Do SGLT2 Inhibitors Affect More Than Renal Cells?

So far, we've been told that SGLT2 inhibitors only work on receptors in the kidneys.  But are SGLT2 receptors found in other organs, and if so, do they have any actions there? 

A new study looking at just this issue revealed a previously unknown function for SGLT2 inhibitors, as well as a new mechanism of action.¹ Its findings suggest that SGLT2 inhibitors, or gliflozins, promote glucagon secretion in pancreatic alpha cells, leading to increased hepatic glucose production. 

The study is the first to show that SGLT2 receptors may play a role in endocrine regulation.

“Glucose metabolism is a homeostatic system which is tightly regulated in order to maintain blood glucose levels within limits. Therefore, the body has developed glucose sensing systems leading to, amongst others, secretion of insulin when glucose is high by beta-cells, and the secretion of glucagon when glucose is low by alpha cells,”  commented lead author Bart Staels, PhD, a professor at the University of Lille in France.

“In our study we found that alpha cells sense glucose levels through the SGLT2 glucose transporter leading to inhibition of glucagon secretion. Pharmacological blocking of SGLT2 using gliflozins mimics the state of low glucose and hence stimulates glucagon secretion.”

Studies have shown that use of gliflozins can increase endogenous glucose production and glucagon, in effect partially counteracting the glucosuria induced by SGLT2 action in the kidneys, although the mechanism has remained unclear.^2,3

“Together with the known function of SGLT2 to re-uptake glucose in the kidney, we identified a new physiological mechanism through which the body keeps glucose homeostasis under control. This mechanism explains the increased endogenous glucose production seen with gliflozins in human trials.”

In the study, Dr Staels and colleagues used confocal imaging analysis of human pancreatic tissues to look at expression of glucagon on islet cells.  In addition, they did Western blot analyses to look at SGLT2 protein expression in human islet cells, and gene expression analyses of the SLC5A2 gene, which encodes SGLT2.  They also did loss of function experiments in human alpha cells to assess whether SGLT2 affects glucagon secretion.

Key results in human alpha cells:

     ● SGLT2 is co-expressed with glucagon on pancreatic alpha cells but not beta cells.

     ● Islet cells from obese and glucose intolerant individuals had higher SLC5A2 expression, compared to lean individuals.

     ● Islet cells from individuals with type 2 diabetes mellitus (T2DM) had lower SLC5A2 expression, which occurred together with the gene encoding glucagon.

     ● Treating isolated human islet cells with dapagliflozin caused increased glucagon secretion.

Do these Results Explain Diabetic Ketoacidosis (DKA) Cases in Patients on SGLT2 Inhibitors?

On May 15, 2015, the US Food and Drug Administration (FDA) issued a warning about the risk of DKA with use of SGLT2 inhibitors in patients with T2DM.⁴ The warning was in response to 20 cases of DKA that occurred between March 2013 and June 6, 2014 in patients receiving SGLT2 inhibitors.

DKA usually occurs in patients with type 1 diabetes mellitus and is accompanied by high blood sugar levels.  The recent cases were not typical for DKA because most of the patients had T2DM and only slightly increased blood sugar levels. Potential triggers, according to the FDA warning, could have included major illness, low food and fluid intake, and decreased insulin dose.

It’s tempting to think that the newly described effect of SGLT2 inhibitors on alpha cells and glucagon secretion could play a role in these cases of DKA, according to Dr. Staels, but this conclusion cannot be reached based on the recent study. 

“Our study focused on normal physiological pathways. We did not study the consequences of our identified mechanisms in patients with T2DM,” he explained, “however, it is clear that glucagon has pronounced effects on the liver in T2DM patients, not only by stimulating gluconeogenesis, but also by impacting lipid metabolism and ketogenesis, which is stimulated upon fasting. Whether this mechanism is involved in the observed effects mentioned in the FDA warning…requires further study.”

References:

1. Bonner C, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015 May;21(5):512-517. Epub 2015 Apr 20.

2. Ferrannini E, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499-508. Epub 2014 Jan 27.

3. Merovci A, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014 Feb;124(2):509-514. Epub 2014 Jan 27.

4. Food and Drug Administration. FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. May 15, 2015. http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm.