Glucagon-like peptide-1

Source: Wikipedia, the free encyclopedia.
For the related medications, see GLP-1 receptor agonist and Dipeptidyl peptidase-4 inhibitor.

diagram
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.

sulphonylureas, 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

posttranslational processing mechanisms, different peptides are produced in the different cells.[1][2]

In the pancreas (α-cells of the islets of Langerhans), proglucagon is cleaved by

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, proglucagon is catalysed by PC 1/3 giving rise to

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

endocrine factors.[2]

GLP-1 is released in a

postprandial activation.[1][2]

Fasting plasma concentrations of biologically active GLP-1 range between 0 and 15 

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

depolarisation
of the L-cell membrane causing an elevated concentration of cytosolic Ca 2+, which in turn induces GLP-1 secretion.
intracellular
Ca 2+ stores and subsequently release of Ca 2+ 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

hepatocytes, 40–50% of the remaining active GLP-1 is degraded across the liver. Thus, due to the activity of 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

diagram
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, further research indicates 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

Epac2, alters cell ion channel
activity, causing elevated levels of cytosolic Ca 2+ that enhance 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

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

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.[citation needed]

Research history

In the early 1980s, Richard Goodman and P. Kay Lund were

American anglerfish islet cells and spliced the DNA into bacteria to find the gene for somatostatin; Lund then joined the Habener laboratory and used Goodman's bacteria to identify the gene for glucagon.[27] In 1982, they published their discovery that the gene for proglucagon actually codes for three peptides, namely glucagon and two novel peptides.[27] Those two novel peptides were later isolated, identified, and investigated by other researchers, and are now known as glucagon-like peptide-1 and glucagon-like peptide-2.[27]

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.[28] 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.[29][30] Mojsov and her collaborators Daniel J. Drucker and Habener showed that small quantities of laboratory-synthesized GLP-1 could trigger insulin.[31][32][33]

Mojsov fought to have her name included in patents, with Mass General eventually agreeing to amend four patents to include her name. She received her one-third of drug royalties for one year.[34]

The discovery of GLP-1's extremely short half-life meant that it was impossible to develop into a drug.[35][36] This caused diabetes research to shift towards other therapeutic options such as targeting the GLP-1 receptor, which then led to the development of GLP-1 receptor agonists.[35][36]

See also

References

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  35. ^ a b Winkler R, Cohen B (23 June 2023). "Monster Diet Drugs Like Ozempic Started With Actual Monsters". The Wall Street Journal. Retrieved 16 October 2024.
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