Glucagon-like peptide-1

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GLP-1 and diabetes

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long

α-helices
from amino acid position 13–20 and 24–35 separated by a linker region.

Alongside

Glucagon-like peptide-1 receptor agonists
gained approval as drugs to treat diabetes and obesity starting in the 2000s.

Endogenous GLP-1 is rapidly degraded primarily by

sulphonylurea, GLP-1-based treatment has been associated with weight loss and a lower risk of hypoglycemia
, two important considerations for patients with type 2 diabetes.

Gene expression

The proglucagon gene is expressed in several organs including the

mRNA in all three cell types, which is further translated to the 180 amino acid precursor called proglucagon. However, as a result of tissue-specific posttranslational processing mechanisms, different peptides are produced in the different cells.[1][2]

In the

prohormone convertase (PC) 2 producing glicentin-related pancreatic peptide (GRPP), glucagon, intervening peptide-1 (IP-1) and major proglucagon fragment (MPGF).[3]

In the gut and brain,

C-terminal arginine resulting in the equally potent GLP-1 (7–36) amide. In humans, almost all (>80%) secreted GLP-1 is amidated, whereas a considerable part remains GLP-1 (7–37) in other species.[3][4]

Secretion

GLP-1 is packaged in secretory granules and secreted into the

endocrine factors.[2]

GLP-1 is released in a

postprandial activation.[1][2]

Fasting plasma concentration of biologically active GLP-1 range between 0 and 15 pmol/L in humans and is increased 2- to 3-fold upon food consumption depending on meal size and nutrient composition. Individual nutrients, such as

dietary fibre
have also shown to stimulate GLP-1 secretion.

intracellular Ca2+ stores and subsequently release of Ca2+ into the cytosol. The mechanisms of protein-triggered GLP-1 secretion are less clear, but the amino acid proportion and composition appear important to the stimulatory effect.[5]

Degradation

Once secreted, GLP-1 is extremely susceptible to the catalytic activity of the proteolytic enzyme

DPP-4 only 10–15 % of secreted GLP-1 reaches circulation intact.[3]

renal clearance appear more significant for the elimination of already inactivated GLP-1.[6]

The resulting

GLP-1 receptors
.

Physiological functions

Functions of GLP-1

GLP-1 possesses several physiological properties making it (and its

diabetes mellitus, as these actions induce long-term improvements along with the immediate effects.[need quotation to verify][7][8][9][10] Although reduced GLP-1 secretion has previously been associated with attenuated incretin effect in patients with type 2 diabetes, it is now granted that GLP-1 secretion in patients with type 2 diabetes does not differ from healthy subjects.[11]

The most noteworthy effect of GLP-1 is its ability to promote insulin secretion in a glucose-dependent manner. As GLP-1 binds to

adenylate cyclase that increases the production of cAMP from ATP.[3] Subsequently, activation of secondary pathways, including PKA and Epac2, alters the ion channel activity causing elevated levels of cytosolic Ca2+ that enhances exocytosis of insulin-containing granules. During the process, influx of glucose ensures sufficient ATP to sustain the stimulatory effect.[3]

Additionally, GLP-1 ensures the β cell insulin stores are replenished to prevent exhaustion during secretion by promoting insulin gene transcription,

mRNA stability and biosynthesis.[2][12] GLP-1 evidently also increases[13] β cell mass by promoting proliferation and neogenesis while inhibiting apoptosis. As both type 1 and 2 diabetes are associated with reduction of functional β cells, this effect is highly interesting regarding diabetes treatment.[12] Considered almost as important as the effect of enhancing insulin secretion, GLP-1 has been shown to inhibit glucagon secretion at glucose levels above fasting levels. Critically, this does not affect the glucagon response to hypoglycemia as this effect is also glucose-dependent. The inhibitory effect is presumably mediated indirectly through somatostatin secretion, but a direct effect cannot be completely excluded.[14][15]

In the brain, GLP-1 receptor activation has been linked with neurotrophic effects including neurogenesis[16][17] and neuroprotective effects including reduced necrotic[18] and apoptotic[19][18] signaling, cell death,[20][21] and dysfunctions.[22] In the diseased brain, GLP-1 receptor agonist treatment is associated with protection against a range of experimental disease models such as Parkinson's disease,[23][17] Alzheimer's disease,[24][25] stroke,[23] traumatic brain injury,[13][18] and multiple sclerosis.[26] In accordance with the expression of GLP-1 receptor on brainstem and hypothalamus, GLP-1 has been shown to promote satiety and thereby reduce food and water intake. Consequently, diabetic subjects treated with GLP-1 receptor agonists often experience weight loss as opposed to the weight gain commonly induced with other treatment agents.[2][15]

In the stomach, GLP-1 inhibits gastric emptying, acid secretion and motility, which collectively decrease appetite. By decelerating gastric emptying GLP-1 reduces postprandial glucose excursion which is another attractive property regarding diabetes treatment. However, these gastrointestinal activities are also the reason why subjects treated with GLP-1-based agents occasionally experience nausea.[14]

GLP-1 has also shown signs of carrying out protective and regulatory effects in numerous other tissues, including heart, tongue, adipose, muscles, bones, kidneys, liver and lungs.

Research history

In the 1980s, Svetlana Mojsov worked on the identification of GLP-1 at Massachusetts General Hospital, where she was head of a peptide synthesis facility.[27] To try to identify whether a specific fragment of GLP-q was an incretin, Mojsov created an incretin-antibody and developed ways to track its presence. She identified that a stretch of 31 amino acids in the GLP-1 was an incretin.[28][29] Mosjov and her collaborators Daniel J. Drucker and Habener showed that small quantities of lab-synthesized GLP-1 could trigger insulin.[30][31][32]

Mojsov fought to have her name included in patents, with the Massachusetts General Hospital eventually agreeing to amend four patents to include her name. She received her one-third of drug royalties for one year.[33]

See also

References

  1. ^
    S2CID 22641629
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  2. ^
    PMID 17498508
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  3. ^
    PMID 17928588
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  4. PMID 19748060
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  5. S2CID 13300428
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  6. S2CID 24730915
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  7. ^ "Diabetes and Intestinal Incretin Hormones: A New Therapeutic Paradigm" at medscape.com (slide 36)
  8. PMID 11502823
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  9. S2CID 2382791
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  10. PMID 27630114
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  11. PMID 23377698
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  12. ^
    PMID 24003936
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  13. ^
    PMID 22892942
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  14. ^
    PMID 18640588
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  15. ^
    PMID 24843404
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  16. S2CID 33327108
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  17. ^
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  18. ^
    PMID 25493285
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  21. S2CID 43716740
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  22. S2CID 206129862
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  23. ^
    PMID 19164583
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  24. S2CID 44318394
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  25. S2CID 83852654
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  26. PMID 27917122
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  27. doi:10.1126/science.adk7627
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  28. PMID 1478791
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  29. PMID 3528148
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  30. PMID 3543057
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  31. PMID 3033647
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  32. S2CID 233131461
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  33. doi:10.1126/science.adk7627
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External links


American diabetes association:link-http://diabetes.diabetesjournals.org/content/56/1/8.full

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