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Incretin Therapies: Current Use and Emerging Possibilities

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Abstract

In the last decade, analogs of the incretin glucagon-like peptide-1 (GLP-1) became an important pillar of the therapy of type 2 diabetes (T2D) and are a fascinating focus of current research. The term “incretin” denotes the entity of hormones that are secreted by the mucosal cells of the intestine and increases the secretion of insulin from the β-cells of the pancreas. The history of studies examining incretin effects goes far. The first comprehensive experiment proving the effects of incretins on the pancreas of animals was reported already as early as in the year 1902 by English physiologists Bayliss and Starling [1]. This was by the way the first description of a hormone at all. In this early research, the jejunum of a dog was cut from all nervous connections, but the blood vessels between the intestine and the pancreas were kept intact. The introduction of a liquid into the jejunum mimicking chyme resulted in an increase of pancreatic secretion. After infusion of the same liquid into the blood vessels supplying the pancreas, this increase of pancreatic secretion was not seen. Authors concluded absolutely correct that “since this part of the intestine was completely cut off from nervous connection with the pancreas, the conclusion was inevitable that the effect was produced by some chemical substance finding its way into the veins of the loop of jejunum in question and being carried in the blood-stream to the pancreatic cells” [1]. Today we know that incretins belong to the group of these “chemical substances” which are secreted after the ingestion of food.

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Abbreviations

ATP:

Adenosine triphosphate

cAMP:

Cyclic adenosine monophosphate

cAMP-GEF-2:

cAMP-guanine nucleotide exchange factor 2

CI:

95% confidence interval

DPP-4:

Dipeptidyl-peptidase 4

fMRI:

Functional magnetic resonance imaging

GIP:

Gastric inhibitory polypeptide (also: glucose-dependent insulinotropic peptide)

GLP-1:

Glucagon-like peptide-1

HbA1c:

Hemoglobin A1c

HR:

Hazard ratio

IgG:

Immunoglobulin G

IV:

Intravenous

KATP channel:

ATP-sensitive potassium channel

KV channel:

Delayed rectifying potassium channel

LAR:

Long-acting release

PYY:

Peptide YY

SC:

Subcutaneous

T1R:

Taste receptor type 1

T2D:

Type 2 diabetes

USFDA:

United States Food and Drug Administration

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Further Reading

  • Furness JB, et al. The gut as a sensory organ. Nat Rev Gastroenterol Hepatol. 2013;10:729–40. This review provides an excellent overview about the molecular mechanism how the gut sensors the content of the intestinal lumen and how this information is further processed to elicit reactions in the human body. This review also provides further information about the receptors on intestinal L-cells which, when activated, trigger GLP-1-secretion.

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  • Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87:1409–39. Comprehensive review from 2007 highlighting GLP-1 physiology with detailed descriptions how GLP-1 affects the pancreas, intestine, liver, and other parts of the body and how GLP-1-physiology is altered in conditions like obesity and diabetes.

    Google Scholar 

  • Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab. 2016;18:317–32. Good overview of head-to-head trials comparing effects of pharmaceutically available GLP-1 analogs.

    Google Scholar 

  • Schlögl H, et al. Exenatide-induced reduction in energy intake is associated with increase in hypothalamic connectivity. Diabetes Care. 2013;36:1933–40. First neuroimaging study which investigates the central nervous effects of GLP-1 analog administration in humans with functional MRI, demonstration changes of hypothalamic activity after GLP-1 analog administration which are accompanied by decreased hunger and reduced energy intake.

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Author information

Authors and Affiliations

  1. University Hospital Leipzig, Department of Internal Medicine, Endocrinology/Diabetes, Leipzig, Germany

    Haiko Schlögl

  2. University Hospital Leipzig, Division of Endocrinology/Diabetes and Nephrology, Leipzig, Germany

    Michael Stumvoll

Authors
  1. Haiko Schlögl
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  2. Michael Stumvoll
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Corresponding author

Correspondence to Michael Stumvoll .

Editor information

Editors and Affiliations

  1. Multidisciplinary Diabetes Center, Mexico City, Mexico

    Joel Rodriguez-Saldana

Glossary

Cardiovascular outcome study

Study demanded from the USFDA since 2008 for all new diabetes drugs to rule out an excess cardiovascular risk. Cardiovascular safety is defined by the USFDA as an upper bound of the two-sided 95% CI for major adverse cardiovascular events of less than 1.8 preapproval and 1.3 postapproval.

Functional magnetic resonance imaging (FMRI)

Technique to assess brain perfusion and thus receive information about the activity of different areas of the brain

Gastric inhibitory polypeptide (GIP, later also termed glucose-dependent insulinotropic peptide)

Peptide hormone produced mainly in the K-cells of the duodenum and the jejunum. Increases insulin secretion of the β-cells of the pancreas when blood glucose is elevated

Glucagon-like peptide 1 (GLP-1)

Peptide hormone produced mainly in the L-cells of the distal ileum and the colon. Increases insulin secretion of the β-cells of the pancreas when blood glucose is elevated. Analogs of GLP-1 were the first incretin mimetics approved for the treatment of diabetes mellitus type 2.

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Schlögl, H., Stumvoll, M. (2019). Incretin Therapies: Current Use and Emerging Possibilities. In: Rodriguez-Saldana, J. (eds) The Diabetes Textbook. Springer, Cham. https://doi.org/10.1007/978-3-030-11815-0_33

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  • DOI: https://doi.org/10.1007/978-3-030-11815-0_33

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-11814-3

  • Online ISBN: 978-3-030-11815-0

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