A groundbreaking study reveals that a crucial digestive hormone diminishes long before diabetes diagnosis, and the decline isn't the same for everyone.
Based on the ADDITION-PRO Study published in Diabetes (2015)
Imagine your body has a sophisticated hormonal "braking system" that helps manage blood sugar levels after eating. Now, research reveals this system begins failing long before type 2 diabetes develops—and the decline affects men and women differently. This is the story of GLP-1, a crucial gut hormone, and the Danish ADDITION-PRO study that uncovered its early warning signals.
Glucagon-like peptide-1 (GLP-1) is a hormone produced in your gut after eating, playing a pivotal role in your body's metabolic regulation 6 7 . Think of it as a master coordinator that manages several crucial processes simultaneously:
It tells your pancreas to produce insulin when blood sugar rises, helping cells absorb glucose for energy.
It prevents your liver from releasing stored sugar, avoiding unnecessary blood sugar spikes.
This natural "brake" on digestion helps you feel fuller longer and allows for more gradual sugar absorption.
When this sophisticated system works properly, GLP-1 acts as your body's natural blood sugar stabilizer and appetite regulator. But when it falters, the metabolic consequences can be significant.
The ADDITION-PRO study was a comprehensive Danish research initiative designed to understand cardiovascular risk and metabolic changes among people at high risk for diabetes 2 9 . Between 2009-2011, researchers conducted detailed health assessments on 2,082 participants who had been identified through a stepwise screening program in Danish general practices 9 .
These participants represented different metabolic health statuses: those with normal glucose tolerance, prediabetes, screen-detected type 2 diabetes, and varying weight categories. The study's robust design included detailed measurements of anthropometry, body composition, biochemistry, and cardiovascular risk factors, creating an ideal dataset to investigate early metabolic changes 2 9 .
Participants
Study Period
High-risk individuals identified through screening
At the heart of the discovery was a standardized procedure called the oral glucose tolerance test (OGTT). Here's how it worked:
Participants fasted overnight to establish baseline measurements.
Each person drank a standardized glucose solution.
Researchers collected blood samples at multiple time points.
Each sample was analyzed for glucose, insulin, and GLP-1 concentrations.
This method allowed scientists to observe precisely how the body responded to a glucose challenge, capturing the dynamic release of GLP-1 and its relationship to metabolic health 1 8 .
The ADDITION-PRO findings revealed a striking pattern of GLP-1 reduction across different metabolic states:
| Metabolic Condition | Reduction in GLP-1 Response | Population Affected |
|---|---|---|
| Prediabetes | 25% lower total response | Women only |
| Screen-detected type 2 diabetes | 25% lower total response | Women only |
| Overweight/Obesity | Up to 20% reduced response | Both men and women (independent of glucose status) |
| All glucose impairment | 16-21% lower 120-minute GLP-1 concentrations | Both men and women |
The research demonstrated that impaired GLP-1 response occurs early in the disease process—potentially before full-blown diabetes develops. This finding was particularly significant because it suggested that GLP-1 deficiency might be part of the progression toward diabetes, not just a consequence of established disease 1 8 .
One of the most intriguing findings was the significant difference between men and women in how GLP-1 response changes with metabolic health:
Women with prediabetes or diabetes showed a 25% reduction in total GLP-1 response compared to women with normal glucose tolerance.
This sex-specific pattern was less pronounced in men, suggesting potentially different hormonal pathophysiology between sexes 1 .
This discovery takes on added significance in light of more recent research showing that women actually experience greater weight loss than men when treated with GLP-1 receptor agonists, despite having more impaired natural GLP-1 responses in prediabetic states 5 .
The study made another crucial discovery: obesity itself is linked to impaired GLP-1 response, independent of glucose status. Overweight and obese individuals showed up to 20% reduced GLP-1 response to oral glucose compared to normal-weight counterparts, regardless of whether they had normal glucose tolerance, prediabetes, or diabetes 1 8 .
Understanding how scientists uncover these metabolic secrets requires a look at their research toolkit:
| Research Tool | Primary Function | Application in ADDITION-PRO |
|---|---|---|
| Oral Glucose Tolerance Test (OGTT) | Assess body's ability to process glucose | Standardized challenge to measure hormonal response |
| GLP-1 Assays | Precisely measure hormone concentrations in blood | Quantified GLP-1 levels at multiple time points |
| Body Composition Analysis | Measure fat distribution, lean mass | Evaluated obesity independent of weight alone |
| Insulin Sensitivity Indices | Calculate how responsive cells are to insulin | Assessed relationship between GLP-1 and metabolic function |
The ADDITION-PRO findings help explain why GLP-1 receptor agonists (medications that mimic GLP-1) have become such powerful tools in managing type 2 diabetes and obesity 3 6 . These drugs essentially compensate for the natural GLP-1 response that the study showed is impaired in these conditions.
These medications have demonstrated benefits extending far beyond blood sugar control and weight loss, including cardiovascular protection and potential kidney benefits 3 . The ADDITION-PRO findings provide important context for why these treatments are so effective—they're replacing a hormonal function that's already compromised.
| Finding | Clinical Significance | Therapeutic Application |
|---|---|---|
| Early GLP-1 reduction in prediabetes | Identifies at-risk individuals before diabetes develops | Opportunities for early intervention with lifestyle or pharmacology |
| Sex differences in GLP-1 response | Suggests need for sex-specific treatment approaches | May explain why women respond differently to GLP-1 medications |
| Obesity-linked GLP-1 impairment | Highlights hormone's role in weight regulation | Supports use of GLP-1 agonists for weight management |
| Correlation with β-cell function | Connects GLP-1 to insulin production capacity | Informs combination treatment approaches |
Drugs that mimic GLP-1 include:
The ADDITION-PRO study fundamentally advanced our understanding of the timeline of metabolic deterioration. By showing that GLP-1 response diminishes early—in prediabetes and obesity, influenced by sex—it opened new avenues for early intervention and personalized treatment approaches.
The researchers concluded that their findings "indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes" 1 8 .
As research continues to unravel the complexities of GLP-1 biology, each discovery brings us closer to more effective, personalized strategies for combating metabolic disease—proving that sometimes, the most powerful medical insights begin with observing what happens when we simply drink a sugary solution.
This article was based on the study "GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study" published in Diabetes (2015).