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  3. METAP®(Globin Peptide)

METAP®

Generic Name:Globin Peptide

METAP® is a peptide mixture derived from enzyme hydrolysis of globin proteins. Among these peptide, it has been found that the Valine-Valine-Tyrosine-Proline tetrapeptide has strong inhibitory activity on neutral fat elevation.
Furthermore, it has also been found to inhibit the increase blood glucose and of blood pressure.

Was it discovered by 'a pig that lost weight!?'

At the time, as a feed additive to make pigs effectively gain weight, a hydrolyzed protein was developed. Upon giving the developed feed to pigs, the pigs contrarily lost weight instead of gaining weight.
Thereafter, many studies were conducted to determine the underlying mechanism for the pigs' weight loss, which led to the creation of the present METAP®.

Suppression of blood triglyceride elevation (Clinical study)

Six test subjects with somewhat high blood neutral fat levels on an empty stomach (blood neutral fat level of 110 - 150 mg/dL) were given either a soft drink containing 1 g of globin peptide, or a placebo, along with a high-fat meal containing 40 g of fat (soup with butter or lard), then the effect on blood neutral fat levels were examined for 6 hours after eating.

Compared to healthy individuals, in the placebo group blood neutral fat levels significantly increased, and did not return to pre-intake levels even 6 hours after meals.
On the other hand, compared to the placebo group, in the globin peptide group the increase in neutral fat level was significantly inhibited at all times. Furthermore, in the globin peptide group, pre-intake levels were restored 6 hours after eating. The area under the curve (AUC) for blood concentrations of the globin peptide group, compared to the placebo group, show that the increase in neutral fat was inhibited by approximately 60 %.

Therefore, we found that globin peptides inhibit the increase in neutral fat.

Furthermore, a similar pattern is seen when remnant-like lipoproteins are measured.

Inhibition of Pancreatic Lipase Activity

When fat is ingested as part of a meal, pancreatic lipase is secreted in to the duodenum from the pancreas.
This pancreatic lipase works to break down fat into fatty acids and glycerol.

Globin peptide inhibits pancreatic lipase activity, and inhibits the absorption of ingested fat.

The concentration used in trials is based on the intragastric concentration when a human ingests 1 g of globin peptide.

Increase of Lipoprotein lipase activity (In Human)

Following meals, blood neutral fat is primarily present in the form of chylomicron, which is a lipoprotein.
Lipoprotein lipase (LPL) works to break down neutral fat into free fatty acids and glycerol.

Ten healthy test subjects were given a high fat meal containing 40 g of fat (soup with butter or lard), with a soft drink containing 1 g of globin peptide or a placebo, and the effect on blood LPL activity was examined.
As a result, blood LPL activity was significantly higher in the globin peptide group compared to in the placebo group.

Promotion of Lipid Metabolism (in vitro)

PPAR α is a nuclear receptor that, when activated, promote fatty acid β oxidation, and has been found to promote fatty acid combustion.

Upon adding each concentration of globin peptides to AML-12 hepatic cells, and examining the amount of PPAR α expression after culturing by real time PCR, the amount of PPAR α increased.

Therefore, it is thought that by increasing the amount of PPAR α expression, globin peptides promote fat combustion.

Promotion of Lipid Metabolism (in vivo)

To examine the combustibility of consumed fat to be used as energy, during meals fat is labelled with 14C radioactivity, and the amount of 14C- CO2 respiratory excretion was measured.

Upon giving mice olive oil labelled with 14C radioactivity and globin peptides, it was found that compared to the control group, the amount of 14C CO2 respiratory excretion was significantly increased for 4 hours after administration, and as energy, the fat tended to be easily burnt.

Therefore, it is thought that globin peptides promote fatty acid β oxidation, and promotes fat-burning.

Increase of adipogenesis (in vitro)

It has been found that when 3T3-L1 fat cells differentiate from precursor cells to mature cells, activity of the enzyme glycerol 3-phosphate dehydrogenase (GPDH) suddenly increases, and thus GPDH activity has been found to be a marker of fat cell differentiation.

Then, to examine whether globin peptide affected cell differentiation and fat accumulation, GPDH activity was measured using 3T3-L1 fat cells during differentiating from precursor cells to mature cells.

