Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Holz, George G.; Chepurny, Oleg G.

doi:10.2174/0929867033456648

Cited by 123 publications

(108 citation statements)

References 170 publications

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“…Unlike GLP-1, exenatide exhibits extended kinetics 5 due to resistance to proteolytic degradation by dipeptidyl peptidase IV (DPPIV), and has up to 3000-fold higher in vivo potency for glucose-lowering in some animal models. 6 Agents that activate the GLP-1 receptor possess high therapeutic potential for the treatment of diabetes; [7][8][9] exenatide is a currently marketed antidiabetic agent that is shown to improve glycemic control in patients with type 2 diabetes. [10][11][12] Glucose-lowering with exenatide, GLP-1 and GLP-1 analogs has been associated with several mechanisms of action, the first of which to be identified was an enhancement of glucose-dependent insulin secretion.…”

Section: Introductionmentioning

confidence: 99%

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Mack¹,

Moore²,

Jodka³

et al. 2006

Int J Obes

127

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Background: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. Objective: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. Methods and results: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 mg/kg/ day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 mg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 mg/kg/day (Po0.05). Decreased body weight gain was associated with a significant decrease in fat mass (Po0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (Po0.05). Exenatide at 10 mg/kg significantly reduced food intake (Po0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. Conclusion: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

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Section: Introductionmentioning

confidence: 99%

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Mack¹,

Moore²,

Jodka³

et al. 2006

Int J Obes

127

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“…The substitution of natural proteins by artificial sequences is a promising approach to resolve this issue. Recently, several therapeutic agents (Drucker, 2001;Drucker, 2002;Holz & Chepurny, 2003) have been proposed to increase www.intechopen.com insulinotropic effect of pancreatic cells and protect them from apoptosis. The most promising agent is glucagon-like peptide 1 (GLP-1) that has an extremely short half-life time (less than 2 min) in vivo (Lee et al, 2005).…”

Section: Poly(ethylene Glycol)-based Gelsmentioning

confidence: 99%

Encapsulation and Surface Engineering of Pancreatic Islets: Advances and Challenges

Kozlovskaya¹,

Zavgorodnya²,

Kharlampieva³

2012

Biomedicine

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“…Glucagon-like peptide-1-(7-36)-amide (GlP-1), a hormone secreted by endocrine l cells of the intestinal tract, has unique insulinotropic and growth factor-like signal transduction properties, which make it a new therapeutic agent for the treatment of T2dM (19). recently, Magnusson et al showed that ZnT-8 is a potential target for the pharmacological manipulation of GlP-1 (20).…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of zinc transporter 8 in the pancreas of db/db mice is rescued by Exendin-4 administration

Liu

Jiang

et al. 2010

Mol Med Rep

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Abstract. recent human genetic studies have revealed that common variants of the zinc transporter 8 (ZnT-8) gene are strongly associated with type 2 diabetes mellitus (T2dM). ZnT-8 has been suggested as a potential candidate in the regulation of insulin secretion in pancreatic β-cells. in this study, we aimed to explore the expression of ZnT-8 in the development of T2dM. The expression of ZnT-8 was investigated in the pancreas and adipose tissue of homozygous db/ db mice compared to heterozygous sibling db/+ mice (n=6-8). Furthermore, the effect of exendin-4 (an analogue of glucagon-like peptide-1) on ZnT-8 expression was examined in the db/db mice. exendin-4 or vehicle (control) was administered (i.p., 1 nmol/kg) to diabetic 8-week-old db/db mice daily for 14 days (n=8). The results revealed that ZnT-8 protein levels in the pancreas of db/db mice were reduced, accompanied by a decrease in ZnT-8 mrna. ZnT-8 mrna and protein levels were also significantly reduced in the epididymal and visceral fat of the db/db mice. Treatment with exendin-4 up-regulated ZnT-8 gene expression in the pancreas of the db/db mice, but did not affect its expression in adipose tissue. These findings suggest that ZnT-8 synthesis in the pancreas and adipose tissue is down-regulated in db/db mice. reduced ZnT-8 production in the pancreas may advance defects in insulin secretion in diabetes. These may be reversed, at least partially, by the administration of exendin-4.

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Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Cited by 123 publications

References 170 publications

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Encapsulation and Surface Engineering of Pancreatic Islets: Advances and Challenges

Down-regulation of zinc transporter 8 in the pancreas of db/db mice is rescued by Exendin-4 administration

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