glucagon-like peptide-1

{{Short description|Gastrointestinal peptide hormone involved in glucose homeostasis}}

{{For|the related medications|GLP-1 receptor agonist|Dipeptidyl peptidase-4 inhibitor}}

Image:Incretins and DPP 4 inhibitors.svg

Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certain neurons within the nucleus of the solitary tract in the brainstem upon food consumption. The initial product GLP-1 (1–37) is susceptible to amidation and proteolytic cleavage, which gives rise to the two truncated and equipotent biologically active forms, GLP-1 (7–36) amide and GLP-1 (7–37). Active GLP-1 protein secondary structure includes two α-helices from amino acid position 13–20 and 24–35 separated by a linker region.

Alongside glucose-dependent insulinotropic peptide (GIP), GLP-1 is an incretin; thus, it has the ability to decrease blood sugar levels in a glucose-dependent manner by enhancing the secretion of insulin. Beside the insulinotropic effects, GLP-1 has been associated with numerous regulatory and protective effects. Unlike GIP, the action of GLP-1 is preserved in patients with type 2 diabetes. 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 dipeptidyl peptidase-4 (DPP-4), as well as neutral endopeptidase 24.11 (NEP 24.11) and renal clearance, resulting in a half-life of approximately 2 minutes. Consequently, only 10–15% of GLP-1 reaches circulation intact, leading to fasting plasma levels of only {{val|0|–|15|ul=pmol/L}}. To overcome this, GLP-1 receptor agonists and DPP-4 inhibitors have been developed to increase GLP-1 activity. As opposed to common treatment agents such as insulin and 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 proglucagon gene is expressed in several organs including the pancreas (α-cells of the islets of Langerhans), gut (intestinal enteroendocrine L-cells) and brain (caudal brainstem and hypothalamus). Pancreatic proglucagon gene expression is promoted upon fasting and hypoglycaemia induction and inhibited by insulin. Conversely, intestinal proglucagon gene expression is reduced during fasting and stimulated upon food consumption. In mammals, the transcription gives rise to identical 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.{{cite journal | vauthors = Marathe CS, Rayner CK, Jones KL, Horowitz M | title = Glucagon-like peptides 1 and 2 in health and disease: a review | journal = Peptides | volume = 44 | pages = 75–86 | date = June 2013 | pmid = 23523778 | doi = 10.1016/j.peptides.2013.01.014 | s2cid = 22641629 }}{{cite journal | vauthors = Baggio LL, Drucker DJ | title = Biology of incretins: GLP-1 and GIP | journal = Gastroenterology | volume = 132 | issue = 6 | pages = 2131–57 | date = May 2007 | pmid = 17498508 | doi = 10.1053/j.gastro.2007.03.054 | doi-access = free }}

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).

In the gut and brain, proglucagon is catalysed by PC 1/3 giving rise to glicentin, which may be further processed to GRPP and oxyntomodulin, GLP-1, intervening peptide-2 (IP-2) and glucagon-like peptide-2 (GLP-2). Initially, GLP-1 was thought to correspond to proglucagon (72–108) suitable with the N-terminal of the MPGF, but sequencing experiments of endogenous GLP-1 revealed a structure corresponding to proglucagon (78–107) from which two discoveries were found. Firstly, the full-length GLP-1 (1–37) was found to be catalysed by endopeptidase to the biologically active GLP-1 (7–37). Secondly, the glycine corresponding to proglucagon (108) was found to serve as a substrate for amidation of the 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.{{cite journal | vauthors = Holst JJ | title = The physiology of glucagon-like peptide 1 | journal = Physiological Reviews | volume = 87 | issue = 4 | pages = 1409–39 | date = October 2007 | pmid = 17928588 | doi = 10.1152/physrev.00034.2006 }}{{cite journal | vauthors = Deacon CF, Holst JJ | title = Immunoassays for the incretin hormones GIP and GLP-1 | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 23 | issue = 4 | pages = 425–32 | date = August 2009 | pmid = 19748060 | doi = 10.1016/j.beem.2009.03.006 }}

Secretion

GLP-1 is packaged in secretory granules and secreted into the hepatic portal system by the intestinal L-cells located primarily in the distal ileum and colon, but also found in the jejunum and duodenum. The L-cells are open-type triangular epithelial cells directly in contact with the lumen and neuro-vascular tissue and are accordingly stimulated by various nutrient, neural and endocrine factors.

