Cystic Fibrosis Transmembrane Conductance Regulator and Diabetes: Comparison
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The most common inherited condition that results in death, particularly in those of Caucasian heritage, is cystic fibrosis (CF). Of all the young adults diagnosed with cystic fibrosis, 20% will develop hyperglycemia as a complication, later classified as a disease associated with cystic fibrosis. Impaired insulin secretion and glucose intolerance represent the primary mechanisms associated with diabetes (type 1 or type 2) and cystic fibrosis.

  • cystic fibrosis
  • diabetes mellitus
  • oxidative stress
  • children

1. Introduction

Cystic fibrosis (CF) is the predominant hereditary disease-causing fatality, especially among individuals of Caucasian descent. It is an autosomal recessive disease that affects approximately one in every 3000 live births [1]. The gene responsible for cystic fibrosis is a regulator called the cystic fibrosis transmembrane conductance regulator (CFTR) gene. As a result, this dysfunctional protein interferes with the regular transportation of chloride ions, disturbing the movement of epithelial lining fluid (mucus) in various organs [2].
Cystic fibrosis-related diabetes (CFRD) represents a frequently encountered complication in individuals with CF, affecting approximately 20% of adult CF patients [3]. The easiest way to define cystic fibrosis-related diabetes is by hyperglycemia and its consequences [4].
A loss of equilibrium between oxygen-reactive species and antioxidant defense systems characterizes oxidative stress. This pathogenic mechanism is vital in triggering other chronic diseases, including cystic fibrosis-related diabetes [5].

