Glucokinin

Glucokinin: A Comprehensive Reference

1. Identity and Nomenclature

Glucokinin is not a single, structurally defined chemical compound but rather a historical and collective term for a class of plant-derived substances that exhibit insulin-like, hypoglycemic activity. It is a historical term for plant-derived substances that lower blood sugar, representing a concept from early research into natural compounds mimicking insulin. The term does not refer to a single molecule but encompasses various plant compounds with glucose-reducing properties.

The name was coined to describe the metabolic activity of these compounds rather than their place of origin. Glucokinins are substances with insulin-type action, coming from plants with guanidine derivatives, able to decrease blood glucose levels.

Collip discovered in plants a compound that functions similarly to insulin but differentiated this compound from insulin by naming it glucokinin; glucokinin exists in diverse organisms in addition to plants. The term is sometimes used interchangeably in the older literature with "plant insulin," though modern research treats these as distinct but related concepts.

The presence of molecules called glucokinins, which are similar to animal insulin molecules, has been reported in some plant species; glucokinins act as both growth factors and regulators of glucose metabolism in plants.

In contemporary scientific usage, the term "glucokinin" is now largely obsolete in modern scientific discourse. Early claims regarding its activity were often difficult to replicate consistently.

1.1 Nomenclature Variants

• Glucokinin — the original term introduced by J.B. Collip (1923) in the Journal of Biological Chemistry
• Plant insulin — an informal synonym used by researchers and in the popular press
• Insulin-like plant proteins/peptides — the preferred modern scientific designation
• Polypeptide-P (also called P-insulin or v-insulin) — a specific, partially characterized insulin-like peptide isolated from Momordica charantia (bitter melon) seeds
• mcIRBP (Momordica charantia insulin receptor-binding protein) — a more recently identified peptide from bitter melon that binds the insulin receptor

1.2 Natural Sources

Since 1980, insulin-like molecules have been found in bacteria, protozoa and fungi, as well as in spinach leaves (Spinacia oleracea), water lentil (Lemma gibba) and maize (Zea mays).

Right after the discovery of insulin, J.B. Collip and C.H. Best reported the presence of insulin-like substances in plant materials like green tops of onions, lettuce leaves, green bean leaves, barley roots, beetroots, and others.

The most extensively studied plant source containing "glucokinin-like" compounds is bitter melon (Momordica charantia), a flowering vine widely cultivated in tropical and subtropical regions across Asia, India, East Africa, and South America.

Leguminous plants, such as beans and lentils, contain peptides with structures analogous to glucokinin, potentially mimicking its glucose-regulating effects. Research indicates certain seeds and grains, including quinoa and amaranth, also harbor glucokinin-like compounds.

Research into specific leguminous species has yielded documented findings: since the discovery of bovine insulin in plants, much effort has been devoted to the characterization of these proteins. Researchers isolated a protein with similar molecular mass and same amino acid sequence to bovine insulin from developing fruits of cowpea (Vigna unguiculata) genotype Epace 10. Insulin was measured by ELISA using an anti-human insulin antibody and was detected both in empty pods and seed coats but not in the embryo. The highest concentrations (about 0.5 ng/µg of protein) of the protein were detected in seed coats at 16 and 18 days after pollination.

A 2017 histochemical study from the National Autonomous University of Mexico examined which specific plant tissues accumulate glucokinin-compatible proteins. Immunolocalisation techniques alongside histochemistry revealed glucokinin primarily in chloroplasts and associated with calcium oxalate crystals in tested species. Species including Opuntia ficus-indica and Bauhinia variegata showed pronounced hypoglycaemic activity correlated with glucokinin accumulation.

1.3 Common Forms and Preparations

Because glucokinin is not a standalone marketable ingredient with a standardized extraction protocol, it reaches the market primarily through preparations of the plants in which it has been identified — most commonly Momordica charantia (bitter melon). The herb can be prepared in various ways. Common forms of M. charantia include injectable extracts, juice, and fried melon pieces. In the dietary supplement marketplace, standardized encapsulated dried fruit powder, freeze-dried fruit powder, aqueous extracts, and concentrated capsules are the most prevalent commercially available formats. Clinical studies have administered bitter melon at doses of 500 mg/day, 1,000 mg/day, and 2,000 mg/day in comparative trials.

