4-Hydroxyisoleucine
4-Hydroxyisoleucine is a natural non-protein amino acid extracted from fenugreek seeds. It glucose-dependently stimulates insulin secretion and improves insulin resistance, supporting stable blood glucose and healthy metabolism. It also helps regulate blood lipids and manage body weight. With high safety and good bioavailability, it is widely used in dietary supplements for glycemic control and metabolic support, making it a premium ingredient for natural health products.
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CAS No.: 55399-93-4
TYPE: JP GRADE & USP GRADE
BRAND: ZNCBIO
MOQ: 20 KGS
Introduction of 4-Hydroxyisoleucine
4-Hydroxyisoleucine is a natural active amino acid mainly found in fenugreek seeds. It glucose-dependently promotes insulin secretion and improves insulin sensitivity, helping stabilize blood glucose, regulate blood lipids, and support metabolic health. With high safety and mild, clear effects, it is widely used in dietary supplements and functional foods for blood glucose management, metabolic regulation and weight control, making it a highly valued ingredient in natural health products.
Basic Information of 4-Hydroxyisoleucine
| Items | Result |
|---|---|
| Chemical Name | L-Isoleucine, 4-hydroxy |
| Molecular Formula | C6H13NO3 |
| Molecular Weight | 147.17 |
| Appearance | White to off-white (Solid) |
| Storage | Store at -20°C |
| Solubility | ≥26 mg/mL in H2O |
| Purity (NMR) | ≥98.0% |
| Conclusion | The product has been tested and complies with the given specifications. |
Function of 4-Hydroxyisoleucine
4-Hydroxyisoleucine (4-HIL) is a naturally occurring non-protein amino acid, primarily isolated from the seeds of the leguminous plant fenugreek (Trigonella foenum-graecum). It is one of the key active components responsible for the hypoglycemic effects of fenugreek.
The following is a detailed description of the effects of 4-HIL, mainly based on current pharmacological research and preclinical data:
1. Core Effect: Promotion of Insulin Secretion (Insulinotropic Effect)
This is the most well-known and thoroughly studied effect of 4-HIL.
Glucose-dependent insulin secretion: 4-HIL can significantly stimulate the secretion of insulin from pancreatic β cells. The key point is that this stimulating effect is glucose-dependent. That is, it only exerts a significant promoting effect on insulin secretion when blood glucose levels are high (such as after a meal), and its promoting effect is weak or not obvious in normal or low blood glucose states. This characteristic makes it have a lower risk of hypoglycemia, unlike sulfonylurea drugs (which may cause severe hypoglycemia).
Mechanism of action:
It may act by inhibiting ATP-sensitive potassium channels on the β cell membrane.
It causes depolarization of the cell membrane, thereby opening voltage-dependent calcium channels and increasing intracellular calcium ion concentration, which triggers the release of insulin vesicles. Research shows that it can also enhance the activity of glucokinase, a key enzyme in glucose sensing.
Applicability: For early-stage type 2 diabetes patients whose pancreatic beta cells still have some function, this component can help restore and improve insulin secretion capacity.
2. Improving Insulin Sensitivity
In addition to directly stimulating insulin secretion, 4-HIL has been proven to improve insulin sensitivity in peripheral tissues such as muscle and fat tissues.
Regulating signaling pathways: Studies have shown that 4-HIL can upregulate the expression of insulin receptor substrate (IRS) and glucose transporter 4 (GLUT4), promoting the entry and utilization of glucose into cells.
Anti-inflammatory effects: Chronic inflammation is an important cause of insulin resistance. 4-HIL shows certain anti-inflammatory properties and can inhibit the release of inflammatory factors such as tumor necrosis factor-α (TNF-α). Some studies suggest that it can reduce the production of soluble TNF-α by regulating the expression of TACE/TIMP3, thereby improving insulin resistance associated with obesity.
3. Antidyslipidemic Effects
4-HIL also has the effect of improving lipid abnormalities, which is particularly important for diabetic patients who often have hyperlipidemia.
Lowering lipids: Animal experiments have shown that supplementation with 4-HIL can reduce total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL-C) levels, and may increase high-density lipoprotein (HDL-C).
Mechanism: This may be related to its inhibition of the activity of key enzymes in lipid synthesis in the liver (such as HMG-CoA reductase) and promotion of fatty acid oxidation.
4. Potential Neuroprotective and Antidepressant Effects
Although not as well-studied as its hypoglycemic effects, some studies suggest that 4-HIL has neuroprotective potential.
Antidepressant-like effects: Some animal model studies have shown that 4-HIL exhibits antidepressant-like effects, possibly related to the regulation of neurotransmitters or reduction of oxidative stress.
Antioxidant: As part of fenugreek extract, it has the ability to scavenge free radicals, helping to reduce oxidative stress damage caused by high blood sugar, which has potential significance in preventing diabetic complications such as neuropathy and nephropathy.