2. The Importance of Oxidative Stress in the Pathophysiology of Diabetes

Diabetes, a chronic metabolic disorder, is characterized by persistent hyperglycemia resulting from insufficient insulin production, impaired insulin action, or both [51][6]. The two major forms of diabetes, type 1 diabetes mellitus (T1DM AND T2DM) AND type 2 diabetes mellitus (T2DM), are differentiated by underlying eti-ological factors. T1DM is characterized by the autoimmune destruction of pancreatic β-cells, resulting in a deficit of insulin. On the other hand, T2DM is linked to insulin resistance and dysfunction of the pancreatic β-cells [51][6]. The other classes of diabetes include gestational diabetes mellitus (GDM) and diabetes that is induced by or linked to particular circumstances and medical conditions [52][7].
Oxidative stress contributes to the development of diabetes, serving as a pivotal factor in their pathogenesis [53,54][8][9]. Studies show that ROS-induced β-cell damage triggers autoimmune responses, culminating in β-cell destruction and insulin deficiency [53,55,56,57][8][10][11][12]. Chronic overnutrition and physical inactivity accentuate oxidative stress, leading to insulin resistance and impaired secretion [26][13].
The imbalance between ROS and antioxidant capacity is the defining element in the progression of diabetes [58][14]. Reactive oxygen species are induced by hyperglycemia, simultaneously reducing the levels of antioxidants [59,60][15][16]. Juan Li et al. [61][17] conducted an analysis focusing on individuals with T2DM diabetes, and the findings revealed a significant correlation between hyperglycemic crises and oxidative stress among diabetic patients. These suggest that in individuals with diabetes, episodes of hyperglycemia are closely associated with heightened oxidative stress.
Monika Grabia et al. [27][18], analyzed serum levels of antioxidant enzymes, minerals, and toxic elements to assess their major impact in diabetes progression. The study revealed that individuals with T1DM exhibited a diminished capacity for antioxidant defense within their system, resulting in elevated oxidative stress levels. Morandi et al. [24][19] conducted a study that found that pediatric patients diagnosed with T1DM exhibited elevated levels of derivatives-reactive oxygen metabolites (D-ROMS) compared to those in good condition. However, it is noteworthy that oxidative stress is not solely triggered by hyperglycemia, as glucose variability also plays a significant role [62][20]. Consequently, glucose variability might contribute to oxidative stress and its associated atherogenic effects among individuals with T1DM, irrespective of their short-term and long-term average glucose levels [24][19].
The protein kinase C (PKC) pathway, activated by ROS, contributes to insulin resistance in diabetes [63,64,65][21][22][23]. Similarly, ROS activation of the kappa-light-chain-enhancer of activated B cells (NF-κB) determines the activation of pro-inflammatory cytokine production, exacerbating β-cell damage and insulin resistance [66][24]. Also, the hexosamine biosynthetic pathway (HBP), influenced by high glucose levels, induces oxidative stress [67][25]. Oxidative stress, besides being a key factor in diabetes pathogenesis, also contributes significantly to the development of diabetes-related complications. Oxidative stress secondary hyperglycemia determines the usual diabetes complications (retinopathy, nephropathy, neuropathy, and cardiovascular diseases) [68[26][27][28][29],69,70,71], thus, mitigating oxidative stress might prove beneficial in preventing or slowing the progression of these complications.
Oxidative stress and insulin resistance are correlated through numerous interrelated processes. Firstly, oxidative stress can destroy mitochondria, impairing their function and resulting in dysfunctional β-cells [72][30]. Furthermore, nuclear transcription factors that are important for the regulation of insulin, such as insulin promoter factor-1, can be inhibited by oxidative stress [73][31]. Additionally, it may be a factor in the decreased expression of glucose transporter type 4 (GLUT-4), which could compromise the uptake of glucose by the cells [73,74][31][32]. The destructive impact on mitochondria by oxidative stress also hampers the availability of energy required for efficient glucose uptake [72,73][30][31]. Lastly, the presence of free radicals can impair the insulin signal transduction pathway, further exacerbating insulin resistance [65][23]. The intricate and multidimensional relationship between oxidative stress and insulin resistance is shown by these interconnected pathways. Oxidative stress and chronic inflammation form the basis of diabetes’ pathophysiology and its complications [18,73,74][31][32][33]. Persistent hyperglycemia releases free radicals in the β-cells, primarily superoxide anions [24,74][19][32].
Multiple mechanisms underlie the relationship between oxidative stress and insulin resistance. These include the destruction of mitochondria by oxidative stress, which results in β-cell dysfunction [72][30], the inhibition of nuclear transcription factors (such as insulin-promoter-factor 1) [74][32], the decreased expression of the glucose transporter type 4 (GLUT-4) [74[32][34],75], the lack of energy needed for glucose uptake due to mitochondrial destruction [72[30][32],74], and the disruption of the insulin signal transduction pathway brought on by free radicals [74][32]. Excessive reactive oxygen species can cause serious diabetes problems that include the kidneys, eyes, and nerves [74,75,76][32][34][35]. Growth factors and pro-inflammatory cytokines are produced in larger quantities when reactive oxygen species are produced excessively. This process and additional metabolic pathways brought on by hyperglycemia control aberrant angiogenesis, tissue ischemia, and vasoconstriction [74][32]. Hyperglycemia causes the mitochondria to produce reactive oxygen species and reduce antioxidants. After analyzing type 2 diabetic patients, Juan Li found a substantial correlation between hyperglycemic crises and oxidative stress in diabetic patients [61,77,78][17][36][37].

