[I10W]tigerinin-1R enhances both insulin sensitivity and pancreatic beta cell function and decreases adiposity and plasma triglycerides in high-fat mice

Srinivasan, Dhanalakshmi; Ojo, Opeolu O.; Owolabi, Bosede O.; Conlon, J. Michael; Flatt, Peter R.; Abdel-Wahab, Yasser

doi:10.1007/s00592-015-0783-3

Cited by 8 publications

(7 citation statements)

References 35 publications

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“…This was associated with improved glucose tolerance following oral and intraperitoneal glucose administration accompanied by enhanced insulin secretion. These observations are broadly consistent with effects of tigerinin-1R [ 12 ], [I10W]-tigerinin-1R [ 30 ] and magainin-AM2 [ 13 ], suggesting a possible similar spectrum of actions in this animal model of obesity and diabetes. We have previously shown that the antidiabetic effects of magainin-AM2 [ 13 ] and [I10W]-tigerinin-1R [ 30 ] were accompanied by improvement in insulin sensitivity.…”

Section: Discussionsupporting

confidence: 81%

“…These in vivo actions were greater with the [D28K] and [C31S] analogues while the in vitro insulinotropic actions of the other peptide analogues were not replicated in vivo . The in vivo effects of [L28K] and [C31K]esculentin-2CHa in these animals were more pronounced than those previously reported for other amphibian skin peptides [ 12 – 14 , 30 ]. Twice-daily administration of [L28K]esculentin-2CHa for 28 days did not affect body weight and food intake but reduced hyperglycaemia and elevated plasma insulin concentrations in the non-fasting state.…”

Section: Discussionmentioning

confidence: 49%

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Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance

et al. 2015

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The frog skin host-defense peptide esculentin-2CHa (GFSSIFRGVA10KFASKGLGK D20LAKLGVDLVA30CKISKQC) displays antimicrobial, antitumor, and immunomodulatory properties. This study investigated the antidiabetic actions of the peptide and selected analogues. Esculentin-2CHa stimulated insulin secretion from rat BRIN-BD11 clonal pancreatic β-cells at concentrations greater than 0.3 nM without cytotoxicity by a mechanism involving membrane depolarization and increase of intracellular Ca2+. Insulinotropic activity was attenuated by activation of KATP channels, inhibition of voltage-dependent Ca2+ channels and chelation of extracellular Ca2+. The [L21K], [L24K], [D20K, D27K] and [C31S,C37S] analogues were more potent but less effective than esculentin-2CHa whereas the [L28K] and [C31K] analogues were both more potent and produced a significantly (P < 0.001) greater maximum response. Acute administration of [L28K]esculentin-2CHa (75 nmol/kg body weight) to high fat fed mice with obesity and insulin resistance enhanced glucose tolerance and insulin secretion. Twice-daily administration of this dose of [L28K]esculentin-2CHa for 28 days had no significant effect on body weight, food intake, indirect calorimetry or body composition. However, mice exhibited decreased non-fasting plasma glucose (P < 0.05), increased non-fasting plasma insulin (P < 0.05) as well as improved glucose tolerance and insulin secretion (P < 0.01) following both oral and intraperitoneal glucose loads. Impaired responses of isolated islets from high fat fed mice to established insulin secretagogues were restored by [L28K]esculentin-2CHa treatment. Peptide treatment was accompanied by significantly lower plasma and pancreatic glucagon levels and normalization of α-cell mass. Circulating triglyceride concentrations were decreased but plasma cholesterol and LDL concentrations were not significantly affected. The data encourage further investigation of the potential of esculentin-2CHa related peptides for treatment of patients with type 2 diabetes.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 49%

Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance

et al. 2015

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“…Consequently, the data provide further support for the contention that naturally occurring tigerinin peptides may serve as templates for the design of nontoxic and long-acting analogues for use in the treatment of patients with type 2 diabetes. 1,8,11 Cytokine Production. In the first series of experiments, all four tigerinins at a concentration of 20 μg/mL produced a significant (P < 0.05) decrease in the production and release of interferon-γ (IFN-γ) by peritoneal cells from C57BL/6 mice (Figure 6A).…”

Section: Journal Of Natural Productsmentioning

confidence: 99%

“…Largely devoid of antimicrobial and cytotoxic properties, tigerinin-1R and its analogues , stimulate insulin release from BRIN-BD11 clonal β-cells and the release of glucagon-like peptide-1 (GLP-1) from the GLUTag cell line at concentrations that are not toxic to the cells. Studies in vivo have shown that tigerinin-1R and its analogues , enhance both insulin sensitivity and pancreatic β-cell function and decrease adiposity and plasma triglycerides when administered to mice given a high-fat diet to produce obesity and insulin resistance. In addition, tigerinin-1R increases production of the anti-inflammatory cytokine interleukin-10 (IL-10) in both spleen cells from C57BL/6 mice and human peripheral blood mononuclear cells without stimulating production of the pro-inflammatory cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23), suggesting a possible role in the treatment of sepsis.…”

