Sodium, Glucose and Dysregulated Glucagon Secretion: The Potential of Sodium Glucose Transporters

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.

Keywords: Alpha cells; SGLT1; SGLT2; dapagliphlozin; diabetes; metabolism.

FIGURE 1

Suggested mechanisms of glucose induced changes in glucagon secretion. 1) In high glucose conditions, glucose is metabolised in mitochondria leading to higher ATP levels. This fully closes the K_ATP channel, depolarising the membrane slightly to inhibit the voltage gated sodium channel. This prevents opening of P/Q type VDCCs, limiting calcium influx and inhibiting glucagon secretion. 2) Fatty acid metabolism fuels the sodium potassium pump in low glucose, maintaining the membrane potential to allow action potential firing and activation of P/Q type VDCCs, resulting in stimulation of glucagon secretion 3) ER calcium stores are emptied in low glucose due to SOCs channel opening, triggering glucagon secretion. When glucose levels rise, this is reversed as the SERCA pump transports calcium from the cytosol into the ER.

FIGURE 2

A central role of SGLTs in alpha cell function. SGLTs mediate sodium influx in pancreatic alpha cells. Intracellular sodium levels are tightly linked to alpha cell function. Disruptions due to hyperglycaemia-mediated accumulation of sodium interfere with alpha cell metabolism. The high intracellular sodium affects the function of sodium proton exchangers, resulting in lowering of pH. Maintenance of pH is crucial in alpha cells, as the intrinsic glucose sensing mechanism depends largely on metabolism. Metabolic enzymes, which are sensitive to pH, will–when disrupted–render the cells glucose blind, resulting in dysregulated glucagon secretion.

FIGURE 3

SGLT inhibitors tackle diabetic symptoms from two angles. SGLTs maintain the sodium flux in alpha cells and glucose reabsorption in the kidneys. In diabetic individuals, the sodium influx in alpha cells leads to dysfunctions in glucagon regulation while the reabsorption of glucose in the kidneys further elevates high blood glucose levels. SGLT inhibitors can – depending on their specificity – lower glycaemia by blocking reabsorption in the kidneys, which also lowers the need for required insulin and simultaneously restores alpha cell function. Together, this results in improved glycaemic control.