Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties

Kerr, Barry D.; Irwin, Nigel; O’Harte, Finbarr; Bailey, Clifford J.; Flatt, Peter R.; Gault, Victor

doi:10.1016/j.bcp.2009.05.037

Cited by 42 publications

(40 citation statements)

References 23 publications

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“…Food intake and body weight were similar to saline-treated control mice, consistent with other feeding studies in rodents (Irwin & Flatt 2009a, Kerr et al 2009, McIntosh et al 2009). As would be expected, a major benefit of twice-daily injection of GIP peptides centred on increased insulin section (Irwin & Flatt 2009a ]GIP(1-30) afforded partial protection of b-cell destruction in streptozotocintreated rats, resulting in greater glycaemic control and insulin responses (Widenmaier et al 2010).…”

Section: Discussionsupporting

confidence: 88%

“…To this end, the results of the present study demonstrate similar beneficial effects of prolonged GIP receptor activation by both GIP-based molecules in high-fat fed mice. GIP(1-42) was confirmed as described previously (Kerr et al 2009;data not shown commencement of studies, the experimental animals were maintained on high-fat diet from 6 weeks of age for 140 days. Obesity, insulin resistance, and hyperglycaemia were clearly manifested compared to similarly aged mice maintained on normal laboratory diet as judged by body weight, plasma insulin, and glucose analyses.…”

Section: Introductionmentioning

confidence: 99%

“…This form, with substitution of the natural L-Ala 2 for the D-Ala 2 isomer in GIP, has been shown in several studies to enhance insulin secretion in vitro and in vivo, mediating significantly improved glucose homeostasis in diabetic animal models (Hinke et al 2002, Maida et al 2009, Widenmaier et al 2010. In light of this, the present study has investigated and compared the biological effects of twice-daily administration of the enzymatically stable analogues of these two naturally occurring forms of GIP, namely [D- ]GIP(1-42) would recapitulate the well-established beneficial effects of prolonged GIP receptor activation on glucose homeostasis and insulin secretion in high-fat fed mice (Kerr et al 2009). However, since GIP(1-30) is reportedly less potent in stimulating lipoprotein lipase activity than GIP(1-42) (Widenmaier et al 2010), the GIP molecules may have diverse effects on circulating blood lipids.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of sub-chronic metabolic effects of stable forms of naturally occurring GIP(1-30) and GIP(1-42) in high fat fed mice

Gault¹,

Porter²,

Irwin³

et al. 2011

Journal of Endocrinology

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Glucose-dependent insulinotropic polypeptide (GIP) is a 42 amino acid hormone secreted from intestinal K-cells, which exhibits a number of actions including stimulation of insulin release. A truncated form, GIP(1-30), has recently been demonstrated in intestine and islet a-cells. To evaluate the potential physiological significance of this naturally occurring form of GIP, the present study has examined and compared the bioactivity of enzymatically stabilised forms, [D-Ala Twice-daily injection of GIP peptides for 42 days had no significant effect on food intake or body weight. However, non-fasting glucose levels were significantly lowered, and insulin levels were elevated in both treatment groups compared to saline controls. The glycaemic response to i.p. In contrast, ambulatory activity was significantly (P!0 . 05) elevated during the light phase in both GIP treatment groups compared to saline controls. The results reveal that sustained GIP receptor activation exerts a spectrum of beneficial metabolic effects in high-fat fed mice. However, no differences were discernable between the biological actions of the enzyme-resistant analogues of the naturally occurring forms, GIP(1-30) and GIP(1-42).

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparison of sub-chronic metabolic effects of stable forms of naturally occurring GIP(1-30) and GIP(1-42) in high fat fed mice

Gault¹,

Porter²,

Irwin³

et al. 2011

Journal of Endocrinology

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“…Peptides were characterised using matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry [23].…”

Section: Methodsmentioning

confidence: 99%

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

2013

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Aims/hypothesis Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively. Methods The actions and overall therapeutic use of (pGluGln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice. Results (pGlu-Gln)-CCK-8 had prominent (p<0.01 to p< 0.001), acute feeding-suppressive effects, which were significantly augmented (p<0.05 to p<0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p<0.05 to p<0.001), energy intake (p<0.01), circulating triacylglycerol (p<0.01), nonfasting glucose (p<0.05 to p<0.001) and triacylglycerol deposition in liver and adipose tissue (p<0.001). All treatment regimens improved glucose tolerance (p<0.05 to p<0.001) and insulin sensitivity (p<0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p<0.001) energy expenditure. Conclusions/interpretationThese studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes.

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“…The specific CCK 1 and CCK 2 receptor antagonists, SR27897 and LY288513, were purchased from Tocris Biosciences (Avonmouth, UK). Peptides were characterised using matrix-assisted laser desorption ionisation time-of-flight (MALDI-TOF) mass spectrometry [17].…”

Section: Methodsmentioning

confidence: 99%

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

et al. 2012

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Aims/hypothesis Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8. Methods The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice. Results (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p<0.05 to p<0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p<0.01 to p<0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p<0.05 to p<0.001), accumulated food intake (p< 0.05 to p<0.001), non-fasting glucose (p<0.05) and triacylglycerol deposition in pancreatic (p<0.01), adipose (p< 0.05) and liver (p<0.001) tissue, and improved oral (p< 0.05) and i.p. (p<0.05) glucose tolerance and insulin sensitivity (p<0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology. Conclusions/interpretation These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

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Fatty acid derivatised analogues of glucose-dependent insulinotropic polypeptide with improved antihyperglycaemic and insulinotropic properties

Cited by 42 publications

References 23 publications

Comparison of sub-chronic metabolic effects of stable forms of naturally occurring GIP(1-30) and GIP(1-42) in high fat fed mice

Comparison of sub-chronic metabolic effects of stable forms of naturally occurring GIP(1-30) and GIP(1-42) in high fat fed mice

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

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