Pharmacogenetics of oral antidiabetes drugs: evidence for diverse signals at the IRS1 locus.

To investigate the role of IRS1 locus on failure to oral antidiabetes drugs (OADs) we genotyped single-nucleotide polymorphisms (SNPs), rs2943641, rs7578326 (tagging all SNPs genome-wide associated with type 2 diabetes (T2D) and related traits at this locus) and rs1801278 (that is, the loss-of-function IRS1 G972R amino acid substitution) in 2662 patients with T2D. Although no association with OAD failure was observed for rs2943641 and rs7578326 SNPs (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.93-1.16 and OR: 0.97, 95% CI: 0.87-1.09 respectively), a significant association was observed for rs1801278 (OR: 1.34, 95% CI: 1.08-1.66). When meta-analyzed with previous published data, an allelic OR of 1.41 (1.15-1.72; P=0.001) was obtained, so that homozygous R972R individuals have >80% higher risk of failing to OADs as compared with their G972G counterparts. In all, though further studies are needed for confirming this finding, our present data point to IRS1 rs1801278 as a potential biomarker for pursuing the goal of stratified medicine in the field of antihyperglycemic treatment in T2D.

Influence of dietary fat and carbohydrates proportions on plasma lipids, glucose control and low-grade inflammation in patients with type 2 diabetes-The TOSCA.IT Study.

PURPOSE: The optimal macronutrient composition of the diet for the management of type 2 diabetes is debated, particularly with regard to the ideal proportion of fat and carbohydrates. The aim of the study was to explore the association of different proportions of fat and carbohydrates of the diet-within the ranges recommended by different guidelines-with metabolic risk factors. METHODS: We studied 1785 people with type 2 diabetes, aged 50-75, enrolled in the TOSCA.IT Study. Dietary habits were assessed using a validated food-frequency questionnaire (EPIC). Anthropometry, fasting lipids, HbA1c and C-reactive protein (CRP) were measured. RESULTS: Increasing fat intake from <25 to ≥35 % is associated with a significant increase in LDL-cholesterol, triglycerides, HbA1c and CRP (p < 0.05). Increasing carbohydrates intake from <45 to ≥60 % is associated with significantly lower triglycerides, HbA1c and CRP (p < 0.05). A fiber intake ≥15 g/1000 kcal is associated with a better plasma lipids profile and lower HbA1c and CRP than lower fiber consumption. A consumption of added sugars of ≥10 % of the energy intake is associated with a more adverse plasma lipids profile and higher CRP than lower intake. CONCLUSIONS: In people with type 2 diabetes, variations in the proportion of fat and carbohydrates of the diet, within the relatively narrow ranges recommended by different nutritional guidelines, significantly impact on the metabolic profile and markers of low-grade inflammation. The data support the potential for reducing the intake of fat and added sugars, preferring complex, slowly absorbable, carbohydrates.

Sex differences in food choices, adherence to dietary recommendations and plasma lipid profile in type 2 diabetes - The TOSCA.IT study.

BACKGROUND AND AIMS: Diabetic women have a more adverse plasma lipid profile than men. Sex differences in dietary habits may play a role, but are little investigated. The study evaluates the quality of diet, adherence to the nutritional recommendations of the Diabetes and Nutrition Study Group and their relation with plasma lipid in men and women with diabetes. METHODS AND RESULTS: We studied 2573 people, aged 50-75, enrolled in the TOSCA.IT study (clinicaltrials.gov; NCT00700856). Plasma lipids were measured centrally. Diet was assessed with a semi-quantitative food frequency questionnaire. Women had a more adverse plasma lipid profile than men. Women consumed significantly more legumes, vegetables, fruits, eggs, milk, vegetable oils, and added sugar, whereas men consumed more starchy foods, soft drinks and alcoholic beverages. This stands for a higher proportion (%) of energy intake from saturated fat and added sugar (12.0 ± 2.4 vs 11.5 ± 2.5 and 3.4 ± 3.2 vs 2.3 ± 3.2, P < 0.04), and a higher intake of fiber (11.2 ± 2.8 vs 10.4 ± 2.6 g/1000 Kcal/day) in women. Adherence to the recommendations for saturated fat and fiber consumption was associated with significantly lower LDL-cholesterol regardless of sex. Adherence to the recommendations for added sugars was associated with significantly lower triglycerides and higher HDL-cholesterol in men and women. CONCLUSIONS: Men and women with diabetes show significant differences in adherence to nutritional recommendations, but sex differences in plasma lipid profile are unlikely to be explained by nutritional factors. Adherence to the nutritional recommendations is associated with a better plasma lipid profile regardless of sex, thus reinforcing the importance of substituting saturated for unsaturated fat sources, increasing fiber and reducing added sugar intake.