Purified polypeptide-p extracted from bitter melon has also been investigated in injectable (subcutaneous) form in patients with type 1 and type 2 diabetes in research settings. This injectable form is not a consumer supplement but is used in clinical investigations.

2. History of the Term and Its Discovery

2.1 Origins: Collip and the Toronto Connection (1923)

The term "glucokinin" originated directly in the aftermath of the discovery of pancreatic insulin. Pancreatic insulin was discovered in 1921–1922 after a collective effort led by Frederick Banting at the University of Toronto. Insulin was crystallized (Abel, 1926) before it was shown to be a protein. Soon after its discovery insulin was established as the universal drug for the treatment of diabetes.

The discovery of insulin stimulated the search for orally active compounds with hypoglycaemic activity, and Collip thought that because plants contained glycogen, they must contain something like insulin. He prepared extracts from various organic materials such as yeast, onion tips, lettuce, sprouted grains of barley, and even lawn grass. These did appear to lower the blood sugar of rabbits, but only after a latent period of hours or days.

In Edmonton, Collip turned his attention to alternative sources of insulin, continuing his research with the help of Prof. Macleod and a Carnegie grant. Collip first looked to clams as a source of insulin, then to yeast, and then, finally, to plant tissue. Believing his early experiments with plant tissue were of tremendous importance, Collip reported his findings at a meeting of the Society for Experimental Biology and Medicine in March 1923, introducing his new plant hormone "glucokinin."

The name "glucokinin" was suggested by Collip as an appropriate term, suggestive of its metabolic activity rather than its place of origin. The original paper was titled "Glucokinin: a new hormone present in plant tissue. Preliminary paper," published in the Journal of Biological Chemistry, volume 56, pages 513–543, in 1923.

The discovery of glucokinin, derived from plants and appearing to have the properties of insulin, was also described by J.J. Willaman, associate professor of biochemistry at the University of Minnesota, who reported successful use of glucokinin on diabetic dogs and rabbits. Clinical tests as yet had not been made on human beings at that early stage.

Best and Scott (1923) suggested that a hormone analogous to insulin must be present wherever glucose is metabolized, and reported insulin-like materials from germinating potatoes and rice. There was no prejudice as to whether plants would not have a need for this hormone. On the contrary, one paper suggested: "In view of these results we believe that insulin may prove to be a constituent of every cell in which carbohydrate is metabolized."

Following this plant insulin extraction protocol, Best (1924) again reported its presence in plants. This time, preparations from the beetroot showed a blood sugar-lowering effect as rapid as those of animal insulin doses given subcutaneously.

A maize geneticist (Ellis and Eyster, 1923) at the University of Missouri reported in Science that they tested the action of insulin and glucokinin on maize germination. They prepared a solution (glucokinin) from onion tops by the method developed by Collip and compared its effect on maize germination with insulin, and found that the higher concentrations of glucokinin retarded growth while the less concentrated ones were beneficial.

2.2 Abandonment and Subsequent Research

Collip proposed the name "glucokinin" for the active ingredient of these extracts, and in his experiments on rabbits, there was sometimes a fall in blood sugar, but it was rather hit-and-miss and often took two or three days. His work led to a plethora of experiments on most known plants and seeds. These products were often claimed to be active, but the claims could hardly ever be replicated, even eventually by Collip himself.

Believing his early experiments with plant tissue were of tremendous importance, Collip reported his findings but went on to publish a series of articles on the effects of glucokinin, and when further research failed to produce any encouraging results, Collip abandoned the pursuit.

Efforts to improve insulin in the 1920s led to Allen's myrtillin (an anthocyanin) and Collip's glucokinin, among other candidate substances; none succeeded as viable insulin replacements. The concept of glucokinin lay dormant for decades before being revived through renewed scientific interest in plant insulin-like proteins, particularly after the 1981 identification of polypeptide-P from Momordica charantia.

3. Traditional and Ethnobotanical Use

While the formal term "glucokinin" dates only to 1923, the plants now understood to contain glucokinin-like compounds have long histories of use in traditional medical systems worldwide for purposes that correspond to glycemic management.

