Glucose production and gluconeogenesis in postabsorptive and starved normal and streptozotocin-diabetic rats

Using a 3-hour primed-continuous infusion of [3- 3 H]glucose and [2- 13 C]glycerol, we measured glucose production, gluconeogenesis, from glycerol, and total gluconeogenesis (using mass isotopomer distribution analysis [MIDA] of glucose) in postabsorptive and starved normal and streptozotocin-diabetic rats. In normal rats, 48 hours of starvation increased ( P <.01) the percent contribution of both gluconeogenesis from glycerol (from 14.4% ± 1.8% to 25.5 ± 4.0%) and total gluconeogenesis (from 52.2% ± 3.9% to 89.8% ± 1.3%) to glucose production, but the absolute gluconeogenic fluxes were not modified, since glucose production decreased. Diabetic rats showed increased glucose production in the postabsorptive state; this decreased with starvation and was comparable to that of controls after 48 hours of starvation. Gluconeogenesis was increased in postabsorptive diabetic rats (69.0% ± 1.3%, P <.05 v controls). Surprisingly, this contribution of gluconeogenesis to glucose production was not found to be increased in 24-hour starved diabetic rats (64.4% ± 2.4%). These rats had significant liver glycogen stores, but gluconeogenesis was also low (42.8% ± 2.1%) in 48-hour starved diabetic rats deprived of glycogen stores. Moreover, in 24 hours starved diabetic rats infused with [3- 13 C]lactate, gluconeogenesis was 100% when determined by comparing circulating glucose and liver pyruvate enrichment, but only 47% ± 3% when calculated from the MIDA of glucose. Therefore, MIDA is not a valid method to measure gluconeogenesis is starved diabetic rats. This was not explained by differences in the labeling of liver and kidney triose phosphates: functional nephrectomy of starved diabetic rats decreased glucose production, but gluconeogenesis calculated by the MIDA method was only 48% ± 3.3%. We conclude that (1) diabetic rats have increased glucose production and gluconeogenesis in the postabsorptive state; (2) starvation decreases glucose production and increases the contribution of gluconeogenesis, but MIDA is not an appropriate method in this situation; and (3) the kidneys contribute to glucose production in starved diabetic rats.