Altered metabolic priming by D-glucose in pancreatic islets from Goto-Kakizaki rats

The possible priming by D-glucose of metabolic events in islets from control rats and Goto-Kakizaki rats (GK rats) was investigated by first incubating the islets for 120 min either in the absence of any exogenous nutrient or presence of 16.7 mM D-glucose. The islets were then incubated for a second period of 120 min either at 2.8 mM or 16.7 mM D-glucose, the hexose being now mixed with tracer amounts of D-[U-C-14]glucose and D-[5-H-3]glucose. In islets from control rats first incubated in the absence of exogenous nutrient the hierarchy in the 16.7 mM/2.8 mM ratio for metabolic variables was as follows: D-[U-C-14]glucose oxidation > D-[5-H-3]glucose utilization and D-[U-C-14]glucose conversion to amino acids > D-[U-C-14]glucose conversion to acidic metabolites. When the islets from control rats were first incubated in the presence of 16.7 mM D-glucose, the preferential stimulation of mitochondrial oxidative events at high hexose concentration, as documented by the increase in the paired ratio between D-[U-C-14]glucose oxidation and D-[5-H-3]glucose utilization, was further enhanced. The 16.7 mM/2.8 mM ratio for the conversion of D-[U-C-14]glucose to amino acids, relative to that for D-[U-C-14]glucose conversion to acidic metabolites, was much lower, however, after a first incubation in the presence of D-glucose, rather than in its absence, probably as a result of the progressive exhaustion of endogenous amino acids considered as transamination partners. The major differences between these results and those obtained in islets from GK rats consisted, in the latter animals, in i) higher absolute values for all metabolic fluxes, ii) lower 16.7 mM/ 2.8 mM ratios, iii) lower paired ratio between D-[U-C-14]glucose oxidation and D-[5-H-3]glucose utilization, and iv) absence of a priming effect of D-glucose (16.7 mM) upon such a paired ratio in the islets incubated at 16.7 mM D-glucose during the second incubation. Taken as a whole, these observations confirm that the preferential stimulation of mitochondrial oxidative events, in response to a rise in D-glucose concentration, is impaired in islets from GK rats and extend this knowledge to the priming action of D-glucose, in high concentration, on the catabolism of the hexose during a subsequent incubation.