Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

Koehler, Jacqueline A.; Baggio, Laurie L.; Cao, Xiemin; Abdulla, Tahmid; Campbell, Jonathan E.; Secher, Thomas; Jelsing, Jacob; Larsen, Brett; Drucker, Daniel J.

doi:10.2337/db14-0883

Cited by 48 publications

(51 citation statements)

References 41 publications

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“…Analysis of the protein expression profile in the mouse pancreas using tandem mass spectroscopy allowed us to deduce the identity of multiple proteins preferentially induced by GLP-1R agonists, including a subset of proteins important for protein translation. In contrast, we did not detect increases in abundance or activity of amylase or lipase (56). Whether these observations in mice are applicable to primates or humans remains unclear, and further work is needed to determine whether GLP-1 induces pancreatic protein synthesis in other species.…”

Section: Nonglycemic Pancreatic Actions Of Incretin Hormonescontrasting

confidence: 62%

Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation: The 2014 Banting Lecture

Drucker

2015

Diabetes

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The Banting Medal for Scientific Achievement is the highest scientific award of the American Diabetes Association (ADA). Given in memory of Sir Frederick Banting, one of the key investigators in the discovery of insulin, the Banting Medal is awarded annually for scientific excellence, recognizing significant long-term contributions to the understanding, treatment, or prevention of diabetes. Daniel J. Drucker, MD, of the Department of Medicine, Mount Sinai Hospital and the Lunenfeld-Tanenbaum Research Institute in Toronto, Ontario, Canada, received the prestigious award at the ADA's 74th Scientific Sessions, 13–17 June 2014, in San Francisco, California. He presented the Banting Lecture, “Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation,” on Sunday, 15 June 2014. Gut peptides convey nutrient-regulated signals to the enteric nervous system and to distal organs, acting as circulating hormones secreted in the basal and postprandial state. Here I provide an overview of the actions of glucagon-like peptide (GLP)-1 and GLP-2, the two major enteroendocrine L-cell peptides. The endogenous physiological actions of GLP-1 have been delineated using antagonists and Glp1r−/− mice and include the control of islet hormone secretion in a glucose-dependent manner, leading to improvement of fasting and postprandial glucose homeostasis. GLP-1 receptors (GLP-1Rs) are also widely distributed in multiple extrapancreatic organs, providing a mechanistic explanation for the nonglycemic actions attributed to GLP-1. The multiple metabolic actions of GLP-1 enable reduction of glycemia and body weight in diabetic and obese subjects, providing the opportunity to reduce glycemia in human subjects with diabetes with a low risk of hypoglycemia. GLP-2 plays a key role in the control of energy absorption and in the integrity of the intestinal mucosa, and a GLP-2R agonist, teduglutide, is now used for augmentation of energy absorption in parenteral nutrition–dependent subjects with short bowel syndrome. GLP-1 and GLP-2 are both cleaved by dipeptidyl peptidase-4 (DPP-4); hence, inhibition of DPP-4 activity enables yet another pathway for potentiation of incretin action and the therapy for type 2 diabetes. Here I review our 30-year experience with the elucidation of gut hormone action and, wherever possible, highlight therapeutic implications of our preclinical studies and future opportunities for incretin research.

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Section: Nonglycemic Pancreatic Actions Of Incretin Hormonescontrasting

confidence: 62%

Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation: The 2014 Banting Lecture

Drucker

2015

Diabetes

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“…A recent rodent study showed that incretin therapy increases pancreas mass by ~30% as a result of enhanced protein synthesis [99]. Although we have reported that there was no change in pancreas volume measured by CT scan 6 months after the initiation of liraglutide treatment [100], a slight increase in amylase or lipase after treatment with GLP-1RA has been consistently observed [100][101][102][103].…”

