Article

Oral Administration of Collagen Hydrolysates Improves Glucose Tolerance in Normal Mice Through GLP-1-Dependent and GLP-1-Independent Mechanisms

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Abstract

The aim of this study was to evaluate the antidiabetic properties of collagen hydrolysates (CHs). CHs exhibited dipeptidyl peptidase-IV inhibitory activity and stimulated glucagon-like-peptide-1 (GLP-1) secretion in vitro. We also determined whether CHs improve glucose tolerance in normal mice. Oral administration of CHs suppressed the glycemic response during the oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT), but the effects were weaker in IPGTT than in OGTT. CHs had no effect on the gastric emptying rate. A pretreatment with the GLP-1 receptor antagonist, exendin 9-39 (Ex9), partially reversed the glucose-lowering effects of CHs, but only when coadministered with glucose. CHs administered 45 min before the glucose load potentiated the glucose-stimulated insulin secretion. This potentiating effect on insulin secretion was not reversed by the pretreatment with Ex9, it appeared to be enhanced. These results suggest that CHs improve glucose tolerance by inhibiting intestinal glucose uptake and enhancing insulin secretion, and also demonstrated that GLP-1 was partially involved in the inhibition of glucose uptake, but not essential for the enhancement of insulin secretion.

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... In addition to the physical effect, it was reported that when proteins are ingested, the transport of proteins from the stomach to the small intestine is inhibited to allow for adequate protein digestion in the stomach [21]. In other words, it has been reported that collagen peptides upregulate GLP-1 secretion, which delays gastric emptying [22,23]. Therefore, it is possible that the SCPs may also delay gastric emptying indirectly via GLP-1 secretion. ...
... Therefore, it was suggested that the SCPs stimulate the secretion of GLP-1 from L-cells, followed by the GLP-1 stimulating the secretion of insulin, resulting in a decrease in blood glucose level. Iba et al. reported that CP increases the level of active GLP-1 [22]. We also found that SCPs increased blood insulin levels, and that SCPs showed DPP-IV inhibitory activity in vitro. ...
... The SCPs did not lower the blood glucose levels in rats without insulin secretory capacity (Figure 8). It was also reported that the hydrolysates prepared from the skin collagens of Atlantic salmon and porcine prevent the degradation of GLP-1 by DPP-IV, thereby maintaining high blood levels of GLP-1, which in turn promote insulin secretion and improve postprandial hyperglycemia [22,35,36]. ...
Article
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In a previous study, we found that the collagen peptides prepared from the by-products of Bester sturgeon had an inhibitory effect on elevated blood glucose levels in a glucose tolerance test with ICR mice. In the present study, we examine the mechanism of the effect of sturgeon collagen peptides (SCPs) in detail. When glucose was orally administered to mice along with the SCPs, it was found that the glucose remained in the stomach for a longer time. In the above tests, the amount of glucose excreted in the feces of mice also increased. On the contrary, it was revealed that the SCPs have a dipeptidyl-peptidase-IV (DPP-IV) inhibitory ability in an in vitro test. In subsequent oral and intravenous glucose administration tests, glucagon-like peptide-1 (GLP-1) and insulin levels in the blood of mice were maintained at high levels. These results suggested the following three mechanisms: SCPs slow the rate of transportation of glucose from the stomach into the small intestine, resulting in delayed glucose absorption; SCPs suppress the absorption of glucose in the small intestine and excrete it from the body; SCPs inhibit DPP-IV in the blood and maintain a high GLP-1 level in blood, which in turn stimulates insulin secretion.
... In vivo ↑ Glycemic control, when given orally or i.p. ↑ plasma insulin at 3 g kg −1 [34] Unicorn leatherjacket a) ...
... An increase in plasma insulin was also shown by Iba et al. [34] ; however, this involved a very high dose (3 g kg −1 bodyweight) which may be difficult to achieve when translating this to human studies. Despite these promising in vivo results, none of the human studies with fish hydrolysates have shown an increase in plasma insulin, while one study showed a decrease in plasma insulin. ...
... [31][32][33]39,40,85,86] The in vivo efficacy of FPH has also been reasonably well established. Acutely, all studies investigating an anti-hyperglycemic effect of FPH has found a reduction in blood glucose with doses as low as 50 mg kg −1 bodyweight, [33] and several exhibiting an increase in plasma insulin [33,34] or GLP-1 [34] ; however, Iba et al. [34] used extremely high doses of 1.5 g kg −1 and 3 g kg −1 bodyweight which would be impossible to translate to a human trial. Other studies have shown the anti-hyperglycemic effect to be even more pronounced in a chronic setting, with the lowest dose used being 100 mg kg −1 bodyweight. ...
Article
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Prevalence of type 2 diabetes and overweight/obesity are increasing globally. Food supplementation as a preventative option has become an attractive option in comparison to increased pharmacotherapy dependency. Hydrolysates of fish processing waste and by-products have become particularly interesting in a climate of increased food wastage awareness and are rapidly gaining traction in food research. This review summarises the available research thus far on the potential effect of these hydrolysates on diabetes and appetite suppression. Scopus and Web of Science were searched using 8 keywords (fish, hydrolysate, peptides, satiating, insulinotropic, incretin, anti-obesity, DPP-4 (dipeptidylpeptidase-4/IV) returning a total of 2,549 results. Following exclusion criteria (repeated appearances, non-fish marine sources (e.g., macroalgae), and irrelevant bioactivities (e.g., immunomodulatory, anti-thrombotic)), 44 relevant publications were included in this review. Stimulation of hormone secretion, regulation of glucose uptake, anorexigenic potential, identified mechanisms of action, and research conducted on the most potent bioactive peptides identified within these hydrolysates are all specifically addressed. Results of this review conclude that despite wide methodological variation between studies, there is significant potential for the application of fish protein hydrolysates in the management of bodyweight and hyperglycaemia. This article is protected by copyright. All rights reserved.
... Further, CH could alter lipid metabolism-related gene expression and the unfolded protein response in mouse liver [32]. The hypoglycemic effects of CH have also been reported [33,34]. It has been reported that CHcan improve glucose tolerance by inhibiting intestinal glucose uptake and enhancing insulin secretion [34], suggesting the anti diabetic property of CH. ...
... The hypoglycemic effects of CH have also been reported [33,34]. It has been reported that CHcan improve glucose tolerance by inhibiting intestinal glucose uptake and enhancing insulin secretion [34], suggesting the anti diabetic property of CH. ...
... Additionally, Cudennec et al. (2015) have demonstrated that a protein hydrolysate from cuttlefish (Sepia officinalis) exhibited DPP-IV inhibitory activity and GLP-1 releasing actions on secretin tumour cell line (STC-1) cells in vitro. Others have demonstrated that a collagen hydrolysate exhibited DPP-IV inhibitory activity and stimulated glucagonlike-peptide-1 (GLP-1) secretion in vitro (Iba et al., 2016). Furthermore, they showed that a collagen hydrolysate also improved glucose tolerance in response to oral glucose in normal mice, which was thought to be mediated partially through enhanced GLP-1 secretion as well as inhibition of intestinal glucose uptake (Iba et al., 2016;Neves et al., 2017). ...
... Others have demonstrated that a collagen hydrolysate exhibited DPP-IV inhibitory activity and stimulated glucagonlike-peptide-1 (GLP-1) secretion in vitro (Iba et al., 2016). Furthermore, they showed that a collagen hydrolysate also improved glucose tolerance in response to oral glucose in normal mice, which was thought to be mediated partially through enhanced GLP-1 secretion as well as inhibition of intestinal glucose uptake (Iba et al., 2016;Neves et al., 2017). The wide range of bioactivities contained within the marine environment has sparked much interest in terms of functional food ingredients and the potential for metabolic disease prevention and management (Zhu et al., 2010;Lordan et al., 2011;Drotningsvik et al., 2016). ...
Article
The anti‐diabetic actions of a boarfish protein hydrolysate (BPH) were investigated in cultured cells and mice. A boarfish (Capros aper) muscle protein hydrolysate was generated using the enzymes Alcalase 2.4 L and Flavourzyme 500 L. Furthermore, the BPH was subjected to simulated gastrointestinal digestion (SGID). BPH and SGID samples (0.01–2.5 mg mL−1) were tested in vitro for DPP‐IV inhibition and insulin and GLP‐1 secretory activity from BRIN‐BD11 and GLUTag cells, respectively. The BPH and SGID samples, caused a dose‐dependent increase (4.2 to 5.3‐fold, P < 0.001) in insulin secretion from BRIN‐BD11 cells and inhibited DPP‐IV activity (IC50 1.18 ± 0.04 and 1.21 ± 0.04 mg mL−1), respectively. The SGID sample produced a 1.3‐fold (P < 0.01) increase in GLP‐1 secretion. An oral glucose tolerance test (OGTT) was conducted in healthy mice (n = 8), with or without BPH (50 mg/kg bodyweight). BPH mediated an increase in plasma insulin levels (AUC(0–120 min), P < 0.05) and a consequent reduction in blood glucose concentration (P < 0.01), after OGTT in mice versus controls. The BPH showed potent anti‐diabetic actions in cells and improved glucose tolerance in mice. Boarfish (Capros aper) protein hydrolysate (BPH) generated by Alcalase + Flavourzme digestion, caused a dosedependent increase in in vitro insulin secretion from pancreatic β‐cells, accompanied by a rise in intracellular calcium, enhanced glucose uptake in adipocytes and improvements in cellular GLP‐1 secretion and DPP‐IV inhibition. Acute studies in mice also showed that BPH was insulinotropic in mice and lowered blood glucose. Overall, BPH showed potent antidiabetic actions in cells and improved glucose tolerance in mice.
... CPs also inhibit dipeptidyl peptidase-IV and stimulate glucagonlike-peptide-1 (GLP-1) secretion. Administration of CPs enhances glucose tolerance through both GLP-1dependent and independent mechanisms in mice (17). In humans, nutritional supplementation with CPs reduces fasting blood glucose and HbA1c levels and improves insulin sensitivity in type-2 diabetic patients (18). ...
... It has been suggested that CPs suppress lipid absorption and reduce plasma lipid levels in rats (19). CPs is also known to improve glucose tolerance by inhibiting intestinal glucose uptake and enhancing insulin secretion (17). We measured fasting blood glucose and plasma lipid concentrations in mice, but further studies on postprandial blood glucose and plasma lipid levels are needed to yield clues for determining the action of CPs. ...
