Phenotyping of type 2 diabetes mellitus at onset on the basis of fasting incretin tone: Results of a two-step cluster analysis.

AIMS/INTRODUCTION: According to some authors, in type 2 diabetes there is a reduced postprandial action of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). However, little is known about the role of fasting incretins in glucose homeostasis. Our aim was to evaluate, through a two-step cluster analysis, the possibility of phenotyping patients with type 2 diabetes at onset on the basis of fasting GLP-1, GIP and ghrelin. MATERIALS AND METHODS: A total of 96 patients with type 2 diabetes within 6 months of onset (mean age 62.40 ± 6.36 years) were cross-sectionally studied. Clinical, anthropometric and metabolic parameters were evaluated. At fasting the following were carried out: assay of GLP-1, GIP, ghrelin, insulin, C-peptide, glucagon and a panel of adipocytokines (visfatin, resistin, leptin, soluble leptin receptor and adiponectin). RESULTS: The analysis resulted in two clusters: cluster 1 (63 patients) had significantly lower levels of GLP-1 (4.93 ± 0.98 vs 7.81 ± 1.98 pmol/L; P < 0.001), GIP (12.73 ± 9.44 vs 23.88 ± 28.56 pmol/L; P < 0.001) and ghrelin (26.54 ± 2.94 vs 39.47 ± 9.84 pmol/L; P < 0.001) compared with cluster 2 (33 patients). Between the two clusters, no differences in age, duration of disease, sex, clinical-anthropometric parameters, insulin sensitivity and adipocytokines were highlighted. However, cluster 1 was associated with significantly higher levels of glycated hemoglobin (7.4 ± 0.61 vs 6.68 ± 0.57%, P = 0.007), glucagon (232.02 ± 37.27 vs 183.33 ± 97.29 ng/L; P = 0.001), fasting glucose (7.85 ± 1.60 vs 6.93 ± 1.01 mmol/L; P = 0.003) and significantly lower levels of C-peptide (0.12 ± 0.11 vs 0.20 ± 0.20 nmol/L; P = 0.017). CONCLUSIONS: The present study suggests that fasting incretins play an important role in the pathophysiology of type 2 diabetes, which requires to further investigation.

Anaplastic Thyroid Carcinoma: A ceRNA Analysis Pointed to a Crosstalk between SOX2, TP53, and microRNA Biogenesis.

It has been suggested that cancer stem cells (CSC) may play a central role in oncogenesis, especially in undifferentiated tumours. Anaplastic thyroid carcinoma (ATC) has characteristics suggestive of a tumour enriched in CSC. Previous studies suggested that the stem cell factor SOX2 has a preeminent hierarchical role in determining the characteristics of stem cells in SW1736 ATC cell line. In detail, silencing SOX2 in SW1736 is able to suppress the expression of the stem markers analysed, strongly sensitizing the line to treatment with chemotherapeutic agents. Therefore, in order to further investigate the role of SOX2 in ATC, a competing endogenous RNA (ceRNA) analysis was conducted in order to isolate new functional partners of SOX2. Among the interactors, of particular interest are genes involved in the biogenesis of miRNAs (DICER1, RNASEN, and EIF2C2), in the control cell cycle (TP53, CCND1), and in mitochondrial activity (COX8A). The data suggest that stemness, microRNA biogenesis and functions, p53 regulatory network, cyclin D1, and cell cycle control, together with mitochondrial activity, might be coregulated.

Visceral adiposity index: an indicator of adipose tissue dysfunction.

The Visceral Adiposity Index (VAI) has recently proven to be an indicator of adipose distribution and function that indirectly expresses cardiometabolic risk. In addition, VAI has been proposed as a useful tool for early detection of a condition of cardiometabolic risk before it develops into an overt metabolic syndrome. The application of the VAI in particular populations of patients (women with polycystic ovary syndrome, patients with acromegaly, patients with NAFLD/NASH, patients with HCV hepatitis, patients with type 2 diabetes, and general population) has produced interesting results, which have led to the hypothesis that the VAI could be considered a marker of adipose tissue dysfunction. Unfortunately, in some cases, on the same patient population, there is conflicting evidence. We think that this could be mainly due to a lack of knowledge of the application limits of the index, on the part of various authors, and to having applied the VAI in non-Caucasian populations. Future prospective studies could certainly better define the possible usefulness of the VAI as a predictor of cardiometabolic risk.

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

OBJECTIVE: Diabetes mellitus (DM) is one of the most frequent complications of Cushing's 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-ß (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 ß-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.