5. Current Clinical Application Status and Limitations
Source form: Currently, it is mainly available in the form of fenugreek extract or dietary supplements on the market, and purified 4-HIL drug preparations have not been widely used as prescription drugs worldwide (although fenugreek has been used for a long time in traditional medical systems such as in India).
Clinical research: Although in vitro experiments and animal model (rat, dog, etc.) data are very positive, demonstrating its hypoglycemic and lipid-regulating effects, large-scale human clinical trials of purified 4-HIL are relatively scarce. Most human studies are based on fenugreek seed powder or extracts containing 4-HIL, and these studies generally support its effectiveness in assisting in the control of blood sugar in type 2 diabetes.
Safety: It is generally considered safe at recommended doses. Possible side effects include mild gastrointestinal discomfort (such as bloating, diarrhea), which is usually related to the fiber and other components in fenugreek. Due to its insulin-stimulating effect, if used in combination with potent hypoglycemic drugs (such as insulin or sulfonylureas), blood sugar should be monitored to prevent hypoglycemia.
Summary 4-Hydroxyisoleucine is a highly promising natural anti-diabetic compound. Its main effects can be summarized as follows:
Intelligent blood sugar reduction: Promoting insulin secretion in a glucose-dependent manner.
Sensitization: Improving insulin resistance and helping cells better utilize glucose.
Lipid regulation: Improving lipid profiles and reducing cardiovascular risks.
Body protection: Potentially delaying diabetic complications through antioxidant and anti-inflammatory actions.
It is considered an important lead compound for the development of new, low-risk anti-diabetic drugs or functional foods, especially suitable for the auxiliary management of type 2 diabetes and prediabetes.
Application of 4-Hydroxyisoleucine
1. Auxiliary treatment and management of type 2 diabetes (T2DM)
This is the core application scenario of 4-HIL.
Early and mid-stage T2DM patients: It is suitable for patients with partial function of pancreatic β cells but with insufficient insulin secretion or insulin resistance. 4-HIL can help restore the first-phase insulin secretion and improve postprandial blood glucose control.
Combined medication regimens: Due to its unique mechanism of action (glucose-dependent), it is often studied for combination with metformin (improving sensitivity) or other non-secretagogue drugs to enhance the hypoglycemic effect while avoiding the risk of hypoglycemia caused by sulfonylureas.
Intervention for prediabetes: For people with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), using products containing 4-HIL may help delay or prevent the development of confirmed type 2 diabetes.
2. Management of metabolic syndrome and dyslipidemia
Given that 4-HIL has dual effects of lowering blood sugar and regulating lipids, it has application value in the comprehensive management of metabolic syndrome.
Mixed hyperlipidemia: It is suitable for patients with both hyperglycemia and hyperlipidemia (high triglycerides, high cholesterol). 4-HIL can help lower lipid levels and reduce the risk of cardiovascular complications.
Metabolic disorders related to obesity: For obese individuals with insulin resistance, 4-HIL may assist in weight management and metabolic health recovery through improving insulin sensitivity and anti-inflammatory effects.
3. Functional foods and dietary supplements
Due to its high safety and extraction mainly from fenugreek, 4-HIL is widely used in health products.
Blood sugar control supplements: As the main active ingredient, it is added to capsules, tablets, or powders, targeting consumers concerned about blood sugar health (especially the middle-aged and elderly).
Sports nutrition products: Although mainly used for diabetes, its potential to promote glucose uptake and muscle synthesis (similar to isoleucine but stronger) makes it a potential candidate for post-exercise recovery and muscle synthesis supplements, helping athletes utilize carbohydrates more efficiently.
Fortified foods: In theory, it can be added to specific formula foods (such as FSMP for diabetes) to provide additional metabolic support.
4. Innovative drug research and development (pharmaceutical industry)
4-HIL is a hot molecule in the pharmaceutical industry, mainly applied in the following research and development directions:
Development of new insulin secretagogues: Pharmaceutical companies are developing synthetic analogs based on the structure of 4-HIL, aiming to improve its bioavailability, stability, and efficacy, and develop it into a new oral hypoglycemic drug with independent intellectual property rights.
Targeted drug delivery systems: Research is being conducted on how to encapsulate 4-HIL in nanocarriers for targeted delivery to pancreatic β cells, further enhancing efficacy and reducing systemic side effects.
Development of compound preparations: Research is underway to develop compound drugs containing 4-HIL and other natural active ingredients (such as berberine, chromium, etc.) to achieve multi-target synergistic treatment.
5. Veterinary field
Animals can also suffer from diabetes (especially cats and dogs), and the application scenarios of 4-HIL have also extended to veterinary clinical practice.
