The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

OBJECTIVE: To evaluate the basal/total ratio of daily insulin dose (b/T) in outpatients with diabetes type 1 (DM1) and type 2 (DM2) on basal-bolus regimen, by investigating whether there is a relationship with HbA1c and episodes of hypoglycemia. METHODS: Multicentric, observational, cross-sectional study in Italy. Adult DM1 (n = 476) and DM2 (n = 541) outpatients, with eGFR >30 mL/min/1.73 m2, on a basal-bolus regimen for at least six months, were recruited from 31 Italian Diabetes services between March and September 2016. Clinicaltrials.govID: NCT03489031. RESULTS: Total daily insulin dose was significantly higher in DM2 patients (52.3 ± 22.5 vs. 46 ± 20.9 U/day), but this difference disappeared when insulin doses were normalized for body weight. The b/T ratio was lower than 0.50 in both groups: 0.46 ± 0.14 in DM1 and 0.43 ± 0.15 in DM2 patients (p = 0.0011). The b/T was significantly higher in the patients taking metformin in both groups, and significantly different according to the type of basal insulin (Degludec, 0.48 in DM1 and 0.44 in DM2; Glargine, 0.44 in DM1 and 0.43 in DM2; Detemir, 0.45 in DM1 and 0.39 in DM2). The b/T ratio was not correlated in either group to HbA1c or incidence of hypoglycemia (<40 mg/dL, or requiring caregiver intervention, in the last three months). In the multivariate analysis, metformin use and age were independent predictors of the b/T ratio in both DM1 and DM2 patients, while the type of basal insulin was an independent predictor only in DM1. CONCLUSION: The b/T ratio was independent of glycemic control and incidence of hypoglycemia.

Correction to: The basal to total insulin ratio in outpatients with diabetes on basal-bolus regimen.

[This corrects the article DOI: 10.1007/s40200-018-0358-2.].

Epicardial adipose tissue inflammation is related to vitamin D deficiency in patients affected by coronary artery disease.

BACKGROUND AND AIMS: Alterations in epicardial adipose tissue (EAT) biology (i.e. increased fat thickness and inflammation) have been described in coronary artery disease (CAD) patients. In addition to its classic role in the regulation of calcium-phosphate homeostasis, vitamin D may exert immune-regulatory and anti-inflammatory effects. Whether EAT inflammation may be linked to vitamin D deficiency is still unknown. In the present study we evaluated plasma 25-hydroxycholecalciferol (25OHD) level in CAD patients and its relationship with EAT ability to locally metabolize vitamin D, EAT expression of inflammation-related molecules and EAT thickness. METHODS AND RESULTS: Plasma 25OHD level was quantified by an immunoluminometric assay. EAT expression of inflammation-related molecules (MCP-1, PTX3, TNFα, IL-6, adiponectin), vitamin D receptor (VDR), CYP27B1 (25OHD-activating enzyme) and CYP24A1 (1,25-dihydroxycholecalciferol-metabolizing enzyme) was performed by microarray. EAT thickness was quantified by echocardiography. Median plasma 25OHD level was 10.85 ng/mL and 83% of CAD patients displayed 25OHD level below 20 ng/mL. At decreasing plasma 25OHD concentration, we observed a down-regulation in CYP27B1 and CYP24A1 level and an increased expression of VDR and pro-inflammatory cytokines (MCP-1, PTX3, TNFα, IL-6) at EAT level. No correlation was observed between plasma 25OHD level and EAT thickness. CONCLUSION: Our data suggest an increased activation of inflammatory pathways at EAT level possibly related to systemic and local vitamin D deficiency in CAD patients. Whether maintaining an optimal vitamin D status may be helpful to reduce EAT inflammation and to prevent CAD and its progression needs further investigation.

Epicardial fat thickness significantly decreases after short-term growth hormone (GH) replacement therapy in adults with GH deficiency.

