Progression to Diabetes in Relatives of Type 1 Diabetic Patients: Mechanisms and Mode of Onset

OBJECTIVE-Relatives of type I diabetic patients are at enhanced risk of developing diabetes. We investigated the mode of onset of hyperglycemia and how insulin sensitivity and beta-cell function contribute to the progression to the disease. RESEARCH DESIGN AND METHODS-In 328 islet cell autoantibody-positive, nondiabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (median age 11 years [interquartile range 81, sequential OGTTs (2,143 in total) were performed at baseline, every 6 months, and 2.7 years [2.7] later, when 115 subjects became diabetic. P-Cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity were obtained by mathematical modeling of the OGTT glucose/C-peptide responses. RESULTS-In progressors, baseline insulin sensitivity, fasting insulin secretion, and total postglucose insulin output were similar to those of nonprogressors, whereas beta-cell glucose sensitivity was impaired (median 48 pmol/min per m(2) per mmol/l [interquartile range 36] vs. 87 pmol/min per m 2 per nimol/l [67]; P < 0.0001) and predicted incident diabetes (P < 0.0001) independently of sex, age, BMI, and clinical risk. In progressors, 2-h glucose levels changed little until 0.78 years before diagnosis, when they started to rise rapidly (similar to 13 mmol . l(-1) . year(-1)); glucose sensitivity began to decline significantly (P < 0.0001) earlier (1.45 years before diagnosis) than the plasma glucose surge. During this anticipation phase, both insulin secretion and insulin sensitivity were essentially stable. CONCLUSIONS-In high-risk relatives, beta-cell glucose sensitivity is impaired and is a strong predictor of diabetes progression. The time trajectories of plasma glucose are frequently biphasic, with a slow linear increase followed by a rapid surge, and are anticipated by a further deterioration of beta-cell glucose sensitivity. Diabetes 59:679-685, 201

Chaos and complexity. Research progress. Cap.5 Redattori: Franco F. Orsucci, Nicoletta Sala

Chaos and noise in the electroencephalogram. In the last decade great attention has been devoted to a possible parametrization of the electroencephalographic phenomenology in terms of a hypothetical underlying low dimensional nonlinear dynamics: an assumption justified by the neuron synchronization. The strong unpredictability of the EEG time series suggests, on its turn, as a possible paradigm for the neuron dynamics, the chaos, namely a dynamics whose trajectories are characterized by explosive divergenc

Metastatic transcriptional pattern reveled by gene expression profiling in primary colorectal carcinoma

: Metastatic spread to the liver is the major contributor to mortality in patients with colorectal carcinoma (CRC). In order to seek for gene expression patterns associated with metastatic potentia in primary CRC, we compared the transcriptional profiles of 10 radically resected primary CRCs from patients who did not develop distant metastases within a 5-year follow-up period with those of 10 primary/metastatic tumor pairs from patients with synchronous liver metastases. To focus selectively on neoplastic cells, the study was conducted on laser-microdissected bioptic tissues. Arrays of 7,864 human cDNAs were utilized. While a striking transcriptional similarity was observed between the primary tumors and their distant metastases, the nonmetastasizing primary tumors were clearly distinct from the primary/metastatic tumor pairs. Of 37 gene expression differences found between the 2 groups of primary tumors, 29 also distinguished nonmetastasizing tumors from metastases. The gene encoding for mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N-acetyl-glucosaminyl-transrerase (GnT-IV) became significantly upregulated in primary/metastatic tumor pairs (p < 0.001). GnT-IV upregulation was confirmed by RT-PCR. These data support the existence of a specific transcriptional signature distinguishing primary colon adenocarcinomas with different metastatic potential, the further pursuit of which may lead to relevant clinical and therapeutic applications. (c) 2005 Wiley-Liss, In