Section: Pancreatic Fat Beta-cell Function and Glucose Intolerancementioning

confidence: 48%

“…Using autopsy pancreas, Butler et al reported that pancreas mass was increased by ~40% in subjects with T2D who had been treated with incretinbased medicine [96], although these results may have been confounded by other factors [97,98]. A recent rodent study showed that incretin therapy increases pancreas mass by ~30% as a result of enhanced protein synthesis [99]. Although we have reported that there was no change in pancreas volume measured by CT scan 6 months after the initiation of liraglutide treatment [100], a slight increase in amylase or lipase after treatment with GLP-1RA has been consistently observed [100][101][102][103].…”

Section: Anti-diabetic Medication and Exocrine Pancreasmentioning

confidence: 99%

Pancreas Volume and Fat Deposition in Diabetes and Normal Physiology: Consideration of the Interplay Between Endocrine and Exocrine Pancreas

Saisho¹

2016

Rev Diabet Stud

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■ AbstractThe pancreas is comprised of exocrine and endocrine components. Despite the fact that they are derived from a common origin in utero, these two compartments are often studied individually because of the different roles and functions of the exocrine and endocrine pancreas. Recent studies have shown that not only type 1 diabetes (T1D), but also type 2 diabetes (T2D), is characterized by a deficit in beta-cell mass, suggesting that pathological changes in the pancreas are critical events in the natural history of diabetes. In both patients with T1D and those with T2D, pancreas mass and exocrine function have been reported to be reduced. On the other hand, pancreas volume and pancreatic fat increase with obesity. Increased beta-cell mass with increasing obesity has also been observed in humans, and ectopic fat deposits in the pancreas have been reported to cause beta-cell dysfunction. Moreover, neogenesis and transdifferentiation from the exocrine to the endocrine compartment in the postnatal period are regarded as a source of newly formed beta-cells. These findings suggest that there is important interplay between the endocrine and exocrine pancreas throughout life. This review summarizes the current knowledge on physiological and pathological changes in the exocrine and endocrine pancreas (i.e., beta-cell mass), and discusses the potential mechanisms of the interplay between the two compartments in humans to understand the pathophysiology of diabetes better.

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“…Circulating GLP-1 has two forms, GLP and GLP [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] amide. About 80% of circulating GLP1 in human is GLP [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] amide [18]. Plasma levels of GLP-1 in the basal level range between 5-10 pM and its level could increase to 50 pM after a meal.…”

Section: Glp-1mentioning

confidence: 99%

“…However, this efect is not caused by the increase in proliferation of islet or ductal cells. Increased protein synthesis in the exocrine acinar cells accounts for the increase of pancreas weight [24]. GLP-1 also inhibits glucagon secretion from pancreatic α cells after meals to lower the blood glucose.…”

Section: Glp-1mentioning

confidence: 99%

Neuroendocrine Control of Hepatic Gluconeogenesis

Mao¹,

Zhang²

2017

Gluconeogenesis

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Glucose is intricately regulated in human body through a complex network of hormonal and neuronal factors. A series of evidence suggests that the gastrointestinal tract and the central nervous system play prominent roles in the regulation of glucose and energy homeostasis. The gut senses the nutrient supply to co-ordinate the release of hormones that activate neuronal networks in the brain, leading to the subsequent modulation of hepatic glucose output via the gut-brain-liver axis. The gut hormones also act on multiple peripheral tissues to regulate glucose level through an insulindependent and/or -independent mechanism. The brain, especially the hypothalamus, could also response to the hormones such as insulin and leptin and diferent nutrients to modulate the glucose homeostasis. In this chapter, we review the gut-brainliver axis and the role of this organ interaction in the control of glucose homeostasis. A beter understanding of these pathways will provide novel strategies for improved glycaemic control.

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Glucagon-Like Peptide-1 Receptor Agonists Increase Pancreatic Mass by Induction of Protein Synthesis

Cited by 48 publications

References 41 publications

Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation: The 2014 Banting Lecture

Deciphering Metabolic Messages From the Gut Drives Therapeutic Innovation: The 2014 Banting Lecture

Pancreas Volume and Fat Deposition in Diabetes and Normal Physiology: Consideration of the Interplay Between Endocrine and Exocrine Pancreas

Neuroendocrine Control of Hepatic Gluconeogenesis

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