Background:During the last decade, epidemiological studies uncovered the tremendous impact of metabolic syndrome/diabetes mellitus type 2 (DM T2) as risk factors of the progression of cancer. Therefore, we studied the impact of diabetogenic glucose and insulin concentrations on the activities of tumour cells, because little is known about how high glucose and insulin levels are influencing gene activities causing changes in the signal cascade activities with respect to kinases involved in the proliferation and migration of cancer cells.Methods:To address this question we analysed the activity of more than 400 gene signatures related to (i) cell cycle, (ii) cell movement as well as (iii) signal transduction. We examined transcriptoms of kinases (PKCα, PI3K), cadherins (E-, N- VE-), integrins and cyclins by comparing physiological (5.5 m) vs diabetogenic (11 m) glucose concentrations (without and with insulin).Results:Proliferation assays revealed that high levels of glucose (11 m) and insulin (100 ng ml−1) did promote the proliferation of the tumour cell lines HT29, SW480, MCF-7, MDA MB468, PC3 and T24. Using a 3D-migration assay, we have shown that high glucose concentrations caused increased motility rates of the tumour cells. The increase in migratory activity at high glucose and insulin concentrations was mediated by an activation of PI3K, PKCα and MLCK, as figured out by the pharmacological inhibitors wortmannin, Go6976 and ML-7.Conclusion:We present molecular and functional data, which could help to understand how hyperglycaemia and hyperinsulinemia might trigger tumour cell proliferation and motility in patients, too.

There is evidence that the rarefaction of the capillary bed is typical for the skeletal muscle of spontaneously hypertensive rats. We were therefore interested to learn whether there is also a rarefaction in skeletal muscle of human hypertensives. The number of capillaries was morphometrically analysed and counted in the quadriceps and the pectoralis major muscles of human normotensives (n = 12) and hypertensives (n = 15). The clinical diagnosis and certain pathological criteria, such as blood pressure (with or without antihypertensive therapy), heart weight, left ventricular wall thickness, the state of kidney arterioles and brain, and heart vessels, were used to classify the patients into two groups. The dissected tissue samples were prepared according to the GMA method and the capillary numbers per area were counted using light microscopy (250 x). The quadriceps muscle had a capillary density (per 2.5 mm2) of 442 +/- 51 in normotensives and 277 +/- 41 in hypertensive patients; in the pectoralis major muscle we counted 477 +/- 30 in controls and 232 +/- 28 in hypertensives. The rarefaction in the quadriceps muscle ranged by about 37%, in the pectoralis major muscle by about 51%. It is suggested that the reduction of the capillary surface area caused by the capillary rarefaction reduces the transcapillary fluid exchange and in that way prevents an overperfusion of the terminal vascular bed.

Reactive hyperemia was studied in cat sartorius muscle by measurement of venous outflow and capillary red cell velocity following occlusions of 5-120 s. The peak value for volume flow rose in a graded manner as occlusion duration increased, reaching a level of 280% above control following 120 s of occlusion. By contrast, peak values for capillary flow were 200% above control even after short (10-15 s) occlusions and increased moderately thereafter to 280% above control following 120-s occlusions.

The mesentery preparation of normotensive rats (NR) (Pcarotis97 +/- 4 mm Hg) and of spontaneously hypertensive rats (SHR) (161 +/- 2 mm Hg) of comparable age (20 +/- 3 weeks) was used to study morphological changes of the microvasculature in established hypertension. The arterioles, classified according to their branching order, had an increased inner diameter in SHR (by 20%). The smooth muscle hypertrophy decreased with smaller vessel size. Pre- and postcapillary vessels were shorter in SHR than in NR by 17 to 35%. The number of these vessels related to the number of the feeding terminal arterioles was found to be reduced by nearly 50% in SHR. The data suggest a lowered arteriolar flow resistance in individual vessels of the hypertensive group concomitant with a gradually disappearing smooth muscle hypertrophy towards the capillary bed. The elevation of the resistance to blood flow in the hypertensive rats is obviously caused by a reduced number of resistance vessels, as seen in the mesentery vascular bed. Similar results were obtained in the true capillaries, which showed greater inner diameters (SHR vs NR:7.2 micron vs 6.4 micron), shortened lengths (141 vs 170 micron) and a reduced number (50 vs 70). Red cell velocity in true capillaries did not differ (0.51 mm/s vs 0.49 mm/s). Arterio-venous shunt vessels were described with an average inner diameter of 11 micron. In SHR these vessels were shorter (424 vs 654 micron) and increased in number. The 'hydraulic hindrance' of AV-shunt vessels and true capillaries together was decreased in SHR; the surface area did not differ between SHR (55.7 . 10(3) micron2) and NR (50.1 . 10(3) micron2) suggesting no major variation in the exchange functions.

The effect of direct sympathetic stimulation on intestinal muscle and submucosal-mucosal vasculatures was studied in the anesthetized rat. Blood flow was calculated from direct measurements of vessel diameter and red cell velocity. Stimulation at 4 Hz caused a slight reduction (4%) in muscle flow, but had no measurable effect on submucosal-mucosal flow; stimulation at 8 and 16 Hz caused muscle flow to decrease to 58.3 +/- 8.7% (SE) and 31 +/- 5.1%, respectively, of control flow, and mucosal flow, to 73 +/- 3.4% and 54.1 +/- 1.2%, respectively, of control flow. Calculations of muscle and mucosal vascular resistances from flows and microvascular pressures indicate that muscle resistance increased proportionately more than mucosal resistance at 4 and 8 Hz. However, during stimulation at 16 Hz, the mucosal resistance is only 55% of control, and muscle resistance is not significantly (P less than 0.05) different from control. Therefore, reduction of muscle and mucosal flows during 16-Hz stimulation must be caused by the intestinal arterioles and venules in series with these vasculatures.