Objective: Glucocorticoids (GCs), such as prednisolone, are associated with adverse metabolic effects, including glucose intolerance and diabetes. In contrast to the well known GC-induced insulin resistance, the effects of GCs on b-cell function are less well established. We assessed the acute and short-term effects of prednisolone treatment on b-cell function in healthy men. Research design and methods: A randomised, double-blind, placebo-controlled trial consisting of two protocols was conducted. In protocol 1 (nZ6), placebo and a single dose of 75 mg of prednisolone were administered. In protocol 2 (nZ23), participants received 30 mg of prednisolone daily or placebo for 15 days. Both empirical and model-based parameters of b-cell function were calculated from glucose, insulin and C-peptide concentrations obtained during standardised meal tests before and during prednisolone treatment (protocols 1 and 2), and 1 day after cessation of treatment (protocol 2). Results: Seventy-five milligrams of prednisolone acutely increased the area under the postprandial glucose curve (AUC gluc ; PZ0.005), and inhibited several parameters of b-cell function, including AUC c-pep /AUC gluc ratio (PZ0.004), insulinogenic index (PZ0.007), glucose sensitivity (PZ0.02) and potentiation factor ratio (PFR; PZ0.04). A 15-day treatment with prednisolone increased AUC gluc (P!0.001), despite augmented C-peptide secretion (PZ0.05). b-cell function parameters were impaired, including the fasting insulin secretory tone (PZ0.02) and PFR (PZ0.007). Conclusions: Acute and short-term exposure to prednisolone impairs different aspects of b-cell function, which contribute to its diabetogenic effects.

OBJECTIVERelatives of type 1 diabetic patients are at enhanced risk of developing diabetes. We investigated the mode of onset of hyperglycemia and how insulin sensitivity and β-cell function contribute to the progression to the disease.RESEARCH DESIGN AND METHODSIn 328 islet cell autoantibody–positive, nondiabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (median age 11 years [interquartile range 8], 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. β-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.RESULTSIn progressors, baseline insulin sensitivity, fasting insulin secretion, and total postglucose insulin output were similar to those of nonprogressors, whereas β-cell glucose sensitivity was impaired (median 48 pmol/min per m2 per mmol/l [interquartile range 36] vs. 87 pmol/min per m2 per mmol/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 (∼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.CONCLUSIONSIn high-risk relatives, β-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 β-cell glucose sensitivity.

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 potential 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 (a-1,3-)-glycoprotein b-1,4-N-acetyl-glucosaminyl-transferase (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. ' 2005 Wiley-Liss, Inc.Key words: DNA microarray; metastasis; colorectal cancer Colorectal carcinoma (CRC) is the second leading cause of cancer deaths in developed countries.1 Metastatic spread, mostly to the liver, is the major cause of mortality in patients with this disease. Yet while the molecular events involved in the CRC adenoma-carcinoma sequence have been largely characterized, 2 little information is available on the mechanisms responsible for the metastatic phenotype. The identification in the primary tumors of molecular factors predictive of metastatic risk may have a relevant clinical impact, allowing for more personalized and effective treatment of CRC patients.Recent evidence based on gene expression profiling has shown that a metastatic fingerprint is detectable in the bulk of primary lung and breast tumors.3,4 On the other hand, no such metastatic signature has been demonstrated in CRC. A general problem related to gene expression studies in the oncologic field is the heterogeneous histology of the bioptic specimens that may contain, in addition to cancer cells, significant fractions of nonneoplastic tissue. Due to this heterogeneity, relevant changes in cancer cell gene expression may be easily overlooked.In order to seek for gene expression patterns specific to metastasis in CRC carcinoma, avoiding interference from nontumoral tissue, we combined laser microdissection of cancer cells and DNA microarray to compare the transcriptional profile of primary colon carcinomas both with that of patient-matched liver metastases and with that of a group of primary tumors of meta...

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