3.1 Ayurvedic and South Asian Traditions

Historically, glucokinin-containing plant extracts have been used across various cultures, particularly in Ayurvedic and folk medicine, to help manage blood sugar levels and support metabolic wellness. Bitter melon (Momordica charantia), identified in modern science as a primary source of glucokinin-like peptides, has a particularly prominent place in traditional South Asian medicine.

Fruits and seeds of M. charantia, popularly known as bitter melon, bitter gourd, or karela, have been used in many cultures to treat diabetes.

3.2 Mexican and Mesoamerican Traditions

Mexico is a megadiverse country with 3,600 to 4,000 species of medicinal plants, of which approximately 800 are used to treat conditions related to diabetes mellitus (DM). A 2017 peer-reviewed histochemical study published in the European Journal of Histochemistry specifically investigated the presence of glucokinin in the top fourteen most-used antidiabetic medicinal plants in Mexican traditional medicine, providing a scientific lens on this ethnobotanical heritage.

The goal of this work was to use histochemistry to detect the accumulation of protein that is immunocytochemically compatible with glucokinin in slide sections of hypoglycaemic species used as remedies for DM2. Proteins were histochemically detected, and the immunocytochemical correspondence of the proteins with glucokinin was investigated using an insulin antibody. All species studied reacted positively to proteins and glucokinin in the same structures.

3.3 Other Cultural Traditions

Developing countries such as Brazil, China, Colombia, Cuba, Ghana, and India have used bitter melon traditionally as a treatment for diabetes. The fruit is used for the treatment of diabetes and related conditions amongst the indigenous populations of Asia, South America, India, and East Africa.

Healers and herbalists would often recommend decoctions or powders of these plants as remedies to maintain healthy glucose metabolism. Traditional preparations included aqueous decoctions (boiling the plant parts in water), fresh juices, and dried powders taken orally.

4. Key Constituents and Active Compounds

The active compounds responsible for glucokinin-like activity are heterogeneous and vary by plant species. The most scientifically characterized source is Momordica charantia.

4.1 Polypeptide-P (Plant Insulin / P-Insulin)

From bitter melon (Momordica charantia), a product called polypeptide-P was isolated and showed hypoglycemic activity in the Indian desert gerbil, Indian langur monkey, and diabetic humans. Despite those in vivo insulin-mimetic effects, polypeptide-P presented certain biochemical properties that differed from those of bovine insulin, such as a molecular weight of approximately 11 kDa, the presence of the amino acid methionine, and the absence of immunoreactivity against anti-bovine insulin antibodies.

Among the components of Momordica charantia, P-insulin is called plant-based insulin. P-insulin has the ability to enhance insulin sensitivity, inhibit glucose absorption, and regenerate the pancreatic beta cells.

4.2 mcIRBP-19 (Momordica charantia Insulin Receptor-Binding Protein-19)

The fruits of Momordica charantia L. are a common tropical vegetable traditionally used to reduce blood glucose. A peptide derived from bitter gourd, Momordica charantia insulin receptor binding peptide-19 (mcIRBP-19), had been demonstrated to possess an insulin-like effect in vitro and in animal studies.

4.3 Charantin and Vicine

Hypoglycemic compounds isolated from M. charantia include insulin-like peptides, vicine, polypeptide-P, alkaloids, charantin, sterol glycosides, mcIRBP, triterpenoids, cucurbutanoid compounds, flavonoids, and phenols, all with hypoglycemic activity.

Charantin and vicine, two active components, are thought to enhance insulin secretion by activating glucokinase enzymes and influencing intracellular calcium signaling pathways within pancreatic beta cells.

Another phyto-component isolated from M. charantia seeds is vicine, a pyrimidine nucleoside that induced hypoglycemia in non-diabetic fasting rats following intraperitoneal administration.

4.4 Insulin-Like Proteins in Legumes

Research indicates that a protein molecule with the same amino acid sequence as bovine insulin is expressed in leguminous plants. In the cowpea (Vigna unguiculata), a protein with sequence homology to bovine insulin has been specifically isolated and characterized, with its presence confirmed by ELISA and N-terminal amino acid sequencing.

