D'Souza Ninoschka C, Aiken Julian A, Hoffman Emily G, Atherley Sara C, Champsi Sabrina, Aleali Nadia, Shakeri Dorsa, El-Zahed Maya, Akbarian Nicky, Nejad-Mansouri Mehran, Bavani Parinaz Z, Liggins Richard L, Chan Owen, Riddell Michael C
School of Kinesiology and Health Science, York University, Toronto, ON, Canada.
Zucara Therapeutics, Vancouver, BC, Canada.
Front Pharmacol. 2024 Feb 28;15:1302015. doi: 10.3389/fphar.2024.1302015. eCollection 2024.
Elevated levels of somatostatin blunt glucagon counterregulation during hypoglycemia in type 1 diabetes (T1D) and this can be improved using somatostatin receptor 2 (SSTR2) antagonists. Hypoglycemia also occurs in late-stage type 2 diabetes (T2D), particularly when insulin therapy is initiated, but the utility of SSTR2 antagonists in ameliorating hypoglycemia in this disease state is unknown. We examined the efficacy of a single-dose of SSTR2 antagonists in a rodent model of T2D. High-fat fed (HFF), low dose streptozotocin (STZ, 35 mg/kg)-induced T2D and HFF only, nondiabetic (controls-no STZ) rats were treated with the SSTR2 antagonists ZT-01/PRL-2903 or vehicle ( = 9-11/group) 60 min before an insulin tolerance test (ITT; 2-12 U/kg insulin aspart) or an oral glucose tolerance test (OGTT; 2 g/kg glucose via oral gavage) on separate days. This rodent model of T2D is characterized by higher baseline glucose and HbA1c levels relative to HFF controls. T2D rats also had lower c-peptide levels at baseline and a blunted glucagon counterregulatory response to hypoglycemia when subjected to the ITT. SSTR2 antagonists increased the glucagon response and reduced incidence of hypoglycemia, which was more pronounced with ZT-01 than PRL-2903. ZT-01 treatment in the T2D rats increased glucagon levels above the control response within 60 min of dosing, and values remained elevated during the ITT (glucagon Cmax: 156 ± 50 vs. 77 ± 46 pg/mL, < 0.01). Hypoglycemia incidence was attenuated with ZT-01 vs. controls (63% vs. 100%) and average time to hypoglycemia onset was also delayed (103.1 ± 24.6 vs. 66.1 ± 23.6 min, < 0.05). ZT-01 administration at the OGTT onset increased the glucagon response without exacerbating hyperglycemia (2877 ± 806 vs. 2982 ± 781), potentially due to the corresponding increase in c-peptide levels (6251 ± 5463 vs. 14008 ± 5495, = 0.013). Treatment with SSTR2 antagonists increases glucagon responses in a rat model of T2D and results in less hypoglycemia exposure. Future studies are required to determine the best dosing periods for chronic SSTR2 antagonism treatment in T2D.
在1型糖尿病（T1D）患者低血糖期间，生长抑素水平升高会削弱胰高血糖素的反调节作用，而使用生长抑素受体2（SSTR2）拮抗剂可改善这种情况。低血糖在2型糖尿病（T2D）晚期也会出现，尤其是在开始胰岛素治疗时，但SSTR2拮抗剂在改善这种疾病状态下低血糖的效用尚不清楚。我们在T2D啮齿动物模型中研究了单剂量SSTR2拮抗剂的疗效。高脂喂养（HFF）、低剂量链脲佐菌素（STZ，35mg/kg）诱导的T2D大鼠和仅高脂喂养的非糖尿病（对照 - 未用STZ）大鼠，在胰岛素耐量试验（ITT；2 - 12U/kg门冬胰岛素）或口服葡萄糖耐量试验（OGTT；经口灌胃给予2g/kg葡萄糖）前60分钟，分别用SSTR2拮抗剂ZT - 01/PRL - 2903或赋形剂（每组n = 9 - 11）进行处理。相对于HFF对照，该T2D啮齿动物模型的特征是基线血糖和糖化血红蛋白水平较高。T2D大鼠在基线时C肽水平也较低，并且在进行ITT时对低血糖的胰高血糖素反调节反应减弱。SSTR2拮抗剂增加了胰高血糖素反应并降低了低血糖发生率，其中ZT - 01比PRL - 2903更明显。T2D大鼠接受ZT - 01治疗后，给药后60分钟内胰高血糖素水平升高至高于对照反应，并且在ITT期间该值保持升高（胰高血糖素Cmax：156±50 vs. 77±46pg/mL，P < 0.01）。与对照相比，ZT - 01降低了低血糖发生率（63% vs. 100%），并且低血糖发作的平均时间也延迟了（103.1±24.6 vs. 66.1±23.6分钟，P < 0.05）。在OGTT开始时给予ZT - 01增加了胰高血糖素反应而未加重高血糖（2877±806 vs. 2982±781），这可能是由于C肽水平相应增加（6251±5463 vs. 14008±5495，P = 0.013）。用SSTR2拮抗剂治疗可增加T2D大鼠模型中的胰高血糖素反应并减少低血糖暴露。未来需要进行研究以确定T2D中慢性SSTR2拮抗治疗的最佳给药周期。
