Suppression of weight gain by glucagon in obese Zucker rats

Chan, Erwin; Mackey, M. A.; Snover, Dale C.; Schneider, Philip D.; Rucker, Richard D.; Allen, C. E.; Buchwald, Hēnry

doi:10.1016/0014-4800(84)90049-2

Cited by 27 publications

(16 citation statements)

References 20 publications

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“…The reduction in body weight ( Fig 8A ) was obtained without changes in food intake ( Fig 8B ), and thus supports the tendency observed in the first experiment. Comparable results on body weight and food intake have been seen in a study with chronic glucagon-treatment of obese zucker rats for 14 months [ 27 ]. Even though, we did not measure metabolic rate it is very likely that the glucagon effect on body weight is due to increased energy expenditure.…”

Section: Discussionmentioning

confidence: 66%

Sustained effect of glucagon on body weight and blood glucose: Assessed by continuous glucose monitoring in diabetic rats

et al. 2018

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Insulin is a vital part of diabetes treatment, whereas glucagon is primarily used to treat insulin-induced hypoglycemia. However, glucagon is suggested to have a central role in the regulation of body weight, which would be beneficial for diabetic patients. Since the glucagon effect on blood glucose is known to be transient, it is relevant to investigate the pharmacodynamics of glucagon after repeated dosing. In the present study, we used telemetry to continuously measure blood glucose in streptozotocin induced diabetic Sprague-Dawley rats. This allowed for a more detailed analysis of glucose regulation compared to intermittent blood sampling. In particular, we evaluated the blood glucose-lowering effect of different insulin doses alone, and in combination with a long acting glucagon analog (LAG). We showed how the effect of the LAG accumulated and persisted over time. Furthermore, we found that addition of the LAG decreased body weight without affecting food intake.In a subsequent study, we focused on the glucagon effect on body weight and food intake during equal glycemic control. In order to obtain comparable maximum blood glucose lowering effect to insulin alone, the insulin dose had to be increased four times in combination with 1 nmol/kg of the LAG. In this set-up the LAG prevented further increase in body weight despite the four times higher insulin-dose. However, the body composition was changed. The insulin group increased both lean and fat mass, whereas the group receiving four times insulin in combination with the LAG only significantly increased the fat mass. No differences were observed in food intake, suggesting a direct effect on energy expenditure by glucagon. Surprisingly, we observed decreased levels of FGF21 in plasma compared to insulin treatment alone. With the combination of insulin and the LAG the blood glucose-lowering effect of insulin was prolonged, which could potentially be beneficial in diabetes treatment.

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Section: Discussionmentioning

confidence: 66%

Sustained effect of glucagon on body weight and blood glucose: Assessed by continuous glucose monitoring in diabetic rats

et al. 2018

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“…In contrast to GLP-1 and insulin, hypoglycaemia causes an increase in glucagon secretion resulting in hepatic glycogenolysis. Administration of intraperitoneal and subcutaneous glucagon in rats reduces food intake and meal size in addition to reducing body weight gain [117,118]. Recently beneficial effects of a glucagon and GLP-1 co-agonist on obesity in rodents have been demonstrated [119,120].…”

Section: Glucagonmentioning

confidence: 99%

The role of gut hormones and the hypothalamus in appetite regulation

et al. 2010

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Abstract. The World Health Organisation has estimated that by 2015 approximately 2.3 billion adults will be overweight and more than 700 million obese. Obesity is associated with an increased risk of diabetes, cardiovascular events, stroke and cancer. The hypothalamus is a crucial region for integrating signals from central and peripheral pathways and plays a major role in appetite regulation. In addition, there are reciprocal connections with the brainstem and higher cortical centres. In the arcuate nucleus of the hypothalamus, there are two major neuronal populations which stimulate or inhibit food intake and influence energy homeostasis. Within the brainstem, the dorsal vagal complex plays a role in the interpretation and relaying of peripheral signals. Gut hormones act peripherally to modulate digestion and absorption of nutrients. However, they also act as neurotransmitters within the central nervous system to control food intake. Peptide YY, pancreatic polypeptide, glucagon-like peptide-1 and oxyntomodulin suppress appetite, whilst ghrelin increases appetite through afferent vagal fibres to the caudal brainstem or directly to the hypothalamus. A better understanding of the role of these gut hormones may offer the opportunity to develop successful treatments for obesity. Here we review the current understanding of the role of gut hormones and the hypothalamus on food intake and body weight control.

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“…It is released together with GLP‐1 and is an agonist both for GLP‐1 and glucagon receptors [55]. Oxyntomodulin has been explored as a potential therapy of overweight, because both GLP‐1 and glucagon receptor activation reduces body weight, and acute administration of glucagon increases energy expenditure [56,57]. A drawback would be the stimulation of hepatic glucose production by glucagon receptor activation.…”

Section: Other Incretins and Bioactive Gastro‐entero‐pancreatic Hormonesmentioning

confidence: 99%

“…Acute administration of glucagon stimulates energy expenditure and inhibits food intake [56,57]. An approach to treat type 2 diabetes would therefore be to stimulate the glucagon receptors, provided that the hyperglycaemic effect of glucagon is prevented.…”

Section: Co‐agonistsmentioning

confidence: 99%

The future of incretin‐based therapy: novel avenues—novel targets

Åhrén

2011

Diabetes Obesity Metabolism

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Incretin-based therapy for type 2 diabetes is based on the antidiabetic effects of glucagon-like peptide-1 (GLP-1) and instituted by GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors targeting the key islet defects of the disease. The treatment is clinically efficient and safe, and associated with a low risk of adverse events. It can be used both in early and late stages of the disease and both as monotherapy and add-on to other therapies. Current research on the future of incretin-based therapy focuses on optimizing its place in diabetes treatment and examines its potential in type 1 diabetes, in subjects with obesity without type 2 diabetes and in cardiovascular and neurodegenerative disorders. Other studies aim at prolonging the duration of action of the GLP-1 receptor agonists to allow weekly administration, and to develop orally GLP-1 receptor agonists. Furthermore, other investigators focus on stimulation of GLP-1 secretion by activating GLP-1-producing L-cells or using gene therapy. Finally, also other gastro-entero-pancreatic bioactive peptides are potential targets for drug development as are synthetic peptides engineered as co-agonists stimulating more than one receptor. We can therefore expect a dynamic development within this field in the coming years.

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Suppression of weight gain by glucagon in obese Zucker rats

Cited by 27 publications

References 20 publications

Sustained effect of glucagon on body weight and blood glucose: Assessed by continuous glucose monitoring in diabetic rats

Sustained effect of glucagon on body weight and blood glucose: Assessed by continuous glucose monitoring in diabetic rats

The role of gut hormones and the hypothalamus in appetite regulation

The future of incretin‐based therapy: novel avenues—novel targets

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