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OBJECTIVE: Recent epidemiological studies suggested that some insulin analogues could be associated with increased risk of cancer. The present study is aimed at assessing the long-term association of different insulin analogues with cancer incidence. RESEARCH DESIGN AND METHODS: A nested case-control study dataset was generated from the cohort study dataset (n = 1,340 insulin-treated diabetic outpatients) by sampling control subjects from the risk sets. For each case subject, the control subjects (up to five) were chosen randomly from those members of the cohort who are at risk for the same follow-up time of the case subject. Five-year age classes, sex, and BMI classes (<18.5, 18.5-24.9, 25-29.9, and ≥30 kg/m²) were considered as additional categorical matching variables. RESULTS: During a median follow-up of 75.9 months (interquartile range 27.4-133.7), 112 case subjects of incident cancer were compared with 370 matched control subjects. A significantly higher mean daily dose of glargine was observed in case subjects than in control subjects (0.24 IU/kg/day [0.10-0.39] versus 0.16 IU/kg/day [0.12-0.24], P = 0.036). Incident cancer was associated with a dose of glargine ≥0.3 IU/kg/day even after adjusting for Charlson comorbidity score, other types of insulin administration, and metformin exposure (odds ratio 5.43 [95% CI 2.18-13.53], P < 0.001). No association between incident cancer and insulin doses was found for human insulin or other analogues. CONCLUSIONS: The possibility of association between cancer and higher glargine doses suggests that dosages should always be considered when assessing the possible association of insulin and its analogues with cancer.

Inflammation Markers and Metabolic Characteristics of Subjects With 1-h Plasma Glucose Levels Gianluca Bardini , MD, PHD , Ilaria Dicembrini , MD , Barbara Cresci , MD and Carlo Maria Rotella , MD From the Section of Endocrinology, Department of Clinical Pathophysiology, University of Florence, Florence, Italy. Corresponding author: Carlo M. Rotella, c.rotella{at}dfc.unifi.it . Abstract OBJECTIVE To assess the association of 1-h plasma glucose (1hPG) and inflammation with normal glucose tolerance (NGT) and pre-diabetes. RESEARCH DESIGN AND METHODS A cohort of 1,062 subjects was enrolled. After oral glucose load (oral glucose tolerance test), we compared subjects with NGT and pre-diabetes above and below the 1hPG cut point (155 mg/dl). Fibrinogen and leukocytes count (white blood cells [WBCs]) for subclinical inflammation, lipid ratios, insulin sensitivity (Matsuda index) were determined. RESULTS Patients with NGT and pre-diabetes (1hPG >155 mg/dl) showed a significant increase of inflammatory markers and lipid ratios (for all, P < 0.05). In age-, sex-, and BMI-adjusted analysis, 1hPG was associated with a significantly higher WBC count and fibrinogen ( P < 0.05). Patients with elevated 1hPG showed a highly significant lower insulin sensitivity than subjects <1hPG ( P < 0.01). CONCLUSIONS Elevated 1hPG in subjects with NGT and pre-diabetes is associated with subclinical inflammation, high lipid ratios, and insulin resistance. Therefore, 1hPG >155 mg/dl could be considered a new “marker” for cardiovascular risk. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received July 22, 2009. Accepted November 2, 2009. © 2010 by the American Diabetes Association.

OBJECTIVE: Metformin is associated with reduced cancer-related morbidity and mortality. The aim of this study was to assess the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients. RESEARCH DESIGN AND METHODS: A nested case-control study was performed in a cohort of 1,340 patients by sampling, for each case subject, age-, sex-, and BMI-matched control subjects from the same cohort. RESULTS: During a median follow-up of 75.9 months, 112 case patients who developed incident cancer and were compared with 370 control subjects. A significantly lower proportion of case subjects were exposed to metformin and sulfonylureas. After adjustment for comorbidity, glargine, and total insulin doses, exposure to metformin, but not to sulfonylureas, was associated with reduced incidence of cancer (odds ratio 0.46 [95% CI 0.25-0.85], P = 0.014 and 0.75 [0.39-1.45], P = 0.40, respectively). CONCLUSIONS: The reduction of cancer risk could be a further relevant reason for maintaining use of metformin in insulin-treated patients.

