Glucagon-like peptide 1 agonists and the development and growth of pancreatic β-cells

Glucagon-like peptide 1 (GLP-1) is an intestine-derived insulinotropic hormone that stimulates glucose-dependent insulin production and secretion from pancreatic β-cells. Other recognized actions of GLP-1 are to suppress glucagon secretion and hepatic glucose output, delay gastric emptying, reduce food intake, and promote glucose disposal in peripheral tissues. All of these actions are potentially beneficial for the treatment of type 2 diabetes mellitus. Several GLP-1 agonists are in clinical trials for the treatment of diabetes. More recently, GLP-1 agonists have been shown to stimulate the growth and differentiation of pancreatic β-cells, as well as to exert cytoprotective, antiapoptotic effects on β-cells. Recent evidence indicates that GLP-1 agonists act on receptors on pancreas-derived stem/progenitor cells to prompt their differentiation into β-cells. These new findings suggest an approach to create β-cells in vitro by expanding stem/progenitor cells and then to convert them into β-cells by treatment with GLP-1. Thus GLP-1 may be a means by which to create β-cells ex vivo for transplantation into patients with insulinopenic type 1 diabetes and severe forms of type 2 diabetes.

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The Incretins and Pancreatic β-Cells: Use of Glucagon-Like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide to Cure Type 2 Diabetes Mellitus

Korean Diabetes Journal ◽

10.4093/kdj.2010.34.1.2 ◽

2010 ◽

Vol 34 (1) ◽

pp. 2 ◽

Cited By ~ 7

Author(s):

Mi-Hyun Kim ◽

Moon-Kyu Lee

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Β Cells ◽

Pancreatic Β Cells ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Fighting Type-2 Diabetes: Present and Future Perspectives

Current Medicinal Chemistry ◽

10.2174/0929867324666171009115356 ◽

2019 ◽

Vol 26 (10) ◽

pp. 1891-1907 ◽

Cited By ~ 2

Author(s):

Cai-Guo Yu ◽

Ying Fu ◽

Yuan Fang ◽

Ning Zhang ◽

Rong-Xin Sun ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glycemic Control ◽

Clinical Results ◽

Diabetic Patients ◽

Β Cells ◽

Receptor Agonists ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Background: Type-2 diabetes mellitus accounts for 80-90% of diabetic patients. So far, the treatment of diabetes mainly aims at elevating insulin level and lowering glucose level in the peripheral blood and mitigating insulin resistance. Physiologically, insulin secretion from pancreatic β cells is delicately regulated. Thus, how insulin-related therapies could titrate blood glucose appropriately and avoid the occurrence of hypoglycemia remains an important issue for decades. Similar question is addressed on how to attenuate vascular complication in diabetic subjects. Methods: We overviewed the evolution of each class of anti-diabetic drugs that have been used in clinical practice, focusing on their mechanisms, clinical results and cautions. Results: Glucagon-like peptide-1 receptor agonists stimulate β cells for insulin secretion in response to diet but not in fasting stage, which make them superior than conventional insulinsecretion stimulators. DPP-4 inhibitors suppress glucagon-like peptide-1 degradation. Sodium/ glucose co-transporter 2 inhibitors enhance glucose clearance through urine excretion. The appearance of these new drugs provides new information about glycemic control. We update the clinical findings of Glucagon-like peptide-1 receptor agonists, DPP-4 inhibitors and Sodium/glucose cotransporter 2 inhibitors in glycemic control and the risk or progression of cardiovascular disease in diabetic patients. Stem cell therapy might be an alternative tool for diabetic patients to improve β cell regeneration and peripheral ischemia. We summarize the clinical results of mesenchymal stem cells transplanted into patients with diabetic limb and foot. Conclusion: A stepwise intensification of dual and triple therapy for individual diabetic patient is required to achieve therapeutic target.

