The effect of starvation on insulin secretion and glucose metabolism in mouse pancreatic islets

Abstract

1. Rates of insulin secretion, glucose utilization, lactate output, incorporation of glucose into glycogen, contents of glucose 6-phosphate, fructose 1,6-diphosphate and ATP, and maximally extractable enzyme activities of hexokinase, high-K(m) glucose-phosphorylating activity (;glucokinase'), glucose 6-phosphatase and unspecific acid phosphatase were measured in isolated pancreatic islets from fed and 48-h-starved mice. 2. In the fed state insulin secretion from isolated islets was increased five- to six-fold when the extracellular glucose concentration was raised from 2.5mm to 16.7mm; 5mm-caffeine potentiated this effect. The secretory response to glucose of islets from mice starved for 48h was diminished at all glucose concentrations from 2.5mm up to approx. 40mm. Very high glucose concentrations (60mm and above) restored the secretory response to that found in the fed state, suggesting that the K(m) value for the overall secretory process had been increased (approx. fourfold) by starvation. Addition of 5mm-caffeine to islets from starved mice also restored the insulin secretory response to 2.5-16.7mm-glucose to normal values. 3. Extractable hexokinase, ;glucokinase', glucose 6-phosphatase and unspecific phosphatase activities were not changed by starvation. 4. Glucose utilization and glycolysis (measured as the rate of formation of (3)H(2)O from [5-(3)H]glucose over a 2h period) was decreased in islets from starved mice at all glucose concentrations up to approx. 55mm. At still higher glucose concentrations up to approx. 100mm, there was no difference between the fed and starved state, suggesting that the K(m) value for the rate-limiting glucose phosphorylation had been increased (approx. twofold) by starvation. Preparation of islets omitting substrates (glucose, pyruvate, fumarate and glutamate) from the medium during collagenase treatment lowered the glucose utilization measured subsequently at 16.7mm-glucose by 38 and 30% in islets from fed and starved mice respectively. Also the 2h lactate output by the islets at 16.7mm extracellular glucose was diminished by starvation. Incorporation of glucose into glycogen was extremely low, but the rate of incorporation was more than doubled by starvation. 5. After incubation for 30min at 16.7mm-glucose the content of glucose 6-phosphate was unchanged by starvation, that of ATP was increased and the concentration of (fructose 1,6-diphosphate plus triose phosphates) was decreased. 6. Possible mechanisms behind the correlated impairment in insulin secretion and islet glucose metabolism during starvation are discussed.

Differential patterns of glucose-induced electrical activity and intracellular calcium responses in single mouse and rat pancreatic islets.

“…The estimated EC 50 values for these parameters lay in the range 5.9-6.9 and 8.3-9.5 mmol/l, respectively, indicating that the dose-response curves for rat ␤-cells are shifted toward lower glucose concentrations compared with mouse ␤-cells. This is in keeping with published data for glucose-induced insulin secretion (20,21) and may relate to the fact that low-K M hexokinase activity accounts for a higher fraction of total glucose phosphorylating activity in rat compared with mouse ␤-cells (49,50). The differential responses to the lower depolarizing glucose concentration used in our study (5.6 mmol/l) are particularly noteworthy: rat ␤-cells display a sustained spiking activity, whereas mouse ␤-cells do not.…”

Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat.

“…Finally, these findings in the intact rat provided a clue as to why, in earlier experiments with isolated pancreas preparations, GSIS was invariably found to be severely depressed after simple starvation of the donor animals (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Might this have been due, at least in part, to the fact that the cited studies were always conducted in the absence of FFA?…”

“…Less well appreciated, however, is the remarkable influence that fasting has on the functioning of the pancreatic ␤ cell. This point, which has been recognized for some three decades (1), and has been reexamined sporadically in the intervening years (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13), is well illustrated by the studies of Burch et al (8). These authors fasted normal rats for increasing periods of time, and then measured the ability of their isolated pancreatic islets to secrete insulin when perifused with a solution containing 10 mM glucose.…”

Insulin release and cyclic AMP accumulation in response to glucose in pancreatic islets of fed and starved rats.

“…This impairment is not complete, rather there is a decreased sensitivity to glucose of the insulin secretory mechanism (10,14,15), and glucose refeeding in vivo (2,4,7,16), or in vitro (15) has been reported to overcome this defect. It has been proposed that starvation specifically impairs a glucose-inducible enzyme system in the pancreatic beta cell (3,7).…”

“…Starvation has been reported to cause a marked reduction of glucose metabolism (14,39) as well as a reduced activity of glucokinase and phosphofructokinase in islets (40). On the basis of these findings, the above authors have proposed that the major starvation-induced defect in the process of glucose recognition in the beta cell is located in the early steps of glucose metabolism through the glycolytic pathway.…”