Cystic Fibrosis Related Diabetes (CFRD)—The End Stage of Progressive Insulin Deficiency

Hameed, Shihab A.; Jaffé, Adam; Verge, Charles F.

doi:10.1002/ppul.21495

Cited by 50 publications

(43 citation statements)

References 122 publications

(170 reference statements)

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“…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)(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Olivier¹,

Yi²,

Sun³

et al. 2012

J. Clin. Invest.

119

143

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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...

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Section: Introductionmentioning

confidence: 99%

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Olivier¹,

Yi²,

Sun³

et al. 2012

J. Clin. Invest.

119

143

View full text Add to dashboard Cite

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“…Accordingly, autopsies from CFRD patients disclosed a reduction in mass and number of ␤-cells along with amyloidal deposition in pancreatic islets (47), which may deteriorate islet architecture, ending up with a decline in insulin secretion. However, further reports disclaimed the common theory that CFRD merely results from severe fibrosis-induced islet destruction and suggested that intrinsic defects in insulin production and secretion might be related to CFTR channel dysfunctions (21). Although additional investigators detected CFTR expression in islet cells of the rat, they concluded that they could not exclude the possibility of contamination of the ␤-cell population by non-␤-cells (7), while others underlined that islets from diabetic CF patients are not more damaged compared with those who remain normoglycemic (61).…”

mentioning

confidence: 99%

CFTR silencing in pancreatic β-cells reveals a functional impact on glucose-stimulated insulin secretion and oxidative stress response

Ntimbane

Mailhot

Spahis

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Cystic fibrosis (CF)-related diabetes (CFRD) has become a critical complication that seriously affects the clinical outcomes of CF patients. Although CFRD has emerged as the most common nonpulmonary complication of CF, little is known about its etiopathogenesis. Additionally, whether oxidative stress (OxS), a common feature of CF and diabetes, influences CFRD pathophysiology requires clarification. The main objective of this study was to shed light on the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in combination with OxS in insulin secretion from pancreatic β-cells. CFTR silencing was accomplished in MIN6 cells by stable expression of small hairpin RNAs (shRNA), and glucose-induced insulin secretion was evaluated in the presence and absence of the valuable prooxidant system iron/ascorbate (Fe/Asc; 0.075/0.75 mM) along with or without the antioxidant Trolox (1 mM). Insulin output from CFTR-silenced MIN6 cells was significantly reduced (∼70%) at basal and at different glucose concentrations compared with control Mock cells. Furthermore, CFTR silencing rendered MIN6 cells more sensitive to OxS as evidenced by both increased lipid peroxides and weakened antioxidant defense, especially following incubation with Fe/Asc. The decreased insulin secretion in CFTR-silenced MIN6 cells was associated with high levels of NF-κB (the major participant in inflammatory responses), raised apoptosis, and diminished ATP production in response to the Fe/Asc challenge. However, these defects were alleviated by the addition of Trolox, thereby pointing out the role of OxS in aggravating the effects of CFTR deficiency. Our findings indicate that CFTR deficiency in combination with OxS may contribute to endocrine cell dysfunction and insulin secretion, which at least in part may explain the development of CFRD.

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“…The extended OGTT approach with criteria used for CFID stages 4 and number of children in each category is depicted in Table 2. The mean weight and BMI z scores for those with CFRD compared to controls were -0.64 vs -0.02 (p=0.005) and -1.26 vs -0.03 (p=0.0001).…”

Section: Resultsmentioning

confidence: 99%

“…By the third and fourth decades the prevalence is estimated at 40%. CFRD has worsening impact on lung function and nutritional status, independent of pre-existing disease 2,4 .…”

Section: Introductionmentioning

confidence: 99%