CT imaging shows specific pancreatic abnormalities in persons with cystic fibrosis related diabetes.

Cystic fibrosis related diabetes (CFRD) is observed in 20-50% of adults with cystic fibrosis (CF). Pancreas abnormalities on imaging, e.g. pancreas lipomatosis, are frequent in subjects with CF. We hypothesized that specific abnormalities may characterize patients with CFRD. We performed a retrospective study comparing the computed tomography (CT) of participants with CF with or without diabetes ("CFRD" and "CF control" groups). We classified the pancreas on imaging according to 3 categories: normal, partial lipomatosis and complete lipomatosis of the pancreas. We also assessed the presence or absence of pancreatic calcifications. Forty-one CFRD and 53 CF control participants were included. Only 2% of the patients with CFRD had a normal pancreas, as compared with 30% of the participants from the CF control group (p = 0.0016). Lipomatosis was more frequent in subjects with CFRD and was related to exocrine pancreatic insufficiency (EPI) and to severe CFTR mutations (classes I to III). Nine participants with diabetes (22%) presented with pancreatic calcifications, versus none of the control participants (p = 0.0003). In conclusion, pancreas imaging was almost always abnormal in subjects with CFRD, while it was normal in a third of the CF control subjects. Pancreatic calcifications were specific of subjects with CFRD.

Screening strategies for glucose tolerance abnormalities and diabetes in people with cystic fibrosis.

The increase in life expectancy of patients with cystic fibrosis has come with new comorbidities, particularly diabetes. The gradual development of glucose tolerance abnormalities means that 30 to 40% of adults will be diabetic. Cystic fibrosis-related diabetes is a major challenge in the care of these patients because it is a morbidity and mortality factor at all stages of the disease. Early glucose tolerance abnormalities observed from childhood, before the stage of diabetes, are also associated with a poor pulmonary and nutritional outcome. The long asymptomatic period justifies systematic screening with an annual oral glucose tolerance test from the age of 10 years. However, this strategy does not take into account the new clinical profiles of patients with cystic fibrosis, recent pathophysiological knowledge of glucose tolerance abnormalities, and the emergence of new diagnostic tools in diabetology. In this paper, we summarise the challenges of screening in the current context of new patient profiles - patients who are pregnant, have transplants, or are being treated with fibrosis conductance transmembrane regulator modulators - and put forward an inventory of the various screening methods for cystic fibrosis-related diabetes, including their applications, limitations and practical implications.

C-peptide level concomitant with hypoglycemia gives better performances than insulin for the diagnosis of endogenous hyperinsulinism: a single-center study of 159 fasting trials.

INTRODUCTION: Diagnosis of endogenous hyperinsulinism relies on the occurrence of a hypoglycemia, concomitant with inadequate high insulin and C-peptide levels. However, diagnostic cutoffs are not consensual among the different learned societies. The objective of this work was to propose optimized cutoffs for these three parameters for the diagnosis of endogenous hyperinsulinism. METHODS: All the patients having performed a fasting trial in Cochin Hospital Endocrinology Department between February 2012 and August 2022 were included. The results of glycemia, insulin and C-peptide levels during fasting trial were collected and analyzed. RESULTS: One hundred and fifty-nine patients were included: 26 with endogenous hyperinsulinism and 133 without endogenous hyperinsulinism. ROC analysis of glycemia nadir during fasting trial identified the value of 2.3 mmol/L as the optimal cutoff, ensuring a sensitivity of 100% associated with a specificity of 81%. ROC analysis of insulin and C-peptide levels concomitant with hypoglycemia <2.3 mmol/L showed very good diagnostic performances of both parameters with respective cutoffs of 3.1 mUI/L (=21.5 pmol/L; sensitivity = 96%; specificity = 92%) and 0.30 nmol/L (sensitivity = 96%; specificity = 100%). Insulin to glycemia ratio as well as C-peptide to glycemia ratio (in pmol/mmol) at the time of glycemia nadir did not show better diagnostic performances than C-peptide alone. CONCLUSION: A C-peptide level 0.3 nmol/L concomitant with a hypoglycemia <2.3 mmol/L appears as the best criterion to make the diagnosis of endogenous hyperinsulinism. Insulin level can be underestimated on hemolyzed blood samples, frequently observed in fasting trial, and thus shows lower diagnostic performances.

