Impaired Insulin Secretion and Enhanced Insulin Sensitivity in Cholecystokinin-Deficient Mice

Lo, Chunmin C.; Obici, Silvana; Dong, H. Henry; Haas, Michael; Lou, Dawnwen; Kim, Dae Hyun; Liu, Min; D’Alessio, David; Woods, Stephen C.; Tso, Patrick

doi:10.2337/db10-0789

Cited by 50 publications

(46 citation statements)

References 38 publications

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“…In addition, we observed consistent improvement of insulin sensitivity with both the hybrid peptide and (pGlu-Gln)-CCK-8 in combination with exendin-4 by the end of the treatment period. This is in agreement with the well-known insulin-sparing actions of GLP-1 (34), and evidence also suggests an integral role for CCK as a regulator of insulin action, especially under conditions of high-fat feeding (35). In this study the islet number, together with both islet area and b-cell area, were increased by all treatment modalities.…”

Section: Discussionsupporting

confidence: 78%

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: 78%

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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“…(pGluGln)-CCK-8 also stimulated insulin secretion from clonal beta cells and acutely improved glucose homeostasis in ob/ob and high-fat-fed mice. These observations demonstrate the glucose-lowering potential of CCK consistent with a beta cell effect under specific conditions such as high-fat feeding [22]. Upregulation of CCK actions is also evident in mice with double genetic knockout of GLP-1 and GIP and in pregnancy, where enhanced beta cell action are key features [23,24].…”

Section: Discussionsupporting

confidence: 60%

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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“…This has been observed in previous work in animals maintained on a high fat diet (27). The impact of glucose on CCK expression may be as a result of the interaction of CCK with insulin.…”

Section: Cholecystokininsupporting

confidence: 64%

“…Lo (2011) using CCK-KO mice, found that when maintained on a low-fat diet animals had a reduced acute insulin response to glucose (27). However, when maintained on a high fat diet, CCK-KO mice developed glucose intolerance.…”

Section: Cholecystokininmentioning

confidence: 99%

Effects of sugar solutions on hypothalamic appetite regulation

Colley¹,

Castonguay²

2015

Physiology & Behavior

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There are multiple hypotheses for the causes of the obesity epidemic. One such hypothesis is that dietary intake patterns have significantly shifted to include unprecedented amounts of refined sugar. We set out to determine some the unique metabolic changes that occur with initial exposure to dilute glucose, sucrose, high fructose corn syrup, or fructose solutions. Rats were given access to food, water and a sugar solution for 24 h, after which blood and tissues were collected. Fructose access (as opposed to other sugars investigated) resulted in a doubling of circulating triglycerides. Glucose consumption resulted in upregulation of 7 satiety related hypothalamic peptides whereas changes in gene expression were mixed for remaining sugars. Also, following multiple verification assays, 6 satiety related peptides were verified as being affected by sugar intake. These data provide evidence that not all sugars are equally effective in affecting the control of intake.

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Impaired Insulin Secretion and Enhanced Insulin Sensitivity in Cholecystokinin-Deficient Mice

Cited by 50 publications

References 38 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

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

Effects of sugar solutions on hypothalamic appetite regulation

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