Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, OX3 7LE, UK.
Department of Physiology, Institute of Neuroscience and Physiology, University of Göteborg, Box 430, Göteborg, SE40530, Sweden.
Nat Commun. 2019 Jan 11;10(1):139. doi: 10.1038/s41467-018-08193-8.
Hypoglycaemia (low plasma glucose) is a serious and potentially fatal complication of insulin-treated diabetes. In healthy individuals, hypoglycaemia triggers glucagon secretion, which restores normal plasma glucose levels by stimulation of hepatic glucose production. This counterregulatory mechanism is impaired in diabetes. Here we show in mice that therapeutic concentrations of insulin inhibit glucagon secretion by an indirect (paracrine) mechanism mediated by stimulation of intra-islet somatostatin release. Insulin's capacity to inhibit glucagon secretion is lost following genetic ablation of insulin receptors in the somatostatin-secreting δ-cells, when insulin-induced somatostatin secretion is suppressed by dapagliflozin (an inhibitor of sodium-glucose co-tranporter-2; SGLT2) or when the action of secreted somatostatin is prevented by somatostatin receptor (SSTR) antagonists. Administration of these compounds in vivo antagonises insulin's hypoglycaemic effect. We extend these data to isolated human islets. We propose that SSTR or SGLT2 antagonists should be considered as adjuncts to insulin in diabetes therapy.
低血糖（血浆葡萄糖水平低）是胰岛素治疗糖尿病的一种严重且潜在致命的并发症。在健康个体中，低血糖会触发胰高血糖素分泌，通过刺激肝葡萄糖生成来恢复正常的血浆葡萄糖水平。这种代偿机制在糖尿病中受损。在这里，我们在小鼠中表明，治疗浓度的胰岛素通过刺激胰岛内生长抑素释放的间接（旁分泌）机制抑制胰高血糖素分泌。当葡萄糖转运蛋白-2（SGLT2）抑制剂达格列净抑制胰岛素诱导的生长抑素分泌，或通过生长抑素受体（SSTR）拮抗剂阻止分泌的生长抑素的作用时，缺失胰岛内生长抑素分泌细胞上胰岛素受体的小鼠会丧失抑制胰高血糖素分泌的能力，此时胰岛素抑制胰高血糖素分泌的能力丧失。这些化合物在体内的给药拮抗了胰岛素的降血糖作用。我们将这些数据扩展到分离的人胰岛。我们提出，SSTR 或 SGLT2 拮抗剂应被视为糖尿病治疗中胰岛素的辅助药物。