Diabetes Therapy and Oxidative Stress

The management of CFRD has traditionally been centered on correcting hyperglycemia through administering insulin combined with dietary modifications and physiotherapy [79][38]. New approaches have been incorporated in recent years, including oral hypoglycemic agents and incretin-based therapies [80,81,82][39][40][41]. However, there are no conclusive data to promote the use of these medications. Some evidence suggests that conventional and novel CFRD therapies can influence oxidative stress biomarkers. For instance, by reducing the generation of ROS, metformin therapy lowers blood glucose levels and oxidative stress [25][42]. By increasing antioxidant enzymes and lowering inflammatory cytokine levels, incretin-based treatments (e.g., glucagon-like peptide-1 (GLP-1) or dipeptidyl peptidase-4 (DPP-4) inhibitors) have shown antioxidative effects [83][43]. Exercise has been regularly proven to increase antioxidant capacity, decrease ROS production, and enhance cellular insulin sensitivity [84][44].
Moreover, physical activity substantially modifies the relationship between glycemic fluctuation at night and oxidative stress during the day [73,85][31][45]. Moreover, incorporating a nutritious diet reduces inflammation and oxidative stress and enhances cellular responsiveness to insulin. Therefore, including natural, antioxidant-rich sources is crucial in mitigating oxidative stress [73][31]. In research of 60 people recently diagnosed with T1DM, Wang et al. analyzed the relationship between the initial insulin dosage and the degree of oxidative stress. Moreover, physical activity substantially modifies the association between glycemic fluctuation at night and oxidative stress during the day [86][46]. The findings indicated that higher insulin doses initially resulted in a rapid decline in blood glucose levels. However, after 2 and 3 weeks, the disparity in glucose reduction became less discernible as lower, moderate, and high insulin doses exhibited similar effectiveness. Notably, the amount of oxidative stress was constant, independent of the amount of insulin given. Thus, reducing oxidative stress in CFRD management can have significant clinical implications.

3. Cystic Fibrosis-Related Diabetes

3.1. Definition and the Importance of the Subject

CFRD is an extrapulmonary complication of CF resulting from abnormal glucose metabolism [87][47]. CFRD shares characteristics with both T1DM and T2DM. However, its distinguishing feature of acute pulmonary complications associated with hyperglycemia and catabolic metabolism, along with a relative insulin deficiency, impacts the application of typical diabetes definitions and therapies. As people with CF live longer lives, it is expected that more than half will acquire CFRD during their lifespan, including up to 20% of adolescents. As the number of persons with CFRD grows, diabetes practitioners will become more aware of the disease [88][48].

3.2. Evolution, Comorbidities and Mutations

Among patients with cystic fibrosis, diabetes associated with the disease is the most prevalent non-pulmonary comorbidity [89][49]. Individuals suffering from cystic fibrosis-related diabetes are prone to greater mortality caused by nutritional status and lung disease exacerbations (more frequently in CFRD) [90][50]. CFRD prevalence increases with age as β-cell dysfunction and destruction progress [91][51]. The primary causing factor of cystic fibrosis-related diabetes is insulin insufficiency [89][49], similar to type 1 diabetes, due to the destruction and impairment of pancreatic cells [92][52]. Nonetheless, people with CFRD may also exhibit partial insulin resistance. Insulin resistance is more significant when using a glucocorticoid treatment, during acute pulmonary exacerbations, and as people age [89][49]. The severity of CFTR mutations is correlated with an increased risk of diabetes [89,90,91,92,93][49][50][51][52][53]. Insulin exocytosis and pancreatic development are mediated by β-cells, which express CFTR [92][52]. Insulin insufficiency and cell dysfunction are also caused by the β-cells’ increased susceptibility to oxidative stress [94,95][54][55]. CFRT is also expressed in α-cells [94][54] and, due to its dysfunction, it determines dysregulated glucagon secretion and contributes to glucose intolerance and CFRD pathophysiology [92][52].

3.3. Associated Genetic Factors

The development of cystic fibrosis-related diabetes is influenced by genetic factors, including the factor 7-like 2 (TCF7L2) gene, which has also been associated with type 2 diabetes. This involvement was confirmed by Blackman et al. in 2013. Also, Blackman et al. identified four new loci that are associated with the disease: cyclin-dependent kinase 5 (CDK5), cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/B), insulin-like growth factor 2 messenger RNA (IGF2BP2), and solute carrier family 26 members 9 (SLC26A9). Additional genes implicated in the development of cystic fibrosis-related diabetes (CFRD) include PM20d1, which is located near the SLC26A9 gene, and PTMA. This gene modifier was found by Aksit et al. [96][56]. The extent of cystic fibrosis manifestations is directly correlated with the CFTR genotype.
Furthermore, the F508del mutation (homozygous and heterozygous states) determined impaired glucose metabolism. Furthermore, homozygous individuals for F508del mutations have diminished insulin sensitivity, reduced insulin levels during oral testing, and decreased first-phase insulin responses during intravenous glucose tolerance tests compared to heterozygotes. In addition, several more genetic modifiers are associated with both CFRD and T2DM besides the genes already mentioned that are believed to affect insulin secretion and β- cell function [92][52].