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

OBJECTIVE: 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. DESIGN: This is a retrospective clinical-based therapy analysis. PATIENTS: Forty-three patients with prolactinoma (eight men, 35 women), aged 33·65 ± 11·23 years, were evaluated metabolically at baseline and after 12 months of CAB treatment. MEASUREMENTS: Body mass index (BMI), systolic and diastolic blood pressure, waist circumference (WC), lipid profile, haemoglobinA1c (HbA1c), glucose and insulin levels (and their areas under the curve, AUC) after an oral glucose tolerance test, homoeostasis model assessment of insulin resistance (Homa-IR) index, insulin sensitivity index (ISI) Matsuda, oral disposition index (DIo) and visceral adiposity index (VAI) were measured at baseline and after 12 months of treatment. RESULTS: Twelve months of CAB reduced WC (P < 0·001), total (P = 0·001) and low-density lipoprotein \terol (P < 0·001), triglycerides (P = 0·024), fasting insulin (P < 0·001), AUCINSULIN (P < 0·001), HbA1c (P = 0·022), Homa-IR (P < 0·001) and VAI (P < 0·001), with a concomitant increase in high-density lipoprotein cholesterol (P < 0·001) and in ISI Matsuda (P < 0·001), regardless of the degree of reduction in prolactin levels. The patients receiving higher doses (>0·50 mg/week) of CAB showed lower BMI (P = 0·009), fasting insulin (P = 0·001), Homa-IR (P < 0·001) and VAI (P = 0·018) and higher ISI Matsuda (P = 0·002) and DIo (P = 0·011), compared with those on lower doses. CONCLUSIONS: A significant metabolic improvement was observed in patients with prolactinoma after 12 months of CAB treatment, especially when higher doses were used, highlighting the importance of considering the metabolic profile in these patients and the role of active treatment with high CAB doses.

Neck lymph nodes in chronic autoimmune thyroiditis: the sonographic pattern.

BACKGROUND: Neck lymph nodes may be involved in the pathogenesis of chronic autoimmune thyroiditis (CAT). This study was undertaken to identify which of the sonographic features of cervical lymph nodes are readily applicable to patients affected by CAT compared to healthy control subjects. METHODS: We recruited 106 patients (92 females and 14 males) with CAT and 70 control subjects (53 females and 17 males) without clinical, biochemical, and ultrasonographic evidence of thyroid and neck diseases. We performed laboratory tests (thyrotropin, antithyroperoxidase antibodies, antithyroglobulin antibodies, and ultrasonography) to evaluate in each group: (i) thyroid function, autoimmunity, and morphology; (ii) number, topographic distribution (levels I-VI), and morphology of neck nodes (long-axis diameter; short-axis diameter; short-axis/long-axis ratio; absence or presence of hilus). RESULTS: Total number of neck nodes with long-axis diameter >10 mm was significantly higher in the CAT group than in the control group (mean±standard deviation [SD]: 3.7±2.4 vs. 0.8±1.3; p<0.001) with significantly increased differences in levels II (1.4±0.8 vs. 0.3±0.5; p<0.001), III (2±1.2 vs. 0.3±0.7; p<0.001), and IV (0.7±0.7 vs. 0.07±0.2; p<0.001). More nodes with a hilus were found in the CAT group than in the control group (mean number of nodes±SD: 2.8±1.9 vs. 0.7±1.1; p<0.001). Short-axis diameter of level III (4.4±1 vs. 3.7±1.2 mm; p=0.002) and level IV nodes (3.9±1 vs. 3.1±0.5 mm p=0.030) was increased in CAT patients when compared with healthy controls. CONCLUSIONS: The present study is the first one aiming at a systematic description of the sonographic pattern of cervical lymph nodes in CAT. An increased number of benign hyperplastic neck nodes, especially in levels II-IV, appears to be a characteristic sonographic finding associated with CAT.

Clinical and metabolic effects of first-line treatment with somatostatin analogues or surgery in acromegaly: a retrospective and comparative study.

