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GLP-1: Actions on Beta-cell Mass and Function

David Joffe, BSPharm, CDE

Tina Burge, PharmD Candidate Florida A&M University

Kiet Ngo, Pharm D Candidate Mercer University

Abnormalities in incretin hormones such as the glucagon-like peptide-1 (GLP-1) contribute to the development of hyperglycemia. GLP-1 was discovered as a peptide encoded by the proglucagon gene and was named glucagon-like because the peptide was approximately 50% homologous to glucagon.

It was the second incretin hormone discovered after gastric inhibitor polypeptide (GIP). The incretin effect is the concept that oral glucose administration promotes a much greater degree of insulin secretion compared to an isoglycemic glucose infusion administered parenterally. This concept highlights the existence of gut-derived factors that enhance glucose-stimulated insulin secretion from pancreatic beta cells.

GLP-1 is released primarily from the ileum and colon in the response to food intake. These hormones act by binding to beta cells in the pancreas, which increase insulin release. GLP-1 also decreases the glucose production from the liver1. In healthy individuals GLP-1 and GIP together add up to about 60% of postprandial insulin secretion.2 However, since GLP-1 is easily degraded within a few minutes by dipeptidyl peptidase 4 (DPP-4), the GLP-1 receptor agonist such as Exenatide and Liraglutide are used to prolong this effect.

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A main complication in Type 2 Diabetes is the deterioration of the beta cells, which usually leads to insulin therapy as the disease progresses. This deterioration of beta cells has been linked to the impaired actions of the incretin hormones, which could be aiding in the increase of beta cell mass, as well as beta cell functions. GLP-1 receptors are in high concentrations on the beta cells within the pancreas, they have many functions; a few are increasing beta-cell proliferation, and neogenesis and beta cell mass. Patients that have diabetes exhibit that there is a shift towards an increase the rate of beta cell apoptosis compared to the new proliferation of beta cells3.
 

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Theories on how GLP-1 can prevent beta cell apoptosis, and possibly cause beta cell regeneration and proliferation:

GLP-1 inhibits apoptosis

Farilla and colleagues, demonstrated in their studies with the isolated human islets, which were separated into groups of those with and without GLP-1. These groups were evaluated on how the effect of GLP-1 had on apoptosis. In this study, GLP-1 increased beta cell mass by decreasing the apoptosis of the beta cells. After treatment with GLP-1, the number of apoptotic cells drastically reduced in the human isolated islets. Following day 5 there was a marked difference between the GLP-1 treated islets and the controls, with 8.9% apoptotic nuclei in the treatment group vs. 18.9% in the controls, P<0.01. Their study concluded that this is evidence that when GLP-1 was added to isolated human islets it was found that it inhibits cell apoptosis.4

GLP-1 Theories on Regeneration and Proliferation

The exact mechanism of GLP-1 binding to GLP-1 receptor coupled with beta cell release of insulin is unknown. According to Woo-Jin Song and colleagues: "Most, if not all effects of GLP-1 and E4 in beta cells appear to require intracellular activation of the adenosine-3′-5′-cyclic monophosphate (cAMP)- protein kinase A (PKA) signaling pathway by the G-protein coupled receptor of GLP-1, which is highly expressed on pancreatic beta cells. A second mechanism of PKA-independent incretin potentiation of glucose-stimulated insulin secretion (GSIS) involves cAMP-regulated guanine nucleotide exchange factor (cAMP-GEF) EPAC2. However, PKA-activity appears to be essential for optimal incretin effects on stimulating insulin vesicle exocytosis." 5

There have been studies performed in animal subjects that show evidence of the pleiotropic effects of GLP-1 on beta cells such as beta cell regeneration and proliferation. According to Riccardo Perfetti and colleagues from Cedars-Sinai Medical Center, Division of Endocrinology in Los Angeles, California, continuous infusion of GLP-1 to both young and old rats demonstrated an up-regulation of pancreatic-duodenum homeobox-1 (PDX-1) expression in islets and total pancreas which is essential for pancreogenesis, pancreatic cell differentiation, and maturation. Induced pancreatic cell proliferation and beta cell neogenesis were also seen in the rats that received treatment. 6

According to a study done by J. Buteau from the University of Montreal in Quebec, Canada and colleagues, GLP-1 at physiological concentrations increased beta cell DNA synthesis that was independent of glucose. GLP-1 increased the expression of mRNA and transcription factors that play a part in the pleiotropic effects such as DNA synthesis in pancreatic beta cells, metabolic enzyme gene expression, and insulin biosynthesis. 7 

According to a study done by Bernardo Yusta from the University of Toronto in Toronto, Canada and colleagues, treatment of diabetic rats with exendin-4 can significantly reduce biochemical markers of islet endoplasmic reticulum (ER) in beta cells. They show that stress of the endoplasmic reticulum (ER) homeostasis of rats impairs insulin biosynthesis, beta cell survival, and glucose homeostasis. They demonstrate that a murine model of diabetes is associated with the development of ER stress in beta cells. The study concludes that GLP-1 receptor signaling directly modulates the ER stress response, which leads to promotion of beta cell adaptation and survival.8

References:
  1. Garber AJ. The Role of GLP-1 and GLP-1 Agonist in Type 2 Diabetes. Living Medical eTextbook, Point in Knowlegde. Little Falls, New Jersey. 2012
  2. Salehi M, Aulinger B, Prigeon RL, et.al. Effect of endogenous GLP-1 on insulin secretion in Type 2 Diabetes. Diabetes. 59:2010
  3. Garber, AJ. Incretin effects on beta-cell function, replication, and mass. DiabetesCare. 34 (2): 2011
  4. Farilla L, Bulotta A, Hirshberg B, et. al. Glucagon-Like Peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. (2003), 144 (12): 5149-5158.
  5. Song WJ, Seshadri M, Ashraf U, Mdluli T, Mondal P, et al. Snapin Mediates Incretin Action and Augments Glucose-dependent Insulin Secretion. Cell Metab. 2011 March 2; 13(3): 308-319.
  6. Perfetti R, Zhou J, Doyle ME, and Egan JM. Glucagon-Like Peptide-1 Induces Cell Proliferation and Pancreatic-Duodenum Homeobox-1 Expression and Increases Endocrine Cell Mass in the Pancreas of Old, Glucose-Intolerant Rats. Endocrinology. 2000 December 1; 14(12) 4600-4605.
  7. Buteau J, Roduit R, Susini S, and Prentki M. Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetologia. 1999; 42: 856-864.
  8. Yusta B, Baggio LL, Estall JL, Koehler JA, Holland DP, et al. GLP-1 receptor activation improves B cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006 Nov; 4(5): 391-406.
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