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

Abstract

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.

Abnormal Glucose Tolerance in Infants and Young Children with Cystic Fibrosis

“…The children with AGT had no higher insulin levels than control subjects and only a modest increase in insulin compared with NGT children with CF despite higher glucose levels, implying that these children lack the ability to appropriately increase insulin secretion in the face of increased demand. Therefore, deficiency in insulin secretion is likely the primary cause of AGT in these children, similar to older children and adults with CF (3,27,28). This may be coupled with increased insulin clearance, which would explain some of the difference found between measures of insulin and C-peptide and is described in others with CF (29).…”

Variabilidad fenotípica de la fibrosis quística: reporte de 2 gemelos con la mutación F508/F508

“…La proteína CFTR es expresada en la membrana apical de las células que recubren el epitelio respiratorio, de los conductos pancreáticos, del sistema gastrointestinal, del tracto genitourinario y de las glándulas sudoríparas 2,3,10 . Esta localización explica las manifestaciones clínicas de la enfermedad, tales como malabsorción de nutrientes secundaria a insuficiencia pancreática, falla pulmonar severa, hiponatremia, pólipos nasales, prolapso rectal, pancreatitis, colelitiasis y diabetes 6,[11][12][13] . El diagnóstico Gold Standard basa principalmente en la medición de electrolitos en sudor mediante una prueba induciendo el sudor con pilocarpina, el test del sudor, sin embargo, ha mostrado ser más útil principalmente en tami-zaje, por lo que se ha planteado su reemplazo por el test de conductancia del sudor 14 .…”

Cystic fibrosis-related diabetes: A distinct condition

“…Cases of fasting hypoglycemia have even been reported. 20,21 That is, there is a lower overall prevalence of IBG. 22,23 An annual OGTT during a phase of clinical stability is usually recommended in patients over 10 years of age, 19 although screening before that age has recently been suggested.…”

“…Therefore, blood glucose levels at 60 and 90 min may be more sensitive for detecting glucose intolerance in these patients. 21,22 Normal random blood glucose levels do not rule out diagnosis, because they depend on the time of day, the last meal, gastric emptying, etc. By contrast, persistently high levels (≥200 mg/dL) allow for diagnosis, and the ADA has therefore incorporated random blood glucose levels as a diagnostic tool.…”