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Pleiotropic Benefits of DPP-4 Inhibitors Beyond Glycemic Control

Clinical Medicine Insights Endocrinology and Diabetes ◽

10.1177/11795514211051698 ◽

2021 ◽

Vol 14 ◽

pp. 117955142110516

Author(s):

Seon Mee Kang ◽

Jeong Hyun Park

Keyword(s):

Type 2 Diabetes ◽

Glucose Level ◽

Glucose Control ◽

Clinical Implications ◽

Β Cells ◽

Pancreatic Β Cells ◽

Beneficial Effects ◽

Physiological Processes ◽

Glucagon Like Peptide

Dipeptidyl peptidase (DPP)-4 inhibitors are oral anti-diabetic medications that block the activity of the ubiquitous enzyme DPP-4. Inhibition of this enzyme increases the level of circulating active glucagon-like peptide (GLP)-1 secreted from L-cells in the small intestine. GLP-1 increases the glucose level, dependent on insulin secretion from pancreatic β-cells; it also decreases the abnormally increased level of glucagon, eventually decreasing the blood glucose level in patients with type 2 diabetes. DPP-4 is involved in many physiological processes other than the degradation of GLP-1. Therefore, the inhibition of DPP-4 may have numerous effects beyond glucose control. In this article, we review the pleiotropic effects of DPP-4 inhibitors beyond glucose control, including their strong beneficial effects on the stress induced accelerated senescence of vascular cells, and the possible clinical implications of these effects.

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Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights

International Journal of Molecular Sciences ◽

10.3390/ijms21134725 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4725 ◽

Cited By ~ 2

Author(s):

Unai Galicia-Garcia ◽

Shifa Jebari ◽

Asier Larrea-Sebal ◽

Kepa B. Uribe ◽

Haziq Siddiqi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Statin Therapy ◽

Statin Treatment ◽

Β Cells ◽

Pancreatic Β Cells ◽

Peripheral Tissues ◽

Increased Risk ◽

Meta Analyses ◽

Diabetes Monitoring

Statins are the gold-standard treatment for the prevention of primary and secondary cardiovascular disease, which is the leading cause of mortality worldwide. Despite the safety and relative tolerability of statins, observational studies, clinical trials and meta-analyses indicate an increased risk of developing new-onset type 2 diabetes mellitus (T2DM) after long-term statin treatment. It has been shown that statins can impair insulin sensitivity and secretion by pancreatic β-cells and increase insulin resistance in peripheral tissues. The mechanisms involved in these processes include, among others, impaired Ca2+ signaling in pancreatic β-cells, down-regulation of GLUT-4 in adipocytes and compromised insulin signaling. In addition, it has also been described that statins’ impact on epigenetics may also contribute to statin-induced T2DM via differential expression of microRNAs. This review focuses on the evidence and mechanisms by which statin therapy is associated with the development of T2DM. This review describes the multifactorial combination of effects that most likely contributes to the diabetogenic effects of statins. Clinically, these findings should encourage clinicians to consider diabetes monitoring in patients receiving statin therapy in order to ensure early diagnosis and appropriate management.

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The complexity of signalling mediated by the glucagon-like peptide-1 receptor

Biochemical Society Transactions ◽

10.1042/bst20150244 ◽

2016 ◽

Vol 44 (2) ◽

pp. 582-588 ◽

Cited By ~ 11

Author(s):

Madeleine M. Fletcher ◽

Michelle L. Halls ◽

Arthur Christopoulos ◽

Patrick M. Sexton ◽

Denise Wootten

Keyword(s):

Type 2 Diabetes ◽

Cell Mass ◽

Peripheral Tissues ◽

Biased Agonism ◽

Temporal Aspects ◽

Class B ◽

Future Drug ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR that is a major therapeutic target for the treatment of type 2 diabetes. The receptor is activated by the incretin peptide GLP-1 promoting a broad range of physiological effects including glucose-dependent insulin secretion and biosynthesis, improved insulin sensitivity of peripheral tissues, preservation of β-cell mass and weight loss, all of which are beneficial in the treatment of type 2 diabetes. Despite this, existing knowledge surrounding the underlying signalling mechanisms responsible for the physiological actions downstream of GLP-1R activation is limited. Here, we review the current understanding around GLP-1R-mediated signalling, in particular highlighting recent contributions to the field on biased agonism, the spatial and temporal aspects for the control of signalling and how these concepts may influence future drug development.

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