To evaluate the metabolic effects of first-line somatostatin analogues or surgery in acromegaly. Retrospective, comparative, 12-month follow-up. Two hundred and thirty one patients (123 men, age 47.32 ± 14.63 years) with active acromegaly, first line treatments were somatostatin analogues in 151 (65.4%) and surgery in 80 (34.6%). Metabolic syndrome (MS) parameters, glucose, insulin and GH during oral glucose tolerance test, stimulated insulin sensitivity by insulin sensitivity index (ISI Matsuda), early and total insulin-secretion rate by insulinogenic index and AUC(INS), visceral adiposity function, expressed by visceral adipose index (VAI). Somatostatin analogues treatment improved all MS parameters and significantly reduced fasting glucose (P < 0.001), HbA1c (P = 0.014) and the prevalence of DM (P = 0.003) when disease control was achieved. Both somatostatin analogues and surgery improved ISI Matsuda (P < 0.001) and reduced AUC(INS) (P < 0.001) and VAI (P < 0.001 and P = 0.003, respectively). Only in controlled somatostatin analogues-treated patients a significant reduction in insulinogenic index (P = 0.010) was observed. ISI Matsuda showed a significant independent correlation with IGF-1 levels (ß = -0.258; P = 0.001) and VAI score (ß = -0.430; P < 0.001). VAI was independently correlated with IGF-1 (ß = 0.183; P = 0.004). Both somatostatin analogues and surgery can safely be used as first-line therapy in acromegaly, without any untoward effects on glucose tolerance. The control of acromegaly is the main determinant of beneficial effects on general features of insulin sensitivity. VAI could represent an additional link between disease control and insulin sensitivity.

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.

The oligomenorrhoic phenotypes of polycystic ovary syndrome are characterized by a high visceral adiposity index: a likely condition of cardiometabolic risk.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) frequently exhibit central obesity, glucose intolerance, atherogenic dyslipidemia and hypertension, which are characteristic features of a condition of cardiometabolic risk. Our objective was to investigate the relationship between visceral adiposity index (VAI) and phenotypic characteristics in women with PCOS. METHODS: We conducted a cross-sectional case-control study in our Endocrinology Outpatients Clinic. A total of 220 women with PCOS (Rotterdam definition) and 144 age- and BMI-matched healthy women were studied. We evaluated hyperandrogenemia and clinical hyperandrogenism, ovarian morphology, hypothalamic-hypophyseal axis and metabolic syndrome parameters. An oral glucose tolerance test (75 g glucose) measured areas under the curve (AUC) for insulin (AUC(2h-insulin)) and for glucose (AUC(2h-glucose)). Homeostasis model assessment of insulin resistance, the Matsuda index of insulin resistance and VAI were determined. RESULTS: Of all the variables examined, at multivariate analysis, only AUC(2h-insulin) [odds ratio (OR): 1.00; 95% confidence interval (CI): 1.00-1.00; P = 0.003] and VAI score (OR: 1.81; 95% CI: 1.20-2.73; P = 0.005) showed an independent association with PCOS. All phenotypes with oligomenorrhea showed a higher VAI score than the control group (oligomenorrhea + hyperandrogenism: 2.49 ± 1.46 versus 1.62 ± 0.84, P < 0.001; oligomenorrhea + polycystic ovary morphology: 2.25 ± 1.4 versus 1.62 ± 0.84, P = 0.001; complete phenotype: 2.45 ± 1.63 versus 1.62 ± 0.84, P < 0.001). CONCLUSIONS: Our data suggest that VAI could be an easy and useful tool in daily clinical practice and in population studies for the assessment of cardiometabolic risk associated with PCOS.

Low estradiol-to-testosterone ratio is associated with oligo-anovulatory cycles and atherogenic lipidic pattern in women with polycystic ovary syndrome.

OBJECTIVE: The estradiol-to-testosterone (E2/T) ratio has been investigated in different diseases but few in vivo data are available with regard to its role in women with ovary syndrome (PCOS). The aim of this study was to evaluate the role of the E2/T ratio in the ovulatory function and metabolic pattern in such women. METHODS: We retrospectively evaluated hyperandrogenemia, clinical hyperandrogenism, ovarian morphology, hypothalamo-hypophyseal axis and metabolic syndrome parameters in a cohort of 202 consecutive women affected by PCOS. An oral glucose tolerance test measured areas under the curve for insulin (AUC(2hIRI)), for glucose (AUC(2hglucose)), and the HOMA-IR and Matsuda index of insulin resistance were evaluated. Serum progesterone (Pg) was determined from day 20 to day 24 of the menstrual cycle and chronic oligo-anovulation was established if two consecutive cycles were anovulatory. RESULTS: Women with PCOS with normal ovulation [66/202 (32.7%)] showed a significantly higher E2/T ratio than women with PCOS with chronic oligo/anovulation [136/202 (67.3%)] (p < 0.05). Using a series of multiple linear regression models, we also investigated which variables correlated with the E2/T ratio. The analysis showed a strongly positive correlation of the E2/T ratio with Pg (ß = 0.473, p < 0.001) and a negative correlation with total cholesterol (ß = -0.433, p < 0.001). CONCLUSIONS: Our data suggest that in women with PCOS a low E2/T ratio is not only associated with chronic oligo-anovulation, but is also a determinant factor of the atherogenic lipid profile.

