Valentina Guarnotta

Body composition assessment for the definition of cardiometabolic risk

Obesity is associated with a major prevalence of cardiovascular risk factors and high risk of cardiovascular events and contributes to the increase in cardiovascular morbidity and mortality worldwide. Beyond the fat mass per se, the pattern of fat distribution has a profound influence on cardiometabolic risk. The increase in abdominal adipose tissue confers an independent risk, while the amount of gluteofemoral body fat is thought to be protective. Changes in the capacity of different depots to store and release fatty acids and to produce adipocytokines are important determinants of fat distribution and its metabolic consequences. Because of the complexity of the assessment of body fat with imaging techniques, great attention has been paid to other measures of adiposity, such as waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR), which provide information on body fat distribution, although body mass index (BMI) is the established clinical measure to estimate the cardiovascular risk disease associated with excessive body weight. Abdominal obesity is a main predictive factor of the metabolic syndrome, so it is certain that it represents a better marker of cardiovascular risk than BMI. Visceral adiposity index (VAI) has recently proven to be a marker of visceral adipose distribution and function, associated with insulin sensitivity in patients at metabolic risk; however, the evidence needs to be further confirmed. In summary, BMI, WC, WHR, WHtR, and VAI are all useful tools for assessing adiposity/obesity in clinical practice, and should be evaluated along with other cardiometabolic risk factors to define cardiovascular risk stratification.

Higher doses of cabergoline further improve metabolic parameters in patients with prolactinoma regardless of the degree of reduction in prolactin levels

Currently available studies that fully analyse the metabolic parameters in patients with prolactinoma are scarce and discordant. The aim of this study was to evaluate the metabolic effects of cabergoline (CAB) treatment in patients with newly diagnosed prolactinoma in relation to disease control and CAB dosage.

Is diabetes in Cushing's syndrome only a consequence of hypercortisolism?

OBJECTIVE Diabetes mellitus (DM) is one of the most frequent complications of Cushings syndrome (CS). The aim of this study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients. DESIGN Cross-sectional study on 140 patients with CS. METHODS A total of 113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7±15.7 years) and 27 men (19 with pituitary disease and eight with adrenal disease, aged 38.1±20.01 years) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes), and diabetes (CS/DM) groups. RESULTS Seventy-one patients had CS/NGT (49.3%), 26 (18.5%) had CS/prediabetes and 43 (30.8%) had CS/DM. Significant increasing trends in the prevalence of family history of diabetes (P<0.001), metabolic syndrome (P<0.001), age (P<0.001) and waist circumference (P=0.043) and decreasing trends in HOMA-β (P<0.001) and oral disposition index (DIo) (P<0.002) were observed among the groups. No significant trends in fasting insulin levels, area under the curve for insulin (AUCINS), Matsuda index of insulin sensitivity (ISI-Matsuda) and visceral adiposity index were detected. CONCLUSIONS Impairment of glucose tolerance is characterized by the inability of β-cells to adequately compensate for insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with the duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in patients with a natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of those at a high risk of metabolic complications.

Metabolically healthy polycystic ovary syndrome (MH-PCOS) and metabolically unhealthy polycystic ovary syndrome (MU-PCOS): a comparative analysis of four simple methods useful for metabolic assessment

STUDY QUESTION Is it possible to distinguish metabolically healthy polycystic ovary syndrome (MH-PCOS) from metabolically unhealthy PCOS (MU-PCOS) by simple diagnostic tools such as body mass index (BMI), waist/hip ratio (WHR), at-risk category suggested by Androgen Excess Society (AES) and visceral adiposity index (VAI)? SUMMARY ANSWER VAI could be an easy and useful tool in clinical practice and in population studies for assessment of MU-PCOS. WHAT IS KNOWN ALREADY VAI is a good indicator of insulin sensitivity and cardiometabolic risk in oligo-ovulatory women with PCOS. STUDY DESIGN, SIZE, DURATION We conducted a cross-sectional study of 232 women with PCOS in a university hospital setting. PARTICIPANTS/MATERIALS, SETTING, METHODS Anthropometric, hormonal and metabolic parameters were evaluated. An oral glucose tolerance test measured areas under the curve (AUC) for insulin (AUC 2h insulin) and for glucose (AUC 2h glucose). Homeostasis model assessment of insulin resistance (HOMA2-IR), the Matsuda index of insulin sensitivity (ISI), the oral dispositional index (DIo) and VAI were determined. MAIN RESULTS AND THE ROLE OF CHANCE The prevalence of MU-PCOS according to the different criteria was: BMI, 56.0%; WHR, 18.1%; at-risk criteria of AES, 72.0% and VAI, 34.5%. The likelihood that a woman would exhibit MU-PCOS (except when diagnosed by the WHR criterion) showed a significant positive association with high HOMA2-IR [BMI criterion: (odds ratio (OR): 1.86; 95% confidence interval (CI): 1.43-2.41); risk criteria of AES (OR: 1.86; 95% CI: 1.36-2.56); VAI criterion (OR: 1.45; 95% CI: 1.17-1.80)] and a significant negative association with low ISI Matsuda [BMI criterion: (OR: 0.81; 95% CI: 0.72-0.91); risk criteria of AES (OR: 0.78; 95% CI: 0.69-0.89); VAI criterion (OR: 0.82; 95% CI: 0.71-0.94)]. Only MU-PCOS according to the VAI criterion showed a significant association with low DIo (OR: 0.85; 95% CI: 0.75-0.96); these women also showed a significant association with low luteal progesterone levels (OR: 0.97; 95% CI: 0.95-0.99). LIMITATIONS, REASONS FOR CAUTION The analysis is limited by the lack of a gold standard definition of metabolic health that would have allowed the execution of a receiver operator characteristic analysis of the four proposed criteria. WIDER IMPLICATIONS OF THE FINDINGS The results will facilitate the early recognition of cardiometabolic risk in women with PCOS before they develop overt metabolic syndrome.