Waist-to-height ratio is the best anthropometric index in association with adverse cardiorenal outcomes in type 2 diabetes mellitus patients.

BACKGROUND/AIMS: Visceral obesity is a potent risk factor for both chronic kidney disease (CKD) and myocardial infarction (MI) in type 2 diabetes mellitus patients (T2DM). Short stature is also associated with higher risk for either coronary or kidney diseases. Thus, the aim of our study was to investigate the association of the frequency of cardiorenal complications with waist-to-height index (W/Ht) in T2DM. METHODS: This was a cross-sectional study where 958 T2DM patients were studied. Subjects with cardiorenal disease (CRD) were defined as those with both kidney dysfunction (KD) and MI. RESULTS: We found a significant excess of MI in patients with KD as compared to those without KD (28 vs. 14%, p < 0.0001). Interestingly, among the commonly used indices of obesity, only W/Ht and BMI were significantly associated with CRD risk. Moreover, only the W/Ht index (but neither BMI nor WC) was significantly associated with the risks for every component of CRD. Lastly, in the multivariate logistic regression analysis, W/Ht proved superior to the other traditional factors associated with risk for CRD. CONCLUSIONS: Our study in a large cohort of subjects demonstrated that a higher W/Ht index is the best anthropometric measure associated with adverse CRD outcomes of T2DM patients.

High systolic blood pressure increases prevalence and severity of retinopathy in NIDDM patients.

OBJECTIVE: To determine whether the severity of retinopathy is higher in a group of NIDDM patients with sBP greater than or equal to 140 mmHg compared with NIDDM patients with sBP less than 140 mmHg. RESEARCH DESIGN AND METHODS: Ophthalmoscopy and FAG were conducted among a group of NIDDM patients with either a sBP above (n = 54) or below (n = 55) 140 mmHg. The groups were matched according to diabetes duration, metabolic control (HbA1c), and AER. RESULTS: Patients with sBP greater than 140 mmHg had a higher prevalence of retinopathy, as established according to a rating scale (4.9 +/- 3.8 vs. 3.2 +/- 3.3, P less than 0.02); furthermore, their BMI values were higher (28.1 +/- 4.5 vs. 24.9 +/- 4.1 kg/m2, P less than 0.001). The group of normotensive subjects showed the highest rate of low grading (0-2) values. However, the highest prevalence rates of 8-10 grading values (proliferative retinopathy) were found in the hypertensive group. CONCLUSIONS: These data suggest that sBP values greater than or equal to 140 mmHg favor the onset of retinopathy in NIDDM patients during their 1st 10 yr of disease.

Influence of free testosterone on antigen levels of plasminogen activator inhibitor-1 in premenopausal women with central obesity.

Women with upper body obesity are at increased risk for cardiovascular disease (CVD). Several studies have demonstrated a reduced fibrinolytic activity in these patients, mainly due to an enhanced activity of plasminogen activator inhibitor-1 (PAI-1). Since an increase of androgenic activity is a feature of central obesity in women, the present study was aimed at evaluating the possibility of a relationship between androgens and PAI-1 (antigen and activity) in 20 premenopausal women, 10 with upper body obesity and 10 controls. In obese women, PAI-1 antigen showed a positive Pearson correlation with free testosterone (FT), insulin, c-peptide, triglycerides (TG), and waist to hip ratio (WHR) (P less than .01), whereas PAI-1 activity correlated positively only with insulin and WHR (P less than .01). In control women, PAI-1 antigen and activity were positively related only to TG (P less than .01). When we applied the multiple regression model with stepwise backward method to our data, both PAI-1 antigen and activity did not maintain any significant association. However, when the data from both the groups were pooled (n = 20), and PAI-1 antigen was considered as the dependent variable, body weight (Sig T = 0.0001), TG (Sig T = 0.0053), FT (Sig T = 0.013), and luteinizing hormone (LH) (Sig T = 0.0474) met the stepwise criteria, suggesting an independent effect of each of these parameters on PAI-1 antigen. On the other hand, when PAI-1 activity was tested as the dependent variable, only body weight maintained a significant relationship with this parameter (Sig T = 0.0006).(ABSTRACT TRUNCATED AT 250 WORDS)

Low dehydroepiandrosterone circulating levels in premenopausal obese women with very high body mass index.

