Amelioration of Hypoglycemia via Somatostatin Receptor Type 2 Antagonism in Recurrently Hypoglycemic Diabetic Rats

  1. Mladen Vranic1,5
  1. 1Department of Physiology, University of Toronto, Toronto, Canada
  2. 2School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Canada
  3. 3Department of Medicine, Peptide Research Labs, Tulane University, New Orleans, USA
  4. 4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
  5. 5Faculty of Medicine, University of Toronto, Toronto, Canada
  1. Corresponding author: Michael C. Riddell, mriddell{at}yorku.ca, and Mladen Vranic, mladen.vranic{at}utoronto.ca

Abstract

Selective antagonism of somatostatin receptor type 2 (SSTR2-) normalizes glucagon and corticosterone responses to hypoglycemic clamp in diabetic rats. The purpose of this study is to determine if SSTR2 antagonism (SSTR2a) ameliorates hypoglycemia in response to overinsulinization in diabetic rats previously exposed to recurrent hypoglycemia. Streptozotocin-diabetic rats (n= 19), previously subjected to 5 hypoglycemia events over 3 days, received an i.v. insulin bolus (10 U/kg) + insulin infusion (50 mU/kg/min) until hypoglycemia ensued (≤ 3.9 mM) (Expt-D1). The next day (Expt-D2), rats were allocated to receive either placebo treatment (n=7) or SSTR2a infusion (3000 nmol/kg/min, n=12) 60-min prior to same insulin regimen. On Expt-D1, all rats developed hypoglycemia by ∼90 minutes, while on Expt-D2 hypoglycemia was attenuated with SSTR2a treatment (nadir = 3.7 ± 0.3 mM vs. 2.7±0.3 mM in SSTR2a and controls, p<0.01). Glucagon response to hypoglycemia on Expt-D2 deteriorated by 20-fold in the placebo group (P<0.001) but improved in the SSTR2a group (3-fold increase in AUC, P<0.001). Corticosterone response deteriorated in the placebo treated rats on Expt-D2 but increased 2-fold in the SSTR2a group. Catecholamine responses were not affected by antagonism. Thus, SSTR2 antagonism following recurrent hypoglycemia improves the glucagon and corticosterone responses and largely ameliorates insulin-induced hypoglycemia in diabetic rats.

  • Received November 2, 2012.
  • Accepted February 15, 2013.

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  1. Diabetes
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