BACKGROUND AND AIM: Growth Hormone Deficiency (GHD) is characterized by increased visceral fat accumulation. Echocardiographic epicardial fat thickness is a new marker of visceral adiposity. Aim of the present study was to evaluate whether epicardial fat thickness can significantly change and therefore serve as a marker of visceral fat reduction after short-term rhGH replacement therapy in patients with adult-onset GHD. METHODS AND RESULTS: Echocardiographic epicardial fat thickness was measured in 18 patients (10 M, 8 F, age 48 ± 11.8 yrs, BMI 29 ± 5.9 kg/m(2)) with adult-onset GHD, at baseline and after 6 and 12 months of rhGH therapy and in 18 healthy matched controls, at baseline. Echocardiographic epicardial fat thickness, conventional anthropometric and metabolic parameters, body fat percentage and quality of life were also evaluated. Epicardial fat thickness in adult GHD patients was higher than in controls (9.8 ± 2.8 vs 8 ± 3 mm, p < 0.05). Epicardial fat thickness significantly decreased after 6-months of rhGH replacement therapy (from 9.8 ± 2.8 to 7.0 ± 2.3 mm, P < 0.01, i.e. -29% from baseline). After 12 months of rhGH replacement therapy, epicardial fat thickness showed a further significant decrease (from 7.0 ± 2.3 to 5.9 ± 3.1 mm, P < 0.01, i.e. -40% from baseline). No significant changes in BMI or waist circumference after 6 or 12 months of rhGH therapy were observed. CONCLUSIONS: Echocardiographic epicardial fat thickness may represent a valuable and easy marker of visceral fat and visceral fat changes during rhGH replacement treatment in patients with adult-onset growth hormone deficiency.

Peripheral insulin-like factor 3 concentrations are reduced in men with type 2 diabetes mellitus: effect of glycemic control and visceral adiposity on Leydig cell function.

BACKGROUND AND AIM: Hypogonadism frequently occurs in men with type 2 diabetes mellitus (T2DM), while the role of glycemic control and visceral obesity is still unclear. This study aimed to assess the Leydig cell function, including the new sensitive marker insulin-like factor 3 (INSL3), in T2DM patients without overt hypogonadism and the influence of either glycemic control or visceral adiposity. SUBJECTS AND METHODS: Thirty T2DM patients (age 57.1+/-6.2 years, body mass index (BMI) 28.0+/-4.3) without overt hypogonadism and 30 age- and BMI-matched controls were studied. Anthropometric, glycometabolic parameters and testosterone, SHBG, LH, INSL3 levels, bioavailable and free testosterone (BT and cFT) were evaluated. The human chorionic gonadotrophin (hCG) test was also performed. RESULTS: Patients had lower total testosterone (452.6+/-130.0 vs 512.6+/-117.3 ng/dl, P=0.06), BT (189.7+/-36.4 vs 237.1+/-94.1 ng/dl, P=0.002), cFT (8.1+/-1.6 vs 10.1+/-4.0 ng/dl, P=0.002), and higher LH levels (3.5+/-1.6 vs 2.6+/-1.2 mU/ml, P=0.01) versus controls. Serum INSL3 concentrations were also lower in patients (1.1+/-0.3 vs 1.5+/-0.7 ng/ml, P=0.01). These hormonal parameters, including INSL3, did not differ between T2DM patients with poor or good glycemic control (HbA1c>9 or <7% respectively). In patients, waist circumferences (97.9+/-12.4 cm) negatively correlated with INSL3 (P=0.03) and basal, as well as hCG-stimulated testosterone levels (P=0.04 and 0.004 respectively). Basal or stimulated hormonal levels and INSL3 concentrations were not different between patients with (40%) or without erectile dysfunction. CONCLUSIONS: An early impairment of the overall Leydig cell function is present in men with T2DM, mainly related to visceral adiposity rather than to glycemic control.

Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients.

