Mechanisms of glucose intolerance in cystic fibrosis

Mohan, Kamlesh; Miller, H.; Dyce, Paul W.; Grainger, R.; Hughes, Rachael A.; Vora, Jiten; Ledson, M.J.; Walshaw, Martin

doi:10.1111/j.1464-5491.2009.02738.x

Cited by 58 publications

(56 citation statements)

References 36 publications

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“…However, quantitative aspects may not be comparable (8,37,40,46). The largest available adult series (37) displayed an average b-cell function as 70% of control values in the whole CF population and 50% of control values in the subgroup with NGT.…”

Section: Discussionmentioning

confidence: 99%

“…The OGTT is the most common diagnostic test for CFRD and can be repeated yearly. Several studies sampled insulin concentrations during OGTT and analyzed insulin secretion using various algorithms and consistently found reduced and delayed insulin responses (8,37,45,46), even in CF patients with normal glucose tolerance (NGT), supporting the concept that insulin secretory defects are inherent to CF.…”

Section: Introductionmentioning

confidence: 99%

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Identification of insulin secretory defects and insulin resistance during oral glucose tolerance test in a cohort of cystic fibrosis patients

Battezzati

Mari

Zazzeron

et al. 2011

European Journal of Endocrinology

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Background: Cystic fibrosis (CF)-related diabetes is a leading complication of CF and is associated with pulmonary and nutritional deterioration, years before an evident hyperglycemia, possibly because of insulin deficiency and resistance. Aim: To evaluate glucose tolerance, insulin secretion, and insulin sensitivity by a widely applicable method suitable for accurate and prospective measurements in a CF population. Methods: A total of 165 CF subjects (80 females) aged 17G5 years and 18 age-and sex-matched healthy controls (CON) received an oral glucose tolerance test with glucose, insulin and C-peptide determinations. Insulin sensitivity was defined on the basis of glucose and insulin concentrations using the oral glucose insulin sensitivity index, whereas b-cell function was determined on the basis of a model relating insulin secretion (C-peptide profile) to glucose concentration. Results: Fifteen percent of CF patients had glucose intolerance and 6% had diabetes without fasting hyperglycemia and 3% had diabetes with fasting hyperglycemia. b-cell function was reduced in CF patients compared with CON (70.0G4.1 vs 117.9G11.6 pmol/min per m 2 per mM, P!0.001) and decreased significantly with age by K2.7 pmol/min per m 2 per mM per year (confidence interval (CI) K4.5 to K0.82), i.e. almost 4% yearly. The early insulin secretion index was also reduced. Insulin sensitivity was similar to CON. CF patients who attained glucose tolerance comparable to CON had lower b-cell function and higher insulin sensitivity. Conclusion: The major alteration in insulin secretion and insulin sensitivity of CF patients is slowly declining b-cell function, consisting of delayed and reduced responsiveness to hyperglycemia, that in CF patients with normal glucose tolerance may be compensated by an increased insulin sensitivity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of insulin secretory defects and insulin resistance during oral glucose tolerance test in a cohort of cystic fibrosis patients

Battezzati

Mari

Zazzeron

et al. 2011

European Journal of Endocrinology

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“…Insulin sensitivity in CFRD patients is generally normal or only slightly decreased, except in the settings of acute infectious pulmonary illness or the use of glucocorticoids, when severe insulin resistance is present (28). Furthermore, insulin clearance may also be increased in CF individuals, whether diabetic or not (29).…”

Section: Novel Mechanistic Views On Cfrd Developmentmentioning

confidence: 99%

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

Barrio¹

2015

European Journal of Endocrinology

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Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). CFTR is primarily present in epithelial cells of the airways, intestine and in cells with exocrine and endocrine functions. Mutations in the gene encoding the channel protein complex (CFTR) cause alterations in the ionic composition of secretions from the lung, gastrointestinal tract, liver, and also the pancreas. CF-related diabetes (CFRD), the most common complication of CF, has a major detrimental impact on pulmonary function, nutrition and survival. Glucose derangements in CF seem to start from early infancy and, even when the pathophysiology is multifactorial, insulin insufficiency is clearly a major component. Consistently, recent evidence has confirmed that CFTR is an important regulator of insulin secretion by islet b-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either b-cell mass reduction or b-cell malfunction. Understanding such mechanisms is crucial for the development of the so-called 'transformational' therapies in CF, including the preservation of insulin secretion. Innovative therapeutic approaches aim to modify specific CFTR mutant proteins or positively modulate their function. CFTR modulators have recently shown in vitro capacity to enhance insulin secretion and thereby potential clinical utility in CFDR, including synergistic effects between corrector and potentiator drugs. The introduction of incretins and the optimization of exocrine pancreatic replacement complete the number of therapeutic options of CFRD besides early diagnosis and implementation of insulin therapy. This review focuses on the recently identified pathogenic mechanisms leading to CFRD relevant for the development of novel pharmacological avenues in CFRD therapy.

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“…This insulin deficiency largely manifests as post-prandial hyperglycemia due to delayed early insulin secretion, 33 but basal insulin secretion is largely preserved until late in the course of CFRD. In non-diabetic CF individuals, despite NGT, β-cell secretory capacity is reduced.…”

Section: Pathophysiologymentioning

confidence: 99%

“…33,44 Studies using oral and intravenous glucose challenges have reported normal insulin sensitivity, which does not worsen over time. 39,40,45 There is emerging evidence for insulin resistance in CF; a decrease in gluconeogenesis due to insulin signal transduction defect caused by reduction of the transcription factor, FOXO1, was recently discovered by Smerieri et al 46 Insulin resistance emerges during periods of stress and is evident in the impaired insulin-mediated suppression of proteolysis in CF.…”

Section: Pathophysiologymentioning

confidence: 99%

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

Sheikh¹,

Kelly²

2015

RRED

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Cystic fibrosis-related diabetes (CFRD) is a common comorbidity in cystic fibrosis (CF) and portends worse clinical outcomes including lower lung function and nutritional status, and decreased survival. CFRD is distinct from other forms of diabetes, but relative insulin deficiency is a predominant feature. The catabolic effects of insulin deficiency coupled with the pro-inflammatory effects of hyperglycemia likely affect clinical outcomes. Posited mechanisms of CFRD development include collateral damage from pancreatic exocrine destruction, inherent β-cell defect, CFTR dysfunction, and incretin deficiency or unresponsiveness. Even though CF clinical care teams are increasingly aware of its implications, CFRD screening and management remain a challenge. Promising clinical and basic research in the fields of diabetes and CF and the advent of novel therapeutics targeting the protein defect in CF have potential to change CFRD care. This review presents newer data on insulin defects and glucose derangements and highlights continuing challenges and unanswered questions.

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Mechanisms of glucose intolerance in cystic fibrosis

Abstract: CFRD is characterized by qualitative and quantitative defects in insulin secretion, but not insulin resistance, and is associated with increased hospital admissions for pulmonary exacerbations.

Cited by 58 publications

References 36 publications

Identification of insulin secretory defects and insulin resistance during oral glucose tolerance test in a cohort of cystic fibrosis patients

Identification of insulin secretory defects and insulin resistance during oral glucose tolerance test in a cohort of cystic fibrosis patients

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

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

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