Predictors of microvascular complications in type 1 diabetic patients at onset: The role of metabolic memory

BACKGROUND Several epidemiological studies showed a close association between metabolic control and microvascular complications in type 1 Diabetes Mellitus (T1DM). The aim of our longitudinal observational study was to evaluate the predictive role of the main clinical and biochemical parameters in determining microvascular complications. METHODS 376 T1DM patients, hospitalized in our division from 1991 to 2005 (mean follow-up=10.93±4.26 years) were studied. Stepwise Cox regression analysis was used to identify the influence of residual ß-cell function, ß-cell autoimmunity, HbA1c levels and other clinical and laboratory parameters in the development of microalbuminuria and retinopathy. RESULTS The probability of developing microalbuminuria was higher in males than in females (HR 1.82; 95% CI 1.01-3.28; p=0.044), in patients with higher mean HbA1c values (HR 2.80; 95% CI 1.63-4.83; p<0.001), longer duration of disease (HR 1.98; 95% CI 1.10-3.57; p=0.022) and younger age of diabetes onset (HR 0.53; 95% CI 0.03-0.92; p=0.026). An increased probability of developing retinopathy was found in patients with higher mean HbA1c levels during follow-up (HR 2.35; 95% CI 1.34-4.12, p=0.003), as well as at onset (HR 1.85; 95% CI 1.06-3.24; p=0.030). CONCLUSIONS Our study suggests that among the clinical, metabolic, immunological and biochemical factors evaluated at onset, only HbA1c is predictive for the microangiopathy development in T1DM.

No phenotypic differences for polycystic ovary syndrome (PCOS) between women with and without type 1 diabetes mellitus.

CONTEXT Women with type 1 diabetes mellitus (DM1) have a higher prevalence of polycystic ovary syndrome (PCOS) than the general population. OBJECTIVE The aim of this study was to clarify, in DM1 women with PCOS (PCOS-DM1), the influence of insulin therapy and glycemic control and evaluate the hormonal and phenotypic differences with age-matched and body mass index (BMI)-matched women with PCOS without diabetes. DESIGN, SETTING, AND PATIENTS We evaluated 103 DM1 women with and without PCOS treated with intensive insulin therapy; 38 age-matched and BMI-matched women with PCOS without diabetes were compared in a cross-sectional study. OUTCOME MEASUREMENTS Clinical, anthropometric, and metabolic parameters were evaluated. Hormonal evaluation and ovary ultrasound were performed during the follicular phase of the menstrual cycle. RESULTS Applying the diagnostic criteria of the Androgen Excess Society, 38 (36.89%) women with DM1 showed PCOS. The 38 PCOS-DM1 women showed no differences in treatment and glycemic control compared with DM1 women without PCOS. The only difference was a higher visceral adiposity index in PCOS-DM1 (1.21±0.70 vs 0.90±0.32; P=.002). PCOS-DM1 showed no phenotypic differences with age-matched and BMI-matched PCOS without diabetes. The hormonal pattern was similar except that higher levels of Δ4androstenedione were found in PCOS-DM1 (12.89±3.49 vs 2.79±1.75 nmol/L; P=.010). CONCLUSIONS The women with PCOS-DM1 do not exhibit particular phenotypic characteristics compared with nondiabetic women with PCOS. However, this pathological disorder must not be underestimated because it could be an additional cardiovascular risk factor in women with DM1.

The treatment of hyperinsulinemic hypoglycaemia in adults: an update

BackgroundTreatment of hyperinsulinemic hypoglycaemia (HH) is challenging due to the rarity of this condition and the difficulty of differential diagnosis. The aim of this article is to give an overview of the recent literature on the management of adult HH.MethodsA search for reviews, original articles, original case reports between 1995 and 2016 in PubMed using the following keywords: hyperinsulinemic hypoglycaemia, insulinoma, nesidioblastosis, gastric bypass, autoimmune hypoglycaemia, hyperinsulinism, treatment was performed.ResultsOne hundred and forty articles were selected and analysed focusing on the most recent treatments of HH.ConclusionsNew approaches to treatment of HH are available including mini-invasive surgical techniques and alternative local–regional ablative therapy for benign insulinoma and everolimus for malignant insulinoma. A correct differential diagnosis is of paramount importance to avoid unnecessary surgical operations and to implement the appropriate treatment mainly in the uncommon forms of HH, such as nesidioblastosis and autoimmune hypoglycaemia.

