Natural history of glucose tolerance, beta-cell function and peripheral insulin sensitivity in cystic fibrosis patients with fasting euglycemia (original) (raw)
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Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion, 2014
diabetes has become a co-morbidity with a negative impact on nutritional status, lung function and survival in cystic fibrosis. To identify any changes in intermediate points after a 2-hour oral glucose tolerance test (OGTT), pancreatic β-cell dysfunction, and insulin resistance in cystic fibrosis-related diabetes. It was carried out a retrospective analysis in a cohort of 64 patients affected of cystic fibrosis, older than 14 years, using the first pathological OGTT. Peripheral insulin resistance was measured using the homeostasis model assessment for insulin resistance (HOMA- IR), and pancreatic β-cell function was calculated according to Wareham. Time to maximum plasma insulin and glucose levels and area under the curve (AUC0-120) were also measured. Twenty-eight women and 36 men with a mean age of 26.8 years were enrolled, of whom 26.7% had normal glucose tolerance (NGT), 18.3% cystic fibrosis-related diabetes without fasting hyperglycemia (CFRD w/o FPG), 10% indeterminate (INDE...
European Journal of Endocrinology, 1994
Cucinotta D, De Luca F, Gigante A, Arrigo T, Di Benedetto A, Tedeschi A, Lombardo F, Romano G, Sferlazzas C. No changes of insulin sensitivity in cystic fibrosis patients with different degrees of glucose tolerance: an epidemiological and longitudinal study. Eur J Endocrinol 1994;130:253–8. ISSN 0804–4643 Plasma glucose and insulin responses to oral glucose and insulin sensitivity by the euglycemic hyperinsulinemic clamp technique were investigated in 30 cystic fibrosis patients with normal fasting blood glucose levels and normal (N = 12), impaired (N = 12) or diabetic (N = 6) glucose tolerance, and in 12 control subjects. In a subgroup of 10 cystic fibrosis patients with non-diabetic glucose tolerance both oral glucose tolerance test and clamp were performed again 48–52 months later. Following oral glucose, glycemic responses were higher in cystic fibrosis patients than in controls, whereas insulin responses were reduced significantly only in the patients with diabetic glucose tole...
Cystic fibrosis-related diabetes: the role of peripheral insulin resistance and ��-cell dysfunction
Diabetic Medicine, 2002
Aims The goal of this study was to identify the glycaemic status and investigate the roles of peripheral insulin resistance (IR) and pancreatic β-cell dysfunction in the pathogenesis of cystic fibrosis-related diabetes (CFRD) in adult cystic fibrosis (CF) patients with no previous history of glycaemic disturbances.Methods The glucose tolerance status of 68 CF patients was determined using 2-h oral glucose tolerance tests (OGTTs). Peripheral IR was measured using the homeostasis model assessment for insulin resistance (HOMA-IR) in the CF group and 46 normal healthy control subjects. Pancreatic β-cell function, calculated as the ratio between the 30-min increment in plasma insulin and the corresponding 30-min post-OGTT plasma glucose concentration, was also measured in a subset of 30 CF patients and 16 normal healthy controls. Extended 180-min OGTTs, with frequent plasma glucose and insulin sampling, were also undertaken in 24 CF patients and eight normal healthy controls to determine glucose-induced insulin response.Results Of the 68 CF patients studied, 41, 18 and nine were found to have normal, impaired and diabetic glucose tolerances, respectively. The mean HOMA-IR values (mU/mmol) in the CF patients, as a whole, were not significantly different compared with the normal healthy controls (CF 2.2 ± 1.1 vs. control 1.8 ± 0.9; NS). Within the CF group, glycaemic status had no impact on HOMA-IR (mU/mmol): 2.2 ± 1.2 (normal glucose tolerance); 2.0 ± 1.0 (impaired glucose tolerance); and 2.3 ± 1.1 (diabetic glucose tolerance). β-cell function (mU/mmol) was not only significantly lower in the CF group (CF 1.65 ± 1.8; P < 0.001) but also in the CF group with normal glucose tolerance (2.25 ± 2.10; P < 0.01) compared with healthy control (4.98 ± 2.38). Mean plasma glucose concentrations were generally higher and mean plasma insulin concentrations lower in the CF group as a whole when compared with normal healthy controls. Within the CF group, there was a progressive decline in glucose-induced insulin release with worsening glycaemic status.Conclusions A lack of difference in peripheral IR, measured using HOMA-IR, in the CF group and healthy controls or within the CF group with differing glycaemic status suggests that IR does not have a significant role in the pathogenesis of CFRD. Pancreatic β-cell function, already subnormal in CF patients with OGTT-defined normal glucose tolerance status, deteriorated further with worsening glycaemic status. This suggests that insulinopenia plays a prominent role in the pathogenesis of glucose intolerance and subsequent development of CFRD.
