Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet‐induced obese and leptin‐deficient rodents

Trevaskis, James L.; Sun, Changqi; Athanacio, Jennifer; D’Souza, Lawrence J.; Samant, Manoj; Tatarkiewicz, Krystyna; Griffin, P. S.; Wittmer, Carrie; Wang, Y.; Teng, Charles; Forood, Bruce; Parkes, David G.; Roth, Jonathan D.

doi:10.1111/dom.12390

Cited by 56 publications

(50 citation statements)

References 62 publications

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“…Importantly, pharmacological studies reveal that CCK 1 , as opposed to CCK 2 , receptor activity is critical for synergy with GLP-1 receptor action (6). We confirmed through the use of specific GLP-1, CCK 1 , and CCK 2 receptor antagonists that the insulinotropic effects of the hybrid were mediated via both GLP-1 and CCK 1 receptors.…”

Section: Discussionsupporting

confidence: 53%

“…It should be noted, however, that earlier clinical studies using infusions of native GLP-1 and CCK peptides in normal human subjects fasted overnight failed to reveal clear synergistic effects (22). This is likely related to important differences between these studies, including the use of infusion rather than bolus injection, normal fasted subjects as opposed to a freely fed diabetic animal model, and native metabolically liable peptides rather than enzymatically stable peptide forms (5,6,22). Therefore, in this research we evaluated the biological actions and therapeutic applicability of a novel stable (pGlu-Gln)-CCK-8/exendin-4 Figure 6-Effects of twice-daily administration of (pGlu-Gln)-CCK-8/exendin-4 hybrid, (pGlu-Gln)-CCK-8, exendin-4, or a combination of both parent peptides on plasma lipid profile in high-fat-fed mice.…”

Section: Discussionmentioning

confidence: 92%

“…By contrast, GLP-1 mimetics have been adopted into the diabetic clinic with great vigor, although weight loss and metabolic control are not as impressive as first hoped (7). In this regard several recent studies revealed that dual agonism of CCK 1 and GLP-1 receptors has marked synergistic metabolic and weight-reduction benefits (5,6). It should be noted, however, that earlier clinical studies using infusions of native GLP-1 and CCK peptides in normal human subjects fasted overnight failed to reveal clear synergistic effects (22).…”

Section: Discussionmentioning

confidence: 99%

“…Crucially, the novel hybrid peptide (pGlu-Gln)-CCK-8/exendin-4 had equally effective beneficial metabolic actions when compared with combined administration of the parent peptides. Indeed, reductions in HbA 1c were observed only in those mice subjected to sustained activation of both CCK 1 and GLP-1 receptors (5,6). Development of specific assays to directly measure each peptide in plasma would be useful to provide more precise details of circulating half-life.…”

Section: Discussionmentioning

confidence: 99%

“…Principal effects of CCK are gallbladder contraction together with the short-term regulation of energy balance, mediated through induction of satiety (4). Thus it is clear that CCK-8 and GLP-1 possess numerous complementary biological actions that suggest potential synergistic therapeutic application for obesity-related diabetes (5,6).…”

mentioning

confidence: 99%

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A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

2015

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Glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) exert important complementary beneficial metabolic effects. This study assessed the biological actions and therapeutic utility of a novel (pGlu-Gln)-CCK-8/exendin-4 hybrid peptide compared with the stable GLP-1 and CCK mimetics exendin-4 and (pGlu-Gln)-CCK-8, respectively. All peptides significantly enhanced in vitro insulin secretion. Administration of the peptides, except (pGlu-Gln)-CCK-8 alone, in combination with glucose significantly lowered plasma glucose and increased plasma insulin in mice. All treatments elicited appetite-suppressive effects. Twice-daily administration of the novel (pGlu-Gln)-CCK-8/exendin-4 hybrid, (pGlu-Gln)-CCK-8 alone, or (pGlu-Gln)-CCK-8 in combination with exendin-4 for 21 days to high-fat–fed mice significantly decreased energy intake, body weight, and circulating plasma glucose. HbA1c was reduced in the (pGlu-Gln)-CCK-8/exendin-4 hybrid and combined parent peptide treatment groups. Glucose tolerance and insulin sensitivity also were improved by all treatment modalities. Interestingly, locomotor activity was decreased in the hybrid peptide group, and these mice also exhibited reductions in circulating triglyceride and cholesterol levels. Pancreatic islet number and area, as well β-cell area and insulinotropic responsiveness, were dramatically improved by all treatments. These studies highlight the clear potential of dual activation of GLP-1 and CCK1 receptors for the treatment of type 2 diabetes.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

2015

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Gut Peptide Agonism in the Treatment of Obesity and Diabetes

Grandl

Novikoff

DiMarchi

et al. 2019

Comprehensive Physiology

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Obesity is a global healthcare challenge that gives rise to devastating diseases such as the metabolic syndrome, type-2 diabetes (T2D), and a variety of cardiovascular diseases. The escalating prevalence of obesity has led to an increased interest in pharmacological options to counteract excess weight gain. Gastrointestinal hormones such as glucagon, amylin, and glucagon-like peptide-1 (GLP-1) are well recognized for influencing food intake and satiety, but the therapeutic potential of these native peptides is overall limited by a short half-life and an often dose-dependent appearance of unwanted effects. Recent clinical success of chemically optimized GLP-1 mimetics with improved pharmacokinetics and sustained action has propelled pharmacological interest in using bioengineered gut hormones to treat obesity and diabetes. In this article, we summarize the basic biology and signaling mechanisms of selected gut peptides and discuss how they regulate systemic energy and glucose metabolism. Subsequently, we focus on the design and evaluation of unimolecular drugs that combine the beneficial effects of selected gut hormones into a single entity to optimize the beneficial impact on systems metabolism.

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The gut–brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies

Clarke,

Page,

Eldeghaidy

2024

Pharmacology Res & Perspec

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The gut–brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut–brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.

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Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet‐induced obese and leptin‐deficient rodents

Abstract: The anti-obesity and antidiabetic potential of combined GLP-1R and CCK1R agonism is an approach that warrants further investigation.

Cited by 56 publications

References 62 publications

A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

Gut Peptide Agonism in the Treatment of Obesity and Diabetes

The gut–brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies

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