Dipeptidyl peptidase 4 (DPP-4) is an enzyme that is produced by endothelial cells in different districts and circulates in plasma. Patients with type 2 diabetes show a reduction in active Glucagon-Like Peptide-1 (GLP-1) that could be due to impairment of secretion or its degradation or both. GLP-1 is rapidly inactivated in vivo, mainly by the DPP-4. Some authors suggest that Metformin has no direct inhibitory effect on DPP-4 activity and that Metformin and the other biguanides enhance GLP-1 secretion; others suggest a possible role of Metformin in the inhibition of the DPP-4 activity. In order to better elucidate the role of insulin sensitizers on the modulation of GLP-1 circulating levels, DPP-4 activity and mRNA expression were measured in cultured human aortic endothelial cells (HAEC) and human microvascular dermal endothelial cells (HMVEC) exposed to high glucose, Metformin and Rosiglitazone. Present data show that hyperglycemia is capable of increasing in a significant manner the DPP-4 activity only in microvascular endothelial cells. Rosiglitazone is able to modulate in a negative manner the expression of DPP-4 but not its activity in macrovascular endothelial cells, while at 24 h of exposure it is able to increase significantly DPP-4 activity but not its expression in microvascular endothelial cells. Metformin at 48 h only in microvascular endothelial cells is able to reduce in a significant manner ( p  = 0.01) the activity of DPP-4 but not its expression. The modulation of DPP-4 is site specific.

Background Insulinoma is a rare tumour representing 1–2% of all pancreatic neoplasms and it is malignant in only 10% of cases. Locoregional invasion or metastases define malignancy, whereas the dimension (> 2 cm), CK19 status, the tumor staging and grading (Ki67 > 2%), and the age of onset (> 50 years) can be considered elements of suspect. Case presentation We describe the case of a 68-year-old man presenting symptoms compatible with hypoglycemia. The symptoms regressed with food intake. These episodes initially occurred during physical activity, later also during fasting. The fasting test was performed and the laboratory results showed endogenous hyperinsulinemia compatible with insulinoma. The patient appeared responsive to somatostatin analogs and so he was treated with short acting octreotide, obtaining a good control of glycemia. Imaging investigations showed the presence of a lesion of the uncinate pancreatic process of about 4 cm with a high sst2 receptor density. The patient underwent exploratory laparotomy and duodenocephalopancreasectomy after one month. The definitive histological examination revealed an insulinoma (T3N1MO, AGCC VII G1) with a low replicative index (Ki67: 2%). Conclusions This report describes a case of malignant insulinoma responsive to octreotide analogs administered pre-operatively in order to try to prevent hypoglycemia. The response to octreotide analogs is not predictable and should be initially assessed under strict clinical surveillance.

Insulin resistance is a clinical condition shared by many diseases besides type 2 diabetes (T2DM) such as obesity, polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD). Experimental evidence, produced over the years, suggests that metformin has many benefits in the treatment of these diseases. Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients, offering a selective pathophysiological approach by its effect on insulin resistance. Moreover, a number of studies have established the favorable effect of metformin on body weight, not only when evaluating BMI, but also if body mass composition is considered, through the reduction of fat mass. In addition, it reduces insulin resistance, hyperinsulinemia, lipid parameters, arterial hypertension and endothelial dysfunction. In particular, a new formulation of metformin extended-release (ER) is now available with different formulation in different countries. Metformin ER delivers the active drug through hydrated polymers which expand safe uptake of fluid, prolonging gastric transit and delaying drug absorption in the upper gastrointestinal tract. In addition, Metformin ER causes a small, but statistically significant decrease in BMI, when added to a lifestyle intervention program in obese adolescents. Because of the suggested benefits for the treatment of insulin resistance in many clinical conditions, besides type 2 diabetes, the prospective exists that more indications for metformin treatment are becoming a reality.

Cancer incidence and mortality trends represent epidemiological indicators of fundamental importance for public health systems. The study's aim is to present recent (2013–2017) short-term cancer incidence and mortality trends in Italy, including 80 % of the Italian population, for different cancer sites by sex, age group, and areas. Joinpoint Regression models were employed. A significantly decreasing trend in the incidence of all cancers was observed for men in Italy (-1.9 % per year), particularly for cancers of the lung (-2.5 %), liver (-3.9 %), stomach (-2.8 %), colorectal (-2.2 %), prostate (-3.4 %), and leukaemias (-3.2 %). The only significant increase was seen for skin melanoma (+5.2 % per year). Among women, overall cancer incidence remained stable, with a decrease in the North (-0.6 %) and an increase in the South and Islands (+0.9 %). Decreasing trends were observed for colorectal (-1.9 %), stomach (-3.5 %), liver (-4.0 %%), and leukaemias (-2.0 %) cancers, while incidence increased for skin melanoma (+6.0 % per year), and lung cancer (2.3 %). Cancer mortality declined consistently in both sexes (-1.8 % per year in men and −0.6 % in women), across different areas, and age groups. The observed trends in men and women partly reflect the impact of risk factors affecting both sexes at different times, mainly in the case of tobacco and lung cancer. Also, some trends may be linked to organized screening initiatives (e.g. colorectal) or the decrease in opportunistic screening (e.g. prostate). The snapshot of cancer trends in Italy may highlight new opportunities for strengthening prevention activities and advancing research on early detection and target treatments. [Display omitted] •We observed decreasing incidence and mortality trends in men and stable incidence and decreasing mortality trends in women.•Skin melanoma incidence increased in both sexes, while lung cancer increased in women and decreased in men.•Stomach, colorectal, liver and leukaemias incidence decreased in both sexes.•We highlighted the need to improve cancer prevention initiatives and research in diagnostic and treatments in Italy

