The ΔF508 Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator Is Associated With Progressive Insulin Resistance and Decreased Functional β-Cell Mass in Mice

Abstract

Cystic fibrosis (CF) is the result of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF-related diabetes affects 50% of adult CF patients. How CFTR deficiency predisposes to diabetes is unknown. Herein, we examined the impact of the most frequent cftr mutation in humans, deletion of phenylalanine at position 508 (ΔF508), on glucose homeostasis in mice. We compared ΔF508 mutant mice with wild-type (WT) littermates. Twelve-week-old male ΔF508 mutants had lower body weight, improved oral glucose tolerance, and a trend toward higher insulin tolerance. Glucose-induced insulin secretion was slightly diminished in ΔF508 mutant islets, due to reduced insulin content, but ΔF508 mutant islets were not more sensitive to proinflammatory cytokines than WT islets. Hyperglycemic clamps confirmed an increase in insulin sensitivity with normal β-cell function in 12- and 18-week-old ΔF508 mutants. In contrast, 24-week-old ΔF508 mutants exhibited insulin resistance and reduced β-cell function. β-Cell mass was unaffected at 11 weeks of age but was significantly lower in ΔF508 mutants versus controls at 24 weeks. This was not associated with gross pancreatic pathology. We conclude that the ΔF508 CFTR mutation does not lead to an intrinsic β-cell secretory defect but is associated with insulin resistance and a β-cell mass deficit in aging mutants.

Cystic fibrosis–related diabetes is caused by islet loss and inflammation

“…Our murine models of β cell-specific CFTR deletion allowed us to determine whether the CFTR contributes directly to β cell function without metabolic and pancreatic abnormalities caused by whole-animal CFTR loss. Integrating our data with other reports (20,25,35) indicates that nutrient intolerance and β cell dysfunction in CF models were not caused directly by β cell CFTR loss but by other effects (i.e., insulin resistance, β cell loss, pancreas/islet inflammation) caused by whole-animal CFTR deletion.…”

“…54), impaired glucose and mixed meal intolerance and impaired islet function have been consistently shown (13,20,35). However, reduced β cell mass (13,20,25), fluctuating insulin resistance (25), pancreatic inflammation (20), and an unidentified exocrine-derived paracrine factor (35) have been reported and linked to nutrient intolerance and β cell dysfunction in these models. In the single report that concluded that β cell CFTR loss in CF mice caused β cell dysfunction and impaired glucose tolerance, β cell mass and insulin sensitivity were not examined (12).…”

“…Conversely, studies of humans and CF animal models have suggested that CFRD results from CF-induced pancreatic autolysis, inflammation, and reduction of β cell mass (17)(18)(19)(20) causing insufficient islet hormone secretion (20)(21)(22)(23)(24)(25)(26)(27). These findings are supported by an association among CFRD, Cystic fibrosis-related (CF-related) diabetes (CFRD) is an increasingly common and devastating comorbidity of CF, affecting approximately 35% of adults with CF.…”

Survival in a bad neighborhood: pancreatic islets in cystic fibrosis

“…Mouse models of cystic fibrosis, including Cftr-knockout and Cftr-ΔF508 mice, exhibit severe gastrointestinal disease and impaired growth but do not develop substantive pancreatic or lung disease. Blood glucose in CF mice is normal (Lanng et al 1993b) or even reduced (Fontes et al 2015) during glucose tolerance testing. Mice with acute-or chronic β-cell-specific Cftr deletion demonstrate normal glucose tolerance and do not exhibit altered insulin release in response to glucose or IBMX (Hart et al 2018).…”

MiRNAs Regulating Insulin Sensitivity Are Dysregulated in Polycystic Ovary Syndrome (PCOS) Ovaries and Are Associated With Markers of Inflammation and Insulin Sensitivity

“…Moreover, miR-320 regulates the expression of NOD2 a cytosolic receptor involved in the proinflammatory cascades in chronic inflammatory bowel diseases (36). MiR-370 is a modulator of IRS1 expression, a scaffold protein involved in the insulin pathway (37,38). MiR-486 directly targets mediators of insulin-like growth factor (IGF) signaling including IGF-I, IGF-I receptor (IGF1R), and PI3K regulatory subunit 1 (alpha) (PIK3R1) and is reduced in plasma of diabetic patients (39,40).…”