“Thus, these data implicate that cystic fibrosis induces defects in glucagon secretion leading to hypoglycemia risk. The association with pancreatic insufficiency suggests a link to pancreatic exocrine disease.” –Andrew Norris
Post by
Andrew Norris, MD PhD
Director, Pediatric Endocrinology & Diabetes
University of Iowa Stead Family Children’s Hospital
Results from an important recent clinical study of hypoglycemia in patients with cystic fibrosis (CF) are now available. The study was conducted at the University of Washington and headed by preeminent diabetes physiologist Dr. Steven Kahn. Non-diabetic adults with cystic fibrosis were challenged with a 3-hour 75-gram frequently-sampled oral glucose tolerance test.
Half (14/27) of the subjects experienced hypoglycemia during the test. The glycemic pattern during the test was similar between these two groups until 135 minutes and thereafter, when the hypoglycemia group diverged downward. Those who exhibited hypoglycemia were more likely to be pancreatic insufficient. Importantly, those with hypoglycemia had lower plasma insulin & C-peptide levels. Modeling suggest that insulin sensitivity was greater in the subjects with hypoglycemia, accounting for the lower insulin levels. Importantly though, the “oral disposition index” did not differ between the two groups. This indicates that the amount of insulin secreted between the two groups would expected to have the same actions on lowering glucose when accounting for insulin sensitivity. Perhaps one could argue that the “oral disposition index” should have been lower in the hypoglycemia group, but in fact there was a trend towards lower values in this group (P=0.16). Plasma GLP-1 and GIP did not differ between the groups. In the hypoglycemia group, plasma epinephrine rose in the hypoglycemia group, albeit modestly. Cortisol did not rise, though it is not clear how many patients reached the lower blood glucose thresholds needed to trigger cortisol secretion. Growth hormone rose in some but not all patients. Perhaps most importantly, glucagon did not rise with hypoglycemia and did not differ at any point between the two groups.
These results suggest an impairment in counterregulatory response in patients with CF and hypoglycemia. Typically, the threshold for glucagon secretion occurs at less severe degrees of hypoglycemia than for other counterregulatory responses (see this nice review from Elizabeth Seaquist). Furthermore, the hypoglycemia in these subjects was mild. Thus, these data implicate that cystic fibrosis induces defects in glucagon secretion leading to hypoglycemia risk. The association with pancreatic insufficiency suggests a link to pancreatic exocrine disease. However, the mechanisms responsible remain to be determined. The manuscript describing these results is now published in the prestigious journal Diabetologia (link to article).