How a Diabetes Drug Reveals New Secrets of Glucagon
The key to a diabetes mystery may not be in the pancreas, but in the intricate network of communication between our organs.
For decades, the fight against type 2 diabetes has revolved around two primary hormones: insulin, which lowers blood sugar, and glucagon, which raises it. The advent of SGLT2 inhibitors, a revolutionary class of drugs including dapagliflozin and empagliflozin, promised a straightforward approach. By blocking a protein in the kidneys responsible for reabsorbing glucose, these drugs help the body expel excess sugar through urine.
However, scientists soon noticed a paradoxical effect. While these drugs successfully lower blood sugar, they also cause a rise in glucagon, the hormone that should theoretically counteract their benefits. This unexpected discovery plunged researchers into a heated debate: are these drugs directly talking to the glucagon-producing alpha cells of the pancreas, or is the story more complex? The answer is challenging our fundamental understanding of pancreatic biology and opening up new frontiers in diabetes treatment.
The core of the scientific debate is deceptively simple: is the SGLT2 protein actually present in the pancreatic alpha cells where glucagon is made?
| Evidence Supporting SGLT2 Presence | Evidence Against SGLT2 Presence |
|---|---|
| RNA-sequencing shows variable SLC5A2 gene expression in human islets 1 | Gene expression analysis finds no SGLT2 mRNA in FACS-purified human alpha cells 3 |
| Protein analysis shows SGLT2 colocalizes with glucagon 1 | Immunodetection with a validated antibody shows no SGLT2 protein in human islet cells 3 |
| SGLT2 inhibitors suppress glucose uptake in alpha-TC1 cell models 2 | Functional studies show no direct effect of SGLT2 inhibitors on glucagon secretion from isolated human islets 3 |
To truly appreciate the complexity of this issue, let's examine a key study that highlights the role of human heterogeneity.
A 2020 study published in Diabetes set out to resolve the controversy by examining human pancreatic islets on a large scale 1 . The researchers began by analyzing the genetic data of islets from 207 deceased donors. They found that the expression of the SGLT2 gene was not a simple on/off switch but existed on a spectrum, with tremendous interindividual variation 1 .
Analysis of islets from 207 donors revealed SGLT2 gene expression exists on a spectrum with high interindividual variation 1 .
Using validated antibodies, researchers confirmed SGLT2 protein presence in islets from 12 donors, primarily colocalized with glucagon-positive alpha cells 1 .
Isolated islets from 31 donors showed variable glucagon secretion in response to dapagliflozin, with some islets completely unresponsive 1 .
| Finding | Implication |
|---|---|
| High interdonor heterogeneity in SGLT2 gene expression | People naturally have different levels of SGLT2 in their pancreas, which could explain varying drug responses. |
| SGLT2 protein colocalizes with glucagon | Confirms that SGLT2, if present, is located in the alpha cells. |
| Glucagon secretion in response to SGLT2 inhibition is variable | The drug does not affect all people's alpha cells in the same way. |
| Some islets were unresponsive to both low glucose and dapagliflozin | Suggests that the mechanism of SGLT2 inhibition is linked to the alpha cell's intrinsic glucose-sensing machinery. |
If SGLT2 inhibitors aren't directly acting on alpha cells, what is causing the rise in glucagon? The leading theories focus on indirect mechanisms:
Pancreatic islets are a tightly knit community of cells. Beta cells (which make insulin) and delta cells (which make somatostatin) powerfully inhibit glucagon release. SGLT2 inhibitors lower blood glucose, which in turn reduces insulin secretion. With this "braking" signal from insulin removed, alpha cells are free to release more glucagon 9 .
SGLT2 inhibition causes a loss of calories through glucose in the urine. The body may perceive this as a state of energy deficit or mild starvation, triggering a hormonal counter-regulatory response that includes the release of glucagon to stimulate the liver to produce more glucose 3 . This would be a systemic, brain-mediated response rather than a direct pancreatic one.
Some researchers suggest we've been focusing on the wrong transporter. SGLT1 is confirmed to be present in human alpha cells and may play a more central role in their glucose sensing 3 9 . Under hyperglycemic conditions, SGLT1-mediated sodium accumulation can disrupt alpha cell function. The effects of SGLT2 inhibitors on glucagon could be partly explained by their off-target effects on SGLT1 9 .
To navigate this complex field, scientists rely on a specific set of tools. The table below details some of the essential reagents and their functions in alpha cell research.
| Reagent / Tool | Function in Research |
|---|---|
| Dapagliflozin / Empagliflozin | Highly selective SGLT2 inhibitors used to block the transporter's activity and study the resulting physiological effects in cells, islets, and whole organisms 2 3 . |
| Sotagliflozin | A dual SGLT1/SGLT2 inhibitor. Used to distinguish the effects of inhibiting SGLT1 (e.g., in the gut and pancreas) from those of selectively inhibiting SGLT2 (e.g., in the kidney) 3 . |
| FACS-Purified Alpha Cells | Fluorescence-Activated Cell Sorting allows researchers to isolate pure populations of alpha cells from human or rodent pancreata for precise gene expression (RNA) analysis, free from contamination by other cell types 3 . |
| Validated Anti-SGLT2 Antibodies | Critical for detecting the presence and location of the SGLT2 protein within pancreatic tissue. Specificity and rigorous validation are paramount due to the controversy in the field 1 3 . |
| Alpha-TC1 Cell Line | A cultured cell line derived from mouse alpha cells. A widely used model for studying alpha cell function in a controlled environment, though it may not fully replicate the complexity of primary human cells 2 . |
| Perfused Pancreas Model | An ex vivo experimental setup where a pancreas is kept alive and perfused with a solution containing nutrients and drugs. It allows for direct measurement of hormone secretion while preserving the islet's native architecture and paracrine interactions 3 . |
The journey to understand how SGLT2 inhibitors affect glucagon secretion has been anything but straightforward. It has exposed significant gaps in our knowledge of basic alpha cell biology and highlighted the incredible diversity of human physiology. The initial, simple model of a drug directly acting on a pancreatic target has given way to a far more complex picture involving individual variation, intricate cellular communication within the islet, and whole-body energy dynamics.
This scientific debate is more than academic. Understanding these mechanisms is crucial for designing better, safer diabetes treatments. If the glucagon rise is an indirect effect of lowering glucose, it may be an acceptable trade-off. If it is driven by a specific, targetable pathway, future drugs could be engineered to harness the blood sugar-lowering power of SGLT2 inhibition without the unwanted glucagon boost.
The alpha cell, long overshadowed by its insulin-producing neighbor, is finally revealing its secrets, demonstrating that even well-established drugs can serve as unexpected guides to new biological frontiers.