Abstract
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.
Highlights
Hyperglycaemia and insufficient release of insulin is characteristic for diabetes (American Diabetes Association., 2009)
Despite the paracrine influence on glucagon regulation, reductions in glucagon secretion from mouse and human islets already occur at glucose concentrations below 5 mM, where paracrine inhibition is absent, indicating that alpha cells have an intrinsic mechanism that directly sense changes in circulating glucose levels
The importance of the sodium-potassium pump for basal secretion, suggests that maintenance of intracellular sodium is important for alpha cell function and in line with this, sodium glucose transporters (SGLT)s have recently been suggested to play a central role for glucagon secretion (Bonner et al, 2015; Muhlemann et al, 2018; Knudsen et al, 2019; Suga et al, 2019)
Summary
Hyperglycaemia and insufficient release of insulin is characteristic for diabetes (American Diabetes Association., 2009). The obvious treatments to counter hyperglycaemia involve reduction of blood glucose by the administration of therapeutic insulin or other medication that reduces circulating glucose levels (American Diabetes Association., 2020). Similar observations of hyperglucagonaemia have been described for type 1 diabetic (T1D) patients after ingestion of a mixed calorie meal (Bengtsen and Moller, 2021). The Potential of SGLT Inhibition patients the role of glucagon, namely the response to hypoglycaemia is absent (Gerich et al, 1973; Cryer et al, 2003) This limits treatment possibilities substantially, since intensive therapeutic interventions via injection of insulin can result in severe and life threatening hypoglycaemia (Banarer et al, 2002). A lack of understanding of the mechanisms that control glucagon secretion has made it difficult to provide treatments that directly target the dysregulated glucagon secretion in both type 1 and type 2 diabetes
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