participants because of a glucose level <2.5 mmol/l. Insulin and Cpeptide concentrations were also lower in the hypoglycaemia group, while incretin hormone responses were not different. Modelling demonstrated that those experiencing hypoglycaemia were more insulin sensitive (439 ± 17.3 vs 398 ± 13.1 ml min −1 m −2 , p = 0.074 based on values until 120 min [n = 14]; 512 ± 18.9 vs 438 ± 15.5 ml min −1 m −2 , p = 0.006 based on values until 180 min [n = 11]). In line with their better insulin sensitivity, those experiencing hypoglycaemia had lower insulin secretion rates (ISR fasting : 50.8 ± 3.2 vs 74.0 ± 5.9 pmol min −1 m −2 , p = 0.002; ISR OGTT : 44.9 ± 5.0 vs 63.4 ± 5.2 nmol/m 2 , p = 0.018) and beta cell glucose sensitivity (47.4 ± 4.5 vs 79.2 ± 7.5 pmol min −1 m −2 [mmol/l] −1 , p = 0.001). Despite the difference in glucose concentrations, there were no significant increases in glucagon, noradrenaline, cortisol or growth hormone levels. Adrenaline increased by only 66% and 61% above baseline at 165 and 180 min when glucose concentrations were 3.8 ± 0.2 and 3.2 ± 0.2 mmol/l, respectively. Conclusions/interpretation Hypoglycaemia occurring late during an OGTT in people with CF was not associated with the expected counterregulatory hormone response, which may be a consequence of more advanced pancreatic dysfunction/ destruction.

Spontaneous and iatrogenic hypoglycemia in cystic fibrosis

“…Adrenaline was higher in the hypoglycemia group. Authors concluded that late hypoglycemia on OGTT was likely due to insufficient counterregulatory response rather than increased or delayed insulin secretion [27] . Overall these data suggest that both dysregulation in insulin secretion and impaired counterregulatory response to lowering glucose may contribute to postprandial hypoglycemia in CF.…”

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

“… 8 , 17 , 18 Insulin levels are lower in the first phase during an oral glucose tolerance test (OGTT) in CF and CFRD patients. 18 – 21 Also, there is an elevated secretion of proinsulin in both CFRD patients and CF patients with impaired glucose tolerance (IGT). 22 , 23 Failure to supress initial glucagon secretion following an OGTT correlates with decreased glucose tolerance among CF patients.…”

“… 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 …”

A tale of two pancreases: exocrine pathology and endocrine dysfunction

“…While basal and stimulated glucagon release is increased with acute pancreatitis [57], glucagon release is reduced in chronic pancreatitis, especially in the presence of diabetes [57,58]. In cystic fibrosis, glucagon release in response to arginine or following hypoglycaemia is reduced [40,42,59]. This defective glucagon release does not occur secondary to a loss of alpha cells.…”