Article
Collagen peptides (CPs) are bioactive molecules that have beneficial effects on bone metabolism and against joint disorders. In the present study, we investigated the effect of CP supplementation on visceral fat mass and plasma lipid concentrations in high-fat diet (HFD)-induced obese mice. Male ddY mice were fed a normal diet or HFD for 3 wk, and assigned to N or NCP groups and to F or FCP groups, respectively. The NCP and FCP group mice were administered experimental diets containing 25 mg/g CPs for 3 wk further. During the experimental period, CP supplementation affected neither the food consumption nor the body weight of the mice. No significant differences in the plasma triglyceride, non-esterified fatty acid, and cholesterol concentrations were observed among all the groups. In contrast, the weight of testicular fat mass was significantly decreased in the FCP group as compared with that in the F group. The expression levels of leptin and tumor necrosis factor (TNF)-α genes in the adipose tissue correlated with the visceral fat mass, although these differences were not significant. These findings indicate that CPs may have a reducing effect on visceral fat content but are less effective in reducing body weight.
... This suggests it may be possible to manage cognitive function by managing diabetes. Intriguingly, collagen hydrolysates (CH) have recently be shown to provide benefits for patients with type 2 diabetes mellitus (T2DM), including the promotion of glucagon-like peptide 1 (GLP-1) secretion and the inhibition of dipeptidyl peptidase IV activity [10,11]. Furthermore, functional studies in humans have demonstrated that, following the oral ingestion of CH, its three bioactive peptides, prolyl-hydroxyproline (Pro-Hyp), hydroxyprolyl-glycine (Hyp-Gly), and glutamyl-hydroxyprolyl-glycine (Glu-Hyp-Gly), were quickly absorbed into the plasma, where they remained for a long period until being excreted into the urine [12][13][14][15][16]. ...
... Importantly, given that T2DM is a risk factor for cognitive decline and dementia, a GLP-1 analog has been reported to exhibit neuroprotective properties and to be a promising therapeutic agent for Alzheimer's disease [36]. It has been reported that CH promotes GLP-1 secretion and inhibits dipeptidyl peptidase 4 activity in vitro [10]. ...
Article
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This study investigated the effects of collagen hydrolysates (CH) on language cognitive function and brain structure. In this open-label study, 5 g CH was administered once a day for 4 weeks to 30 healthy participants aged 49–63 years. The primary outcome measures were the brain healthcare quotients based on gray matter volume (GM-BHQ) and fractional anisotropy (FA-BHQ). The secondary outcome measures were changes in scores between week 0 and week 4 for word list memory (WLM) and standard verbal paired associate learning (S-PA) tests as well as changes in the physical, mental, and role/social component summary scores of the Short Form-36(SF-36) quality of life instrument. CH ingestion resulted in significant improvements in FA-BHQ (p = 0.0095), a measure of brain structure, as well in scores for the WLM (p = 0.0046) and S-PA (p = 0.0007) tests, which measure cognitive function. There were moderate correlations between the change in WLM score and the change in GM-BHQ (r = 0.4448; Spearman’s rank correlation) and between the change in S-PA score and the change in FA-BHQ (r = 0.4645). Daily ingestion of CH changed brain structure and improved language cognitive function.
... Over recent years, various beneficial effects have been reported on the consumption of collagen hydrolysates that includes improvements in joint pains, 2 wound healing, 3,4 blood pressure, 5 and glucose tolerance, 6 as well as the moisture, elasticity, and wrinkles of facial skin 7 and epidermal barrier function. 8 Although the mechanism of most of these effects remains unknown, several studies have observed a transient increase in collagen-derived peptides, especially of Pro-Hyp, 9−11 in the blood 12−14 and skin 15 after ingestion of collagen hydrolysate. ...
Article
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Collagen hydrolysate is a well-known dietary supplement for the treatment of skin aging, however its mode of action remains unknown. Previous studies have shown that the oral ingestion of collagen hydrolysate leads to elevated levels of collagen-derived peptides in the blood but whether these peptides reach the skin remains unclear. Here, we analyzed the plasma concentration of collagen-derived peptides after ingestion of high tri-peptide containing collagen hydrolysate in humans. We identified 17 types of collagen-derived peptides transiently, with a particularly enrichment in Gly-Pro-Hyp. This was also observed using an in vivo mouse model in the plasma and skin, albeit with a higher enrichment of Pro-Hyp in the skin. Interestingly, this Pro-Hyp enrichment in the skin was derived from Gly-Pro-Hyp hydrolysis, as the administration of pure Gly-Pro-Hyp peptide led to similar results. Therefore, we propose that functional peptides can be transferred to the skin by dietary supplements of collagen.
... By using FBS that is free from LMW hydroxyprolyl peptides, the present study clearly confirms that Pro-Hyp and Hyp-Gly play crucial roles in proliferation of fibroblasts attached on collagen gel. It has been demonstrated that hydroxyprolyl peptides exert many functions, such as anti-hypertention [20], anti-inflammation [21], and improvement of glucose tolerance [22], in addition to improving skin and joint conditions. Therefore, researchers who use cell culture systems to evaluate biological activities should be aware of the presence of bioactive hydroxyprolyl peptides in FBS. ...
Article
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Prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine (Hyp-Gly) appear in human blood after ingestion of collagen hydrolysate and trigger growth of fibroblasts attached on collagen gel, which has been associated with beneficial effects upon ingestion of collagen hydrolysate, such as improvement of skin and joint conditions. In the present study, inconsistent results were obtained by using different lots of fetal bovine serum (FBS). Fibroblasts proliferated in collagen gel without adding Pro-Hyp and Hyp-Gly and did not respond to addition of Pro-Hyp and Hyp-Gly, which raises doubts about conclusions from prior research. Unexpectedly high levels of hydroxyprolyl peptides, including Pro-Hyp, however, were present in the FBS (approximately 100 µM), and also in other commercially available forms of FBS (70–80 µM). After removal of low molecular weight (LMW, < 6000 Da) compounds from the FBS by size exclusion chromatography, Pro-Hyp and Hyp-Gly again triggered growth of fibroblasts attached on collagen and increased the number of fibroblasts migrated from mouse skin. These results indicate the presence of bioactive hydroxyprolyl peptides in commercially available FBS, which can mask effects of Pro-Hyp and Hyp-Gly supplementation; our work confirms that Pro-Hyp and Hyp-Gly do play crucial roles in proliferation of fibroblasts.
... Together, the increasing knowledge about the signaling characteristics of collagen peptides [30,31,37], as well as the aforementioned encouraging findings in animal studies, make the results of the current investigations comprehensible, although considerably more data are needed from human studies. ...
Article
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Introduction: Investigations in rodents as well as in vitro experiments have suggested an anabolic influence of specific collagen peptides (SCP) on bone formation and bone mineral density (BMD). The goal of the study was to investigate the effect of 12-month daily oral administration of 5 g SCP vs. placebo (CG: control group) on BMD in postmenopausal women with primary, age-related reduction in BMD. Methods: 131 women were enrolled in this randomized, placebo-controlled double-blinded investigation. The primary endpoint was the change in BMD of the femoral neck and the spine after 12 months. In addition, plasma levels of bone markers - amino-terminal propeptide of type I collagen (P1NP) and C-telopeptide of type I collagen (CTX 1) - were analysed. Results: a total of 102 women completed the study, but all subjects were included in the intention-to-treat (ITT) analysis (age 64.3 ± 7.2 years; Body Mass Index, BMI 23.6 ± 3.6 kg/m2; T-score spine -2.4 ± 0.6; T-score femoral neck -1.4 ± 0.5). In the SCP group (n = 66), BMD of the spine and of the femoral neck increased significantly compared to the control group (n = 65) (T-score spine: SCP +0.1 ± 0.26; CG -0.03 ± 0.18; ANCOVA p = 0.030; T-score femoral neck: SCP +0.09 ± 0.24; CG -0.01 ± 0.19; ANCOVA p = 0.003). P1NP increased significantly in the SCP group (p = 0.007), whereas CTX 1 increased significantly in the control group (p = 0.011). Conclusions: These data demonstrate that the intake of SCP increased BMD in postmenopausal women with primary, age-related reduction of BMD. In addition, SCP supplementation was associated with a favorable shift in bone markers, indicating increased bone formation and reduced bone degradation.
... Peptides with proline as the penultimate N-terminal residue have shown to possess DPP IV inhibitory activity in Streptozotocin induced diabetic rats [19]. Recent study by Iba et al. [20] showed that collagen peptides similar to those used in this study have DPP IV inhibitory activity and the stimulation of GLP-1 secretion in vitro, and evaluated the anti-diabetic properties of collagen peptides in animal models. The authors observed that coadministration of collagen peptides (3g/Kg) with glucose (4g/Kg) significantly increased active GLP-1 levels in the plasma after 15 min while the administration of collagen peptides 45 minutes before glucose, potentiated the glucose stimulated secretion of insulin. ...
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Link: https://www.somatopublications.com/journal_clinical_nutrition_food_science/article_in_press.php ● https://www.somatopublications.com/double-blind-randomized-clinical-study-to-evaluate-efficacy-of-collagen-peptide-as-add-on-nutritional-supplement-in-type-2-diabetes.pdf
... Peptides with proline as the penultimate N-terminal residue have shown to possess DPP IV inhibitory activity in Streptozotocin induced diabetic rats [19]. Recent study by Iba et al. [20] showed that collagen peptides similar to those used in this study have DPP IV inhibitory activity and the stimulation of GLP-1 secretion in vitro, and evaluated the anti-diabetic properties of collagen peptides in animal models. The authors observed that coadministration of collagen peptides (3g/Kg) with glucose (4g/Kg) significantly increased active GLP-1 levels in the plasma after 15 min while the administration of collagen peptides 45 minutes before glucose, potentiated the glucose stimulated secretion of insulin. ...