Therefore, it is thought that globin peptides inhibit the accumulation of fat.

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Suppression of Blood Glucose Elevation

To examine the effect of globin peptides on blood glucose levels, we performed a glucose tolerance test using normal ICR mice.

Upon oral administration of glucose and 1 g or 2 g of globin peptide to mice, at both concentrations the increase in blood glucose levels was significantly inhibited at 30 minutes after glucose loading.

Promotion of glucose uptake (in vivo)

When blood sugar is not incorporated into cells normally, it leads to hyperglycemia, however the sugar transporter GLUT4 plays a key role in maintaining blood glucose levels by way of insulin stimulation. In the absence of insulin stimulation, GLUT 4 accumulates in the cell vesicle, however in the presence of insulin stimulation in the receptors of the cell membrane, GLUT4 is translocated to the cell membrane, and glucose in the blood is transported into the cell.

Therefore, we simultaneously administered 2 g of globin peptide and glucose orally to KKAy mice, which is the type 2 diabetes model, and examined the translocation of Glut 4 to the cell membrane in muscles. As a result, compared to the control group, the globin peptide group exhibited increased translocation of GLUT 4 to the cell membrane.

Thus it is thought that globin peptides promote sugar uptake by GLUT 4, and promotes the use of sugar.

Improvement of Insulin resistance (in vitro)

TNF-α works to inhibit insulin signaling, and not only inhibits the expression of GLUT4, which incorporates blood glucose into cells, but also its functioning.
In this way, TNF-α causes insulin resistance, and thus it is important to inhibit the production of TNF-α.

Thus, we examined TNF-α production during LPS stimulation of RAW 264 macrophages.
As a result, when globin peptide was added, TNF-α production was significantly inhibited.

Globin peptide inhibits TNF-α production, and is thus thought to improve insulin resistance.

Suppression of blood glucose (in human)

At China's Center for Disease Control and Prevention (CDC), to examine the effect of globin peptides on patients with type 2 diabetes, 50 test subjects were given either tablets containing 1 g of globin peptide, or a placebo twice a day for 30 days, and the effect on blood glucose levels was examined.

As a result, compared to pre-intake values and the placebo group, the globin peptide group exhibited significantly lower blood glucose levels at fasting. Furthermore, with regards to blood glucose levels at 2 hours after eating, the increase in blood glucose levels was significantly inhibited in the globin peptide group compared to the pre-intake values, and the placebo group.
Moreover, in this human experiment, there were no side effects caused by globin peptide observed.

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The effect on blood pressure in single-dose administration (animal experiment)

To examine the effect of globin peptide on blood pressure, we conducted an experiment in which spontaneously hypertensive rats (SHR) were orally administered 0.5 g or 1 g/ kg of globin peptide. As a result, 2 and 6 hours after globin peptide administration, a significant decrease in systolic blood pressure was observed. This blood pressure-lowering effect tended to be somewhat reduced at 8 hours after administration.

Furthermore, in a different trial examine, the effect on blood pressure was examined when normal SD rats were orally administered 1 g/kg of globin peptide, however there was no effect on normal blood pressure observed.

Therefore, globin peptide has no effect on the normal blood pressure, and it was found that blood pressure was lowered when in a hypertensive state.

The effect on blood pressure in repeated administration (animal experiment)

Spontaneously hypertensive rats (SHR) have accelerated sympathetic nerve function, in conjunction with resistance vessel abnormality, and thus in animals with spontaneous onset of hypertension, as in the control group, blood pressure increases as age in weeks increases.

Upon giving these rats feed containing 0.5 % globin peptide for 12 weeks, blood pressure elevation was inhibited.

Suppression of ACE activity

Angiotensin-converting enzyme (ACE) is an enzyme that converts angiotensin I into II, and angiotensin II is a substance associated with blood pressure elevation. By binding to such receptors, angiotensin II promotes 'aldosterone secretion', 'vascular contraction', and 'water and sodium reabsorption'.
Furthermore, aldosterone is a hormone that increases blood pressure, and increases resistance of peripheral blood vessels by way of vascular contraction. Moreover, by promoting water and sodium reabsorption, the volume of blood in the entire body is increased, which leads to increased cardiac output.