OCT is not useful for detection of minimal diabetic retinopathy in type 1 diabetes.

Optical coherence tomography (OCT) has been proven useful in measuring retinal thickness (RT) in patients with diabetes, although with discordant results in different studies. We examined RT in patients with type 1 diabetes (T1D) with or without minimal diabetic retinopathy (MDR) to test whether OCT is able to identify early retinal changes and potential correlations with metabolic parameters. RT of 102 patients with T1D (53 females, 49 males, aged 27.03 +/- 7.4 years) and of 42 healthy controls was examined, with analysis of nine different sectors (fovea, four pericentral and four peripheral sectors). According to the results of basal fundus photography, patients were divided into two groups, without MDR (48 cases) and with MDR (54 cases). Patients with proliferative DR or macular edema were excluded. No difference was found between patients with or without MDR and the control group for all OCT parameters investigated. Mean HbA1c of the last 5 years (P < 0.001), microalbuminuria (P = 0.002), total (P = 0.046) and LDL cholesterol (P = 0.007) and triglyceride (P < 0.001) levels were higher in patients with MDR, along with higher prevalence of hypertension (P = 0.013), younger age at diagnosis (P = 0.018) and longer diabetes duration (P < 0.001) with regard to the patients without MDR and controls, although no significant correlation between these parameters and RT was found. Our study suggests that MDR without macular edema in patients with T1D cannot be detected with OCT. Therefore, the conventional diagnostic methods are mandatory to detect early DR.

Insulin resistance and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in humans, affecting approximately 7-8% of women of reproductive age. Despite the criteria adopted, PCOS is considered to be a predominantly hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory. Most women with PCOS also exhibit features of the metabolic syndrome, including insulin resistance, obesity and dyslipidaemia. While the association with type 2 diabetes is well established, whether the incidence of cardiovascular disease is increased in women with PCOS remains unclear. Acknowledging the strong impact of insulin-resistance in the genesis of PCOS could be helpful not only to make the diagnosis more robust, but also for conferring better cardiovascular risk prevention. Several current studies support a strong recommendation that women with PCOS should undergo comprehensive evaluation for the metabolic syndrome and recognized cardiovascular risk factors, and receive appropriate treatment as needed. Lifestyle modifications remain the first-line therapy for all obese women with PCOS. However, many of these women do not lose weight easily. Insulin-sensitizing drugs are discussed as a promising and unique therapeutic option for the chronic treatment of PCOS.

The evaluation of metabolic parameters and insulin sensitivity for a more robust diagnosis of the polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is considered predominantly as a hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory. CONTEXT: PCOS diagnostic criteria [National Institute of Health (NIH), Rotterdam Consensus (ROT), Androgen Excess Society (AES)] are unanimous recognized. We aimed to assess in women with suspected PCOS whether the application of the three diagnostic criteria differently characterizes the metabolic profile and insulin sensitivity. DESIGN: Retrospective study in a cohort of women admitted to our Outpatient Clinic for suspected PCOS. PATIENTS: Two hundred and four women with suspected PCOS in comparison to a group of normal, age-matched Sicilian women (N = 34) without signs of metabolic syndrome. MEASUREMENTS: We evaluated hyperandrogenaemia and clinical hyperandrogenism, ovarian morphology, hypothalamo-hypophyseal axis and metabolic syndrome parameters. An oral glucose tolerance test (OGTT; 75 g glucose) measured areas under the curve (AUC) for insulin, C peptide and homeostasis model assessment of insulin-resistance (HOMA-IR) were performed. RESULTS: The prevalence of PCOS was 51% according to NIH, 83% to ROT and 70.6% to AES, and only 100 patients were qualified simultaneously under these three criteria. The prevalence of the metabolic syndrome in PCOS women was 26.92% (NIH), 21.77% (ROT) and 23.61% (AES), respectively. In comparison to healthy women, PCOS women showed increased fasting insulinaemia (PCOS/ROT: P = 0.028; PCOS/NIH: P = 0.007; PCOS/EAS: P = 0.023), 120 min insulin after OGTT insulinaemia (for the three criteria: P < 0.001), AUC(2h) insulin (for the three criteria: P < 0.001) and AUC(2h) C peptide (for the three criteria: P < 0.001). CONCLUSIONS: Our study highlights the fact that regardless of the diagnostic criteria used, evaluation of the metabolic parameters and insulin sensitivity is important for a correct diagnosis of PCOS and a therapeutic approach.