Elimination of glucagon-like peptide 1R signaling does not modify weight gain and islet adaptation in mice with combined disruption of leptin and GLP-1 action.

Scrocchi, Louise A.; Hill, Melissa L.; Saleh, Jumana; Perkins, Bruce A.; Drucker, Daniel J.

doi:10.2337/diabetes.49.9.1552

Cited by 58 publications

(37 citation statements)

References 65 publications

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“…Consistent with the cardiovascular effects of GLP-1 in rodents, GLP-1R Ϫ/Ϫ mice exhibit defective cardiovascular responses to stress (92). Despite the potential importance of GLP-1R circuits for transducing the anorectic action of leptin (93), GLP-1R Ϫ/Ϫ mice retain normal to enhanced leptin sensitivity (94,95). Similarly, food intake and body weight are not significantly perturbed in GLP-1R…”

Section: Glp-1 Preclinical Studies and Physiological Actions -mentioning

confidence: 81%

Enhancing Incretin Action for the Treatment of Type 2 Diabetes

2003

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OBJECTIVE—To examine the mechanisms of action, therapeutic potential, and challenges inherent in the use of incretin peptides and dipeptidyl peptidase-IV (DPP-IV) inhibitors for the treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS—The scientific literature describing the biological importance of incretin peptides and DPP-IV inhibitors in the control of glucose homeostasis has been reviewed, with an emphasis on mechanisms of action, experimental diabetes, human physiological experiments, and short-term clinical studies in normal and diabetic human subjects. RESULTS—Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) exert important effects on β-cells to stimulate glucose-dependent insulin secretion. Both peptides also regulate β-cell proliferation and cytoprotection. GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of GLP-1, but not GIP, are preserved in subjects with type 2 diabetes. However, native GLP-1 is rapidly degraded by DPP-IV after parenteral administration; hence, degradation-resistant, long-acting GLP-1 receptor (GLP-1R) agonists are preferable agents for the chronic treatment of human diabetes. Alternatively, inhibition of DPP-IV–mediated incretin degradation represents a complementary therapeutic approach, as orally available DPP-IV inhibitors have been shown to lower glucose in experimental diabetic models and human subjects with type 2 diabetes. CONCLUSIONS—GLP-1R agonists and DPP-IV inhibitors have shown promising results in clinical trials for the treatment of type 2 diabetes. The need for daily injections of potentially immunogenic GLP-1–derived peptides and the potential for unanticipated side effects with chronic use of DPP-IV inhibitors will require ongoing scrutiny of the risk-benefit ratio for these new therapies as they are evaluated in the clinic.

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Section: Glp-1 Preclinical Studies and Physiological Actions -mentioning

confidence: 81%

Enhancing Incretin Action for the Treatment of Type 2 Diabetes

2003

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“…The sections were examined using a Leica (Leitz Labor Lux S; Leica Microsystem, Heerbrugg, Switzerland) microscope equipped with a video camera and connected to a computer with imaging software (Q500MC; Leica Microsystem). Estimates of islet area, islet number, number of BrdU immunopositive cells, and total pancreatic area were determined in a blinded manner as described (29,31). Statistics.…”

Section: Methodsmentioning

confidence: 99%

Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate

Kim

Baggio²,

Bridon³

et al. 2003

Diabetes

206

115

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“…GLP-1RϪ/Ϫ ␤ cells exhibit reduced levels of cAMP, defects in glucose-stimulated insulin secretion (32), and abnormalities in glucose-stimulated calcium signaling (65). Nevertheless, ob/ob:GLP-1RϪ/Ϫ mice exhibit enhanced islet proliferation and up-regulation of islet mass despite the complete absence of GLP-1R signaling (34). In contrast, the finding that GLP-1RϪ/Ϫ ␤ cells exhibit enhanced susceptibility to STZ-induced apoptosis demonstrates that GLP-1 receptor signaling is an important physiological determinant of ␤-cell survival following external injury.…”

Section: Discussionmentioning

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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Elimination of glucagon-like peptide 1R signaling does not modify weight gain and islet adaptation in mice with combined disruption of leptin and GLP-1 action.

Cited by 58 publications

References 65 publications

Enhancing Incretin Action for the Treatment of Type 2 Diabetes

Enhancing Incretin Action for the Treatment of Type 2 Diabetes

Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate

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

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