Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN.
Diabetes. 2022 Mar 1;71(3):511-519. doi: 10.2337/db21-0769.
Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (n = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic-hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on α-cell function.
1 型糖尿病患者的低血糖胰高血糖素反调节反应受损。钠-葡萄糖共转运蛋白 (SGLT) 抑制剂可增加胰高血糖素浓度。我们评估了 SGLT 抑制是否可恢复低血糖时的胰高血糖素反调节激素反应。一项随机、双盲、交叉研究中，22 例 1 型糖尿病成人接受 SGLT2 抑制剂达格列净（每天 5mg）或安慰剂治疗 4 周。在每个治疗阶段后，参与者接受高胰岛素-低血糖钳夹试验。与安慰剂相比，达格列净治疗后基础胰高血糖素浓度升高 32%，中位个体内差异为 2.75 pg/mL（95%CI 1.38-12.6）。然而，基础胰高血糖素水平升高与低血糖发生率降低无关，因此似乎不能预防低血糖。在低血糖钳夹试验中，SGLT2 抑制并未改变反调节激素浓度、低血糖恢复时间、低血糖症状或认知功能。因此，尽管 SGLT 抑制剂治疗可升高基础胰高血糖素浓度，但并未恢复对低血糖的受损胰高血糖素反应。我们提出，这些药物与临床低血糖减少相关是由于糖尿病治疗的改变（例如，较低的胰岛素剂量或改善的血糖变异性），而不是这些药物对α细胞功能的直接生理作用所致。
