How GLP-1 and GIP Are Transforming Type 2 Diabetes Treatment
For decades, the management of type 2 diabetes followed a relatively straightforward path: medications that primarily focused on forcing the body to produce more insulin or use it more efficiently. While these treatments saved lives, they often came with significant limitations, including weight gain and the risk of dangerous blood sugar crashes. But what if the body already possessed its own sophisticated system for managing blood sugar—one that we could harness rather than override?
Key Insight: Enter glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)—two hormones produced naturally in our gut that have sparked what many are calling the most significant revolution in diabetes treatment since the discovery of insulin itself.
Once obscure scientific curiosities, these incretin hormones have become the foundation for a new generation of therapies that are transforming how we treat not just diabetes, but obesity and cardiovascular disease as well 2 4 .
Substantial weight reduction compared to traditional treatments
Reduced risk of heart attacks and strokes
Glucose-dependent action reduces dangerous lows
The story of incretins begins with a fascinating observation made by scientists in the 1960s: our bodies release two to three times more insulin when we consume glucose orally compared to when it's delivered directly into our bloodstream intravenously 2 8 .
Oral glucose stimulates 2-3x more insulin release
Intravenous glucose stimulates less insulin
Discovered in the early 1970s, GIP was initially named "gastric inhibitory polypeptide" because it was observed to inhibit stomach acid secretion. However, researchers soon discovered its more important role: stimulating insulin release.
| Characteristic | GIP | GLP-1 |
|---|---|---|
| Production Sites | K-cells in duodenum/jejunum | L-cells in ileum/colon |
| Primary Stimuli | Fat, carbohydrates | Carbohydrates, mixed meals |
| Key Functions | Stimulates insulin secretion; promotes fat storage | Stimulates insulin; suppresses glucagon; slows gastric emptying; promotes satiety |
| Fasting Levels | 10-20 pM | 5-15 pM |
| Postprandial Peak | 80-150 pM | 15-75 pM |
The Perfect Partnership: While both hormones stimulate insulin release, they complement each other beautifully. GIP acts as the immediate responder, kicking into action quickly when food first arrives. GLP-1 serves as the sustained manager, providing longer-term regulation of blood sugar and appetite 2 .
The initial therapeutic breakthrough came from an unexpected source: the venom of the Gila monster, a lizard native to the southwestern United States. Researcher John Eng discovered that this creature produced a substance called exendin-4 that resembled human GLP-1 but lasted much longer in the body 4 . This led to the development of exenatide, the first GLP-1 receptor agonist approved for diabetes treatment in 2005 8 .
Despite the success of GLP-1 drugs, researchers noticed something intriguing: combining GLP-1 with its sister hormone GIP produced even more powerful effects. This led to the development of tirzepatide, the first dual GIP/GLP-1 receptor agonist 4 .
Weight loss with tirzepatide
(about 50 pounds)Weight loss with semaglutide
(about 33 pounds)| Therapy Type | Representative Drugs | Average HbA1c Reduction | Average Weight Loss | Key Advantages |
|---|---|---|---|---|
| GLP-1 RAs | Liraglutide, Semaglutide | ~1.0-1.5% | ~2.9-6.8 kg | Lower hypoglycemia risk, cardiovascular benefits |
| Dual GIP/GLP-1 RAs | Tirzepatide | ~1.6-2.0% | ~15-20% body weight | Superior glucose control and weight loss |
| Future: Triple Agonists | Retatrutide | Under investigation | ~24% in phase 2 trials | Potential for even greater efficacy |
Comparative HbA1c reduction across incretin therapies
Why Do Two Hormones Work Better Than One? The superior efficacy of dual agonists stems from the complementary actions of GIP and GLP-1. While both stimulate insulin secretion, they work through different mechanisms and receptors. GLP-1 activates both Gαs and Gαq proteins in pancreatic β-cells, while GIP selectively activates Gαs 2 .
While most research has focused on the metabolic effects of incretin hormones, a fascinating 2025 study investigated their impact on an unexpected aspect of health: bone metabolism 1 .
This randomized, crossover study enrolled ten individuals with type 2 diabetes and compared six different experimental conditions:
The researchers measured changes in two key bone turnover markers: β-CTX-I (bone resorption) and PINP (bone formation) 1 .
Measures bone resorption (breakdown)
Measures bone formation
The findings revealed several important patterns:
This experiment demonstrates that the postprandial suppression of bone resorption is mediated by the additive effects of multiple gut hormones, not just a single agent 1 . The findings suggest that incretin-based therapies might have benefits beyond glucose control—potentially influencing bone health.
The combination of GIP + GLP-1 + GLP-2 produced bone resorption suppression comparable to oral glucose
| Intervention | Effect on β-CTX-I (Bone Resorption) | Effect on PINP (Bone Formation) |
|---|---|---|
| OGTT | Significant suppression | Significant reduction |
| IIGI + Saline | Less suppression than OGTT | Significant reduction |
| IIGI + GIP | Moderate suppression | No reduction |
| IIGI + GLP-1 | Moderate suppression | No reduction |
| IIGI + GLP-2 | Moderate suppression | Significant reduction |
| IIGI + GIP+GLP-1+GLP-2 | Suppression comparable to OGTT | No reduction |
Modern incretin research relies on sophisticated laboratory tools and methods. Here are essential components of the incretin researcher's toolkit:
Radioimmunoassays and ELISA kits for measuring hormone levels in plasma samples.
Synthetic versions of GIP, GLP-1, and GLP-2 for infusion studies.
Added to blood samples to prevent rapid degradation of incretin hormones.
Engineered cell lines expressing human receptors to study activation pathways.
OGTT and IIGI methods for studying the incretin effect in humans.
Tests for bone turnover markers and other specific biomarkers.
The applications of incretin-based therapies are expanding rapidly beyond their original focus on diabetes management.
GLP-1 receptor agonists have demonstrated significant cardiovascular benefits in large outcome trials. Drugs like liraglutide, semaglutide, and dulaglutide have been shown to reduce major adverse cardiovascular events 6 .
Cardiovascular risk reduction with GLP-1 therapy
Research is exploring potential applications in neurodegenerative diseases like Parkinson's and Alzheimer's, where GLP-1 receptor agonists have shown promise in slowing disease progression 4 .
Emerging Research Areas: Additional studies suggest benefits for conditions as diverse as obstructive sleep apnea, alcohol use disorder, and even obesity-related cancers 7 . With oral formulations in development 9 , these therapies promise to address not just single conditions but the complex interplay of metabolic, cardiovascular, and neurological health.
The journey from the initial discovery of the incretin effect to the development of dual and triple agonists represents one of the most exciting chapters in modern medicine.
What began as basic scientific curiosity about how our bodies respond to food has evolved into a therapeutic revolution that is transforming patient care. The future of incretin-based medicine looks increasingly personalized and multifaceted, promising to address not just single conditions but the complex interplay of metabolic, cardiovascular, and neurological health.
As research continues to unravel the intricate communication between our gut, pancreas, brain, and other organs, we're witnessing the emergence of a more holistic understanding of metabolic health—one that honors the body's innate wisdom while leveraging scientific innovation to restore balance when systems go awry.
The gut-hormone revolution reminds us that sometimes the most powerful solutions come not from overriding our biology, but from understanding and amplifying its natural elegance.