OBJECTIVES: Aberrant cAMP signaling is involved in the pathogenesis of somatotropinomas. The aim of the study was to screen acromegalic patients for the presence of variants of phosphodiesterase type 11A (PDE11A) gene, which have been recently identified in adrenocortical and testicular tumors. SUBJECTS AND METHODS: We sequenced the PDE11A gene-coding region in 78 acromegalic patients and 110 controls. Immunohistochemistry for PDE11A was performed in a subgroup of adenomas and normal pituitary samples. RESULTS: We found 15 nonsynonymous germline substitutions in 13 acromegalic patients (17%), i.e. 14 missense variants (Y727C in six, R804H in one, R867G in four, and M878V in three) and one truncating mutation (FS41X), with a prevalence only slightly higher than that observed in controls (14%). Immunohistochemistry revealed PDE11A expression higher in somatotropinomas than in normal somatotrophs, without significant difference between tumors with or without PDE11A variants, with the exception of two tumors (one with loss of heterozygosity (LOH) at the PDE11A locus and one with FS41X mutation) showing markedly reduced PDE11A staining. No significant differences in hormonal and clinical parameters between patients with or without PDE11A variants were observed, although patients with PDE11A changes showed a tendency to have a more aggressive tumor compared with patients with wild-type sequence (extrasellar extension in 69 vs 45%). CONCLUSIONS: This study first demonstrated the presence of PDE11A variants in a subset of acromegalic patients, which was only slightly more frequent than in controls. The normal expression of the enzyme in the majority of tumor tissues together with the lack of significant clinical phenotype suggests that these variants might only marginally contribute to the development of somatotropinomas.

Echocardiographic alterations in patients with non-functioning adrenal incidentaloma.

OBJECTIVE: While left ventricular (LV) dysfunction has been described in patients with Cushing's syndrome (CS), data concerning morphologic and functional cardiac alterations in patients with incidentally discovered adrenal masses [adrenal "incidentaloma" (AI)], without overt hypercortisolism, are lacking. In this study the echocardiographic characteristics of patients with AI were evaluated and then compared with those of lean and obese normotensive subjects. SUBJECTS AND METHODS: Twenty-one patients with AI, without clinical or subclinical hypercortisolism, 18 normotensive obese subjects matched for gender and body mass index (BMI) and 20 normotensive lean subjects were studied. Echocardiography was performed in all subjects. In all patients plasma ACTH, serum cortisol, and DHEA-S levels were measured. RESULTS: Patients with AI showed greater impairment of several echocardiographic indices of LV hypertrophy and diastolic dysfunction compared to normotensive lean subjects (p<0.05), but did not differ from those in obese subjects. Hypertensive AI patients showed a greater alteration of echocardiographic parameters (p<0.05) and higher BMI (p<0.01) and cortisol values (p<0.05) than normotensive ones. Plasma ACTH and serum cortisol were similar in AI patients and in obese controls, while DHEA-S levels were lower in AI (p<0.05). No correlations between cortisol secretion and echocardiographic parameters were found. CONCLUSION: In patients with non-functioning AI there is an impairment of cardiac morphology and function. These data suggest that patients with AI should be carefully screened also by means of echocardiographic studies.

Soluble adhesion molecules levels in patients with Cushing's syndrome before and after cure.

OBJECTIVE: Patients with Cushing's syndrome (CS) show a high prevalence of cardiovascular risk factors and atherosclerosis, persisting even after cure. Soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) are surrogate markers of endothelial function involved in the initiation of atherosclerosis. This study aimed to evaluate sICAM-1 and sVCAM-1 levels in patients with CS before and after successful cure. SUBJECTS AND METHODS: sICAM-1 and sVCAM-1 levels were evaluated in 28 patients with active CS and in 12 patients with Cushing's disease (CD), 6-12 months after disease remission. Body mass index (BMI), blood pressure, glucose, serum lipids, ACTH, cortisol and urinary free cortisol (UFC) were measured in basal conditions in all patients. RESULTS: At baseline, sICAM-1 levels positively correlated with BMI (r=0.443, p<0.01), while no correlations between sICAM/sVCAM levels and ACTH, cortisol or UFC were found. Plasma ACTH, serum cortisol, and UFC levels significantly decreased in 12 cured patients, but ICAM-1 and VCAM-1 levels were unchanged (12.7+/-1.8 vs 10.1+/-0.9 ng/ml and 33.5+/-4.4 vs 35.8+/-4.0 ng/ml, respectively). Obesity, hypertension, and impaired glucose metabolism persisted 1 yr after the biochemical cure of hypercortisolism. A significant reduction in ICAM-1 levels was observed in 4 out of 12 cured patients as well as a remission from diabetes, hypertension or obesity. CONCLUSIONS: ICAM/VCAM-1 levels show a great variability in patients with active CS, not correlated with cortisol levels, and are slightly modified in some cured patients with CD. The persistence of obesity, hypertension, and impaired glucose metabolism may be responsible for the maintenance of a subclinical endothelial dysfunction, making these subjects still at high cardiovascular risk and needing a long-term follow-up.