3.4. Glucose Homeostasis in Cystic FRDibrosis-Related Diabetes, Pathogeny of CFRystic Fibrosis-Related Diabetes

The insulin secretion impairment associated with cystic fibrosis determines the hyperglycemia to install. The physiological process of insulin is to be produced by beta-cells of the pancreas and stimulated by glucose load during meals or stress [97][57]. It is a peptidic hormone synthesized and stored in the Langerhans cells. After secretion, insulin action reduces glucose levels as the primary target. As previously discussed, cystic fibrosis causes the loss of cells in the pancreas by replacing healthy tissue with fibrosis and amyloid [97][57].
Secondary to this step, the first phase of insulin secretion diminishes, causing hyperglycemia [98][58]. It is thought that reduced exocytosis affects the production of enough insulin to cover the necessities or lessen the intensity of the insulin peak. It causes postprandial hyperglycemia, leading to diabetes over time. Insulin resistance encountered in type 2 diabetes represents an alternative pathway leading to glucose abnormalities. Hyperglycemia influences the insulin-sensitive channels on cell surfaces, significantly decreasing the abundance of glucose transporters, specifically glucose transporter type 4 [93][53]. The importance of the transporter is to easily diffuse glucose in muscle and adipose tissue. As an immediate effect, insulin resistance is triggered and accentuated. As a hallmark of cystic fibrosis, glycemic fluctuation is often encountered, accentuated by disease evolution and complication worsening, especially respiratory exacerbations, treatment, hormonal imbalances, and nutritional status. Less muscular and adipose tissues will make stocking glucose impossible [93,99][53][59].

3.5. Oxidative Stress in Cystic FRibrosis-Related Diabetes

Cystic fibrosis-associated diabetes in individuals diagnosed with cystic fibrosis manifests as a stand-alone variant. CFRD development is intricately associated with oxidative stress [23][60]. Maintaining cellular functioning under normal conditions relies on the delicate equilibrium between reactive oxygen species (ROS) and their counteraction by antioxidants [100][61]. Nevertheless, in the context of cystic fibrosis (CF), there is an atypical excessive generation of reactive oxygen species (ROS), which leads to detrimental effects on the pancreatic β-cells responsible for insulin release [101][62]. The resulting impaired insulin secretion initiates the onset of glucose intolerance, which is a hallmark of CFRD [4].
Further aggravating the condition, the chronic inflammation characteristic of CF can amplify oxidative stress, thereby accelerating the progression of CFRD [10,102][63][64]. Identifying and quantifying oxidative stress biomarkers in CFRD patients is crucial for understanding the pathophysiology of the disease and informing potential treatment strategies. Elevated concentrations of malondialdehyde (MDA) and protein carbonyls in the plasma have been recognized as dependable indicators of oxidative stress, indicating the occurrence of lipid and protein oxidation, respectively [47][65]. Furthermore, the diminished concentrations of reduced glutathione (GSH) observed in individuals with cystic fibrosis-related diabetes (CFRD) highlight the degraded condition of the body’s antioxidant mechanisms [27][18]. The development of improved detection methods has also facilitated the discovery of novel biomarkers, including F2-isoprostanes and 8-hydroxy-2’-deoxyguanosine (8-OHdG) [102,103][64][66].
In their study, Ntimbane et al. examined the levels of blood glutathione and 4-hydroxynonenal-protein adducts (HNE-P), urine 1,4-dihydroxy nonane-mercapturic acid conjugate (DHN-MA), and plasma fatty acid (FA) in a cohort of young patients (aged 10–18) following an oral glucose tolerance test (OGTT). They concluded that children with cystic fibrosis displayed higher oxidative stress and poorer glucose metabolism. Nutritional recommendations may help to postpone the onset of CFRD [23][60]. In a separate investigation carried out by Ntimbane et al., it was determined that the presence of a faulty CFTR protein amplified the compromised antioxidant defense mechanism of β-cells, rendering them more susceptible to oxidative stress occurrences [101][62].
Hunt et al. conducted a study to assess the systemic redox balance and levels of pro-inflammatory cytokines in patients with cystic fibrosis (CF) both before and after undergoing an oral glucose tolerance test (OGTT). When comparing individuals with prediabetes and cystic fibrosis-related diabetes (CFRD) to those with cystic fibrosis (CF) and standard glucose tolerance (NGT), as well as healthy controls (HC), it was shown that the baseline systemic redox potential of the former group was significantly more oxidized. The glucose administration resulted in a significant and notable increase in systemic oxidation two hours later in all groups with cystic fibrosis, including those with standard glucose tolerance, prediabetes, and cystic fibrosis-related diabetes. The redox imbalance observed at the two-hour mark was consistent across all three groups of individuals with cystic fibrosis and did not show any correlation with the severity of hyperglycemia. In summary, the study conducted by Hunt et al. yielded the finding that a notable association existed between heightened systemic oxidation and diminished insulin secretion [104][67].