Thus, upon examining the effect of globin peptides on ACE activity, globin peptides were found to block ACE activity.

in this way, by inhibiting ACE activity, it is thought that globin peptides inhibit blood pressure elevation.

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Safety

  • Acute toxicity in mice

Mice were given a single oral dose of globin peptide at 10g / kg of body weight and observed for 7 days, however there were no abnormal findings observed.

  • Subacute toxicity in rats

Rats were orally administered globin peptide at a dose of 4 g/ kg/day for 28 consecutive days and observed, however there were no abnormal findings.

  • Mutagenicity

The following 3 types of mutagenicity tests were performed, however there were no abnormalities caused by globin peptide observed.
1) reverse mutation test using bacteria
2) chromosome aberration test using cultivated cells
3) micronucleus test using mice

  • Allergy

Subject blood was examined using the Ouchterlony method, however there were no antibodies to globin peptides observed.

Furthermore, from the globin peptide powder there were no allergens detected that were derived from specific raw ingredients (egg, wheat, milk, buck wheat, peanut, prawn, and crab). (using simple kit to detect food allergens)

Origin

Erythrocyte hemoglobin is primarily imported from Europe, and erythrocytes derived from pigs that are confirmed to be healthy are used.

Property

Description White to light yellow powder
Solubility Water solubility
Stability Stability in acid solution, thermostability
Application METAP® is possible to apply to various foods.

Specifications

Quantity 10kg in PE bag wrapped in craft bag
Ingredient name Globin peptide
Expiration date 5 years
Storage Room temperature in a dry-state

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Research paper

  • Hypotensive effect of magnesium hydroxide and globin digest in mild hypertensive subjects ―A double-blind, placebo-controlled, parallel group study―

    (Jpn Pharmacol Ther, 44 (1), 101-111, 2016)

  • Effect of the combination of magnesium hydroxide with globin digest on the blood pressure and life span in stroke-prone spontaneously hypertensive rats

    (Jpn Pharmacol Ther, 43 (6), 807-814, 2015)

  • Effect of globin digest on the blood pressure in spontaneously hypertensive rats

    (Jpn Pharmacol Ther, 43 (6), 799-806, 2015)

  • Effects of globin digest and its active ingredient Trp-Thr-Gln-Arg on galactosamine/lipopolysaccharide-induced liver injury in ICR mice

    Life Sci, 90 (5-6), 190-199, 2012

  • Hepatoprotective effects of globin digest and its active ingredient Trp-Thr-Gln-Arg on galactosamine-induced liver injury in SD rats

    (Jpn Pharmacol Ther, 39 (8), 741-749, 2011)

  • Safety evaluation of 12 weeks ingestion of globin digest-containing "napple®GD" in children

    (Jpn Pharmacol Ther, 39 (7), 657-664, 2011)

  • Effect of globin digest on the liver injury and hepatic gene expression profile in galactosamine-induced liver injury in SD rats

    Life Sci, 88 (15-16), 701-712, 2011

  • Hepatoprotective effect of globin digest on liver injury ―Galactosamine-induced liver injury in SD rats―

    (Jpn Pharmacol Ther, 38 (6), 513-519, 2010)

  • Hepatoprotective effect of globin digest on liver injury ―Alcohol-induced acute liver injury in ICR mice―

    (Jpn Pharmacol Ther, 38 (6), 507-512, 2010)

  • Anti-diabetic effects of globin digest and its active ingredient Leu-Ser-Glu-Leu in ICR mice, streptozotocin-induced diabetic mice and KK-Ay mice

    Life Sci, 86 (11-12), 424-434, 2010

  • II. Effect of globin digest on blood glucose and serum insulin ―Type 2 diabetes―

    (Jpn Pharmacol Ther, 36 (11), 1045-1050, 2008)

  • I. Effect of globin digest on blood glucose and serum insulin ―Type 1 diabetes―

    (Jpn Pharmacol Ther, 36 (11), 1039-1044, 2008)

  • Globin digest suppresses postprandial elevation of remnant−like particles by activation of lipoprotein lipase and hepatic triglyceride lipase

    (Jpn Pharmacol Ther, 36 (6), 531-540, 2008)

