Defective regulation of glucokinase in rat pancreatic islet cell tumours

Abstract

The role of glucokinase in the regulation of insulin secretion was examined in normal rat pancreatic islets and in chemically-and radiation-induced rat pancreatic B-cell tumours which show an impaired insulin secretory response to glucose. In normal rats glucokinase activity in cytoplasmic fractions of pancreatic islets was decreased with the duration of fasting and increased by refeeding or insulin administration. This observation is consistent with the induction of glucokinase by insulin. Hexokinase activity was only slightly reduced during fasting. Glucokinase activity decreased in cytoplasmic fractions of streptozotocin-nicotinamideinduced rat pancreatic islet cell tumours. Glucokinase activity contributed about 75% to the total glucose phosphorylation capacity in cytoplasmic fractions of normal pancreatic islets and of small (< 1 mg) streptozotocin-nicotinamide-tumours. This proportion decreased to about 20% in the large streptozotocin-nicotinamide tumours. Glucokinase activity in cytoplasmic fractions of transplantable radiation-induced NEDH (New England Deaconess Hospital) rat B-cell tumours was seven times lower than in normal pancreatic islets and contributed only 15% to the total glucose phosphorylation capacity. In contrast, hexokinase activity of the NEDH tumour B-cells was 2.5 times higher than normal. Decreased glucokinase activity in the chemically-and radiation-induced tumour B-cells appears to result from a loss of the ability of insulin to induce this enzyme and may explain the lack of insulin secretory responsiveness of these tumour B-cells.

Nutrient-dependent distribution of insulin and glucokinase immunoreactivities in rat pancreatic beta cells

“…The analysis of different levels of metabolic and secretory activity shows that the state of functional activity is characterized by a distinct pattern of glucokinase immunoreactivity. A heterogeneous pattern of glucokinase immunostaining with areas of polarized high density in beta cells, in particular in association with blood vessels, under conditions of feeding and refeeding can be correlated functionally with high glucokinase enzyme activities [3,[13][14][15]. The high density of glucokinase immunoreactivity in plasma membrane areas in contact with blood vessels may be explained by an interaction with the GLUT2 glucose transporter, as suggested by functional studies in bioengineered insulin-producing cell lines [7].…”

A Fresh View of Glycolysis and Glucokinase Regulation: History and Current Status

“…Only later did it became evident that glucokinase regulation is different in hepatocytes and pancreatic beta cells. Following 48 h of starvation, glucokinase enzyme activity was reduced in the liver by nearly two-thirds (47,48), and gene expression was reduced to nearly zero (47,49), whereas glucokinase activity and gene expression were reduced by only 50% in pancreatic beta cells (47,48). Refeeding experiments indicated that the restoration of starvation-reduced glucokinase enzyme activity, as well as glucokinase gene expression, is insulin-dependent in the liver but glucose-dependent in beta cells (47).…”

Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia

“…45 Glucose phosphorylating enzyme activity was determined in total protein extracted from 1.1B4 cells by an enzyme-coupled photometric assay. 46 Glucokinase activity was measured by subtracting the hexokinase activity at 1 mM/l glucose from total activity at 100 mM/l glucose.…”