Article
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Dipeptidyl peptidase IV (DPP IV) inhibitors are currently used to manage Type 2 diabetes mellitus. Peptides derived from collagen has been stated to have DPP IV inhibitory properties. A double blind randomized trial has been conducted to evaluate the effectiveness of collagen peptides (CPT) as nutritional supplement in subjects with type 2 diabetes. Resistant dextrin, a non-digestible dietary polymer, has been used as active comparator in this study. The subjects have been advised to consume 10g per day either CPT or resistant dextrin for 90 days. There is significant reduction in fasting blood glucose (FBG) and HbA1C in three months study period in subjects who have taken oral ingestion of CPT. Insulin sensitivity measured in as HOMA IR has been improved significantly
... When gelatin is degraded, for example, by using specific enzymes, the resultant mixture of various small peptides is termed collagen hydrolysate. There is increasing scientific evidence that demonstrates the efficacy of collagen hydrolysate to benefit skin parameters related to cutaneous physiology and aging, such as transepidermal water loss (TEWL), elasticity, and wrinkles [9], as well as to improve glucose tolerance [10], wound healing [11,12], and joint pains [13]. It has been shown that collagen peptides exert stimulatory effects on type 1 collagen and other extracellular matrix molecules in human fibroblasts [14]. ...
Article
Collagen hydrolysate is a well-known nutritional supplement for the improvement of healthy skin. Here, collagen peptide NS (CPNS) from fish scale was prepared, and its physicochemical properties were investigated. Gly-Pro was revealed as a representative low molecular weight peptide of CPNS, by performing prep-HPLC and LC-MS/MS. CPNS treatment attenuated matrix metalloproteinase-1 production and increased the synthesis of type 1 procollagen in HDF cells. After orally administering CPNS to rats, the plasma concentrations of Gly-Pro and Pro-Hyp increased dramatically. To examine the protective effects of CPNS against ultraviolet B (UVB)-induced photoaging in vivo, the dorsal skins of hairless mice were exposed to UVB and supplemented with CPNS for 12 weeks. The CPNS consumption significantly attenuated UVB-induced wrinkle formation, transepidermal water loss, and epidermis thickness, and increased skin hydration. Collectively, these results suggest that bioactive peptides of CPNS, Gly-Pro and Pro-Hyp, exert beneficial effects on skin health.
... Currently, the effects of hydrolysate collagen in managing type 2 diabetes and its complications have been studied both in animal models and directly in diabetic patients related to reduced levels of blood glucose, cholesterol, and fatty acids, inflammation, increased insulin sensitivity, insulin secretion and glucose tolerance [4,9]. However, there has been no report of its effect in inhibiting the activity of the α-glucosidase enzyme. ...
Article
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Controlling of postprandial hyperglycemia using α-glucosidase inhibitors is one of the therapeutic approaches for the treatment of type 2 diabetes. Collagen hydrolysate, as an α-glucosidase inhibitor has not been reported. Therefore, This study intends to evaluate the activity and kinetics of inhibition of collagen hydrolysate against the α-glucosidase enzyme. Collagen hydrolysate was prepared from Thunnus albacares bone enzymatically using bacterial collagenase at hydrolysis times (0; 0.5; 1; 2; 3; 4; 5 and 6 h). The type of inhibition was determined by enzyme kinetics analysis. Collagen hydrolysate obtained at hydrolysis time of 1 h has the highest inhibitory activity of 24.47 %. Based on enzyme kinetics analysis, collagen hydrolysate showed a show a type of competitive inhibition. These results revealed that collagen hydrolysate has the potential as a natural antidiabetic in controlling blood glucose levels in type 2 diabetes.
... Due to the decrease of collagen synthesis in the body, its demand for the skin, hair, and bone tissues increases with aging (Iwai et al. 2005). Over recent years, various beneficial effects have been reported on the consumption of hydrolyzed collagen that includes improvements of joint pains (Clark et al. 2008), wound healing (Zhang et al. 2011), inhibition of intestinal glucose uptake (Iba et al. 2016), improvement of moisture and elasticity, and reduction of wrinkles of facial skin (Inoue et al. 2016) as well as suppression of UV-B-induced skin damage and photoaging (Tanaka et al. 2009). ...
Chapter
The current fish processing practically generates large amounts of byproducts, accounting for up to 75% of the total fish weight. Fish processing byproducts contain a wide range of nutritional components, especially lipid and protein fractions as well as functional compounds or nutraceuticals. Collagen, gelatin, as well as hydrolyzed collagen can be produced from collagenous materials such as bone, scale, or skin, etc. In addition to fish proteins and oil, other valuable components, including enzymes, nucleic acids, minerals, and other bioactive compounds such as chondroitin sulfate, etc. can be recovered from those leftovers. To ensure better utilization of fish processing byproducts for applications in food, nutraceutical, cosmetic, or medical products, it is necessary to use high quality byproducts; increase the yield of recovered products; develop the standardized and controlled processes accounting for variation in raw material, providing stable, healthy, and high‐quality products; and measure and enhance the selected properties, especially bioactivities.
... Fish collagen peptide, derived from the skin, bones and scales is used as a functional food or dietary supplement as they are digested and absorbed by the body quickly. Oral Administration of Collagen Hydrolysates Improves Glucose Tolerance in Normal Mice through GLP-1-Dependent and GLP-1-Independent Mechanisms [7]. The polypeptide chains of collagen molecules are composed of numerous repeats of a tripeptide unit, Gly-X-Y, where X and Y are generally proline and hydroxyproline. ...
Article
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Dipeptidyl peptidase-4 (DPP-4) inhibitors constitute an innovative class of oral agents for the treatment of Type 2 Diabetes Mellitus (T2DM). DPP-4 inhibitors increase glucagon-like peptide-1 (GLP-1) availability and correct the "incretin defect" seen in T2DM patients. Peptides derived from collagen have been reported to have DPP-4 inhibitory properties. A double blind randomized trial has been conducted to evaluate the effectiveness of Collagen peptides (CPT) as nutritional supplement in subjects with T2DM. Resistant dextrin (RD), a non-digestible dietary polymer, has been used as active comparator in this study. The clinical study was conducted over a total duration of 12 weeks of treatment period. The study was conducted on 66 enrolled subjects randomized in a 2:2:1:1 ratio as a four arm clinical study design. The subjects consumed either CPT (2.5/5 g) or resistant dextrin (2.5/5 g) for 90 days. The results showed that the consumption of 5 g CPT resulted in significant reduction in fasting blood glucose (FBG) and Glycosylated Haemoglobin (HbA1c) in three months study period in subjects. Insulin sensitivity measured in as HOMA IR has also been improved significantly in the group. Thus this study demonstrates the potential role of CPT as add on nutritional supplement for the management of T2DM.
... Fish collagen peptide, derived from the skin, bones and scales is used as a functional food or dietary supplement as they are digested and absorbed by the body quickly. Oral Administration of Collagen Hydrolysates Improves Glucose Tolerance in Normal Mice through GLP-1-Dependent and GLP-1-Independent Mechanisms [7]. The polypeptide chains of collagen molecules are composed of numerous repeats of a tripeptide unit, Gly-X-Y, where X and Y are generally proline and hydroxyproline. ...
... Fish collagen peptide, derived from the skin, bones and scales is used as a functional food or dietary supplement as they are digested and absorbed by the body quickly. Oral Administration of Collagen Hydrolysates Improves Glucose Tolerance in Normal Mice through GLP-1-Dependent and GLP-1-Independent Mechanisms [7]. The polypeptide chains of collagen molecules are composed of numerous repeats of a tripeptide unit, Gly-X-Y, where X and Y are generally proline and hydroxyproline. ...
... Peptides from food have been reported to have antihypertensive, antidiabetes, and antiobesity potential (Manikkam, Vasiljevic, Donkor, & Mathai, 2016;Mojica et al., 2017). Food peptide products fed orally include various staple food protein-derived hydrolysates (Girgih, Nwachukwu, Onuh, Malomo, & Aluko, 2016;Iba et al., 2016), commercial oligopeptides (Miralles et al., 2018), and medical oral peptides used in the treatment of diseases (Fosgerau & Hoffmann, 2015;Zhang, 2011). ...
Chapter
Animal studies can increase the accuracy in revealing the molecular mechanisms of bioactive peptides from food sources regarding specific disease prevention. However, so far, methods of animal models for assessing active food peptides are not well classified. For instance, the most effective route of administration, the dosage selection of active peptides in animal experiments, and the age and sex of the animals depending on the biological activity pursued. The establishment of an adequate animal model affects the experimental results and the presentation of the molecular mechanisms of the active peptides. Also, the processing of extensive data and multiple methods of data analysis, bioethics, and safety are of paramount importance. This chapter presents detailed methodologies on animal models for the evaluation of bioactivity of food peptides, especially for the prevention of hypertension and metabolic dysfunction. Several publications were obtained from the Web of Science, Elsevier databases, the website of the US Department of Agriculture, among others. The objectives of this chapter were to focus on the description of methods to administer peptides from food sources in animal models. In addition the classification of assays and the optimal selection for animal models which are essential to evaluate hypertension and its related cardiovascular diseases and metabolic dysfunction were investigated. Finally, to introduce the multivariate data analysis methods targeted at extensive data. The animal model approach needs to be tailored to the specific bioactivity of the food peptides. This chapter describes the rat and mice models used in the prevention of hypertension and metabolic dysfunction.
... Several studies have reported that collagen hydrolysates from different sources provide strong antioxidant activity, such as collagen peptides obtained from skipjack tuna (Katsuwonus pelamis) bone (Ding et al. 2019), snakehead (Channa striatus) fish skin (Haniffa et al. 2014), Allaska Pollack fish skin (Byun & Kim 2001), and cod fish skin (Carvalho et al. 2018). Besides antioxidants, collagen hydrolysates also provide antidiabetic effects in which the collagen hydrolysates from bone or fish skin were found to inhibit the DPP-IV enzyme and stimulate the secretion of GLP-1 when given to male rats orally and intraperitoneally (Iba et al. 2016). However, research into the ability of collagen hydrolysate from lamuru fishbone to inhibit free radicals and the α-glucosidase enzyme has not been found; therefore, it is necessary to undertake research into this type of collagen hydrolysate as an antioxidant and inhibitor of the α-glucosidase enzyme. ...