GLP-1 is released in a biphasic pattern with an early phase after 10–15 minutes followed by a longer second phase after 30–60 minutes upon meal ingestion. As the majority of L-cells are located in the distal ileum and colon, the early phase is likely explained by neural signalling, gut peptides or neurotransmitters. Other evidence suggests the L-cells located in the proximal jejunum are sufficient to account for the early-phase secretion through direct contact with luminal nutrients. Less controversially, the second phase is likely caused by direct stimulation of L-cells by digested nutrients. The rate of gastric emptying is therefore an important aspect to consider, as it regulates the entry of nutrients into the small intestine where the direct stimulation occurs. One of the actions of GLP-1 is to inhibit gastric emptying, thus slowing down its own secretion (negative feedback) upon postprandial activation.

Fasting plasma concentrations of biologically active GLP-1 range between {{val|0|and|15|ul=pmol/L}} in humans and are increased 2- to 3-fold upon food consumption depending on meal size and nutrient composition. Individual nutrients, such as fatty acids, essential amino acids and dietary fibre have also been shown to stimulate GLP-1 secretion.

Sugars have been associated with various signalling pathways, which initiate depolarisation of the L-cell membrane causing an elevated concentration of cytosolic Ca2+, which in turn induces GLP-1 secretion. Fatty acids have been associated with the mobilisation of intracellular {{ion|Ca|2+}} stores and subsequently release of {{ion|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.{{cite journal | vauthors = Ma X, Guan Y, Hua X | title = Glucagon-like peptide 1-potentiated insulin secretion and proliferation of pancreatic β-cells | journal = Journal of Diabetes | volume = 6 | issue = 5 | pages = 394–402 | date = September 2014 | pmid = 24725840 | doi = 10.1111/1753-0407.12161 | s2cid = 13300428 }}

Degradation

Once secreted, GLP-1 is extremely susceptible to the catalytic activity of the proteolytic enzyme dipeptidyl peptidase-4 (DPP-4). Specifically, DPP-4 cleaves the peptide bond between Ala⁸-Glu⁹ resulting in the abundant GLP-1 (9–36) amide constituting 60–80% of total GLP-1 in circulation. DPP-4 is widely expressed in multiple tissues and cell types and exists in both a membrane-anchored and soluble circulating form. Notably, DPP-4 is expressed on the surface of endothelial cells, including those located directly adjacent to GLP-1 secretion sites. Consequently, less than 25% of secreted GLP-1 is estimated to leave the gut intact. Additionally, presumably due to the high concentration of DPP-4 found on 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.

Neutral endopeptidase 24.11 (NEP 24.11) is a membrane-bound zinc metallopeptidase widely expressed in several tissues, but found in particularly high concentrations in the kidneys, which is also identified accountable for the rapid degradation of GLP-1. It primarily cleaves peptides at the N-terminal side of aromatic or hydrophobic amino acids and is estimated to contribute by up to 50% to GLP-1 degradation. However, the activity only becomes apparent once the degradation of DPP-4 has been prevented, as the majority of GLP-1 reaching the kidneys has already been processed by DPP-4. Similarly, renal clearance appear more significant for the elimination of already inactivated GLP-1.{{cite journal | vauthors = Deacon CF | title = Circulation and degradation of GIP and GLP-1 | journal = Hormone and Metabolic Research | volume = 36 | issue = 11–12 | pages = 761–5 | year = 2004 | pmid = 15655705 | doi = 10.1055/s-2004-826160 | s2cid = 24730915 }}

The resulting half-life of active GLP-1 is approximately 2 minutes, which is however sufficient to activate GLP-1 receptors.