Dehydroepiandrosterone (DHEA) has an anti-obesity effect in rodents and reduces body fat in normal men. Therefore, the plasma levels of DHEA were evaluated in nine premenopausal healthy women and in 13 menstrually active nondiabetic obese women, including patients (n = 6) with body mass index (BMI) over 40. In the obese group, a significant inverse correlation between DHEA levels and BMI was found. These results suggest that patients with severe obesity are unable to increase the DHEA adrenal production rate in order to parallel the increase in the hormone metabolic clearance rate (due to enlargement of body fat mass per se). The deficiency of this mechanism might itself contribute to the progressive fat accumulation in severe obesity.

Effects of the repetitive administration of progesterone by nasal spray in postmenopausal women.

OBJECTIVE: To study the effects of 10 days of nasal spray P treatment on P serum levels and the endometrium. DESIGN: Prospective. SETTING: University Medical School. PATIENTS: Eight postmenopausal women received oral conjugated estrogens at a daily dose of 0.625 mg for 4 weeks immediately before vaginal surgery for prolapse. For the first 9 of the last 10 days the patients also received a nasal spray dosage of 11.2 mg P three times a day; on the 10th day they received only one dose. MAIN OUTCOME MEASURES: Blood samples were taken at 8:00 A.M. on treatment days 1, 3, 5, 7, 10, and 11 to follow P serum concentration levels. Endometrial samples for histologic examination were collected before P administration and immediately after surgery to evaluate the end-organ effect. RESULTS: Mean P serum levels increased sixfold after 9 days of nasal spray P administration [from 0.612 +/- 0.280 ng/mL (1.958 +/- 0.896 nmol/L) to 3.925 +/- 1.553 ng/mL (12.560 +/- 4.970 nmol/L)] and declined thereafter, returning to the before treatment levels 24 hours after the last administration. In all subjects, the first histologic evaluation showed proliferative endometrium; the second showed clear secretive changes. CONCLUSIONS: Repetitive nasal spray P administration for 10 days in postmenopausal women led to increasing P serum levels and, when the estrogen stimulation was adequate, to secretory changes in the endometrium (end-organ effect).

Plasma concentrations of progesterone are higher in the uterine artery than in the radial artery after vaginal administration of micronized progesterone in an oil-based solution to postmenopausal women.

OBJECTIVE: To verify the occurrence of preferential distribution of vaginally administered progesterone to the uterus compared with extrapelvic regions in vivo and in humans. DESIGN: Prospective clinical study. SETTING: University medical school. PATIENT(S): Twenty postmenopausal women undergoing transabdominal hysterectomy for benign pathologies. INTERVENTION(S): Forty-five minutes before surgery, the women received a single vaginal administration of an oil-based micronized progesterone (100 mg) solution currently available on the market for IM use. During the operation, parallel blood samples were drawn from the uterine and radial arteries. MAIN OUTCOME MEASURE(S): Plasma levels of progesterone were measured by RIA. RESULT(S): Mean (+/- SD) plasma levels of progesterone were significantly higher in the uterine artery than in the radial artery (9.75 +/- 3.21 vs. 5.12 +/- 2.06 ng/mL, respectively). CONCLUSION(S): Vaginal administration allows a preferential distribution of progesterone to the uterus, which confirms the existence of the so-called "first uterine pass effect."

High frequency of incidental diagnosis of extrathyroidal neoplastic diseases at the fine-needle aspiration biopsy of laterocervical lymph nodes in patients with thyroid nodules.

