Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations

Greig, Nigel H.; Holloway, Harold W.; Ore, K. A. De; Jani, Dilip; Wang, Y.; Zhou, Jie; Garant, Michael J.; Egan, Josephine M.

doi:10.1007/s001250051111

Cited by 190 publications

(170 citation statements)

References 20 publications

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“…The normalization of HbA1c with both 1-mg and 2-mg doses of Boc5 suggests that effects may have been near maximal and that efficacy may have been seen at lower doses. Differences in HbA1c comparable to those reported here were observed in db/db mice treated for 13 weeks with daily injections of exendin-4 (21).…”

Section: Boc5 Is Consistent With Its Behaving As a Glp-1r Agonist In supporting

confidence: 87%

A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db / db mice

Chen

Liao

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

157

143

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Section: Boc5 Is Consistent With Its Behaving As a Glp-1r Agonist In supporting

confidence: 87%

A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db / db mice

Chen

Liao

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

157

143

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“…STZ (Sigma) (50 mg/kg body weight, intraperitoneal injection once daily for 5 days) was administered as a freshly prepared solution in 0.1 mM sodium citrate pH 5.5. Exendin-4 (Ex-4; 24 nmol/kg body weight, a dose selected based on therapeutic efficacy in previous mouse experiments (30)) was administered as a single daily intraperitoneal injection. For studies depicted in Figs.…”

Section: Methodsmentioning

confidence: 99%

Glucagon-like Peptide-1 Receptor Signaling Modulates β Cell Apoptosis

Li¹,

Hansotia²,

Yusta³

et al. 2003

Journal of Biological Chemistry

556

379

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Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and augments ␤ cell mass via activation of ␤ cell proliferation and islet neogenesis. We examined whether GLP-1 receptor signaling modifies the cellular susceptibility to apoptosis. Mice administered streptozotocin (STZ), an agent known to induce ␤ cell apoptosis, exhibit sustained improvement in glycemic control and increased levels of plasma insulin with concomitant administration of the GLP-1 agonist exendin-4 (Ex-4). Blood glucose remained significantly lower for weeks after cessation of exendin-4. STZ induced ␤ cell apoptosis, which was significantly reduced by co-administration of Ex-4. Conversely, mice with a targeted disruption of the GLP-1 receptor gene exhibited increased ␤ cell apoptosis after STZ administration. Exendin-4 directly reduced cytokine-induced apoptosis in purified rat ␤ cells exposed to interleukin 1␤, tumor necrosis fator ␣, and interferon ␥ in vitro. Furthermore, Ex-4-treated BHK-GLP-1R cells exhibited significantly increased cell viability, reduced caspase activity, and decreased cleavage of ␤-catenin after treatment with cycloheximide in vitro. These findings demonstrate that GLP-1 receptor signaling directly modifies the susceptibility to apoptotic injury, and provides a new potential mechanism linking GLP-1 receptor activation to preservation or enhancement of ␤ cell mass in vivo.Glucagon-like peptide-1 (GLP-1) 1 is derived from posttranslational processing of proglucagon in enteroendocrine L cells (1) and is secreted from the distal gut after nutrient ingestion (2). The termination of GLP-1 action by the enzyme dipeptidyl peptidase IV occurs within minutes following GLP-1 secretion (3-5), yet GLP-1 exerts several rapid metabolic actions including stimulation and inhibition of insulin and glucagon secretion, respectively (6 -10). GLP-1 action is essential for glucose homeostasis, because GLP-1 receptor blockade with the antagonist exendin (9 -39) increases blood glucose and decreases levels of circulating insulin in human and rodent studies (11)(12)(13)(14).Activation of GLP-1 receptor signaling leads to enhanced expression of mRNA transcripts for glucokinase, GLUT-2, Pdx-1, and insulin in ␤ cell lines (15-17) and in both normal and diabetic rodents (18 -20). Furthermore, GLP-1 and exendin-4 promote differentiation of exocrine cell lines toward a ␤ cell phenotype (21), a process that appears to depend on the expression of Pdx-1 (22, 23).GLP-1 receptor signaling is also coupled to formation of new ␤ cells through enhanced proliferation of existing ␤ cells (24) and via induction of islet neogenesis (25). The mitogenic actions of GLP-1 are detectable in normal rodents (20,24) and in the setting of experimental diabetes (19,25). Administration of GLP-1 or exendin-4 to newborn rats treated with the ␤ cell toxin streptozotocin (STZ) leads to increased ␤ cell mass at postnatal day 7, which persists and remains increased at 2 months of age. The increased ␤ cell mass in the GLP-1/exendin-4 treated rats was attributed to both enhan...

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“…urine and cerebrospinal fluid, with typical amounts of less than 5% of the total signal. The ratio of lean tissue: body fat expressed as weight: weight was calculated from the NMR data [17].…”

Section: Methodsmentioning

confidence: 99%

Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

et al. 2008

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Aims/hypothesis Exercise ameliorates oxidative stressmediated diabetic vascular endothelial dysfunction through poorly defined mechanisms. We hypothesised that, in addition to improving metabolic parameters, upregulation of antioxidants such as superoxide dismutase (SOD) mediates exercise-induced reductions of oxidative stress and increased nitric oxide (NO) bioavailability, and also restores vasodilatation. Methods Type 2 diabetic db/db and normoglycaemic wildtype mice were exercised at moderate intensity for 1 h a day for 7 weeks, leading to a 10% body weight loss. Sedentary animals or those undergoing a low-intensity exercise regimen causing non-significant weight loss were also used. We examined aortic endothelial cell function, NO bioavailability and various biomarkers of oxidative stress. Results Moderate-intensity exercise lowered body weight, increased mitochondrial manganese SOD (MnSOD) and both total and phosphorylated (Ser1177) endothelial nitric oxide synthase (eNOS) protein production; it also reduced wholebody (plasma 8-isoprostane) and tissue oxidative stress (nitrotyrosine immunostaining or protein carbonyl levels in the aorta). Low-intensity exercise did not alter body weight; however, it upregulated cytosolic Cu/Zn-SOD instead of MnSOD, and still demonstrated all the above benefits in the db/db aorta. Importantly, both exercise protocols improved endothelial-dependent vasodilatation and NO bioavailability without altering hyperglycaemic status in db/db mice. Conclusions/interpretation Exercise reverses diabetic vascular endothelial dysfunction independently of improvements in body weight or hyperglycaemia. Our data suggest that upregulation of eNOS and specific SOD isoforms could play important roles in improving NO bioavailability, as well as in reversing endothelial dysfunction in type 2 diabetes patients through lifestyle modifications in the management of diabetes.

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Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations

Cited by 190 publications

References 20 publications

A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db / db mice

A nonpeptidic agonist of glucagon-like peptide 1 receptors with efficacy in diabetic db / db mice

Glucagon-like Peptide-1 Receptor Signaling Modulates β Cell Apoptosis

Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

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