Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass

Abstract

Diabetes is a common and significant comorbidity in cystic fibrosis (CF). The pathogenesis of CF-related diabetes (CFRD) is incompletely understood. Because exocrine pancreatic disease is similar between humans and pigs with CF, the CF pig model has the potential to contribute significantly to the understanding of CFRD pathogenesis. We determined the structure of the endocrine pancreas in fetal, newborn and older CF and non-CF pigs and assessed endocrine pancreas function by intravenous glucose tolerance test (IV-GTT). In fetal pigs, pancreatic insulin and glucagon density was similar between CF and non-CF. In newborn and older pigs, the insulin and glucagon density was unchanged between CF and non-CF per total pancreatic area, but increased per remnant lobular tissue in CF reflecting exocrine pancreatic loss. Although fasting glucose levels were not different between CF and non-CF newborns, CF newborns demonstrated impaired glucose tolerance and increased glucose area under the curve during IV-GTT. Second phase insulin secretion responsiveness was impaired in CF newborn pigs and significantly lower than that observed in non-CF newborns. Older CF pigs had elevated random blood glucose levels compared to non-CF. In summary, glycemic abnormalities and insulin secretion defects were present in newborn CF pigs and spontaneous hyperglycemia developed over time. Functional changes in CF pig pancreas were not associated with a decline in islet cell mass. Our results suggest that functional islet abnormalities, independent of structural islet loss, contribute to the early pathogenesis of CFRD.

Cystic fibrosis-related diabetes: links, challenges, and future directions

“…62 The CF pig model similarly reveals glucose and insulin secretion abnormalities in the absence of loss of islet mass. 63 Together these data support a direct role of CFTR in pancreatic islet function. Reports of improved glucose status in patients Research and with at least one of ten rare mutations, who are treated with the CFTR modulator, ivacaftor, 64,65 are prompting human investigations of the underlying mechanisms.…”

Cystic Fibrosis and the Nervous System

“…115 Similar observations have been made in CF animal models. 76,116 Over time, insulin deficiency and insulin resistance develop. CFTR has been found in key neural regions, such as the hypothalamus and sympathetic nervous system, 56,58,61 that exert control over the allocation of glucose and endocrine pancreatic function.…”

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

“…In older animals, the exocrine pancreatic lesions progress and pancreas is mostly replaced by fat and fibrosis. The islets are morphologically intact, but functionally abnormal [41]. As in humans [42], the pancreatic fluid is acidic, low in volume and high in protein and concentrated in CF pigs at birth [43].…”