Glucose Tolerance and Insulin Secretion, Morbidity, and Death in Patients with Cystic Fibrosis
The Journal of Pediatrics, 2008
Objectives To describe the history, mechanisms, and consequences of cystic fibrosis (CF)-related diabetes, from childhood to early adulthood. Study design Pancreatic -cell function was estimated from the plasma insulin/glucose ratios during oral glucose tolerance test (total area under the curve and ⌬I 30-0min /G 30min , homeostasis model assessment [HOMA]%B), insulin sensitivity with the HOMA%S index, in 237 children with CF (109 boys, 128 girls). Progression of glucose metabolism abnormalities was evaluated by analysis for interval censored data; rates of pulmonary transplantation and death by Kaplan-Meier analysis. Results Impaired glucose tolerance was found in 20% of patients at 10 years, 50% at 15 years, 75% at 20 years, 82% at 30 years; for diabetes, >20% at 15 year, 45% at 20 years, 70% at 30 years; for insulin treatment, 30% at 20 years, 40% at 30 years. Early impairment was associated with lower survival rates and higher rates of lung transplantation. The area under the curve glucose correlated with decreased body mass index and height. Decrease in early insulin secretion (⌬I 30-0min /G 30min) was associated with impaired glucose tolerance, in all estimates of insulin secretion with diabetes. HOMA%S did not differ between the groups. Increased inflammation correlated with insulin resistance and impaired glucose tolerance. Conclusions CF-related diabetes, mainly because of -cell deficiency, is frequent early in life and associated with impaired nutritional state and growth, increased rates of terminal respiratory failure, and death.
European Journal of Endocrinology, 2005
Objective: To evaluate insulin-secretion kinetics and insulin sensitivity in cystic fibrosis (CF) patients with normal glucose tolerance (CF-NGT), impaired glucose tolerance (CF-IGT) or CF-related diabetes (CFRD), and the potential effects of moderate hyperglycemia on clinical and nutritional status. Design and methods: Cross-sectional study including 50 outpatients with CF. Patients underwent both oral (OGGT) and intravenous (IVGTT) glucose tolerance tests in order to assess insulin secretion and peripheral insulin sensitivity. Homeostasis assessment model and OGGT were used to investigate insulin sensitivity. Forced expiratory volume in the first second (FEV 1 ) and forced vital capacity (FVC) were measured to evaluate pulmonary function. Body mass index (BMI) was determined to assess nutritional status. Results: Insulin secretion was significantly decreased (and delayed at OGTT) in the CFRD group (n ¼ 9) versus the CF-IGT group (n ¼ 10) and the CF-IGT versus the CF-NGT group (n ¼ 31). Insulin sensitivity was significantly different in the CF-IGT and CFRD groups versus the CF-NGT group. FEV 1 , FVC and BMI presented a significant linear correlation with plasma glucose value at 120 min at OGTT and were significantly lower in both CF-IGT and CFRD versus the CF-NGT group, whereas no differences were found between the CF-IGT and CFRD groups. Conclusions: CF patients with IGT present diminished insulin secretion and increased peripheral insulin resistance, correlating with a worse clinical status, undernutrition and impaired pulmonary function. These findings open the question of whether early treatment of mild alterations of glucose metabolism with insulin secretagogues or short-action insulin may lead to improvement of clinical status in CF patients.
Journal of Pediatric Endocrinology and Metabolism, 1994
The aim of our study was to determine whether first-phase insulin response to intravenous (i.v.) glucose could be used as a simple and rapid test to identify cystic fibrosis (CF) patients at risk to develop diabetes mellitus. Forty consecutive CF patients with normal fasting blood glucose values but with different degrees of glucose tolerance on the standard oral glucose tolerance test (22 with normal glucose tolerance, 16 with impaired glucose tolerance, 2 with diabetes mellitus) and 12 normal subjects, matched for age and body mass index, underwent an i.v. glucose bolus to evaluate early phase insulin release. When compared to the normal subjects, CF patients had significantly reduced basal (76 ± 50 vs 108 ± 30 pM/1, 2p<0.02) and glucose stimulated insulin levels (1+3 min insulin=456 ± 275 vs 951 ± 170 pM/1, 2p<0.01). Early phase insulin release, however, did not differentiate between CF patients with normal and impaired glucose tolerance; also in the two diabetic patients insulin levels did not clearly differ from those observed in the other groups of CF subjects. In conclusion, first-phase insulin response may identify an impairment of B-cell function in CF subjects; however, it does not discriminate between different degrees of glucose tolerance, as determined by the oral glucose tolerance test and, therefore, it does not reliably identify those patients who will eventually develop overt diabetes mellitus.