Management of pet diabetes: As a component of pet prescription food or supplements, it helps cats and dogs with diabetes control blood sugar and reduce the frequency of insulin injections. Livestock industry: In the breeding of ruminants or poultry, explore its application as a feed additive to regulate the sugar and lipid metabolism of animals, improve the quality of meat/milk or reduce the occurrence of metabolic diseases.
6. Scientific research and laboratory studies
Mechanism research tools: In basic medical research, 4-HIL is often used as a tool molecule to study ATP-sensitive potassium channels
The specific regulatory mechanisms of calcium ion signaling pathways and glucokinase in insulin secretion.
Cell model construction: To build a high-glucose-induced pancreatic β-cell injury model for testing the protective effects of other compounds.
The Mechanism of Action of 4-hydroxyisoleucine
4-Hydroxyisoleucine works mainly through glucose-dependent insulinotropic effects:
1、It directly stimulates insulin secretion from pancreatic β‑cells, but only in the presence of glucose, lowering hypoglycemia risk.
2、Improves insulin sensitivity in muscle and adipose tissue.
3、Reduces hepatic glucose output.
4、Modulates glucose and lipid metabolism pathways, supporting metabolic health and weight management.
Contact Details
SHANGHAI ZNCBIO
Precautions for 4-Hydroxyisoleucine
For manufacturers, when applying 4-hydroxyisoleucine (4-HIL) to dietary supplements, functional foods, or drug development, they must strictly pay attention to the entire process from raw material procurement to final product compliance. Due to the significant biological activity of 4-HIL (especially its hypoglycemic effect), its production and application involve higher technical thresholds and regulatory risks.
The following are the key points that manufacturers need to pay special attention to:
1. Raw Material & Quality Control (Raw Material & QC)
This is the most crucial part, as the content of 4-HIL in natural extracts varies greatly.
Standardization:
Problem: The natural content of 4-HIL in carob seeds is greatly affected by the origin, climate, and harvest season.
Solution: Manufacturers should not only purchase “carob extract”, but also purchase raw materials with standardized 4-HIL content (for example: clearly label 20%, 40%, or 98% 4-HIL). The lower and upper limits of 4-HIL must be specified in the specification sheet (COA).
Identification and purity testing:
Steric isomers: 4-HIL has stereoisomers, and only the specific configuration (usually (2S,3R,4S)-4-hydroxyisoleucine) has biological activity. Manufacturers must ensure that the detection method (such as chiral HPLC) can distinguish active isomers from inactive/low-active isomers to avoid the inclusion of ineffective components.
Impurity control: Strict detection of heavy metals, pesticide residues, aflatoxins (common in legumes), and microbial indicators is required.
Stability testing: The stability of 4-HIL to heat, moisture, and light needs to be evaluated to determine the optimal storage conditions and shelf life.
2. Regulatory Compliance & Claims Management (Regulatory Compliance & Claims)
Different countries and regions have different regulatory classifications for 4-HIL, and manufacturers must strictly comply with local laws.
Product classification definition:
USA (FDA): Usually managed as a dietary supplement (Dietary Supplement). It can claim “supports healthy blood sugar levels”, but cannot claim “treats diabetes” or substitutes for drugs. It must comply with cGMP (21 CFR Part 111) specifications.
EU (EFSA): Attention should be paid to the approval status of novel foods. If not approved, it may not be sold in the EU market. Health claims (Health Claims) must be approved by EFSA through scientific assessment. Currently, specific monomer claims for 4-HIL may be limited, mostly based on the overall carob.
Label warnings: Given its hypoglycemic activity, it is recommended to add warning statements on the label, indicating that people with diabetes, pregnant women, and lactating women should consult a doctor before use, and indicating that it may interact with hypoglycemic drugs.
3. Manufacturing & Technology Challenges
Optimization of extraction process:
Traditional alcohol extraction or water extraction may lead to 4-HIL loss or excessive impurities. Manufacturers should adopt advanced separation and purification technologies (such as membrane separation, column chromatography) to improve purity and yield.
Attention should be paid to the issue of solvent residues, especially if organic solvents are used for purification.
Formula compatibility: 4-HIL is an amino acid derivative and may react with other components in the formula (such as certain minerals, strong oxidants). Compatibility stability studies need to be conducted.
Masking flavor treatment: Barley extract usually has a special bitter taste and a curry-like odor (from saponins and volatile oils), and the high-purity 4-HIL may also have a specific flavor. Manufacturers need to consider coating technology or adding flavor modifiers to improve the taste and enhance consumer compliance.
Dosage control:
The window between the effective dose and the safety dose needs to be determined through literature and experiments. Excessive dosage may cause gastrointestinal discomfort (diarrhea, flatulence) or the risk of hypoglycemia. During production, it is necessary to ensure the uniformity of the dosage for each unit of product (tablet/capsule).
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