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A Battezzati, A Mari, L Zazzeron, G Alicandro, L Claut, P M Battezzati and C Colombo

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 17±5 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 β-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. β-cell function was reduced in CF patients compared with CON (70.0±4.1 vs 117.9±11.6 pmol/min per m2 per mM, P<0.001) and decreased significantly with age by −2.7 pmol/min per m2 per mM per year (confidence interval (CI) −4.5 to −0.82), 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 β-cell function and higher insulin sensitivity.

Conclusion

The major alteration in insulin secretion and insulin sensitivity of CF patients is slowly declining β-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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A Battezzati, P M Battezzati, D Costantini, M Seia, L Zazzeron, M C Russo, V Daccò, S Bertoli, A Crosignani and C Colombo

Objective: Diabetes frequently complicates cystic fibrosis (CF) without fasting hyperglycemia or despite spontaneous hypoglycemia (anecdotally ascribed to malnutrition), whose prevalence, clinical meaning, and relationship with glucose tolerance and clinical/nutritional status were not previously investigated. The relationship of CF genotype with insulin secretion control is also unclear.

Design and methods: A total of 129 CF patients without stable diabetes received 188 oral glucose tolerance tests. Distribution of fasting plasma glucose (FPG), glucose, insulin and C-peptide responses, clinical/nutritional variables, and their relationships were analyzed.

Results: FPG < 60 mg/dl (3.3 mmo/l) was detected in 14% of studies and reactive hypoglycemia (PG < 50 mg/dl (2.8 mmo/l)) in 15%. OGTT-based diabetes frequency was similar in the lowest quartile (Q1) and Q2–3 for FPG (10 and 8%), with higher glucose increment and area under the curve in Q1. Insulin and C-peptide levels were similar among FPG quartiles. Class I cystic fibrosis transmembrane conductance regulator mutation carriers had higher insulin concentrations than class II, especially in Q1 for FPG. Age, sex, nutritional, and anthropometric parameters including fat and lean body mass were unrelated to FPG. Lower FPG was associated with more frequent hospitalization rates (P = 0.002) and lower Shwachman scores (P = 0.041). Steroids weaning was accurately evaluated but then excluded as a possible cause of hypoglycemia.

Conclusions/interpretation: Fasting asymptomatic hypoglycemia is frequent and possibly related to inappropriate insulin secretion control in class I mutation carriers. Low FPG does not exclude impaired glucose tolerance (IGT) and diabetes in CF and reflects worse clinical status.

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S Bertoli, P Magni, V Krogh, M Ruscica, E Dozio, G Testolin and A Battezzati

Objective: Aging is associated with appetite decline, weight loss, reduced fat-free mass (FFM), and increased fat mass (FM). Ghrelin and leptin are short- and long-term determinants of energy balance respectively, whose dysregulation could alter food intake. We evaluate the relationship of circulating ghrelin and leptin responses to standardized oral mixed nutrient load (SOMNL) with body composition, daily food intake, and insulin sensitivity in healthy elderly subjects (ES).

Design and methods: Twenty-six ES (12/14 M/F, 69±4 years) and ten young healthy controls (LY) (5/5 M/F, 27±3 years) were studied at the International Center for the Assessment of Nutritional Status (Milan, Italy) with air plethysmography, dual energy X-ray absorptiometry, indirect calorimetry, and dietary intake assessment. Basal and postprandial ghrelin, leptin, testosterone, glucose, insulin and C-peptide concentrations, and insulin resistance (homeostasis model assessment (HOMA-R)) and sensitivity (quantitative insulin-sensitivity check index (QUICKI)) were evaluated.

Results: Basal ghrelin levels were similar in ES and LY, whereas leptin was higher in ES than LY, in agreement with the higher amount of FM. Basal and percentage change in ghrelin were inversely related to FFM, appendicular skeletal muscle mass (SMM), and QUICKI, but not to FM. Basal and percentage change in leptin were directly related to FM and not to FFM indexes. Ghrelin basal concentration was negatively correlated with energy and protein intake and with QUICKI. Percentage change in Ghrelin after SOMNL correlated negatively with protein intake, but positively with resting energy expenditure and energy intake, and glucose, insulin, C-peptide basal concentrations, and HOMA-R.

Conclusion: In ES, basal and postprandial ghrelin increases with FFM, specifically SMM, reduction, whereas leptin increases with relative FM increases.