Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Abstract

Diabetes is a common comorbidity in cystic fibrosis (CF) that worsens prognosis. The lack of an animal model for CF-related diabetes (CFRD) has made it difficult to dissect how the onset of pancreatic pathology influences the emergence of CFRD. We evaluated the structure and function of the neonatal CF endocrine pancreas using a new CFTR-knockout ferret model. Although CF kits are born with only mild exocrine pancreas disease, progressive exocrine and endocrine pancreatic loss during the first months of life was associated with pancreatic inflammation, spontaneous hyperglycemia, and glucose intolerance. Interestingly, prior to major exocrine pancreas disease, CF kits demonstrated significant abnormalities in blood glucose and insulin regulation, including diminished first-phase and accentuated peak insulin secretion in response to glucose, elevated peak glucose levels following glucose challenge, and variably elevated insulin and C-peptide levels in the nonfasted state. Although there was no difference in lobular insulin and glucagon expression between genotypes at birth, significant alterations in the frequencies of small and large islets were observed. Newborn cultured CF islets demonstrated dysregulated glucose-dependent insulin secretion in comparison to controls, suggesting intrinsic abnormalities in CF islets. These findings demonstrate that early abnormalities exist in the regulation of insulin secretion by the CF endocrine pancreas. IntroductionCystic fibrosis (CF) is caused by defects in the CF transmembrane conductance regulator (CFTR) chloride channel. Cystic fibrosisrelated diabetes (CFRD) is a common complication of CF and affects 20%-25% of adolescents and 40%-50% of individuals over 30 years of age (1,2). CFRD is associated with worsening clinical status, including reduced pulmonary function, increased frequency of pulmonary exacerbations, and a decline in nutritional status (3-7). Furthermore, CFRD leads to increased mortality compared with CF patients without diabetes (4,8). Thus, early diagnosis and treatment are vital to improving clinical outcome of CFRD patients.While the pathophysiology of CFRD is multifactorial, delayed insulin secretion appears to be a key hallmark of disease progression (9-12), and the health of CF patients is improved by insulin therapy prior to and following diagnosis of overt diabetes (13,14). Partial insulin deficiency occurs in part due to islet loss associated with exocrine pancreas disease (15-18). However, CF pancreata at CFRD autopsy demonstrate that remaining islets contain roughly half the number of insulin-positive cells found in non-CF controls (17,18), and this degree of β cell loss is thought to be insufficient to explain diabetes (19). Thus, insulin deficiency in CFRD is relative and not absolute. All stages of CFRD are characterized by abnormalities in circulating insulin levels (10,12,20,21). Impaired first-phase insulin (IFPI) responses are common in CFRD patients, but also occur in approximately 50% of CF children with normal glucose tolerance (9). Cu...

Cftr controls lumen expansion and function of Kupffer’s vesicle in zebrafish

“…Development 140 (8) associated with CF might arise during development (Imrie et al, 1979;Olivier et al, 2012;Sturgess, 1984), a stage that remains difficult to access in these models with limited genetic tools. A developmentally accessible model will provide valuable insights into CFTR regulation and CF pathophysiology in various organs.…”

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.…”

MANAGEMENT OF ENDOCRINE DISEASE: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues

“…For these patients, impaired insulin secretion is mostly apparent during the first phase, strongly indicating a defect at the level of the pancreatic b-cell. Studies in animal models for CF with modification of CFTR develop multi-system disease, including pancreas and lung disease that have very similar pathology to that in patients (47,48,49). Endocrine pancreas function in the CFTR-null ferret is abnormal from birth, which suggests that it is an intrinsic defect in b-cell function in CF (47).…”