This study was undertaken to evaluate the frequency of the incidental diagnosis of extrathyroidal lymph node diseases at ultrasound-guided fine-needle aspiration biopsy/cytology (FNAB/C) being done to check the presence of metastatic thyroid cancer in 30 subjects with thyroid nodule (TN) and enlarged cervical lymph nodes (CLN). The patients in whom cytology suggested the presence of malignancy in the TN or in the CLN underwent surgical removal for histologic diagnosis. The spectrum of diseases revealed by this survey included: (1) 10 benign diseases including 1 case of Piringer-Kuchinka lymphadenitis with benign TN; (2) 10 metastatic thyroid cancers (2 anaplastic and 8 papillary cancers); (3) 3 benign TN associated with metastatic invasion of cervical lymph nodes from lung (2 cases) and breast (1 case) cancer; (4) 1 Hodgkin's lymphoma of the cervical lymph nodes with hyperplastic TN; (5) 3 nodal lymphomas with benign thyroid nodule and 2 cases of thyroid lymphoma with nodal invasion; and (6) 1 nodal sarcoidosis with benign TN. The results of this study demonstrate that important neoplastic and hematologic diseases affecting the cervical lymph nodes may frequently be incidentally detected using ultrasonography (US) and FNAB/C in the diagnostic procedure for thyroid nodule.

Diagnostic utility of thyroglobulin detection in fine-needle aspiration of cervical cystic metastatic lymph nodes from papillary thyroid cancer with negative cytology.

Cystic changes in metastatic cervical lymph nodes (CLN) from papillary thyroid cancer (PTC) may be a diagnostic pitfall in fine-needle aspiration biopsy (FNAB) cytology. We investigated in a series of CLN metastases from thyroid cancers (TC), including cystic PTC, and from a wide spectrum of extrathyroidal malignancies, the diagnostic role for metastatic TC of the rapid detection of thyroglobulin in eluates from FNAB (FNAB-Tg) of CLN. The study was carried out in a group of 79 subjects (22/57 M/F; median age, 56 years; range, 20-86 years) with enlarged CLN and thyroid nodules (TN), examined for potential metastatic TC, and harboring a large spectrum of incidentally diagnosed extrathyroidal malignancies (n = 24, mostly represented by lymphomas, lung, and breast cancers), CLN metastases from thyroid cancers (n = 28, including 6 cystic metastatic PTC), 6 specific lymphadenitis and 21 reactive lymphadenitis mostly detected (n = 16) during follow-up of patients with previously ablated TC. Markedly high FNAB thyroglobulin (Tg) values were found in all metastatic CLN TC. Two of the six cases with cystic metastatic CLN PTC were diagnosed by FNAB-Tg but not by cytology. In conclusion, FNAB-Tg has been confirmed as an easy modality and fast procedure to diagnose CLN metastasis from TC and high FNAB-Tg values with nondiagnostic cystic cytology strongly suggest cystic metastatic PTC.

[Adenylate cyclase response to beta-adrenergic agonists in heart and brown adipose tissue]. / Risposta dell'adenilciclasi ad agonisti beta-adrenergici in cuore e tessuto adiposo bruno.

Some sympathomimetic compounds (i.e. BRL37344) increase brown adipose tissue (BAT) thermogenesis with minimal cardiac effects. They act through an "atypical" beta-adrenergic receptor (beta-AR). Since beta-AR responses involve Adenylate Cyclase (AC) activation, we investigate the AC answer to isoproterenol and BRL37344 in rat plasmamembranes of heart (beta 1-ARs) and BAT (atypical beta-ARs). AC dose-response curves were obtained by incubating membrane fractions with different concentrations of isoproterenol and BRL37344 (1 nM-100 microM) at 25 degrees C for 15 min. In our study BRL37344 is 40-times more potent than isoproterenol in stimulating AC activity of BAT (EC50s: BRL37344 = 0.02 microM, isoproterenol = 0.7 microM). Furthermore it is more potent in stimulating BAT AC than heart AC (BRL37344 EC50 ratio heart/BAT = 38). However on BAT membranes, BRL37344 intrinsic sympathomimetic activity (ISA) vs. Isoproterenol is 0.87. Since isoproterenol and BRL37344 show a similar ISA for BAT respiration and lipolysis, we may argue that AC maximal activity is not required for maximal lipolytic and thermogenic responses.

[Various types of reducing diets]. / I vari tipi di diete dimagranti.