Article
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The Lamuru fish (Caranx ignobilis) is mostly found in tropical waters of the indo-pacific region, namely Indonesia. It is believed to contain collagen and this study aims to isolate collagen from its bone and determine the collagen’s antioxidant and α-glucosidase inhibitory activity. In our study, the collagen was extracted using acetic acid which was hydrolyzed by collagenase enzyme from Clostridium histolyticum at a temperature of 37 °C, and pH 7.0. During hydrolysis, the degree of hydrolysis (DH) was calculated and collagen hydrolysates were characterized by SDS -PAGE, UV-Visible spectroscopy and FT-IR spectroscopy. After characterization, the collagen hydrolisate of lamuru ( CHL) fish was analyzed for its antioxidant properties and α-glucosidase inhibitory activity. The result shows that a higher percentage degree of hydrolysis was obtained, 31.17%, at 120 min of hydrolysis. The CHL characterization by SDS -PAGE showed its molecular weight ranging from 35,000-180,000 Daltons and identified the collagen as type I. The UV-Vis analysis of CHL provided a maximum absorbance at a wavelength of 233 nm. At the same time, the FT-IR analysis showed the presence of amides I, II, and III, which confirms the formation of the collagen triple helix. For its bioactivity assay, the CHL shows that CHL provided DPPH radical reduction activity reaching 51.45±1.24% (IC50 at 485.9 µg/mL). The ferric reduction antioxidant power of CHL (FRAP value) showed a significant reduction of Fe3+ to Fe2+ with a value of 711.27 µM/g. The CHL inhibition activity of α-glucosidase enzyme IC50 was determined to be 574 µg/mL. Based on the antioxidant bioactivity and α-glucosidase inhibition, the collagen peptide enables its use as a therapeutic development for a variety of disorders caused by oxidative stress, such as diabetes mellitus.
... Furthermore, FGH could improve glucose tolerance via two mechanisms: the suppression of intestinal glucose uptake and the improvement of insulin secretion. The GLP-1 may play a role in the inhibition of glucose uptake (Iba et al., 2016). Another enzyme involved in diabetes disease is α-glucosidase which can be inhibited by several inhibitors. ...
Article
The global interests in food with functional properties and fewer artificial preservatives have enlightened manufacturers to use new emerging natural bioactive compounds in food industries due to their technological and functional applications. On the other hand, by-products of the fish processing industry with over 50 percent of its biomass, are good sources of gelatin hydrolysates with techno-functional properties. This review focuses on highlighting the productions of fish gelatin hydrolysates (FGH) with different pretreatment techniques and their technical applications that have in the food industry including packaging, coating, and use of ingredients as well as their functional applications such as antihypertensive, antidiabetic, anticancer, and immunomodulatory activities. However, in vivo and in silico methods have not been carried out as much as in vitro assays. We also recommend elucidating the mechanism of action of the bio/multi-functionality of peptides obtained from different origins (based on the fish habitat as cold/warm-water fishes).
... Hence, the incretin regulation is the prime focus for T2D treatment and prevention. Inhibition of DPP-IV is considered as the step of defense to avoid GLP-1 cleavage, thereby protecting incretins (Iba et al., 2016). Several synthetic antidiabetic drugs including alogliptin, sitagliptin, saxagliptin, and vildagliptin have been approved by the United States and Europe, although gliptin treatment appears to be of low risk and side effects such as nasopharyngitis, cystitis, and headache have been reported (Ketnawa et al., 2019). ...
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Fish processing industries result in an ample number of protein‐rich byproducts, which have been used to produce protein hydrolysate (PH) for human consumption. Chemical, microbial, and enzymatic hydrolysis processes have been implemented for the production of fish PH (FPH) from diverse types of fish processing byproducts. FPH has been reported to possess bioactive active peptides known to exhibit various biological activities such as antioxidant, antimicrobial, angiotensin‐I converting enzyme inhibition, calcium‐binding ability, dipeptidyl peptidase‐IV inhibition, immunomodulation, and antiproliferative activity, which are discussed comprehensively in this review. Appropriate conditions for the hydrolysis process (e.g., type and concentration of enzymes, time, and temperature) play an important role in achieving the desired level of hydrolysis, thus affecting the functional and bioactive properties and stability of FPH. This review provides an in‐depth and comprehensive discussion on the sources, process parameters, purification as well as functional and bioactive properties of FPHs. The most recent research findings on the impact of production parameters, bitterness of peptide, storage, and food processing conditions on functional properties and stability of FPH were also reported. More importantly, the recent studies on biological activities of FPH and in vivo health benefits were discussed with the possible mechanism of action. Furthermore, FPH‐polyphenol conjugate, encapsulation, and digestive stability of FPH were discussed in terms of their potential to be utilized as a nutraceutical ingredient. Last but not the least, various industrial applications of FPH and the fate of FPH in terms of limitations, hurdles, future research directions, and challenges have been addressed.
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Fish skin collagen hydrolyzate has demonstrated the potent inhibition of dipeptidyl peptidase-IV (DPP-IV), one of the treatments for type-2 diabetes mellitus (type-2 DM), but the precise mechanism is still unclear. This study used in silico method to evaluate the potential of the active peptides from tilapia skin collagen (Oreochromis niloticus) for DPP-IV inhibitor. The methodology includes collagen hydrolysis using BIOPEP, which is the database of bioactive peptides; active peptide selection; toxicity, allergenicity, sensory analysis of active peptides; and binding of active peptides to DPP-IV compared with linagliptin. The result indicated that in silico enzymatic hydrolysis of collagen produced active peptides with better prediction of biological activity than intact collagen. There are 13 active peptides were predicted as non-toxic and non-allergenic, some of which have a bitter, salty, and undetectable taste. Docking simulations showed all active peptides interacted with DPP-IV through hydrogen bonds, van der Waals forcehydrophobic interaction, electrostatic force, π-sulfur, and unfavorable interaction, where WF (Trp-Phe), VW (Val-Trp), WY (Trp-Tyr), and WG (Trp-Gly) displayed higher binding affinities of 0.8; 0.5; 0.4; and 0.3 kcal/mol compared with linagliptin. In this study, we successfully demonstrated antidiabetic type-2 DM potential of the active peptides from tilapia skin collagen. The obtained data provided preliminary data for further research in the utilization of fish skin waste as a functional compound to treat the type-2 DM patients. Alternatively, this treatment can be synergistically combined with the available antidiabetic drugs to improve the insulin secretion of the type-2 DM patients.
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Osteoarthritis (OA) were scarcely researched among diabetes mellitus patients. This study aims to confirm the prevent and treat effects of the undenatured type II collagen (UC II) on OA in...
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The aim of this study was to investigate the DPP-IV inhibition and metabolic stability of a casein-derived peptide Val-Pro-Tyr-Pro-Gln (VPYPQ) and its fragments as well as their release from casein following hydrolysis. Results showed that VPYPQ was the most potent DPP-IV inhibitory peptide among them with an IC50 value of 41.45 μM. This might be due to its two internal Pro residues at positions 2 and 4. Moreover, VPYPQ was resistant to hydrolysis by gastrointestinal enzymes and was relatively more stable to hydrolysis by DPP-IV and peptidases in plasma compared with its fragments. Additionally, oral administration of VPYPQ at a dose of 90 μmol/kg body weight could reduce the postprandial blood glucose levels in mice. More importantly, VPYPQ could be released efficiently from casein following hydrolysis by a combination of papain and in vitro digestion, reaching up to 3211.15 μg/g. Therefore, VPYPQ was a promising casein-derived DPP-IV inhibitor.
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Milk and fish are two important nutrient rich foods that have shown to possess positive effects in the management of type 2 diabetes mellitus (T2DM). Recent evidence from several interventional studies in humans have demonstrated the beneficial effects of bioactive proteins, peptides, and fatty acids derived from fish and milk sources in the prevention and management of T2DM. The anti-diabetic compounds present in the fish are proteins, peptides, and ω-3 polyunsaturated fatty acids (PUFA), while milk bioactive compounds are casein, casein derived peptides, whey proteins, and whey protein derived peptides. Fish and milk derived bioactive proteins, peptides and fatty acids exhibited anti-diabetic effects through several mechanisms. This review mainly focuses on the recent studies related to the anti-diabetic activities of fish and milk derived bioactive compounds (proteins, peptides, fatty acids) in humans, animals and in vitro, and mechanisms of action of these bioactive compounds in the management of T2DM.
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We prepared collagen peptides (SCP) from sturgeon by‐products: the skin, fin, and bone. The materials were pretreated and hydrolyzed by papain. Finally, we obtained 85.1 g of dried SCP powder from 864 g (wet weight) of the materials. In oral glucose tolerance test (OGTT) with ICR mice, blood glucose levels of SCP group were significantly lower than those of control group. Then, we fractionated SCP by Sephadex column chromatography and all fractions showed hypoglycemic effect. Further, we separated each peptide in the fractions by reversed‐phase HPLC. Most of the peptides in these peaks consisted of Gly‐X‐Y (X and Y are optional amino acid residues) repetitive sequences which are common to the triple helical region of the collagen molecules. Moreover, many peptides contained Pro and Ala residues, which promises to serve as a DPP‐IV inhibitor. Altogether, these results suggest the hypoglycemic effect of SCP may be caused by these structural properties. Practical applications While sturgeon is famous and highly valuable for its salted egg “caviar” and meat, other parts such as skin, fin, and bone, that is, by‐products are not fully utilized in seafood industry. In this study, we focused on whole utilization of a sturgeon and prepared collagen peptides (SCP) from sturgeon by‐products. The yield of SCP was approximately 100 g SCP/kg wet by‐products. In animal experiments, SCP showed hypoglycemic effect. Moreover, the effect is probably caused by Gly‐X‐Y repetitive sequences derived from the triple helical region of a collagen molecule. The mechanism might be related to DPP‐IV inhibitory activity. SCP was white, odorless, and easily soluble in water and it could be advantages in using SCP as an ingredient for functional foods preventing Type 2 diabetes mellitus. The by‐products of sturgeon will be a new fishery resource which could be used as a material for collagen peptides providing the hypoglycemic effect.
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Background Maintaining body weight homeostasis is a huge challenge for many people in developed as well as developing societies, where overweight and obesity are fast increasing. New strategies are needed to combat this trend. Scope and approach In this review we examine the effectiveness of the various approaches to modulating food intake. We analyze several pharmacological treatments that act on the brain and gut, focusing specifically on those that act on the gastrointestinal tract in order to change enteroendocrine hormones. Key findings and conclusions An initial review of the pharmacological approaches to limiting food intake in humans shows that acting on specific targets of the central nervous system (CNS) is not very effective. Instead, surgical approaches that limit the functionality of gastrointestinal fragments, which concomitantly changes the profile of secretion of several enterohormones, are the most effective. Since effectiveness seems to be mediated by multiple targeting, we review the bioactivity of various food-related compounds for different functions of the gastrointestinal tract. Treatments that limit ghrelin production within a threshold and activate anorexigenic enterohormones seem to be the most effective. We therefore suggest that an integrative approach based on the modulation of multiple targets with foods could help to limit food intake.
