Effects of 3 Months of Continuous Subcutaneous Administration of Glucagon-Like Peptide 1 in Elderly Patients With Type 2 Diabetes

Meneilly, Graydon S.; Greig, Nigel H.; Tildesley, Hugh D.; Habener, Joel F.; Egan, Josephine M.; Elahi, Dariush

doi:10.2337/diacare.26.10.2835

Cited by 94 publications

(64 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As blood glucose levels are already normalized at 2 weeks after treatment, GLP-1 may not affect fasting glucagon levels at this time. This result is consistent with previous findings, which showed that continuous infusion of GLP-1 or treatment with GLP-1 analog had no effect on fasting glucagon levels (6,43,44). An increase in hepatic triglyceride synthesis and secretion is observed in type 2 diabetes (45).…”

Section: Glp-1 Therapy In Obese Diabetic Micesupporting

confidence: 83%

Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis

et al. 2007

View full text Add to dashboard Cite

Long-term treatment with glucagon-like peptide (GLP)-1 or its analog can improve insulin sensitivity. However, continuous administration is required due to its short half-life. We hypothesized that continuous production of therapeutic levels of GLP-1 in vivo by a gene therapy strategy may remit hyperglycemia and maintain prolonged normoglycemia. We produced a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) under the cytomegalovirus promoter, intravenously injected it into diabetic ob/ob mice, and investigated the effect of this treatment on remission of diabetes, as well as the mechanisms involved. rAd-GLP-1-treated diabetic ob/ob mice became normoglycemic 4 days after treatment, remained normoglycemic over 60 days, and had reduced body weight gain. Glucose tolerance tests found that exogenous glucose was cleared normally. rAd-GLP-1-treated diabetic ob/ob mice showed improved ␤-cell function, evidenced by glucose-responsive insulin release, and increased insulin sensitivity, evidenced by improved insulin tolerance and increased insulin-stimulated glucose uptake in adipocytes. rAd-GLP-1 treatment increased basal levels of insulin receptor substrate (IRS)-1 in the liver and activation of IRS-1 and protein kinase C by insulin in liver and muscle; increased Akt activation was only observed in muscle. rAd-GLP-1 treatment reduced hepatic glucose production and hepatic expression of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fatty acid synthase in ob/ob mice. Taken enhances ␤-cell function; stimulates ␤-cell growth, survival, differentiation, and proliferation; and promotes satiety and delaying gastric emptying (1,2). Furthermore, impaired GLP-1 secretion was observed in patients with type 2 diabetes (3). Therefore, GLP-1 has been proposed as a treatment for type 2 diabetes. Treatment with GLP-1 or its analog, exendin-4, improved insulin sensitivity and glucose tolerance and reduced hyperinsulinemia in animal models of type 2 diabetes (4,5). In type 2 diabetic patients, subcutaneous infusion of GLP-1 for 6 weeks resulted in improved insulin sensitivity and ␤-cell function (6). However, the precise mechanisms by which insulin sensitivity and glucose tolerance are improved are not known.Although subcutaneous injections or intravenous or subcutaneous infusions of GLP-1 showed therapeutic effects on lowering blood glucose levels, the short half-life (ϳ2 min) and rapid clearance of GLP-1 limits the maintenance of therapeutic levels by exogenous administration. GLP-1 is degraded by the enzyme dipeptidyl peptidase IV (7,8); therefore, GLP-1 agonists that are resistant to dipeptidyl peptidase IV degradation and inhibitors of dipeptidyl peptidase IV have been investigated for the treatment of type 2 diabetes (9). We hypothesized that continuous expression of GLP-1 in vivo by a gene therapy strategy may remit hyperglycemia and maintain normoglycemia. In this study, we produced a recombinant adenovirus that expresses and secretes GLP-1 under the control of the cytomegalovirus promoter (recombinant adenovir...

show abstract

Section: Glp-1 Therapy In Obese Diabetic Micesupporting

confidence: 83%

Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis

et al. 2007

View full text Add to dashboard Cite

show abstract

“…The weight loss as well as reduced gluco-and lipotoxicity induced by GLP-1 were considered likely explanations for the improved insulin sensitivity. Similar findings were made in a study involving 3 mo of continuous subcutaneous infusion of GLP-1 to diabetic subjects (183). However, the same group reported acute augmentation by GLP-1 of insulin-mediated glucose uptake in elderly patients with diabetes (185) and also reported insulin-mimetic effects of GLP-1 in obese subjects compared with nonobese matched controls (60).…”

Section: Whole Body Effects Peripheral Effects and Effects On Insupporting

confidence: 62%

The Physiology of Glucagon-like Peptide 1

Holst¹

2007

Physiological Reviews

2,667

2,385

View full text Add to dashboard Cite

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the “ileal brake” mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.

show abstract

“…In contrast, in a 3-month study in elderly patients switched from oral therapy to continuous GLP-1 infusion, as compared with those remaining on their previous oral therapy, found no effect of GLP-1 on glucagon, and the authors interpreted this as a loss of effect on glucagon with chronic treatment [102]. Another study explored the effects of 1 week of treatment with liraglutide on measures of alpha cell function in patients with type 2 diabetes.…”

Section: Acute Effects Of Exogenous and Endogenous Glp-1 On Alpha Celmentioning

confidence: 99%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

View full text Add to dashboard Cite

Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

show abstract

Effects of 3 Months of Continuous Subcutaneous Administration of Glucagon-Like Peptide 1 in Elderly Patients With Type 2 Diabetes

Cited by 94 publications

References 39 publications

Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis

Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis

The Physiology of Glucagon-like Peptide 1

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Contact Info

Product

Resources

About