  • In vivo mouse micronucleus assay for globin digest

    (Jpn Pharmacol Ther, 34 (11), 1185-1187, 2006)

  • In vitro chromosomal aberration assay for globin digest

    (Jpn Pharmacol Ther, 34 (11), 1179-1183, 2006)

  • Bacterial reverse mutation assay for globin digest

    (Jpn Pharmacol Ther, 34 (11), 1173-1178, 2006)

  • Repeated dose toxicity studies of globin digest in rats

    (Jpn Pharmacol Ther, 34 (11), 1165-1172, 2006)

  • Single dose toxicity studies of globin digest in mice

    (Jpn Pharmacol Ther, 34 (11), 1163-1164, 2006)

  • Physiological functions of globin digest and its application

    (Food processing and ingredients, 35 (8), 51-53, 2000)

  • Hypotriglyceridemic effect of globin digest on subjects with borderline hyperlipidemia

    (Jpn Soc Nutr Food Sci, 52 (2), 71-77, 1999)

  • Suppressive effect of globin digest on postprandial hyperlipidemia in male volunteers

    J Nutr, 128 (1), 56-60, 1998

  • Globin digest, acidic protease hydrolysate, inhibits dietary hypertriglyceridemia and Val-Val-Tyr-Pro, one of its constituents, possesses most superior effect

    Life Sci, 58 (20), 1745-1755, 1996

  • Functional peptides with fat absorption inhibitory action, and lipid metabolism promoting action.

    Technical J Food Chemistry & Chemicals, 6 (2), 80-84, 1990

Research presentation

  • The effect of he combined uptake of magnesium hydroxide and globin protein resolvent on SHRSP/Izm blood pressure and survival.

    50th Annual Meeting of the Society for Hypertension Related Disease Model Research, 53, 2014

  • Globin peptide and the improvement of metabolic syndrome

    Summary of 3rd Symposium on Pharmaceutical Food Science, 192-194, 2009

  • Globin Digest (Food for specified health uses "active ingredients" research presentation (2) abstract)

    J Nutr Food, 2 (2), 77-79, 1999

  • Globin digest inhibits dietary hyperlipidemia in man

    1st International Peptide Symposium, Satellite Symposium, 1997

  • Hypolipidemic effect of oligopeptides 7) Effect on human body fat

    Summary of 49th Annual Meeting of Japan Society of Nutrition and Food Science, 157, 1995

  • Hypolipidemic effect of oligopeptides 6) Effect on body fat

    Folia Pharmacol Jpn, 105 (2), 70P, 1995

  • Hypolipidemic effect of oligopeptides 5) Clinical study and study using labeled fat

    Summary of 33rd Annual Meeting of Japan Society of Nutrition and Food Science, Meeting of Kinki Branch, 26, 1994

  • Effect of oligopeptides on adipocyte and identification of active ingredients

    Record of 14th Annual Meeting of Japan Society for the Study of Obesity, 145-147, 1994

  • Effect of oligopeptides on lipid metabolism 4) in vivo and in vitro effect on adipocyte differentiation

    Japan J Pharmacol, 61 (Supple.Ⅰ), 79P, 1993

  • Effect of oligopeptides on lipid metabolism 3) Effect of oligopeptides form various protein digestants on lipid abnormalities in serum and liver

    Japan J Pharmacol, 58 (Supple.Ⅰ), 80P, 1992

  • Hypolipidemic effect of oligopeptides 2) Effect on dietary obesity

    Folia Pharmacol Jpn, 98, 52P, 1991

  • Hypolipidemic effect of oligopeptides 1) Effect of a single dose

    Folia Pharmacol Jpn, 97, 38P, 1991

Textbooks

  • Globin Peptide

    Materials for Functional Food III, Supervisor Meiichi Ota, pp.309-311, CMC Publishing, Tokyo, 2005

  • napple drink

    Iwanami Shinsho "Health Food Note", Author Shiro Segawa, pp.106-110, Iwanami Shoten, Tokyo, 2002

  • Fat metabolism-regulating peptides

    Material Handbook for New Food Development, Editors Satoshi Yoshizumi, et. al., pp.395-398, Korin, Tokyo, 1991

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