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The definition of metabolic syndrome (MetS) fairly varies from one to another guideline and health organization. Per description of world health organization, occurrence of hyperinsulinemia or hyperglycemia in addition to two or more factors of dyslipidemia, hypoalphalipoproteinemia, hypertension and or large waist circumference factors would be defined as MetS. Conventional therapies and drugs, commonly with adverse effects, are used to treat these conditions and diseases. Nonetheless, in the recent decades scientific community has focused on the discovery of natural compounds to diminish the side effects of these medications. Among many available bioactives, biologically active peptides have notable beneficial effects on the management of diabetes, obesity, hypercholesterolemia, and hypertension. Marine inclusive of fish peptides have exerted significant bioactivities in different experimental in-vitro, in-vivo and clinical settings. This review exclusively focuses on studies from the recent decade investigating hypoglycemic, hypolipidemic, hypercholesterolemic and anti-obesogenic fish and fish peptides. Related extraction, isolation, and purification methodologies of anti-MetS fish biopeptides are reviewed herein for comparison purposes only. Moreover, performance of biopeptides in simulated gastrointestinal environment and structure-activity relationship along with absorption, distribution, metabolism, and excretion properties of selected oligopeptides have been discussed, in brief, to broaden the knowledge of readers on the design and discovery trends of anti-MetS compounds.
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Type 2 diabetes (T2D), one of the major common human health problems, is growing at an alarming rate around the globe. Alpha-glucosidase and dipeptidyl peptidase IV (DPP-IV) enzymes play a significant role in development of T2D. Hence, reduction or inhibition of their activity can be one of the important strategies in management of T2D. Studies in the field of bioactive peptides have shown that dietary proteins could be natural source of alpha-glucosidase and DPP-IV inhibitory peptides. The purpose of this review is to provide an overview of food protein-derived peptides as potential inhibitors of alpha-glucosidase and DPP-IV with major focus on milk proteins. Efforts have been made to review the available information in literature on the relationship between food protein-derived peptides and T2D. This review summarizes the current data on alpha-glucosidase and dipeptidyl peptidase IV inhibitory bioactive peptides derived from proteins and examines the potential value of these peptides in the treatment and prevention of T2D. In addition, the proposed modes of inhibition of peptide inhibitors are also discussed. Studies revealed that milk and other food proteins-derived bioactive peptides play a vital role in controlling T2D through several mechanisms, such as the satiety response, regulation of incretin hormones, insulinemia levels, and reducing the activity of carbohydrate degrading digestive enzymes. The bioactive peptides could be used in prevention and management of T2D through functional foods or nutraceutical supplements. Further clinical trials are necessary to validate the findings of in vitro studies and to confirm the efficiency of these peptides for applications.
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In our previous study, Atlantic salmon skin gelatin hydrolysed with flavourzyme possessed 42.5% DPP-IV inhibitory activity at the concentration of 5 mg/mL. The oral administration of hydrolysate (FSGH) at single dose of 300 mg/d in streptozotocin (STZ)-induced diabetic rats for 5 weeks was evaluated for its antidiabetic effect. During the 5-week experiment, body weight was increased, food and water intake were reduced by FSGH in diabetic rats. The daily administration of FSGH for 5 weeks was effective to lower the blood glucose levels of diabetic rats during oral glucose tolerance test (OGTT). After 5-week treatment, plasma dipeptidyl peptidase (DPP)-IV activity was inhibited; plasma active glucagon-like peptide-1 (GLP-1), insulin and insulin-to-glucagon ratio were increased by FSGH in diabetic rats. The results indicate that FSGH has the function of inhibiting GLP-1 degradation by DPP-IV, resulting in the enhancement of insulin secretion and improvement of glycemic control in STZ-induced diabetic rats.
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BACKGROUND: Recent studies show that enzymatically hydrolyzed collagen, the collagen peptide is absorbed and distributed to joint tissues and has analgesic and anti-inflammatory properties. A double blind placebo controlled randomized trial with collagen peptides isolated from pork (PCP) and bovine bone (BCP) sources was carried out to study the effectiveness of orally supplemented collagen peptide to control the progression of osteoarthritis in patients diagnosed with knee osteoarthritis. Improvement in treatment was assessed with reduction in Western Ontario McMaster Universities (WOMAC), visual analogue scale (VAS) and Quality of Life (QOL) scores from baseline to 13 weeks (Visit 7). Safety and tolerability were also evaluated. RESULTS: There was significant reduction from base line to Visit 7 in the primary end points of WOMAC and VAS scores and in the secondary end point of QOL score in subjects with PCP and BCP groups, while in subjects with placebo group the end point indices remained unaltered. Furthermore, all the score levels of WOMAC, VAS and QOL decreased significantly (p < 0.01) in study group compared to placebo group in Visit 7. CONCLUSION: The study demonstrated that the collagen peptides are potential therapeutic agents as nutritional supplements for the management of osteoarthritis and maintain joint health.
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Clinical trials have demonstrated that it is possible to prevent diabetes through lifestyle modification, pharmacological intervention, and surgery. This review aims to summarize the effectiveness of these various therapeutic interventions in reducing the risk of progression of prediabetes to diabetes, and address the challenges to implement a diabetes prevention program at a community level. Strategies focusing on intensive lifestyle changes are not only efficient but cost-effective and/or cost-saving. Indeed, lifestyle intervention in people at high risk for type 2 diabetes mellitus (T2DM) has been successful in achieving sustained behavioral changes and a reduction in diabetes incidence even after the counseling is stopped. Although prediabetes is associated with health and economic burdens, it has not been adequately addressed by interventions or regulatory agencies in terms of prevention or disease management. Lifestyle intervention strategies to prevent T2DM should be distinct for different populations around the globe and should emphasize sex, age, ethnicity, and cultural and geographical considerations to be feasible and to promote better compliance. The translation of diabetes prevention research at a population level, especially finding the most effective methods of preventing T2DM in various societies and cultural settings remains challenging, but must be accomplished to stop this worldwide epidemic.
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Postprandial plasma glucose concentrations are an important contributor to glycemic control. There is evidence suggesting that postprandial hyperglycemia may be an independent risk factor for cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that predominantly reduce postprandial plasma glucose levels. DPP-4 inhibitors are associated with fewer gastrointestinal side effects than GLP-1 receptor agonists and are administered orally, unlike GLP-1 analogs, which are administered as subcutaneous injections. GLP-1 receptor agonists are somewhat more effective than DPP-4 inhibitors in reducing postprandial plasma glucose and are usually associated with significant weight loss. For these reasons, GLP-1 receptor agonists are generally preferred over DPP-4 inhibitors as part of combination treatment regimens in patients with glycated hemoglobin levels above 8.0%. This article reviews the pathogenesis of postprandial hyperglycemia, the mechanisms by which GLP-1 receptor agonists and DPP-4 inhibitors reduce postprandial plasma glucose concentrations, and the results of recent clinical trials (ie, published 2008 to October 2012) that evaluated the effects of these agents on postprandial plasma glucose levels when evaluated as monotherapy compared with placebo or as add-on therapy to metformin, a sulfonylurea, or insulin. Findings from recent clinical studies suggest that both GLP-1 receptor agonists and DPP-4 inhibitors could become valuable treatment options for optimizing glycemic control in patients unable to achieve glycated hemoglobin goals on basal insulin, with the added benefits of weight loss and a low risk of hypoglycemia.
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This article reviews the recent trends, developments, and future applications of bio-based polymers produced from renewable resources. Bio-based polymers are attracting increased attention due to environmental concerns and the realization that global petroleum resources are finite. Bio-based polymers not only replace existing polymers in a number of applications but also provide new combinations of properties for new applications. A range of bio-based polymers are presented in this review, focusing on general methods of production, properties, and commercial applications. The review examines the technological and future challenges discussed in bringing these materials to a wide range of applications, together with potential solutions, as well as discusses the major industry players who are bringing these materials to the market. Electronic supplementary material The online version of this article (doi:10.1186/2194-0517-2-8) contains supplementary material, which is available to authorized users.
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Ingested protein is a well-recognised stimulus for glucagon-like peptide-1 (GLP-1) release from intestinal L cells. This study aimed to characterise the molecular mechanisms employed by L cells to detect oligopeptides. GLP-1 secretion from murine primary colonic cultures and Ca(2+) dynamics in L cells were monitored in response to peptones and dipeptides. L cells were identified and purified based on their cell-specific expression of the fluorescent protein Venus, using GLU-Venus transgenic mice. Pharmacological tools and knockout mice were used to characterise candidate sensory pathways identified by expression analysis. GLP-1 secretion was triggered by peptones and di-/tripeptides, including the non-metabolisable glycine-sarcosine (Gly-Sar). Two sensory mechanisms involving peptide transporter-1 (PEPT1) and the calcium-sensing receptor (CaSR) were distinguishable. Responses to Gly-Sar (10 mmol/l) were abolished in the absence of extracellular Ca(2+) or by the L-type calcium-channel blocker nifedipine (10 μmol/l) and were PEPT1-dependent, as demonstrated by their sensitivity to pH and 4-aminomethylbenzoic acid and the finding of impaired responses in tissue from Pept1 (also known as Slc15a1) knockout mice. Peptone (5 mg/ml)-stimulated Ca(2+) responses were insensitive to nifedipine but were blocked by antagonists of CaSR. Peptone-stimulated GLP-1 secretion was not impaired in mice lacking the putative peptide-responsive receptor lysophosphatidic acid receptor 5 (LPAR5; also known as GPR92/93). Oligopeptides stimulate GLP-1 secretion through PEPT1-dependent electrogenic uptake and activation of CaSR. Both pathways are highly expressed in native L cells, and likely contribute to the ability of ingested protein to elevate plasma GLP-1 levels. Targeting nutrient-sensing pathways in L cells could be used to mobilise endogenous GLP-1 stores in humans, and could mimic some of the metabolic benefits of bariatric surgery.