Pattern of C-peptide response to oral glucose tolerance test: Interest and cut-off values.

OBJECTIVE: The oral glucose tolerance test (OGTT) classifies subjects as normal, glucose intolerant or diabetic depending on glycemia at 120 min (T120) post-test. Five insulin profiles associated with different incidences of diabetes over 10 years' follow-up were previously described following OGTT. However, insulin measurement is sensitive to hemolysis, and can be replaced by C-peptide assay on hemolyzed samples. However, little is known about patterns of C-peptide response to OGTT. DESIGN AND METHODS: In total, 128 patients were included, to establish preliminary baseline C-peptide values and to evaluate C-peptide response to OGTT in comparison to insulin response, using the Liaison XL immunoanalyzer. RESULTS: Hundred patients had a normal glycemic response, 19 were classified as glucose intolerant and 9 as diabetic. In normal subjects, median C-peptide values (nmol/L, with 5-95 percentiles) were 0.53 (0.23-1.37) at baseline, peaking at 2.36 (0.94-1.83) at T60, and decreasing to 2.09 (1.13-4.36) at T120. The C-peptide response pattern was similar but flatter than the insulin pattern because of different catabolism pathways. Nevertheless, C-peptide and insulin response profiles were discordant in only 9.4% of cases. Profile 3 (C-peptide peaking at T60) was the most prevalent in normal patients whereas profile 4 (peak at 120 min and lower level at T30 than at T60) was the most prevalent in glucose intolerant and diabetic patients. CONCLUSIONS: In OGTT, C-peptide could replace insulin determination on hemolyzed blood samples to predict the risk of type 2 diabetes.

Renal involvement in cystic fibrosis: diseases spectrum and clinical relevance.

BACKGROUND AND OBJECTIVES: Clinically relevant kidney involvement is uncommonly described in adult patients with cystic fibrosis (CF). We sought to report on a series of patients with CF and kidney biopsy-documented renal involvement. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective study was undertaken in two referral centers for adult patients with CF in Paris, France. Patients who had undergone a biopsy of native kidneys between 1992 and 2008 were identified, and their medical records were reviewed. RESULTS: We identified 13 adult patients with CF and renal disease. Proteinuria was present in all but two cases and was associated with progressive renal impairment in four patients (median serum creatinine 85 micromol/L; range 53 to 144 micromol/L). Renal biopsy disclosed a heterogeneous spectrum of nephropathies including AA amyloidosis (n = 3), diabetic glomerulopathy (n = 3), FSGS (n = 2), minimal-change disease (n = 1), postinfectious glomerulonephritis (n = 1), IgA nephropathy related to Henoch-Schönlein purpura (n = 1), membranous nephropathy (n = 1), and chronic interstitial nephropathy (n = 1). Chronic renal failure occurred in five patients, and one patient reached ESRD. CONCLUSIONS: Although rare, clinically significant renal disease may arise in young adult patients with CF. Given the wide spectrum of diseases that may be encountered, definite diagnosis by kidney biopsy is mandatory to optimize clinical treatment of these complex patients, particularly in the perspective of organ transplantation.

Comparison of once- versus twice-daily administration of insulin detemir, used with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes: assessment of detemir administration in a progressive treat-to-target trial (ADAPT).

