Why is insulin only given by injection and not as an oral drug?

October 11, 2025 •

4 min read

Globally, an estimated 537 million adults are living with diabetes, with 150 to 200 million depending on insulin therapy [1.6.2, 1.6.4]. A common question is, 'Why is insulin only given by injection and not as an oral drug?' The answer lies in its molecular structure.

Quick Summary

Insulin, a protein hormone, cannot be taken orally because the digestive system's acids and enzymes break it down, rendering it ineffective. Injections bypass this, allowing insulin to enter the bloodstream directly and regulate blood sugar.

Key Points

Protein Nature: Insulin is a protein, and its structure is destroyed by stomach acid and digestive enzymes, rendering it useless if swallowed [1.2.1, 1.2.2].
Injection Bypasses Digestion: Subcutaneous injections deliver insulin into the fatty layer under the skin, allowing it to be absorbed directly into the bloodstream without being degraded [1.4.4].
Oral Insulin Challenges: Developing an oral insulin involves protecting it from stomach acid and enzymes and helping the large molecule get absorbed through the intestinal wall [1.3.1, 1.3.4].
Bioavailability Issue: The oral bioavailability of unprotected insulin is less than 1%, making it an ineffective delivery method [1.3.5].
Future Research: Scientists are using nanocarriers, enteric coatings, and enzyme inhibitors to create a viable insulin pill, with some candidates in clinical trials [1.3.2, 1.5.2].
Alternative Technologies: Automated Insulin Delivery (AID) systems, which connect a glucose monitor to an insulin pump, are rapidly becoming the standard of care for Type 1 diabetes [1.5.5].
Absorption Varies by Site: The speed at which injected insulin works depends on the injection site, with the abdomen being the fastest and the buttocks the slowest [1.4.3].

The Fundamental Challenge: Insulin is a Protein

Insulin is a complex protein hormone essential for regulating blood glucose levels [1.2.5]. Its specific three-dimensional structure is crucial for its function—acting like a key to unlock cells and allow glucose to enter for energy [1.2.5, 1.2.7]. When a drug is taken orally, it must survive the harsh environment of the gastrointestinal (GI) tract. For a protein like insulin, this journey is destructive. The highly acidic environment of the stomach (pH 1.5-3.5) causes the insulin protein to denature, or unfold, which is the first step in destroying its function [1.2.1, 1.3.5]. Following this, powerful digestive enzymes in the stomach and small intestine, such as pepsin, trypsin, and chymotrypsin, break down the unfolded protein into smaller, inactive amino acids, just as they would with protein from food [1.2.2, 1.3.1]. Because of this enzymatic degradation, orally administered insulin has a bioavailability of less than 1% [1.3.5].

How Injections Overcome the Barrier

The standard method of insulin administration is a subcutaneous injection, meaning it's injected into the fatty tissue just beneath the skin [1.4.4]. Common sites include the abdomen, thighs, buttocks, and the back of the upper arms [1.4.3]. This method bypasses the digestive system entirely. Once injected, the insulin forms a small depot in the fat layer, from which it is slowly and predictably absorbed into the bloodstream through tiny capillaries [1.4.1, 1.4.2]. This allows the intact insulin molecule to travel to cells throughout the body and perform its glucose-regulating function effectively [1.2.2]. The absorption rate can vary depending on the injection site; for example, insulin is absorbed most quickly from the abdomen and most slowly from the buttocks [1.4.3].

A Comparison of Delivery Methods

To better understand the limitations and advantages, a direct comparison is useful.


Feature	Subcutaneous Injection	Oral Administration (Hypothetical)
Efficacy	High; bypasses digestive system for direct absorption into the blood [1.2.2].	Very Low (<1%); insulin is a protein destroyed by stomach acid and digestive enzymes [1.3.1, 1.3.5].
Bioavailability	High and predictable.	Extremely low and variable due to enzymatic degradation [1.3.1].
Patient Experience	Can cause pain, skin irritation, and requires proper technique and site rotation [1.4.4].	Non-invasive and convenient, leading to better patient compliance [1.3.3].
Dosage	Precise and adjustable based on blood glucose monitoring.	Difficult to determine due to unpredictable degradation in the GI tract [1.3.3].
Mechanism	Insulin is absorbed from a fat depot into capillaries, entering systemic circulation [1.4.1].	Insulin would need to survive the GI tract and be absorbed through the intestinal wall [1.3.1].