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The prevalence of type 2 diabetes mellitus (T2DM) is increasing in the UK and worldwide. Before the onset of T2DM, there are two conditions characterised by blood glucose levels that are above normal but below the threshold for diabetes. If screening for T2DM in introduced, many people with impaired glucose tolerance (IGT) will be found and it is necessary to consider how they should be treated. The number would depend on what screening test was used and what cut-offs were chosen. To review the clinical effectiveness and cost-effectiveness of non-pharmacological interventions, including diet and physical activity, for the prevention of T2DM in people with intermediate hyperglycaemia. Electronic databases, MEDLINE (1996-2011), EMBASE (1980-2011) and all sections of The Cochrane Library, were searched for systematic reviews, randomised controlled trials (RCTs) and other relevant literature on the effectiveness of diet and/or physical activity in preventing, or delaying, progression to T2DM.The databases were also searched for studies on the cost-effectiveness of interventions. The review of clinical effectiveness was based mainly on RCTs, which were critically appraised. Subjects were people with intermediate hyperglycaemia, mainly with IGT. Interventions could be diet alone, physical activity alone, or the combination. For cost-effectiveness analysis, we updated the Sheffield economic model of T2DM. Modelling based on RCTs may not reflect what happens in routine care so we created a 'real-life' modelling scenario wherein people would try lifestyle change but switch to metformin after 1 year if they failed. Nine RCTs compared lifestyle interventions (predominantly dietary and physical activity advice, with regular reinforcement and frequent follow-up) with standard care. The primary outcome was progression to diabetes. In most trials, progression was reduced, by over half in some trials. The best effects were seen in participants who adhered best to the lifestyle changes; a scenario of a trial of lifestyle change but a switch to metformin after 1 year in those who did not adhere sufficiently appeared to be the most cost-effective option. Participants in the RCTs were volunteers and their results may have been better than in general populations. Even among the volunteers, many did not adhere. Some studies were not long enough to show whether the interventions reduced cardiovascular mortality as well as diabetes. The main problem is that we know what people should do to reduce progression, but not how to persuade most to do it. In people with IGT, dietary change to ensure weight loss, coupled with physical activity, is clinically effective and cost-effective in reducing progression to diabetes. The National Institute for Health Research Health Technology Assessment programme.
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A reduced incretin effect is one of the well-known characteristics of patients with type 2 diabetes, and impaired release of glucagon-like peptide-1 (GLP-1) has been reported to be at least partly involved. In this study, we investigated the effect of nateglinide on GLP-1 release in vivo and in vitro. The GLP-1 level in the portal blood at 20 min after oral administration of nateglinide to Wistar rats was about twice that in vehicle-treated rats. To clarify whether this effect of nateglinide was related to direct stimulation of intestinal cells, in vitro studies were performed using human intestinal L cells (NCI-H716). Nateglinide stimulated GLP-1 release in a concentration-dependent manner from 500 µM, along with transient elevation of the intracellular calcium level. However, diazoxide, nitrendipine, and dantrolene did not block this effect of nateglinide. In addition, the major metabolite of nateglinide, tolbutamide, and mitiglinide, all of which augment insulin secretion by the pancreatic islets, had no effect on GLP-1 release by this cell line. On the other hand, capsazepine significantly inhibited the promotion of GLP-1 release by nateglinide in a concentration-dependent manner. These findings indicate that nateglinide directly stimulates GLP-1 release by intestinal L cells in a K(ATP) channel-independent manner. A novel target of nateglinide may be involved in increasing intracellular calcium to stimulate GLP-1 release, e.g., the transient receptor potential channels. Taken together, the present findings indicate that promotion of GLP-1 release from intestinal L cells may be another important mechanism by which nateglinide restores early-phase insulin secretion and regulates postprandial glucose metabolism.
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Truncated glucagon-like peptide (GLP)-1 is a potent incretin. Its synthesis and secretion are modulated by food, but the influence of individual nutrients remains to be established. The hypothesis that protein hydrolysates (peptones) can directly regulate both GLP-1 secretion and proglucagon (PG) gene transcription was tested in this study, ex vivo in the isolated vascularly perfused rat intestine and in vitro in the murine enteroendocrine cell line STC-1. Peptones were albumin egg hydrolysate (AEH) and meat hydrolysate (MH). We demonstrate in these two models that peptones dose-dependently stimulate GLP-1 release, whereas isocaloric quantities of bovine serum albumin or of an amino acid mixture had no stimulatory effect. A strong and rapid increase of PG RNA level was observed in STC-1 cells treated with peptones (14-fold and 7-fold increase after 4 h of incubation with 3% wt/vol MH and AEH, respectively). Peptones also increased the PG RNA level in the colonic PG-expressing cell line GLUTag. In contrast, peptones did not modify the PG RNA level in two pancreatic glucagon-producing cell lines, namely, the RINm5F and INR1G9 cells. The peptone effect in STC-1 cells was completely abolished by blocking transcription before MH treatment. The stability of proglugacon transcripts was not modified by MH treatment, but nascent transcripts were more abundant in STC-1 cells preincubated with MH. Finally, MH treatment strongly stimulated (15-fold stimulation) the transcriptional activity of two PG gene promoter fragments (-1100 and -350 base pair) linked to the CAT reporter gene transiently transfected in STC-1 cells. Overall, peptones evoke an as yet undescribed release of GLP-1 when brought into contact with native intestinal L-cells or with STC-1 enteroendocrine cells. The increased transcription of the glucagon gene in the latter system suggests an important role of protein hydrolysates in the control of not only the secretion but also the synthesis of the incretin hormone.
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Type 2 diabetes is widespread and its prevalence is increasing rapidly. In the US alone, approximately 41 million individuals have prediabetes, placing them at high risk for the development of diabetes. The pathogenesis of type 2 diabetes involves inadequate insulin secretion and resistance to the action of insulin. Suggestive data link insulin resistance and accompanying hyperglycemia to an excess of abdominal adipose tissue, a link that appears to be mediated partially by adipocyte secretion of multiple adipokines that mediate inflammation, thrombosis, atherogenesis, hypertension, and insulin resistance. The adipokine adiponectin has reduced expression in obesity and appears to be protective against the development of type 2 diabetes. Current recommendations to prevent type 2 diabetes center on lifestyle modifications, such as diet and exercise. Clinical trials have established the efficacy of lifestyle intervention, as well as pharmacologic interventions that target glycemic control or fat metabolism. However, diabetes did develop in a substantial percentage of individuals who received intensive intervention in these trials. Thus there is an unmet need for additional strategies in high-risk individuals. Recent data suggest thiazolidinediones and blockade of the endocannabinoid system represent novel therapeutic approaches that may be used for the prevention of diabetes.
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The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose-lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, GLP-1 is suggested to directly stimulate hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorised as being short- or long-acting, with each having unique islet-cell and gastrointestinal effects which lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. In contrast, long-acting agonists reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamics differences may allow for personalised antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual beta-cell function.
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A healthy dietary pattern is a cornerstone for the prevention and treatment of cardiovascular disease (CVD) and type 2 diabetes (T2DM). Compelling scientific evidence has shown many health effects of individual foods (including herbs and spices), beverages, and their constituent nutrients and bioactive components on risk of chronic disease and associated risk factors. The focus of functional foods research that is reviewed herein has been on assessing the health effects and underlying mechanisms of action of fruits and vegetables, whole grains, dairy products including fermented products, legumes, nuts, green tea, spices, olive oil, seafood, red wine, herbs, and spices. The unique health benefits of these functional foods have been the basis for recommending their inclusion in a healthy dietary pattern. A better understanding of strategies for optimally including functional foods in a healthy dietary pattern will confer greater benefits on the prevention and treatment of CVD and T2DM.
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Oral supplementation with collagen hydrolysate (CH) has been shown to improve the condition of the skin in humans and experimental animals. Several hydroxyproline-containing oligo-peptides were previously detected in human peripheral blood after the ingestion of CH, and the two dipeptides, prolyl-hydroxyproline (PO) and hydroxyprolyl-glycine (OG), have been proposed to have beneficial effects on human health. When HR-1 hairless mice were fed a HR-AD diet, which lacked magnesium and zinc, transepidermal water loss (TEWL) increased and water content of stratum corneum decreased. In the present study, we investigated the effects of dietary PO and OG on skin barrier dysfunction in HR-1 hairless mice. Mice were fed a HR-AD diet with or without PO (0.15%) and OG (0.15%) for 35 consecutive days. The administration of PO and OG significantly decreased TEWL, and significantly increased water content of stratum corneum. A DNA microarray analysis of the dorsal skin revealed differences in gene expression between the group administered PO and OG and the control group. We also identified muscle-related Gene Ontology as a result of analyzing the up-regulated genes. These results suggested that the administration of PO and OG improved skin barrier dysfunction and altered muscle-related gene expression. Copyright © 2014. Published by Elsevier Inc.
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Existing concepts and models for glucose-stimulated insulin secretion (GSIS) are overviewed and a newer perspective has been formulated toward the physiological understanding of GSIS. A conventional model has been created on the basis of in vitro data on application of a square wave high glucose in the absence of any other stimulatory inputs. Glucose elicits rapid insulin release through an adenosine triphosphate-sensitive K+ channel (KATP channel)-dependent mechanism, which is gradually augmented in a KATP channel-independent manner. Biphasic GSIS thus occurs. In the body, the β-cells are constantly exposed to stimulatory signals, such as glucagon-like peptide 1 (GLP-1), parasympathetic inputs, free fatty acid (FFA), amino acids and slightly suprathreshold levels of glucose, even at fasting. GLP-1 increases cellular cyclic adenosine monophosphate, parasympathetic stimulation activates protein kinase C, and FFA, amino acids and glucose generate metabolic amplification factors. Plasma glucose concentration gradually rises postprandially under such tonic stimulation. We hypothesize that these stimulatory inputs together make the β-cells responsive to glucose independently from its action on KATP channels. Robust GSIS in patients with a loss of function mutation of the sulfonylurea receptor, a subunit of KATP channels, is compatible with this hypothesis. Furthermore, pre-exposure of the islets to an activator of protein kinase A and/or C makes β-cells responsive to glucose in a KATP channel- and Ca2+-independent manner. We hypothesize that GSIS occurs in islet β-cells without glucose regulation of KATP channels in vivo, for which priming with cyclic adenosine monophosphate, protein kinase C and non-glucose nutrients are required. To understand the physiology of GSIS, comprehensive integration of accumulated knowledge is required.
