Somatostatin Receptor Antagonism Reverses Glucagon Counterregulatory Failure in Recurrently Hypoglycemic Male Rats

Endocrinology. 2021 Sep 3:bqab189. doi: 10.1210/endocr/bqab189. Online ahead of print.ABSTRACTRecent antecedent hypoglycemia is a known source of defective glucose counterregulation in diabetes; yet, the mechanisms perpetuating the cycle of progressive α-cell failure and recurrent hypoglycemia remain unknown. Somatostatin has been shown to supress the glucagon response to acute hypoglycemia in rodent models of type 1 diabetes. We hypothesized that somatostatin receptor 2 antagonism (SSTR2a) would restore glucagon counterregulation and delay the onset of insulin-induced hypoglycemia in recurrently hypoglycemic, non-diabetic male rats. Healthy, male, Sprague-Dawley rats (n=39) received bolus injections of insulin (10 U/kg, 8 U/kg, 5 U/kg) on 3 consecutive days to induce hypoglycemia. On day 4, animals were then treated with SSTR2a (10 mg/kg; n=17) or vehicle (n=12) one-hour prior to the induction of hypoglycemia using insulin (5 U/kg). Plasma glucagon level during hypoglycemia was ~30% lower on day 3 (150±75 pg/ml; P<0.01), and 68% lower on day 4 in the vehicle group (70±52 pg/ml; P<0.001) compared to day 1 (219±99 pg/ml). On day 4, SSTR2a prolonged euglycemia by 25±5 min (P<0.05) and restored the plasma glucagon response to hypoglycemia. Hepatic glycogen content of SSTR2a-treated rats was 35% lower than vehicle controls after hypoglycemia induction on day 4 (vehicle: 20±7.0 vs SSTR2a: 13±4.4 µmol/g; P<0.01). SSTR2a treatment reverses the cumulative glucagon...
Source: Endocrinology - Category: Endocrinology Authors: Source Type: research