Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Diabetes. 2013 Aug;62(8):2968-77. doi: 10.2337/db13-0164. Epub 2013 Apr 29.
Impaired counterregulation during hypoglycemia in type 1 diabetes (T1D) is partly attributable to inadequate glucagon secretion. Intra-islet somatostatin (SST) suppression of hypoglycemia-stimulated α-cell glucagon release plays an important role. We hypothesized that hypoglycemia can be prevented in autoimmune T1D by SST receptor type 2 (SSTR2) antagonism of α-cells, which relieve SSTR2 inhibition, thereby increasing glucagon secretion. Diabetic biobreeding diabetes-prone (BBDP) rats mimic insulin-dependent human autoimmune T1D, whereas nondiabetic BBDP rats mimic prediabetes. Diabetic and nondiabetic rats underwent a 3-h infusion of vehicle compared with SSTR2 antagonist (SSTR2a) during insulin-induced hypoglycemia clamped at 3 ± 0.5 mmol/L. Diabetic rats treated with SSTR2a needed little or no glucose infusion compared with untreated rats. We attribute this effect to SSTR2a restoration of the attenuated glucagon response. Direct effects of SSTR2a on α-cells was assessed by resecting the pancreas, which was cut into fine slices and subjected to perifusion to monitor glucagon release. SSTR2a treatment enhanced low-glucose-stimulated glucagon and corticosterone secretion to normal levels in diabetic rats. SSTR2a had similar effects in vivo in nondiabetic rats and promoted glucagon secretion from nondiabetic rat and human pancreas slices. We conclude that SST 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.
1 型糖尿病（T1D）患者在低血糖期间的代偿功能受损部分归因于胰高血糖素分泌不足。胰岛内生长抑素（SST）对低血糖刺激的α细胞胰高血糖素释放的抑制作用发挥着重要作用。我们假设，通过 SSTR2 拮抗 α 细胞，可缓解 SSTR2 对 α 细胞的抑制，从而增加胰高血糖素的分泌，从而预防自身免疫性 T1D 患者的低血糖。糖尿病生物繁殖易感型（BBDP）大鼠模拟了依赖胰岛素的人类自身免疫性 T1D，而非糖尿病 BBDP 大鼠模拟了糖尿病前期。在胰岛素诱导的低血糖期间，糖尿病和非糖尿病大鼠分别接受了 3 小时的载体输注，而非糖尿病大鼠则接受了 SSTR2 拮抗剂（SSTR2a）输注，低血糖被钳制在 3±0.5mmol/L。与未治疗的大鼠相比，用 SSTR2a 治疗的糖尿病大鼠需要很少或不需要葡萄糖输注。我们将这种效果归因于 SSTR2a 恢复了减弱的胰高血糖素反应。通过切除胰腺来评估 SSTR2a 对 α 细胞的直接作用，将胰腺切成细片并进行灌注，以监测胰高血糖素的释放。SSTR2a 治疗可增强糖尿病大鼠的低葡萄糖刺激的胰高血糖素和皮质酮的分泌，使其恢复到正常水平。SSTR2a 在非糖尿病大鼠体内具有相似的作用，并促进了非糖尿病大鼠和人胰腺切片的胰高血糖素分泌。我们得出结论，SST 有助于自身免疫性 T1D 患者对低血糖时胰高血糖素反应受损。SSTR2a 治疗可完全恢复低血糖刺激的胰高血糖素释放，足以使糖尿病和糖尿病前期的大鼠恢复正常血糖水平。