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Background: Protein induces an increase in insulin concentrations when ingested in combination with carbohydrate. Increases in plasma insulin concentrations have been observed after the infusion of free amino acids. However, the insulinotropic properties of different amino acids or protein (hydrolysates) when co-ingested with carbohydrate have not been investigated. Objective: The aim of this study was to define an amino acid and protein (hydrolysate) mixture with a maximal insulinotropic effect when co-ingested with carbohydrate. Design: Eight healthy, nonobese male subjects visited our laboratory, after an overnight fast, on 10 occasions on which different beverage compositions were tested for 2 h. During those trials the subjects ingested 0.8 g*kg(-)(1)*h(-)(1) carbohydrate and 0.4 g*kg(-)(1)*h(-)(1) of an amino acid and protein (hydrolysate) mixture. Results: A strong initial increase in plasma glucose and insulin concentrations was observed in all trials, after which large differences in insulin response between drinks became apparent. After we expressed the insulin response as area under the curve during the second hour, ingestion of the drinks containing free leucine, phenylalanine, and arginine and the drinks with free leucine, phenylalanine, and wheat protein hydrolysate were followed by the largest insulin response (101% and 103% greater, respectively, than with the carbohydrate-only drink; P < 0.05). Conclusions: Insulin responses are positively correlated with plasma leucine, phenylalanine, and tyrosine concentrations. A mixture of wheat protein hydrolysate, free leucine, phenylalanine, and carbohydrate can be applied as a nutritional supplement to strongly elevate insulin concentrations.
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Inhibitors of the enzymes dipeptidyl peptidase (DPP)-IV and α-glucosidase are two classes of pharmacotherapeutical agents used for the treatment of type 2 diabetes. In the present study, whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin, serum albumin and lactoferrin hydrolysates obtained by peptic digestion were investigated for their potential to serve as natural sources of DPP-IV and α-glucosidase inhibitors. While inhibition of DPP-IV activity was observed in all pepsin-treated whey proteins studied, the α-lactalbumin hydrolysate showed the greatest potency with an IC50 value of 0.036 mg/mL. Conversely, only WPI, β-lactoglobulin and α-lactalbumin hydrolysates displayed some inhibitory activity against α-glucosidase. This study suggests that peptides generated from whey proteins may have dual beneficial effects on glycemia regulation and could be used as functional food ingredients for the management of type 2 diabetes.
Article
We have previously demonstrated that ileal administration of the dietary protein hydrolysate (ZeinH) prepared from corn zein stimulated glucagon-like peptide-1 (GLP-1) secretion and attenuated hyperglycemia in rats. In this study, to examine whether oral administration of ZeinH improves glucose tolerance by stimulating GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) secretions, glucose tolerance tests were performed in normal Sprague-Dawley male rats and diabetic Goto-Kakizai (GK) male rats. The test solution was gavaged before intraperitoneal (i.p.) glucose injection in normal rats or gavaged together with glucose in GK rats. Blood samples were collected from the tail vein or by using the jugular catheter to measure glucose, insulin, GLP-1, and GIP levels. In the intraperitoneal glucose tolerance test, oral administration of ZeinH (2 g/kg) significantly suppressed the glycemic response accompanied with immediate increase in plasma GLP-1 and GIP levels in normal rats. In contrast, oral administration of another dietary peptide, meat hydrolysate, did not elicit a similar effect. The glucose-lowering effect of ZeinH was attenuated by a GLP-1 receptor antagonist or by a GIP receptor antagonist. Furthermore, oral ZeinH induced GLP-1 secretion and reduced glycemic response in GK rats under the oral glucose tolerance test. These results indicate that the oral administration of the dietary peptide ZeinH improves glucose tolerance in normal and diabetic rats by its incretin-releasing activity, namely, the incretinotropic effect.
Article
Whey protein hydrolysates (WPHs) represent novel antidiabetic agents that affect glycemia in animals and humans, but little is known about their insulinotropic effects. The effects of a WPH were analyzed in vitro on acute glucose-induced insulin secretion in pancreatic BRIN-BD11 β cells. WPH permeability across Caco-2 cell monolayers was determined in a 2-tiered intestinal model. WPH effects on insulin resistance were studied in vivo following an 8-wk oral ingestion (100 mg/kg body weight) by ob/ob (OB-WPH) and wild-type mice (WT-WPH) compared with vehicle control (OB and WT groups) using a 2 × 2 factorial design, genotype × treatment. BRIN-BD11 cells showed a robust and reproducible dose-dependent insulinotropic effect of WPH (from 0.01 to 5.00 g/L). WPH bioactive constituents were permeable across Caco-2 cell monolayers. In the OB-WPH and WT-WPH groups, WPH administration improved glucose clearance after a glucose challenge (2 g/kg body weight), as indicated by differences in the area under curves (AUCs) (P ≤ 0.05). The basal plasma glucose concentration was not affected by WPH treatment in either genotype. The plasma insulin concentration was lower in the OB-WPH than in the OB group (P ≤ 0.005) but was similar between the WT and WT-WPH groups; the interaction genotype × treatment was significant (P ≤ 0.005). Insulin release from pancreatic islets isolated from the OB-WPH group was greater (P ≤ 0.005) than that from the OB group but did not differ between the WT-WPH and WT groups; the interaction genotype × treatment was not significant. In conclusion, an 8-wk oral administration of WPH improved blood glucose clearance, reduced hyperinsulinemia, and restored the pancreatic islet capacity to secrete insulin in response to glucose in ob/ob mice. Hence, it may be useful in diabetes management.
Article
Recent advances highlight that nutrient receptors (such as T1R1/T1R3 heterodimer, Ca sensing receptor and GPR93 for amino acids and protein, GPR40, GPR41, GPR43 and GPR120 for fatty acids, T1R2/T1R3 heterodimer for monosaccharides) are expressed in the apical face of the gut and sense nutrients in the lumen. They transduce signals for the regulation of nutrient transporter expressions in the apical face. Interestingly, they are also localised in enteroendocrine cells (EEC) and mainly exert a direct control on the secretion in the lamina propria of gastro-intestinal peptides such as cholecystokinin, glucagon-like peptide-1 and peptide YY in response to energy nutrient transit and absorption in the gut. This informs central nuclei involved in the control of feeding such as the hypothalamus and nucleus of the solitary tract of the availability of these nutrients and thus triggers adaptive responses to maintain energy homoeostasis. These nutrient receptors then have a prominent position since they manage nutrient absorption and are principally the generator of the first signal of satiation mechanisms mainly transmitted to the brain by vagal afferents. Moreover, tastants are also able to elicit gut peptides secretion via chemosensory receptors expressed in EEC. Targeting these nutrient and tastant receptors in EEC may thus be helpful to promote satiation and so to fight overfeeding and its consequences.
Article
The dipeptidyl-peptidase IV (DPP-IV)-inhibitory activity of peptides derived from Atlantic salmon skin gelatin hydrolyzed by alcalase (ALA), bromelain (BRO), and Flavourzyme (FLA) was determined. The FLA hydrolysate with the enzyme/substrate ratio of 6% showed the greatest DPP-IV-inhibitory activity. The hydrolysate was fractionated by ultrafiltration with 1 and 2.5 kDa cutoff membranes, and the <1 kDa fraction had the highest DPP-IV-inhibitory activity with an IC(50) value of 1.35 mg/mL. The F-1 fraction further isolated by HPLC showed the IC(50) value against DPP-IV of 57.3 μg/mL, and the peptide sequences were identified as Gly-Pro-Ala-Glu (372.4 Da) and Gly-Pro-Gly-Ala (300.4 Da). The synthetic peptides showed dose-dependent inhibition effects on DPP-IV with IC(50) values of 49.6 and 41.9 μM, respectively. The results suggest that the peptides derived from Atlantic salmon skin gelatin would be beneficial ingredients for functional foods or pharmaceuticals against type 2 diabetes.
Article
Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). GIP is secreted by K cells from the upper small intestine while GLP-1 is mainly produced in the enteroendocrine L cells located in the distal intestine. Their effect is mediated through their binding with specific receptors, though part of their biological action may also involve neural modulation. GIP and GLP-1 are both rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV (DPP-IV). In addition to its effects on insulin secretion, GLP-1 exerts other significant actions, including stimulation of insulin biosynthesis, inhibition of glucagon secretion, inhibition of gastric emptying and acid secretion, reduction of food intake, and trophic effects on the pancreas. As the insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide was likely to be developed as a therapeutic agent for this disease.
Article
The effect of daily ingestion of collagen hydrolysate (CH) on skin extracellular matrix proteins was investigated. Four-week-old male Wistar rats were fed a modified AIN-93 diet containing 12% casein as the reference group or CH as the treatment group. A control group was established in which animals were fed a non-protein-modified AIN-93 diet. The diets were administered continuously for 4 weeks when six fresh skin samples from each group were assembled and subjected to extraction of protein. Type I and IV collagens were studied by immunoblot, and activities of matrix metalloproteinase (MMP) 2 and 9 were assessed by zymography. The relative amount of type I and IV collagens was significantly (P < .05) increased after CH intake compared with the reference diet group (casein). Moreover, CH uptake significantly decreased both proenzyme and active forms of MMP2 compared with casein and control groups (P < .05). In contrast, CH ingestion did not influence on MMP9 activity. These results suggest that CH may reduce aging-related changes of the extracellular matrix by stimulating anabolic processes in skin tissue.
Article
Marine collagen peptides (MCPs) from deep sea fish are shown to ameliorate hyperlipidemia in animal models. The study aimed at examining the effects of MCPs on glucose and lipid metabolism in Chinese patients with type 2 diabetes mellitus (T2DM) and primary hypertension. One hundred patients with T2DM and primary hypertension and 50 healthy subjects (normal controls) were recruited for a randomized double blind study. The patients were randomized into MCPs treatment or patient control groups (n = 50 per group). Both patient controls and normal controls were given carboxymethylcellulose twice daily whereas the MCPs treatment group was given MCPs twice daily for 3 months. Blood pressure, glucose and lipid metabolism, serum high-sensitivity C-reactive protein, cytochrome P450, nitric oxide, bradykinin, prostacyclin, creatinine, uric acid and adipokines were measured at baseline, 1.5 and 3 months after treatment. All patients received regular medicines for control of hyperglycemia and hypertension. Compared with patient controls, significantly reduced levels of fasting blood glucose, HbA1c, diastolic blood pressure, mean arterial pressure and creatinine but increased levels of Insulin Sensitivity Index and Insulin Secretion Index were observed in patients receiving MCPs treatment. Furthermore, significantly reduced levels of serum triglycerides, total cholesterol, low-density lipoprotein, free fatty acids, cytochrome P450, nitric oxide and prostacyclin but increased levels of high-density lipoprotein, bradykinin and adiponectin were detected in patients taking MCPs. MCPs supplement may benefit glucose and lipid metabolism, insulin sensitivity, renal function and hypertension management in Chinese patients with T2DM and hypertension.