4.5 Structural Nature of Glucokinin

The chemical structure of glucokinin is a peptide composed of amino acids linked in a specific sequence, determining its unique three-dimensional conformation and biological activity. This allows it to interact with specific receptors in the body, modulating blood sugar levels.

It is important to note that the precise chemical identity, standardized structure, and molecular weight of "glucokinin" as a distinct single entity remain unresolved in modern biochemistry. The term continues to function as a general descriptor for the class of insulin-like plant peptides rather than naming a single well-characterized molecule.

5. Mechanisms of Action

Multiple distinct mechanisms have been proposed for the hypoglycemic activities of glucokinin-containing plant preparations. These mechanisms are inferred largely from preclinical (animal and in vitro) research.

5.1 Direct Insulin Receptor Binding

The active ingredient polypeptide-P from Momordica charantia is a protein resembling insulin; mechanisms theorized by researchers suggest that the herb is involved in an increase in insulin secretion, tissue glucose uptake, liver muscle glycogen synthesis, glucose oxidation, and decreased hepatic output.

The insulin receptor-binding mechanism has been confirmed at a molecular level in more recent research. Studies on mcIRBP-19 have demonstrated that this peptide triggers insulin receptor signaling pathways, enhancing glucose uptake both in vitro and in vivo.

5.2 Inhibition of Hepatic Glucose Output

Some plant extracts can decrease the liver's glucose output by inhibiting key enzymes like glucose-6-phosphatase and fructose-1,6-bisphosphatase. Compounds found in bitter melon, for instance, reduce gluconeogenesis, limiting glucose released into the bloodstream. This multifaceted approach helps maintain balanced blood sugar levels.

5.3 Stimulation of Insulin Secretion

These plant compounds may also stimulate the pancreas to produce more insulin. Charantin and vicine, two active components, are thought to enhance insulin secretion by activating glucokinase enzymes and influencing intracellular calcium signaling pathways within pancreatic beta cells.

5.4 Pancreatic Beta Cell Regeneration

Evidence also suggests certain plant extracts can promote the repair and regeneration of damaged pancreatic beta cells, improving natural insulin production. These compounds also enhance insulin sensitivity.

5.5 Alpha-Glucosidase Inhibition

Due to the strong reaction of glucokinin in laticifers, secretory canals, and chloroplastic parenchyma, glucokinin could be expected to be a contributor of insulin activity as well as an inhibitor of alpha-glucosidase, which would make the plant traditionally effective for the treatment of DM2.

A substance in bitter melon, trehal, suppresses α-glucosidase activities by 40%.

5.6 AMPK Activation and Lipid Metabolism

Body weight, body fat mass, and plasma lipid levels decreased when administering bitter melon extract orally in an animal model with high-fat diet-induced diabetes; SIRT1, AMPK, and PPARα factors related to glucose consumption increased, whereas factors associated with fat accumulation such as SREBP1c decreased significantly.

6. Scientific Evidence by Area of Use

6.1 Glycemic Control and Type 2 Diabetes

Overview: Bitter melon has been used in traditional medicine because of its numerous medicinal benefits, including having hypoglycemic effects. Several clinical trials have provided evidence that orally administered bitter melon extract can reduce A1C and blood sugar levels in diabetes patients.

In vitro and in vivo mechanistic studies suggest that bitter melon's anti-diabetic actions work through intra- and extra-pancreatic mechanisms.

Key clinical trials:

Thai multicenter randomized controlled trial (2011): This study was conducted to assess the efficacy and safety of three doses of bitter melon compared with metformin. This 4-week, multicenter, randomized, double-blind, active-control trial randomized patients into 4 groups to receive bitter melon 500 mg/day, 1,000 mg/day, and 2,000 mg/day, or metformin 1,000 mg/day. All patients were followed for 4 weeks. There was a significant decline in fructosamine at week 4 of the metformin group (−16.8; 95% CI, −31.2, −2.4 µmol/L) and the bitter melon 2,000 mg/day group (−10.2; 95% CI, −19.1, −1.3 µmol/L). Bitter melon 500 and 1,000 mg/day did not significantly decrease fructosamine levels.

mcIRBP-19 randomized controlled trial: A randomized, double-blind, placebo-controlled, parallel comparison study was conducted on 41 participants to evaluate the hypoglycemic efficacy of mcIRBP-19-containing bitter gourd extracts in subjects with type 2 diabetes who had taken antidiabetic medications but failed to achieve treatment goals. Participants were randomly assigned to the mcIRBP-19-BGE group (n=20) and the placebo group (n=20). Of the 40 subjects who completed the study, 29 participants were used for subgroup analysis. Groups received study products orally for 12 weeks of either placebo 300 mg of starch, or 600 mg of mcIRBP-19-BGE. The oral administration of mcIRBP-19-BGE decreased with borderline significance fasting blood glucose (P=0.057) and HbA1c (P=0.060). These results did not reach conventional statistical significance thresholds.

