No abstract

To study the cell cycle and regulation by glucose of Bcell proliferation, B-cell-rich pancreatic islets of rat fetuses (22 days gestational age) were maintained in tissue culture at various glucose concentrations. The proliferating islet cells were synchronized with hydroxyurea and their rate of progress through the cell cycle studied by pulse labeling with 3 H-thymidine and after exposure to colchicine. 0.5 h. Although glucose significantly stimulated B-cell proliferation, the progression of cells through the cell cycle was similar at different glucose concentrations. The experiments furthermore suggested that only a limited pool of islet cells was able to proliferate. Glucose seemed to stimulate B-cell proliferation by increasing the number of cells entering the cell cycle.From the cell cycle data it was possible to calculate the rate of formation of new B-cells, which ranged from 4.2%/24 h in 2.7 mM glucose to 10.4%/24 h in 16.7 mM. When the accumulation of mitotic figures during colchicine treatment was used as an alternative method for estimation of newly formed B-cells the cell birth rates were found to be 3.1 and 6.0%/24 h at 2.7 and 16.7 mM glucose, respectively.The notion that only a small fraction of B-cells takes part in proliferation would explain the limited regenerative capacity of this cell type. It remains to be established whether such a limitation is of significance in the development of maturity-onset diabetes.

We review some key aspects of the maturation of stimulus-secretion coupling and the regulation of DNA replication in the fetal beta-cell. During fetal life, the beta-cell shows a poor insulin response to glucose, although it responds to several other nonnutrient stimuli. However, chronic exposure to glucose in excess of basal levels can induce maturation of the stimulus-secretion coupling. Studies of glucose metabolism and the transmembrane flow of K+ and Ca2+ indicate that the attenuated glucose-stimulated insulin release is due to an immature glucose metabolism resulting in impaired regulation of ATP-sensitive K+ channels in the plasma membrane of the fetal beta-cell. In late fetal life, glucose is also a strong stimulus to beta-cell replication, and metabolism of glucose is a prerequisite for this process. Glucose stimulates proliferation by recruiting beta-cells from a resting state into a proliferative compartment composed of cells in an active cell cycle. The proliferative compartment comprises less than 10% of the total islet cell population even at maximal stimulation. The proliferation of fetal beta-cells is also regulated by several peptide growth factors such as growth hormone, insulinlike growth factor I, and platelet-derived growth factor. The observation that glucose can both induce precocious maturation of the stimulus-secretion coupling and stimulate proliferation of the fetal beta-cell explains the intrauterine hyperinsulinemia and beta-cell hyperplasia of the offspring of diabetic mothers with relatively mild hyperglycemia. However, severe hyperglycemia, at least when induced in rats, seems to retard rather than stimulate beta-cell growth.

The effect of a limited period of protein-calorie malnutrition in young rats on glucose tolerance, insulin secretory response to glucose, and tissue composition in the adult was studied. Three-week-old rats were weaned onto semisynthetic diets containing either 5% protein (low protein; LP) or 15% protein (control; C) and maintained for 3 wk on their respective diets. At 6 wk of age all rats were returned to a commercial rat chow diet (18% protein). Glucose tolerance, insulin secretory response to glucose, and the protein/DNA ratio in liver, skeletal muscle, heart, kidney, small intestine, and lung were investigated at 3, 6, and 12 wk of age. Rats receiving LP diet failed to gain weight, but growth resumed immediately when they were transferred to commercial rat chow. They did not, however, catch up with C rats. Glucose tolerance and insulin secretory response to glucose remained similar between 3 and 12 wk in C rats. In 6-wk-old LP rats, glucose tolerance was impaired, and the insulin secretory response to glucose was absent. At 12 wk of age the glucose tolerance of the LP rats had normalized, but the insulin secretory response was still blunted. In 6-wk-old LP rats there was an inhibition of the age-dependent increase in cell size, shown by lowered protein/DNA ratios in all tissues studied. This decrease in cell size persisted at 12 wk in liver, skeletal muscle, heart, and lung. We conclude that protein-calorie malnutrition early in life persistently impairs the insulin secretion. The persistently lowered protein/DNA ratios in many tissues may be related to this lowered capacity for insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)