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confidence: 99%

Purification, Conformational Analysis, and Properties of a Family of Tigerinin Peptides from Skin Secretions of the Crowned Bullfrog Hoplobatrachus occipitalis

et al. 2016

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Four host-defense peptides belonging to the tigerinin family (tigerinin-1O: RICTPIPFPMCY; tigerinin-2O: RTCIPIPLVMC; tigerinin-3O: RICTAIPLPMCL; and tigerinin-4O: RTCIPIPPVCF) were isolated from skin secretions of the African crowned bullfrog Hoplobatrachus occipitalis. In aqueous solution at pH 4.8, the cyclic domain of tigerinin-2O adopts a rigid amphipathic conformation that incorporates a flexible N-terminal tail. The tigerinins lacked antimicrobial (MIC > 100 μM) and hemolytic (LC50 > 500 μM) activities but, at a concentration of 20 μg/mL, significantly (P < 0.05) inhibited production of interferon-γ (IFN-γ) by peritoneal cells from C57BL/6 mice without affecting production of IL-10 and IL-17. Tigerinin-2O and -4O inhibited IFN-γ production at concentrations as low as 1 μg/mL. The tigerinins significantly (P ≤ 0.05) stimulated the rate of insulin release from BRIN-BD11 clonal β-cells without compromising the integrity of the plasma membrane. Tigerinin-1O was the most potent (threshold concentration 1 nM) and the most effective (395% increase over basal rate at a concentration of 1 μM). Tigerinin-4O was the most potent and effective peptide in stimulating the rate of glucagon-like peptide-1 release from GLUTag enteroendocrine cells (threshold concentration 10 nM; 289% increase over basal rate at 1 μM). Tigerinin peptides have potential for development into agents for the treatment of patients with type 2 diabetes

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“…In vitro studies have shown that it stimulates the release of insulin, even at concentrations as low as 0.1 nM, and exhibits no hemolytic activity against human erythrocytes at concentrations up to 500 nM [ 22 ]. In vivo studies have shown that administration of tigerinin-1R or some of its analogs to high-fat fed mice significantly enhanced insulin release and improved glucose tolerance [ 20 , 22 , 23 , 24 ]. Ojo et al suggests that a C-terminally amidated amino acid is necessary for the potency of the peptide.…”

Section: Introductionmentioning

confidence: 99%

Role of Disulfide Bonds in Activity and Stability of Tigerinin-1R

Chen

Huang

et al. 2018

IJMS

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Tigerinin-1R (Arg–Val–Cys–Ser–Ala–Ile–Pro–Leu–Pro–Ile–Cys–His–NH2), a cationic 12-mer peptide containing a disulfide bond extracted from frog skin secretions, lacks antibacterial activity, but has the ability to stimulate insulin release both in vitro and in vivo. To study the structure–function relationships of tigerinin-1R, we designed and synthesized five analogs, including tigerinin-cyclic, tigerinin-1R-L4, tigerinin-linear, [C3K]tigerinin-1R, and [C11K]tigerinin-1R. Tigerinin-1R promoted insulin secretion in a concentration-dependent manner in INS-1 cells without obvious cytotoxicity. At a concentration of 10−5 M, [C11K]tigerinin-1R exhibited the highest stimulation ability, suggesting that the positive charge at the C-terminus may contribute to the in vitro insulin-releasing activity of tigerinin-1R. Tigerinin-1R peptides stimulated insulin release in INS-1 cells through a universal mechanism that involves mobilization of intracellular calcium without disrupting the cell membrane. In vivo experiments showed that both tigerinin-1R and [C11K]tigerinin-1R improved glucose tolerance in overnight-fasted mice. Due to its structural stability, tigerinin-1R showed superior hypoglycemic activity to [C11K]tigerinin-1R, which suggested a critical role of the disulfide bonds. In addition, we also identified a protective effect of tigerinin-1R peptides in apoptosis induced by oxidative stress. These results further confirm the potential for the development of tigerinin-1R as an anti-diabetic therapeutic agent in clinical practice.

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[I10W]tigerinin-1R enhances both insulin sensitivity and pancreatic beta cell function and decreases adiposity and plasma triglycerides in high-fat mice

Abstract: This study shows that [I10W]tigerinin-1R improves insulin sensitivity, islet function and glycaemic control in high-fat-fed mice and has potential as a template for development of novel anti-diabetic agents.

Cited by 8 publications

References 35 publications

Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance

Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance

Purification, Conformational Analysis, and Properties of a Family of Tigerinin Peptides from Skin Secretions of the Crowned Bullfrog Hoplobatrachus occipitalis

Role of Disulfide Bonds in Activity and Stability of Tigerinin-1R

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