3.6. Screening and Diagnosis

From the age of 10, screening is recommended for all cystic fibrosis children [89,105][49][68]. Furthermore, patients that should be screened for CFRD include individuals with pulmonary exacerbation under glucocorticoid and antibiotic therapy, enteral or parenteral nutrition support, and undergoing transplantation. The screening and diagnostic methods for cystic fibrosis-related diabetes (CFRD) include the oral glucose tolerance test (considered the gold standard), hemoglobin A1c, fasting plasma glucose, random blood glucose testing, and glucose monitoring [89][49]. Although other indicators such as fructosamine, glycated albumin, and 1,5-anhydroglucitol are utilized to evaluate glycemic control instead of hemoglobin A1c, they are not indicated for the screening and diagnosis of cystic fibrosis-related diabetes (CFRD) [89,106][49][69]. However, studies showed that CGM (continuous glucose monitoring) may be more effective [107,108][70][71]. In a study conducted by Taylor–Cousar, continuous glucose monitoring (CGM) showed a higher level of impaired glucose metabolism in adult patients diagnosed with cystic fibrosis (CF) compared to the widely accepted gold standard oral glucose tolerance test (OGTT). Additionally, individuals who experienced the onset of cystic fibrosis-related diabetes (CFRD) within a certain period were effectively detected by continuous glucose monitoring (CGM) when their glucose levels surpassed 200 mg/dL on two separate occasions [108][71].
Boudreau et al. studied the OGGT results of 152 adult patients without known diabetes. They concluded that alterations in insulin sensitivity were associated with variations in glucose tolerance in adult individuals with CF who had considerably decreased insulin secretion [109][72].
The study conducted by Chan et al. aimed to investigate the correlation between continuous glucose monitoring (CGM) and estimations of β-cell function generated from oral glucose tolerance tests (OGTT). Additionally, the researchers wanted to assess the potential of CGM as a screening tool for prediabetes and cystic fibrosis-related diabetes (CFRD) as defined by OGTT. The researchers’ investigation concluded a negative correlation between increased glycemic fluctuation measured by continuous glucose monitoring (CGM) and β-cell function. Nevertheless, the performance of continuous glucose monitoring (CGM) was inaccurately differentiating between patients diagnosed with oral glucose tolerance test (OGTT)-defined cystic fibrosis-related diabetes (CFRD) and those without CFRD, as well as individuals with prediabetes [110][73].

3.7. Cystic Fibrosis Exacerbations Treatment and the Effect on Blood Glucose

Steroid use (typically prednisolone or methylprednisolone) is prevalent in CF patients and may cause transitory hyperglycemia or decrease glucose control in those with pre-existing CFRD. National guidelines recommend more frequent CBG monitoring and the use of insulin to treat hyperglycemia [111,112][74][75].

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