Article
Leu-Ser-Glu-Leu (LSEL) is the main active ingredient of globin digest (GD) that has an anti-diabetic effect. Here, we investigated the anti-diabetic effect of LSEL for the first time. The anti-diabetic effects of GD and LSEL in ICR mice, streptozotocin (STZ)-induced diabetic mice and KK-Ay mice were examined. GD and LSEL suppressed the elevation of blood glucose in an oral glucose tolerance test (OGTT) in ICR mice, STZ-induced diabetic mice and KK-Ay mice as well as in an oral sucrose tolerance test in ICR mice and in an insulin tolerance test (ITT) in KK-Ay mice. GD and LSEL decreased the blood glucose levels in the basal state in STZ-induced diabetic mice and KK-Ay mice. Furthermore, GD and LSEL elevated the serum insulin levels in an OGTT in ICR mice and KK-Ay mice and promoted the use of insulin in an ITT in KK-Ay mice. GD and LSEL increased the translocation or expression of the glucose transporter 4 in the muscle of ICR mice, STZ-induced diabetic mice and KK-Ay mice and increased the expression of the uncoupling protein 2 (UCP2) in the muscle of ICR mice. These results indicate that GD and LSEL control blood glucose through the promotion of glucose uptake in the muscle of the mice. The acceleration of glucose uptake by GD and LSEL may be controlled by the promotion of insulin secretion and the up-regulation of UCP2 expression. GD and LSEL seem to be useful for lowering the incidence of hyperglycemia.
Article
Glucagon-like peptide-1 (GLP-1) is released from enteroendocrine cells (L cells) in response to food ingestion. The mechanism by which dietary peptides stimulate GLP-1 secretion in the gut is unknown. In the present study, we found that a hydrolysate prepared from zein, a major corn protein [zein hydrolysate (ZeinH)], strongly stimulates GLP-1 secretion in enteroendocrine GLUTag cells. Stimulatory mechanisms of GLP-1 secretion induced by ZeinH were investigated in the rat small intestine under anesthesia. Blood was collected through a portal catheter before and after ZeinH administration into different sites of the small intestine. The duodenal, jejunal, and ileal administration of ZeinH induced dose-dependent increases in portal GLP-1 concentration. GLP-1 secretion in response to the ileal administration of ZeinH was higher than that in the duodenal or jejunal administration. Capsaicin treatment on esophageal vagal trunks abolished the GLP-1 secretion induced by duodenal ZeinH but did not affect the secretion induced by jejunal or ileal ZeinH. These results suggest that ZeinH in the jejunum or ileum directly stimulates GLP-1 secretion but duodenal ZeinH indirectly stimulates GLP-1 secretion via the vagal afferent nerve. A direct blood sampling method from the duodenal vein and ileal mesenteric vein revealed that ZeinH administered into the ligated duodenal loop enhanced GLP-1 concentration in the ileal mesenteric vein but not in the duodenal vein. This confirmed that ZeinH in the duodenum induces GLP-1 secretion from L cells located in the ileum by an indirect mechanism. These results indicate that a potent GLP-1-releasing peptide, ZeinH, induces GLP-1 secretion by direct and indirect mechanisms in the rat intestine.
Article
Monounsaturated fatty acids, such as oleic acid (OA), and certain milk proteins, especially whey protein (WP), have insulinotropic effects and can reduce postprandial glycemia. This effect may involve the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). To explore this, we examined the release and inactivation of GIP and GLP-1 after administration of glucose with or without OA or WP through gastric gavage in anesthetized C57BL/6J mice. Insulin responses to glucose (75 mg) were 3-fold augmented by addition of WP (75 mg; P < 0.01), which was associated with enhanced oral glucose tolerance (P < 0.01). The insulin response to glucose was also augmented by addition of OA (34 mg; P < 0.05) although only 1.5-fold and with no associated increase in glucose elimination. The slope of the glucose-insulin curve was increased by OA (1.7-fold; P < 0.05) and by WP (4-fold; P < 0.01) compared with glucose alone, suggesting potentiation of glucose-stimulated insulin release. WP increased GLP-1 secretion (P < 0.01), whereas GIP secretion was unaffected. OA did not affect GIP or GLP-1 secretion. Nevertheless, WP increased the levels of both intact GIP and intact GLP-1 (both P < 0.01), and OA increased the levels of intact GLP-1 (P < 0.05). WP inhibited dipeptidyl peptidase IV activity in the proximal small intestine by 50% (P < 0.05), suggesting that luminal degradation of WP generates small fragments, which are substrates for dipeptidyl peptidase IV and act as competitive inhibitors. We therefore conclude that fat and protein may serve as exogenous regulators of secretion and inactivation of the incretin hormones with beneficial influences on glucose metabolism.
Article
Glucagon-like peptide-1 (GLP-1) is a potent insulin secretagogue released from L-cells in the intestine. Meat hydrolysate (MH) is a powerful activator of GLP-1 secretion in the human enteroendocrine NCI-H716 cell line, but the mechanisms involved in nutrient-stimulated GLP-1 secretion are poorly understood. The objective of this study was to characterize the intracellular signalling pathways regulating MH- and amino acid-induced GLP-1 secretion. Individually, the pharmacological inhibitors, SB203580 (inhibitor of p38 mitogen-activated protein kinase (MAPK)), wortmannin (inhibitor of phosphatidyl inositol 3-kinase) and U0126 (inhibitor of mitogen activated or extracellular signal-regulated protein kinase (MEK1/2) upstream of extracellular signal-regulated kinase (ERK)1/2) all inhibited MH-induced GLP-1 secretion. Further examination of the MAPK pathway showed that MH increased the phosphorylation of ERK1/2, but not p38 or c-Jun N-terminal kinase over 2-15 min. Incubation with SB203580 resulted in a decrease in phosphorylated p38 MAPK and a concomitant increase in the phosphorylation of ERK1/2. Phosphorylation of ERK1/2 was augmented by co-incubation of MH with SB203580. Inhibitors of protein kinase A and protein kinase C did not inhibit MH-induced GLP-1 secretion. In contrast to non-essential amino acids, essential amino acids (EAAs) increased GLP-1 secretion and similar to MH, activated ERK1/2. However, they also activated p38-suggesting type of protein may affect GLP-1 secretion. In conclusion, there appears to be a crosstalk between p38 and ERK1/2 MAPK in the human enteroendocrine cell with the activation of ERK1/2 common to both MH and EAA. Understanding the cellular pathways involved in nutrient-stimulated GLP-1 secretion has important implications for the design of new treatments aimed at increasing endogenous GLP-1 release in type-2 diabetes and obesity.
Article
This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 are both secreted within minutes of nutrient ingestion and facilitate the rapid disposal of ingested nutrients. Both peptides share common actions on islet beta-cells acting through structurally distinct yet related receptors. Incretin-receptor activation leads to glucose-dependent insulin secretion, induction of beta-cell proliferation, and enhanced resistance to apoptosis. GIP also promotes energy storage via direct actions on adipose tissue, and enhances bone formation via stimulation of osteoblast proliferation and inhibition of apoptosis. In contrast, GLP-1 exerts glucoregulatory actions via slowing of gastric emptying and glucose-dependent inhibition of glucagon secretion. GLP-1 also promotes satiety and sustained GLP-1-receptor activation is associated with weight loss in both preclinical and clinical studies. The rapid degradation of both GIP and GLP-1 by the enzyme dipeptidyl peptidase-4 has led to the development of degradation-resistant GLP-1-receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes. These agents decrease hemoglobin A1c (HbA1c) safely without weight gain in subjects with type 2 diabetes. GLP-1 and GIP integrate nutrient-derived signals to control food intake, energy absorption, and assimilation. Recently approved therapeutic agents based on potentiation of incretin action provide new physiologically based approaches for the treatment of type 2 diabetes.
Article
The principal target of the relaxant neurotransmitter nitric oxide (NO) is soluble guanylate cyclase (sGC). As the alpha(1)beta(1)-isoform of sGC is the predominant one in the gastrointestinal tract, the aim of this study was to investigate the role of sGC in nitrergic regulation of gastric motility in male and female sGCalpha(1) knock-out (KO) mice. In circular gastric fundus muscle strips, functional responses and cGMP levels were determined in response to nitrergic and non-nitrergic stimuli. sGC subunit mRNA expression in fundus was measured by real-time RT-PCR; in vivo gastric emptying of a phenol red meal was determined. No changes were observed in sGC subunit mRNA levels between wild-type (WT) and KO tissues. Nitrergic relaxations induced by short trains of electrical field stimulation (EFS) were abolished, while those by long trains of EFS were reduced in KO strips; the latter responses were abolished by 1H[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The relaxations evoked by exogenous NO and the NO-independent sGC activator BAY 41-2272 were reduced in KO strips but still sensitive to ODQ. Relaxations induced by vasoactive intestinal peptide (VIP) and 8-bromo-cGMP were not influenced. Basal cGMP levels were decreased in KO strips but NO, long train EFS and BAY 41-2272 still induced a moderate ODQ-sensitive increase in cGMP levels. Gastric emptying, measured at 15 and 60 min, was increased at 15 min in male KO mice. sGCalpha(1)beta(1) plays an important role in gastric nitrergic relaxation in vitro, but some degree of nitrergic relaxation can occur via sGCalpha(2)beta(1) activation in sGCalpha(1) KO mice, which contributes to the moderate in vivo consequence on gastric emptying.
Protein hydrolysate enriched in peptides inhibiting dpp-iv and their use
  • Jwp Boots
Boots JWP: Protein hydrolysate enriched in peptides inhibiting dpp-iv and their use. Google Patents 2006.