It must be readily understood that the only possibility of fighting obesity is by bringing about a reversal in the energy balance so that inputs are smaller than outputs. At least theoretically, then, obesity's special quality is that it does not present any therapeutic problem. Restriction in food intake is currently the treatment of choice; to be effective, food intake must be cut so that the energy provided is below the obese person's daily consumption, on average below 1200 calories per day, while at the same time holding a comparatively high intake of indispensable elements (proteins, vitamins, certain minerals and oligo-elements). The physician has a choice of various possibilities represented by fasting, a variety of free or controlled diets, protein diets or diets with low carbohydrate content and with a variable fat content; dissociated, zig-zag, one food diets etc. Substantially all these tend to limit the total quantity of glycides and boost the feeling of satiety by increasing the total volume of good while keeping total calories unvaried. It is clear that each of them has specific indications and clear-cut contraindications. The aim is to produce a calory shortfall, not cause denutrition. The diet must therefore be suited to the individual directed during subsequent stages of weight loss in relation to the patient's specific requirements (number of meals, etc.).

[Papillary carcinoma of the thyroglossal duct cyst: a case report]. / Il carcinoma papillifero della cisti del dotto tireoglosso: caso clinico.

The thyroglossal duct cyst is the most common anomaly in thyroid development. To date, approximately 250 cases have been reported, the majority being papillary thyroid carcinomas. In most cases the diagnosis is established only after excision of a clinically benign thyroglossal duct cyst. Controversies exist in relation to a rational and effective therapeutic approach. A further case of thyroglossal duct papillary carcinoma affecting a 52 years-old man is presented to highlight the clinicopathological features of this condition. FNAC resulted false negative. Surgery consisted in a Sistrunk procedure, followed by total thyroidectomy and central lymphectomy after definitive histological diagnosis. In view of the prolonged course of papillary carcinoma, long-term follow-up is mandatory.

A six month mitotane course induced sustained correction of hypercortisolism in a young woman with PPNAD and Carney complex.

A low-dose mitotane (MT) regimen was evaluated as a pharmacological approach for correcting the severe hypercortisolism in a young woman affected by Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD). In the first 12 week period, the MT daily dose was progressively increased from 0.5 to 4.0 g/day. This dosage was maintained for an additional 16 weeks (cumulative dose 602 g, plasma MT maximum level 12 microg/ml), and then stopped because of sustained signs of hypoadrenalism requiring prednisone replacement. Complete regression of seborrhea, acne, and plethora was observed after 8 weeks of treatment (cumulative dose 95 g). Regular menses returned after 13 weeks (cumulative dose 197 g, plasma MT 8 microg/ml). Profound decrease of both serum cortisol (from 615 to 220 nmol/l) and urinary free cortisol (UFC) values (from 1498 to 477 nmol/day) was noted after 16 weeks of treatment (cumulative dose 314 g, plasma MT 8 microg/ml). MT treatment was associated with mild gastric discomfort and reversible increase of cholesterol plasma levels. Low serum cortisol and UFC were still observed 41 weeks after MT was discontinued (plasma MT 0.2 microg/ml). Our report demonstrates that low dose MT treatment may be a safe and effective modality for a sustained correction of hypercortisolism by PPNAD in subjects with CNC waiting for surgery.

D-(-)-beta-hydroxybutyrate inhibits catecholamine-stimulated lipolysis and decreases beta-adrenoceptors' affinity in human fat cells but not in lymphomonocytes.

The effect of D-(-)-beta-hydroxybutyrate, at concentrations commonly achieved during ketoacidosis in humans (10 mmol/l), on human fat cell lipolysis in vitro was the aim of this study. The basal lipolysis was not modified and beta-hydroxybutyrate did not affect forskolin- or dibutyryl-cAMP-stimulated glycerol release, whereas it markedly inhibited isoproterenol-stimulated lipolysis. In membranes of intact adipocytes exposed to D-(-)-beta-hydroxybutyrate for 1 h, we found a decrease in beta-adrenoceptor affinity in saturation experiments and a shift to the right of the isoproterenol-mediated radioligand [( 125I]-cyanopindolol) displacement curve. These findings suggest that beta-hydroxybutyrate inhibits catecholamine-stimulated lipolysis by decreasing beta-adrenoceptor affinity. No effect of beta-hydroxybutyrate was found on beta-adrenoceptor binding of intact mononuclear cells of peripheral blood. In conclusion, the beta-adrenoceptor affinity lowering effect of beta-hydroxybutyrate is seemingly specific to human fat cells and might represent a feed-back mechanism that prevents an uncontrolled breakdown of triglycerides and indirectly regulates its own production rate.