Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment

Abstract

The study aim was to investigate the effect of the route of insulin treatment on the glucagon and glucose production (GP) responses to hypoglycemia in the diabetic rat. Experiments were performed in 4 groups of rats: (1) streptozotocin (STZ)-induced diabetic, untreated (D, n = 7), (2) diabetic treated with subcutaneous insulin (DSC, n = 8), (3) diabetic treated with intraperitoneal insulin (DIP, n = 6), and (4) normal control (N, n = 10). Slow-release insulin implants were used in DSC and DIP rats for 10 to 14 days (3 U/d). A hyperinsulinemic (120 pmol · kg −1 · min −1 insulin)-hypoglycemic (glycemia = 2.5 ± 0.1 mmol/L) clamp following an isoglycemic basal period was performed in 5-hour fasted rats. Basal plasma glucose was normalized in both DSC and DIP rats; however, in DSC but not DIP rats, glucose normalization required peripheral hyperinsulinemia. Tracer-determined GP, which was elevated in D rats, was completely normalized in DIP but only partially corrected in DSC rats. Basal glucagon levels were similar in all groups. During hypoglycemia, GP was suppressed in D rats (Δ, −28.9 ± 5.0 μmol · kg −1 · min −1), moderately increased in DSC rats (Δ, 6.1 ± 5.6, P < .01 v D), but markedly increased in DIP and N rats (Δ, 34.5 ± 4.5 for DIP and 16.8 ± 2.8 for N; P < .01 v D, P < .05 for DIP v DSC or N). Plasma glucagon increased 6-fold in N (945 ± 129 pg/mL), only doubled in D (424 ± 54), and tripled in DSC (588 ± 83), but increased 5-fold in DIP rats (1,031 ± 75, P < .05 v D and DSC). We conclude that in STZ-diabetic rats, (1) intraperitoneal but not subcutaneous insulin treatment normalizes basal GP, and (2) intraperitoneal insulin treatment as compared with subcutaneous treatment alleviates peripheral hyperinsulinemia and results in increased glucagon and GP responses to hypoglycemia.