Armour Sarah L, Frueh Alexander, Knudsen Jakob G
Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Front Pharmacol. 2022 Feb 14;13:837664. doi: 10.3389/fphar.2022.837664. eCollection 2022.
Diabetes is defined by hyperglycaemia due to progressive insulin resistance and compromised insulin release. In parallel, alpha cells develop dysregulation of glucagon secretion. Diabetic patients have insufficient glucagon secretion during hypoglycaemia and a lack of inhibition of glucagon secretion at higher blood glucose levels resulting in postprandial hyperglucagonaemia, which contributes to the development of hyperglycaemia. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an efficient pharmacologic approach for the treatment of hyperglycaemia in type 2 diabetes. While SGLT2 inhibitors aim at increasing glycosuria to decrease blood glucose levels, these inhibitors also increase circulating glucagon concentrations. Here, we review recent advances in our understanding of how SGLTs are involved in the regulation of glucagon secretion. Sodium plays an important role for alpha cell function, and a tight regulation of intracellular sodium levels is important for maintaining plasma membrane potential and intracellular pH. This involves the sodium-potassium pump, sodium-proton exchangers and SGLTs. While the expression of SGLT2 in alpha cells remains controversial, SGLT1 seems to play a central role for alpha cell function. Under hyperglycaemic conditions, SGLT1 mediated accumulation of sodium results in alpha cell dysregulation due to altered cellular acidification and ATP production. Taken together, this suggests that SGLT1 could be a promising, yet highly underappreciated drug target to restore alpha cell function and improve treatment of both type 1 and 2 diabetes.
糖尿病的定义是由于进行性胰岛素抵抗和胰岛素分泌受损导致的高血糖症。与此同时，α细胞的胰高血糖素分泌出现失调。糖尿病患者在低血糖期间胰高血糖素分泌不足，而在较高血糖水平时缺乏对胰高血糖素分泌的抑制，导致餐后高胰高血糖素血症，这促使了高血糖症的发展。钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂是治疗2型糖尿病高血糖症的一种有效药物方法。虽然SGLT2抑制剂旨在增加糖尿以降低血糖水平，但这些抑制剂也会增加循环中的胰高血糖素浓度。在此，我们综述了近期在理解SGLT如何参与胰高血糖素分泌调节方面的进展。钠对α细胞功能起着重要作用，严格调节细胞内钠水平对于维持质膜电位和细胞内pH至关重要。这涉及钠钾泵、钠-质子交换体和SGLT。虽然SGLT2在α细胞中的表达仍存在争议，但SGLT1似乎在α细胞功能中起核心作用。在高血糖条件下，SGLT1介导的钠积累由于细胞酸化和ATP生成的改变而导致α细胞失调。综上所述，这表明SGLT1可能是恢复α细胞功能以及改善1型和2型糖尿病治疗的一个有前景但尚未得到充分重视的药物靶点。