Korean randomized controlled trial (2020): A randomized, placebo-controlled study of Momordica charantia (MC), known as bitter melon, demonstrated that the extract has glucose-lowering effects, and that experimental animal studies have shown that bitter melon has hypoglycemic effects by stimulating glucose uptake into skeletal muscle cells or by increase in insulin secretion. However, proving the glucose-lowering effects and safety of bitter melon in humans is important. Ninety subjects were included in the final analysis for glucose-lowering efficacy of bitter melon.

Inconsistent findings in prior studies: Many animal trials have demonstrated that the extract of Momordica charantia and its ingredients are beneficial in lowering blood glucose; however, results of the Momordica charantia extract in human trials are not consistent. Two clinical trials reported results showing no effect on controlling blood glucose. One of the trials recruited patients with type 2 diabetes and administered bitter gourd extract capsules for 3 months, and the other treated type 2 diabetic patients with pills made from an entire dried bitter gourd for 1 month.

Positive findings in other human studies: A randomized, double-blind trial reported that the level of fructosamine in the blood was effectively reduced among newly diagnosed type 2 diabetes patients who were administered Momordica charantia fruit extract capsules (1,000 mg/day) for 1 month. Another study showed that oral bitter gourd extracts (1,000 mg/day) had a significant reduction in HbA1c in type 2 diabetic patients.

Overall evidence quality: A few clinical studies have reported the glucose-lowering efficacy of bitter melon in patients with type 2 diabetes mellitus; however, most of these studies were not randomized, lacked proper controls, were of short duration, used small sample sizes, and reported inconsistent findings. The overall body of human clinical evidence for glucokinin-containing preparations in diabetes management is therefore characterized as preliminary and inconsistent. Larger, well-designed trials with standardized preparations and rigorous endpoints are lacking.

6.2 Type 1 Diabetes and Subcutaneous Polypeptide-P

Fasting blood glucose levels decrease when purified polypeptide-P extracted from bitter melon is injected subcutaneously in patients with type 1 and type 2 diabetes. This evidence is from research investigations; subcutaneous administration of polypeptide-P is not a commercially available supplement intervention. Evidence in this form is limited to small, early-phase studies.

6.3 Metabolic Syndrome and Lipid Profile

Animal model data suggest glucokinin-containing plant preparations may have effects beyond glucose regulation. M. charantia (bitter melon) has beneficial effects on metabolic syndrome parameters and exerts antidiabetic, anti-hyperlipidemic, and anti-obesity activities. However, in clinical trials, there was no effect on lipid profile after 12 weeks of Momordica charantia (bitter melon) extract treatment. The current human evidence for lipid-lowering effects is therefore not established.

6.4 Prediabetes

A 12-week randomized clinical study in Korean prediabetes participants was conducted, though results remain limited and preliminary. Certain clinical trials suggested that bitter melon products may be promising phytomedicines to manage hyperglycemia in at-risk individuals, but dedicated, adequately powered prediabetes studies remain scarce.

6.5 Plant Physiology: Role in Plants Themselves

N-terminal amino acid sequencing of insulin was performed on the protein purified by C4-HPLC from cowpea. The significance of the presence of insulin in these plant tissues is not fully understood, but researchers speculate that it may be involved in the transport of carbohydrate to the fruit.

Despite the lack of direct evidence of insulin effects on carbohydrate metabolism in plants, many literature reports suggest the existence of proteins with functions, localization, and sequences of the corresponding gene or protein similar to proteins that are members of the insulin pathways characteristic of vertebrates.