The Future of Insulin Delivery: The Quest for an Oral Pill

For decades, researchers have pursued the goal of an effective oral insulin pill to improve the quality of life for millions. The primary challenges remain the same: protecting the insulin from the GI tract's harsh environment and ensuring it can be absorbed through the intestinal wall [1.3.4, 1.3.5].

Current Research and Innovative Approaches

Scientists are exploring various advanced strategies to overcome these barriers:

Enteric Coatings: These are special coatings designed to withstand stomach acid, dissolving only when they reach the less acidic environment of the small intestine [1.3.7].
Nanocarriers: Encapsulating insulin in tiny nanoparticles made from materials like chitosan or polymers can protect it from enzymes and help it cross the intestinal lining [1.3.2]. One promising technology uses "nano-carriers" that shield the insulin until it reaches the liver, with a protective coating that only breaks down when blood sugar is high [1.5.2].
Enzyme Inhibitors: Combining insulin with substances that temporarily block the action of protein-digesting enzymes like trypsin is another strategy. Oramed's ORMD-0801 formulation, which included a trypsin inhibitor, showed some promise in early trials but ultimately failed to meet its primary endpoint in a Phase III trial, highlighting the immense difficulty in achieving consistent efficacy [1.3.2, 1.3.5].
Permeation Enhancers: These are chemicals that can temporarily open the tight junctions between cells in the intestinal wall, allowing large molecules like insulin to pass through into the bloodstream [1.3.4].

While significant progress has been made, with some formulations reaching clinical trials, a commercially available, effective oral insulin pill is not yet a reality [1.3.2, 1.3.6]. A new oral insulin candidate is expected to enter human trials in 2025 [1.5.2].

Other Emerging Delivery Systems

Beyond oral pills, other non-invasive methods are also in development:

Smart Patches: These are skin patches with microneedles that can monitor glucose levels and release insulin automatically.
Automated Insulin Delivery (AID) Systems: Often called "artificial pancreas" systems, these are rapidly becoming the standard of care. They link a continuous glucose monitor (CGM) with an insulin pump, using AI algorithms to automatically adjust insulin delivery 24/7, improving glycemic control and reducing user burden [1.5.1, 1.5.5, 1.5.7].

Conclusion

The reason insulin is given by injection is a matter of biochemistry. As a protein, its delicate structure, which is essential for its function, cannot survive the destructive forces of the human digestive system. Injections provide a reliable and direct route into the bloodstream. While the daily routine of injections can be a burden, intensive research into oral insulin, smart patches, and increasingly sophisticated AID systems offers hope for a future where diabetes management is less invasive and more automated. The journey to a viable insulin pill has been long, but scientific innovation continues to bring it closer to possibility.

For more information on diabetes care and research, one authoritative resource is the American Diabetes Association: https://diabetes.org/

Frequently Asked Questions

In the stomach, the highly acidic environment (pH 1.5-3.5) causes the insulin protein to denature, which means its complex 3D structure unfolds. Then, enzymes like pepsin begin to break it down, a process that continues in the small intestine, destroying the hormone's function [1.2.1, 1.3.1].

While significant research is ongoing and some oral insulin formulations have reached late-stage clinical trials, none have yet proven consistently effective enough for widespread commercial use [1.3.2]. However, a new candidate is slated for human trials in 2025, showing continued progress [1.5.2].

Insulin is injected into the subcutaneous fat layer for slow, predictable absorption. If injected into muscle, it is absorbed too quickly, which can lead to a rapid drop in blood glucose (hypoglycemia) and may not last as long as needed [1.4.4].

Yes, other methods exist and are being developed. Automated Insulin Delivery (AID) systems, which use an insulin pump connected to a glucose monitor, are becoming a standard of care [1.5.5]. Research is also exploring transdermal patches with microneedles.

It is unlikely. Due to the challenges of absorption, the dosage for oral insulin would need to be carefully calibrated and might be much higher than an injection dose to account for the portion that still gets degraded. This is a major challenge in its development [1.3.3].

Yes, the injection site affects how quickly the insulin is absorbed. The abdomen is the fastest absorption site, followed by the arms, thighs, and buttocks (slowest). It is also important to rotate injection sites to prevent the buildup of hard lumps (lipohypertrophy), which can impair absorption [1.4.3, 1.4.4].

Generally, no, for the same reasons as insulin. Most protein and peptide drugs are broken down by digestion [1.3.3]. However, there are rare exceptions, like the oral formulation of semaglutide, which uses special technology to enable absorption, but its bioavailability is still very low [1.3.3].