The visceral adiposity index is associated with insulin sensitivity and IGF-I levels in adults with growth hormone deficiency

The visceral adiposity index, based on anthropometric and metabolic parameters, has been shown to be related to adipose tissue function and insulin sensitivity. We aimed to evaluate the performance of the visceral adiposity index in adult patients with growth hormone deficiency. We enrolled 52 patients(mean age 51 ± 13 years) with newly diagnosed growth hormone deficiency and 50 matched healthy subjects as controls at baseline. At baseline and after 12 and 24 months of treatment we evaluated anthropometric measures, lipid profile, glucose and insulin during an oral glucose tolerance test, hemoglobin A1c, homeostasis model assessment estimate of insulin resistance, quantitative insulin sensitivity check index, insulin sensitivity index Matsuda, insulin-like growth factor-I and visceral adiposity index. At baseline growth hormone deficiency patients showed higher waist circumference (p < 0.001), low-density lipoprotein cholesterol (p < 0.001) and visceral adiposity index (p = 0.003) with lower insulin sensitivity index (p = 0.007) and high-density lipoprotein cholesterol (p = 0.001) than controls. During growth hormone treatment we observed a significant increase in insulin-like growth factor-I (p < 0.001), high-density lipoprotein (p < 0.001) with a trend toward increase in insulin sensitivity index (p = 0.055) and a significant decrease in total cholesterol (p < 0.001) and visceral adiposity index (p < 0.001), while no significant changes were observed in other clinical and metabolic parameters. The visceral adiposity index was the only parameter that significantly correlated with growth hormone peak at diagnosis (p < 0.001) and with insulin-like growth factor-I and insulin sensitivity index both at diagnosis (p = 0.009 and p < 0.001) and after 12 (p = 0.026 and p = 0.001) and 24 months (p < 0.001 and p = 0.001) of treatment. The visceral adiposity index, which has shown to be associated with both insulin-like growth factor-I and insulin sensitivity, proved to be the most reliable index of metabolic perturbation, among the most common indexes of adiposity assessment and a marker of benefit during treatment in adult growth hormone deficiency patients.

Efficacy and safety of everolimus in extrapancreatic neuroendocrine tumor: A comprehensive review of literature

BACKGROUND Everolimus, an oral mTOR (mammalian target of rapamycin) inhibitor, is currently approved for the treatment of progressive pancreatic neuroendocrine tumors (NETs). Although promising, only scattered data, often from nondedicated studies, are available for extrapancreatic NETs. PATIENTS AND METHODS A systematic review of the published data was performed concerning the use of everolimus in extrapancreatic NET, with the aim of summarizing the current knowledge on its efficacy and tolerability. Moreover, the usefulness of everolimus was evaluated according to the different sites of the primary. RESULTS The present study included 22 different publications, including 874 patients and 456 extrapancreatic NETs treated with everolimus. Nine different primary sites of extrapancreatic NETs were found. The median progression-free survival ranged from 12.0 to 29.9 months. The median time to progression was not reached in a phase II prospective study, and the interval to progression ranged from 12 to 36 months in 5 clinical cases. Objective responses were observed in 7 prospective studies, 2 retrospective studies, and 2 case reports. Stabilization of the disease was obtained in a high rate of patients, ranging from 67.4% to 100%. The toxicity of everolimus in extrapancreatic NETs is consistent with the known safety profile of the drug. Most adverse events were either grade 1 or 2 and easy manageable with a dose reduction or temporary interruption and only rarely requiring discontinuation. CONCLUSION Treatment with everolimus in patients with extrapancreatic NETs appears to be a promising strategy that is safe and well tolerated. The use of this emerging opportunity needs to be validated with clinical trials specifically designed on this topic. IMPLICATIONS FOR PRACTICE The present study reviewed all the available published data concerning the use of everolimus in 456 extrapancreatic neuroendocrine tumors (NETs) and summarized the current knowledge on the efficacy and safety of this drug, not yet approved except for pancreatic NETs. The progression-free survival rates and some objective responses seem promising and support the extension of the use of this drug. The site-by-site analysis seems to suggest that some subtypes of NETs, such as colorectal, could be more sensitive to everolimus than other primary NETs. No severe adverse events were usually reported and discontinuation was rarely required; thus, everolimus should be considered a valid therapeutic option for extrapancreatic NETs.

Pasireotide versus pituitary surgery: a retrospective analysis of 12 months of treatment in patients with Cushing's disease

Pituitary surgery represents the first-line treatment for most patients with Cushing’s disease (CD) [1, 2]. In the case of surgery failure, additional treatment options are required [3–6]. Pasireotide has shown favourable results in the first-line treatment of patients with CD, who are not candidates for surgery or in the second-line when surgery has failed [7–9]. The aim of the current study is to compare the effects of surgery and pasireotide treatment in a cohort of patients with CD, and to evaluate the differences in response rate in terms of hormonal and clinical control, and improvement of metabolic complications.