7. Body Systems and Health Areas

• Endocrine system / Pancreatic function: Proposed stimulation of beta cells and insulin secretion; possible partial mimicry of insulin receptor signaling.
• Glucose metabolism / Glycemic regulation: The primary documented area of interest; multiple mechanisms involving hepatic glucose output, peripheral glucose uptake, and alpha-glucosidase inhibition.
• Cardiovascular and lipid metabolism: Animal data suggest potential anti-hyperlipidemic effects; human evidence is not yet established.
• Gastrointestinal system: Alpha-glucosidase inhibition at the intestinal level would slow postprandial glucose absorption. Bitter melon has also been used for gastric ulcer diseases.
• Immune and anti-infective function: Bitter melon has antibacterial, antiviral, anticancer, and anti-inflammatory effects, though these are not specifically attributable to glucokinin-type peptides specifically.

8. Dosage Forms and Doses Reported in Studies

No standardized dosage guidance for isolated "glucokinin" exists, as it is not commercially available as a purified, single-compound supplement. Dosage information in the literature applies to whole-plant preparations — primarily Momordica charantia extracts — in which glucokinin-like compounds are present.

• Dried bitter melon powder (oral): Three doses were evaluated in one randomized trial: 500 mg/day, 1,000 mg/day, and 2,000 mg/day. Only the 2,000 mg/day dose produced a statistically significant effect in this study.
• mcIRBP-19-containing bitter gourd extract (oral): A randomized controlled trial used 600 mg of mcIRBP-19-BGE orally for 12 weeks.
• Bitter melon fruit extract capsules (oral): 1,000 mg/day for 1 month was reported to reduce fructosamine in newly diagnosed type 2 diabetes patients in one double-blind trial.
• Polypeptide-P (subcutaneous injection): Used only in research settings; not a consumer supplement.

Four clinical trials found bitter melon juice, fruit, and dried powder to have a moderate hypoglycemic effect, but these studies were small and were not randomized or double-blind.

9. Scientific Status and Evidence Limitations

The presence of insulin in plants is not accepted by the scientific community in general. A 2003 peer-reviewed review in the Brazilian Journal of Plant Physiology titled "Plant insulin or glucokinin: a conflicting issue" summarizes the longstanding scientific debate: while multiple lines of evidence suggest that insulin-like molecules exist in plants, their functional equivalence to animal insulin remains contested, and the physiological role of these molecules in the plants themselves is poorly understood.

The practical limitations that prevented glucokinin from being developed as an insulin substitute in the 1920s remain partly relevant today:

• Oral bioavailability of peptides is inherently limited by proteolytic digestion in the gastrointestinal tract.
• Standardization of glucokinin content in plant-derived preparations is not established.
• Clinical human evidence is sparse, uses small sample sizes, and gives inconsistent outcomes across studies.
• The mechanism of action of M. charantia has not been fully elucidated.

10. Safety Considerations and Known Interactions

Reported adverse effects of bitter melon include hypoglycemic coma and convulsions in children, reduced fertility in mice, a favism-like syndrome, increases in gamma-glutamyltransferase and alkaline phosphatase levels in animals, and headaches.

Although comas and convulsions in children due to hypoglycemia and paroxysmal atrial fibrillation have been reported, no toxic side effects have been reported including death. Bitter melon is also contraindicated during pregnancy because of the high risk of miscarriage.

Regarding drug interactions, preclinical data indicate that bitter melon preparations containing glucokinin-like compounds may interact with antidiabetic medications. Bitter melon (Momordica charantia) is widely used in traditional medicine for its blood sugar-lowering effects, but the strength of those effects creates significant interaction risks with diabetes medications. These mechanisms can combine with drugs like insulin, metformin, and sulfonylureas.

One animal study found that combining bitter gourd juice with metformin twice daily might induce hypoglycemia, whereas once-daily administration was better tolerated. In one positive randomized clinical study (n=15 non-insulin-dependent diabetics), bitter melon was observed to act in synergy with two oral hypoglycemics (metformin, glibenclamide).

The favism-like syndrome associated with bitter melon use is attributable to its vicine content; vicine can provoke hemolytic reactions in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The use of Momordica charantia (bitter melon) extract was generally safe in a clinical trial context, though adverse event monitoring in existing clinical trials has been limited in scope and duration.

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