How Tiny Immune Cells Fuel the Diabetes Fire
They are the body's first responders, but in diabetes, these cellular soldiers turn into agents of chaos, their internal machinery hijacked by high blood sugar.
When we think about diabetes, we often focus on the usual suspects: the pancreas that fails to produce enough insulin, the body's cells that resist its effects, or the sugar circulating in our blood. But groundbreaking research is revealing a surprising new character in this complex drama: the neutrophil.
Percentage of white blood cells that are neutrophils
Neutrophils produced daily in bone marrow
Making up 50% to 70% of our white blood cells, neutrophils are the most abundant immune cells in our body and our first line of defense against invaders 9 . They are the rapid-response force, rushing to sites of infection within minutes. Yet, in the environment of diabetes, these cellular defenders undergo a dramatic transformation. Their metabolism—the very engine that powers their function—gets rewired by high blood sugar, turning them from protectors into contributors to the disease itself. This metabolic hijacking creates a vicious cycle where diabetes worsens immune function, and dysfunctional immunity, in turn, exacerbates diabetes.
Imagine a microscopic world inside your body where constant surveillance is underway. Neutrophils are the patrol officers of this world, produced in the bone marrow at an astonishing rate of 100-200 billion cells per day 9 . They circulate in the bloodstream as dormant sentinels until they detect signs of trouble—a chemical signal from a wound or an invading pathogen.
Once alerted, they spring into action, becoming the first immune cells to arrive at the scene. Their job is to locate, engulf, and destroy threats through several sophisticated mechanisms:
To perform these energy-intensive tasks, neutrophils need fuel—and lots of it. Though they contain few mitochondria (the powerplants of most cells), they are metabolically agile, able to shift between different energy sources depending on the situation 2 .
Their primary energy pathway is glycolysis, a rapid though inefficient way to break down glucose for quick energy. This allows for immediate responses to threats. Under glucose-deprived conditions, they can also utilize:
Breaking down stored glycogen
Creating new glucose
Burning fats for energy
Converting amino acids
This metabolic flexibility ensures neutrophils can function in various environments, from oxygen-rich blood vessels to oxygen-deprived damaged tissues 2 .
In diabetes, the body exists in a state of nutrient excess, particularly of glucose and lipids. This metabolic imbalance creates a chronic, low-grade inflammation throughout the body, especially in adipose (fat) tissue 6 . Neutrophils are both responders to and drivers of this inflammatory state.
The constant exposure to high glucose levels fundamentally reprograms neutrophil metabolism. Under normal conditions, most glucose is processed through glycolysis. But when glucose levels become excessively high, as in diabetes, alternative metabolic pathways become overactive 2 .
One particularly problematic pathway is the polyol pathway. Normally limited in activity, this pathway becomes significantly active under high-glucose conditions, triggering a cascade of problems:
A crucial molecule for producing reactive oxygen species and recycling antioxidants gets depleted
An osmotically active sugar alcohol builds up, potentially disrupting cellular function
The body's master antioxidant diminishes, leaving cells vulnerable to oxidative stress
This metabolic shift creates a neutrophil that is simultaneously hyperactive yet ineffective—primed for inflammation but impaired in its ability to perform its essential defensive functions 2 .
The repercussions of this neutrophil dysfunction are profound and wide-ranging:
With impaired phagocytosis and microbial killing, people with diabetes face higher risks of common and severe infections
Poor neutrophil function contributes to the chronic, non-healing wounds that frequently complicate diabetes
Neutrophils release inflammatory molecules that can interfere with insulin signaling in other tissues
Emerging evidence links neutrophil dysfunction to the development of kidney, eye, and cardiovascular complications of diabetes
This dysfunctional state creates the perfect environment for the development of diabetic complications, including nephropathy (kidney disease), where the neutrophil-to-lymphocyte ratio (NLR) has emerged as a promising diagnostic marker 5 .
One of the most compelling pieces of evidence linking neutrophils to diabetes comes from the CORDIOPREV study, a landmark clinical trial conducted in Spain. This study took 183 newly-diagnosed type 2 diabetes patients who weren't on any glucose-lowering medication and randomized them to follow either a Mediterranean diet or a low-fat diet for five years 8 .
Researchers made a crucial discovery: patients who achieved diabetes remission—defined as maintaining normal blood sugar levels without medication for at least two consecutive years—had significantly different neutrophil profiles compared to those who didn't achieve remission.
The research team employed a comprehensive approach:
Classifying participants as "Responders" and "Non-Responders"
Tracking neutrophil counts over five years
Monitoring through check-ins and biomarkers
Adjusting for confounding factors
The findings revealed a powerful connection between neutrophil levels and likelihood of diabetes remission, particularly for those following the Mediterranean diet.
Patients in the lowest neutrophil tertile were over four times more likely to achieve diabetes remission compared to those in the highest tertile. Source: CORDIOPREV Study 8
The neutrophil differences weren't just predictive—they were dynamic. Patients who achieved diabetes remission showed significant decreases in neutrophil counts over the five years, while non-responders maintained their elevated levels.
Perhaps most importantly, the decrease in neutrophil counts among responders was associated with measurable improvements in insulin sensitivity and beta-cell function (as measured by the Disposition Index), providing a potential mechanism for how reducing inflammation might facilitate diabetes remission 8 .
Understanding neutrophil function in diabetes requires sophisticated tools and methods. Here are some key approaches and reagents used in this fascinating field of research:
Approximately 19 hours in circulation
Cannot be frozen and revived effectively
Must work quickly with newly isolated cells
Results vary considerably between individuals
| Reagent | Function in Research |
|---|---|
| fMLF | Bacterial tripeptide used as a potent neutrophil chemoattractant to study migration 7 |
| PMA | Phorbol ester that directly activates protein kinase C, used to induce NETosis and respiratory burst 7 |
| ATRA | Differentiating agent that transforms HL-60 cells into neutrophil-like cells for experimentation 4 |
| CXCL8/IL-8 | Primary human chemokine that guides neutrophil migration to sites of inflammation 7 |
| 2-Deoxyglucose | Glycolysis inhibitor used to study metabolic requirements of neutrophil functions 2 |
| G-CSF | Granulocyte colony-stimulating factor used to study neutrophil production and maturation 9 |
The emerging picture reveals neutrophils as crucial players in the diabetes story—not merely passive bystanders but active contributors to both the development and potential remission of the disease. The metabolic reprogramming of these cells in response to high blood sugar creates a self-perpetuating cycle of inflammation and dysfunction.
Managing diabetes may require not just monitoring blood sugar, but also calming the overactive immune cells that fuel its fire.
Yet there is hope in these findings. The CORDIOPREV study demonstrates that dietary interventions, particularly the Mediterranean diet, can lower neutrophil counts and help break this cycle. The ability of neutrophil measurements to predict both diabetes risk and remission likelihood offers clinicians potential new tools for identifying high-risk patients and monitoring treatment response.
As research continues to unravel the complex dialogue between metabolism and immunity, we move closer to novel therapies that might target neutrophil function directly. The humble neutrophil, long overlooked in the diabetes narrative, has emerged as both a culprit and a clue—a tiny cell with enormous implications for millions living with diabetes worldwide.