Journal of Cystic Fibrosis, 2016
Background: Reduced insulin secretion is a key factor to explain high prevalence of glucose intolerance in patients with cystic fibrosis (CF). However, the role of insulin sensitivity remains unclear. The aim of this study is to investigate the association of insulin secretion and sensitivity with the evolution of glucose tolerance. Methods: A total of 152 patients without known diabetes from the Montreal CF cohort underwent two 2-h oral glucose tolerance tests (OGTT) at baseline and again after 21.2 ± 5.5 months. Pulmonary function and anthropometric measurements were also collected at each visit. At both visits, based on their OGTT results, patients were categorized in glucose tolerance groups (normal glucose tolerance, impaired glucose tolerance or CFrelated diabetes) and stratified in 3 groups according to the variation of their glucose tolerance: stable, improved or deteriorated. Results: At baseline, patients in the deteriorated group had a better sensitivity to insulin than those in the improved group (P = 0.029). At follow-up glucose tolerance remained stable in 55.3%, improved in 14.5% and deteriorated in 30.3% of patients. During follow-up, insulin secretion remained stable in all 3 groups. While insulin sensitivity remained stable in patients without changes in glucose tolerance it worsened in patients who deteriorated glucose tolerance (P b 0.001) and improved in patients who improved their glucose tolerance (P = 0.003). Conclusion: In a context of significantly reduced insulin secretion, variations of insulin sensitivity are associated with variations of glucose tolerance in adult patients with CF.
Increased glucose excursion in cystic fibrosis and its association with a worse clinical status
Journal of Cystic Fibrosis, 2007
Background: Abnormal glucose tolerance is a frequent co-morbidity in cystic fibrosis patients (CF), and is associated with a worse prognosis. The objectives are to investigate (a) the relative contribution of insulinopenia and insulin resistance (IR) for glucose tolerance and (b) the association between various glucose parameters and CF clinical status. Methods: Oral glucose tolerance tests were performed in 114 consecutive CF patients not known to be diabetic as well as 14 controls similar for age and BMI. Results: Abnormal glucose tolerance was found in 40% of patients with CF: 28% had impaired glucose tolerance (IGT) and 12% had new cystic fibrosis related diabetes (CFRD). Compared to control subjects, all CF patients were characterized by an increased glucose excursion (AUC). While reduced early insulin release characterised CF, IGT and CFRD patients also present IR thus both mechanisms significantly contribute to glucose tolerance abnormalities. Increased glucose AUC and reduced early insulin release but not glucose tolerance categories were associated with a reduced pulmonary function (FEV 1 ). Conclusion: In CF, early insulin secretion defect but also IR contribute to glucose intolerance. Early in the course of the disease, increased glucose AUC and reduced early insulin secretion are more closely associated with a worse clinical status than conventional glucose tolerance categories.
Insulin production and resistance in cystic fibrosis: effect of age, disease activity, and genotype
Journal of endocrinological investigation, 2012
To assess the major determinants of glucose tolerance between age, genotype, and clinical status in cystic fibrosis (CF) patients, and study if defects of insulin secretion and insulin sensitivity were associated with the onset of CF-related diabetes (CFRD). One hundred and nineteen patients, in stable clinical condition were studied. They were subdivided into 3 groups based on age, and 2 groups based on Schwachman-Kulczycki clinical score. All patients were genotyped, and subsequently divided into 3 groups. Ninety-four healthy normal-weight controls, comparable for sex and age were also studied. All subjects had baseline blood samples taken for glucose and insulin, C-peptide, and glycated hemoglobin. Homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose/insulin ratio (FGIR) were calculated as indices of IR and insulinogenic index as a marker of pancreatic β-cell function. All patients underwent an oral glucose tolerance test, and 57 underwent an IVGTT for th...
The Journal of Clinical Endocrinology & Metabolism, 2020
Context Oral glucose tolerance test (OGTT)-related hypoglycemia is common in pancreatic-insufficient cystic fibrosis (PI-CF), but its mechanistic underpinnings are yet to be established. Objective To delineate the mechanism(s) underlying OGTT-related hypoglycemia. Design and Setting We performed 180-minute OGTTs with frequent blood sampling in adolescents and young adults with PI-CF and compared results with those from a historical healthy control group. Hypoglycemia (Hypo[+]) was defined as plasma glucose <65 mg/dL. We hypothesized that CF-Hypo[+] would demonstrate impaired early phase insulin secretion and persistent late insulin effect compared with control-Hypo[+], and explored the contextual counterregulatory response. Main Outcome Measure OGTT 1-hour and nadir glucose, insulin, C-peptide, and insulin secretory rate (ISR) incremental areas under the curve (AUC) between 0 and 30 minutes (early) and between 120 and 180 minutes (late), and Δglucagon120-180min and Δfree fatty ac...