OBJECTIVE: The purpose of this study was to compare effects of insulin detemir once daily versus twice a day in a basal-bolus insulin regimen. RESEARCH DESIGN AND METHODS: In this open-label, 7-month study, 520 patients with type 1 diabetes were randomly assigned to receive detemir once daily or twice daily with mealtime insulin aspart. Insulin doses were titrated over 1 month, with patients followed up over the subsequent 3 months. Thereafter, patients were able to switch from one regimen to the other, with an additional nonrandomized 3-month follow-up, to a total of 7 months. The primary end point was A1C at 4 months, with noninferiority defined as a difference <0.4% between groups. RESULTS: A1C at 4 months was 8.1 +/- 0.9 versus 8.0 +/- 1.0% with once- and twice-daily detemir, respectively, with an adjusted between-group difference of 0.12% (95% CI -0.01 to 0.25%), showing noninferiority for once-daily dosing. Similar results were found in the per protocol population. Improvement in A1C was similar in both groups (-0.4 +/- 0.8 vs. -0.5 +/- 0.8%; P = 0.09, NS) but with differences in the 7-point glucose profile. Detemir doses were lower (29 +/- 18 vs. 39 +/- 20 units/day, P < 0.001), but aspart doses were higher (34 +/- 17 vs. 26 +/- 14 IU/day, P < 0.001) with once-daily detemir. At 7 months, A1C decreased slightly in patients switched from once-daily to twice-daily administration (8.2 +/- 0.8 vs. 8.0 +/- 0.8%; P = 0.34, NS) in association with increased total insulin doses (P < 0.05), but A1C increased in those switched from twice-daily to once-daily administration (7.2 +/- 0.9 vs. 7.6 +/- 0.8%, P < 0.05) in association with decreased doses (P < 0.05). CONCLUSIONS: Although some individuals may benefit from twice-daily dosing, the most suitable routine starting schedule for detemir in a basal-bolus regimen for type 1 diabetes is once-daily injection.

The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3.

OBJECTIVE: The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-alpha (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS: We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS: Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P = 10(-4)). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03). CONCLUSIONS: These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.

Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome of various causes.

We assessed the value of midnight salivary cortisol for the initial diagnosis of Cushing's syndrome. Sixty-three patients with various causes of Cushing's syndrome (37 with Cushing's disease, 17 with adrenal Cushing's syndrome, and nine with ectopic ACTH syndrome) and 54 control subjects with simple obesity were studied. All patients with Cushing's syndrome excreted more than 90 microg urinary free cortisol (UFC)/d (248 nmol/d), and all controls excreted less than 90 microg/d UFC. All patients with Cushing's syndrome had a midnight salivary cortisol concentration above 2.0 ng/ml (5.52 nmol/liter), whereas only three controls did so [2.0 ng/ml (5.52 nmol/liter); 2.05 ng/ml (5.66 nmol/liter); and 3.6 ng/ml (9.96 nmol/liter)]. This cut-off provides a sensitivity of 100% and a specificity of 96%. In patients with Cushing's syndrome, midnight salivary cortisol concentrations were correlated with UFC collected over the same period of time (0800-0800 h). Salivary cortisol measurements taken every 4 h showed a typical lack of circadian variation. The daily measurement of midnight salivary cortisol concentrations for 2 wk or more in five other out-patients (with obvious Cushing's disease, subclinical adrenal Cushing's syndrome, suspected Cushing's syndrome, pituitary incidentaloma, and prolactinoma) demonstrated the clinical utility of this factor. Measuring midnight salivary cortisol is an easy and noninvasive means of diagnosing hypercortisolism. Its diagnostic accuracy is identical to, if not better than, that of previously described gold standards.

Adrenal incidentalomas.

The term adrenal incidentaloma refers to an adrenal mass occasionally and unexpectedly discovered by an abdominal imaging procedure performed for reasons a priori unrelated to adrenal dysfunction. The prevalence of adrenal incidentalomas as discovered by computed tomographic scan examination is estimated to be between 1% and 4%. The vast majority of these lesions are of adrenocortical origin, most often adenomas. Identification of steroid or catecholamine-secreting tumors is important but usually solved with appropriate endocrinologic investigations. A difficult problem, however, is to distinguish between benign and malignant primary or secondary tumors. Size less than 4 cm and an unenhanced computed tomographic attenuation under 10 Hounsfield Units (HU) are findings in favor of a benign adrenocortical adenoma, as is a positive NP 59 scintigraphic examination. The pathogenesis of adrenal tumors is not well understood. However, alterations of the cyclic AMP signalling pathway have recently been observed in benign adrenocortical lesions and molecular defects associated with insulin-like growth factor-II overexpression in malignant adrenocortical tumors.