Impaired counterregulation during hypoglycemia in type-1 diabetes (T1D) is in part due to inadequate glucagon secretion. Intra-islet somatostatin suppression of hypoglycemia-stimulated alpha-cell glucagon release plays an important role. We hypothesized that hypoglycemia can be prevented in autoimmune T1D by somatostatin receptor type-2 (SSTR2) antagonism of alpha-cells, which relieve SSTR2 inhibition, thereby increasing glucagon secretion. Diabetic (D) Biobreeding diabetes-prone (BBDP) rats mimic insulin-dependent human autoimmune T1D, whereas non-diabetic (N) BBDP rats mimic prediabetes. D and N rats underwent a 3-h infusion of vehicle vs SSTR2 antagonist (SSTR2a) during insulin-induced hypoglycemia clamped at 3±0.5 mmol/L. D, treated with SSTR2a, needed little or no glucose infusion compared to untreated rats. We attribute this effect to SSTR2a restoration of the attenuated glucagon response. Direct effects of SSTR2a on alpha-cells was assessed by resecting the pancreas, cut into fine slices and subjected to perifusion to monitor glucagon release. SSTR2a treatment enhanced low glucose-stimulated glucagon and corticosterone secretion to normal in D. SSTR2a had similar effects in vivo on N, and promoted glucagon secretion from N and human pancreas slices. We conclude that somatostatin contributes to impaired glucagon responsiveness to hypoglycemia in autoimmune T1D. SSTR2a treatment can fully restore hypoglycemia-stimulated glucagon release sufficient to attain normoglycemia in both diabetic and prediabetic stages.
- Received January 30, 2013.
- Accepted April 23, 2013.
- © 2013 by the American Diabetes Association.
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