Italy, home to one of the world’s oldest populations, has traditionally shown geographic differences in cancer incidence, with rates decreasing from north to south. The cancer registries that have been accredited by the Italian Cancer Registry Network (AIRTUM), during the last 20 years altogether cover the 90 % of the Italian population, aiming to improve data quality, standardize procedures, and promote research. This study presents the methodological approaches used for data collection, quality control, and analysis to describe current patterns of cancer incidence, mortality, and survival across Italy's three macro-areas (North, Central, South). Estimates of incidence rates and case numbers for 2025 were also produced. Data from 34 accredited cancer registries were analyzed, comprising over 4.6 million cases from 1981 to 2020, with a detailed focus on the 2008–2017 period, which includes over 3 million cases. Cancer incidence and mortality data were collected according to ICD-O-3 and ICD-10 classifications and processed for statistical analysis using tools such as SEERPrep, SEERStat, and the Joinpoint Regression Program. Age-standardized rates were calculated, and incidence and mortality trends from 2013 to 2017 were modeled. Five-year cumulative net survival was estimated using the Pohar-Perme method to adjust for competing risks. Survival trends were analyzed by geographic areas and cancer sites, revealing regional disparities in cancer outcomes. •Cancer registries provide affordable population-based statistics on cancer epidemiology.•Incidence, mortality and survival are the main indicators used for cancer surveillance.•Appropriate methodologic approaches make comparisons intelligible.•In Italy there are historical differences in cancer figures by macro-areas.•There is a need to provide cancer statistics updated to the pre-Covid-19 era in Italy.

We report the results of the quality assessment on data collected by cancer registries belonging to the Italian network of Cancer Registries (AIRTUM). For all malignant cancers diagnosed in 2013–2017, overall percentages of cases known from the death certificate only (DCO), and those of cases with cyto-histological confirmation (MV), were provided. The overall percentage of DCOs was small (1.2 %). The percentage of microscopic verification was overall high (87.6 %), with some variations among registries. DCO proportion varied from 0.1 % for cutaneous melanoma to 3.8 % for liver and pancreatic tumours. Differences across sites in MV proportion were linked to the different diagnostics. The rate of cases lost to follow-up was on average very low (0.7 %). This quality evaluation confirmed that data provided by the Italian cancer registries were affordable. •Data from Italian cancer registries have long been included in IARC and ENCR publications.•Data from cancer registries should not be produced only for cancer registries.•Quality indices should also address aspects that are more useful and understandable for other stakeholders.•The Italian network of cancer registries (AIRTUM) has provided updated cancer statistics

Metabolic syndrome (MS) has been associated with microalbuminuria and kidney disease. In the present cohort study, different methods for the estimation of glomerular filtration rate (GFR) on the basis of serum creatinine were compared with respect to their association with MS and their predictive value for incident diabetes mellitus. The present analysis was performed on the cohort of subjects enrolled in the FIBAR study, a screening program for diabetes. GFR was estimated (eGFR) using three different methods: Cockroft-Gault (CG) formula, using actual body weight (CAW), CG formula using ideal body weight (CIW), and Modification of Diet in Renal Disease formula (M). The study was performed on 2,694 nondiabetic subjects, without history of renal insufficiencey or serum creatinine at baseline >1.5 mg/dl. Mean follow-up was 27.8 ± 11.5 months. Elevated eGFR, estimated with different methods, was associated with increased prevalence of most components of MS; however, an association between elevated clearance and MS was observed only when using CAW, which overestimates filtration in obese subjects. During follow-up, 40 new cases of diabetes were recorded (0.5/100 patient*years). After adjusting for age and sex, the HR (with 95% confidence intervals) for diabetes for patients in the highest quintile of eGFR was 1.14 [0.44–2.99], 0.89 [0.31–2.51], and 1.01 [0.42–2.41] for formula CAW, CIW, and M, respectively (all p  > 0.7). Elevated eGFR, estimated through methods which do not produce a systematic overestimate in obese subjects, is not associated with the diagnosis of MS, and does not predict diabetes.