Physiological functions

File:FunctionsOfGLP-1.png

GLP-1 possesses several physiological properties making it (and its functional analogs) a subject of intensive investigation as a potential treatment of diabetes mellitus, as these actions induce long-term improvements along with the immediate effects.{{Request quotation|date=June 2017}}[http://www.medscape.com/viewprogram/3418_pnt "Diabetes and Intestinal Incretin Hormones: A New Therapeutic Paradigm" at medscape.com (slide 36)]{{cite journal | vauthors = Toft-Nielsen MB, Madsbad S, Holst JJ | title = Determinants of the effectiveness of glucagon-like peptide-1 in type 2 diabetes | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 8 | pages = 3853–60 | date = August 2001 | pmid = 11502823 | doi = 10.1210/jcem.86.8.7743 | doi-access = free }}{{cite journal | vauthors = Meier JJ, Weyhe D, Michaely M, Senkal M, Zumtobel V, Nauck MA, Holst JJ, Schmidt WE, Gallwitz B | title = Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes | journal = Critical Care Medicine | volume = 32 | issue = 3 | pages = 848–51 | date = March 2004 | pmid = 15090972 | doi = 10.1097/01.CCM.0000114811.60629.B5 | s2cid = 2382791 }}{{cite journal | vauthors = Graaf C, Donnelly D, Wootten D, Lau J, Sexton PM, Miller LJ, Ahn JM, Liao J, Fletcher MM, Yang D, Brown AJ, Zhou C, Deng J, Wang MW | title = Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes | journal = Pharmacological Reviews | volume = 68 | issue = 4 | pages = 954–1013 | date = October 2016 | pmid = 27630114 | pmc = 5050443 | doi = 10.1124/pr.115.011395 }} 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.{{cite journal | vauthors = Calanna S, Christensen M, Holst JJ, Laferrère B, Gluud LL, Vilsbøll T, Knop FK | title = Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies | journal = Diabetologia | volume = 56 | issue = 5 | pages = 965–72 | date = May 2013 | pmid = 23377698 | doi = 10.1007/s00125-013-2841-0 | pmc = 3687347 }}

The most noteworthy effect of GLP-1 is its ability to promote insulin secretion in a glucose-dependent manner. As GLP-1 binds to GLP-1 receptors expressed on pancreatic β cells, the receptors couple to G-protein subunits and activate adenylate cyclase, which increases the production of cAMP from ATP. Subsequently, activation of secondary pathways, including protein kinase A (PKA) and Epac2, alters cell ion channel activity, causing elevated levels of cytosolic {{ion|Ca|2+}} that enhance exocytosis of insulin-containing granules. During the process, influx of glucose ensures sufficient ATP to sustain the stimulatory effect.

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.{{cite journal | vauthors = Rondas D, D'Hertog W, Overbergh L, Mathieu C | title = Glucagon-like peptide-1: modulator of β-cell dysfunction and death | journal = Diabetes, Obesity & Metabolism | volume = 15 Suppl 3 | issue = 3 | pages = 185–92 | date = September 2013 | pmid = 24003936 | doi = 10.1111/dom.12165 | doi-access = free }} GLP-1 also increases{{cite journal | vauthors = Rachmany L, Tweedie D, Li Y, Rubovitch V, Holloway HW, Miller J, Hoffer BJ, Greig NH, Pick CG | title = Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice | journal = Age | volume = 35 | issue = 5 | pages = 1621–36 | date = October 2013 | pmid = 22892942 | pmc = 3776106 | doi = 10.1007/s11357-012-9464-0 }} 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 desirable in diabetes treatment. An additional important effect of GLP-1, is inhibition of 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.{{cite journal |vauthors=Gautier JF, Choukem SP, Girard J |title=Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes |journal=Diabetes & Metabolism |volume= 34 |pages= S65–S72 |year= 2008 |doi= 10.1016/S1262-3636(08)73397-4 |pmid=18640588 }}{{cite journal | vauthors = Seino Y, Fukushima M, Yabe D | title = GIP and GLP-1, the two incretin hormones: Similarities and differences | journal = Journal of Diabetes Investigation | volume = 1 | issue = 1–2 | pages = 8–23 | date = April 2010 | pmid = 24843404 | pmc = 4020673 | doi = 10.1111/j.2040-1124.2010.00022.x }}

In the brain, GLP-1 receptor activation has been linked with neurotrophic effects including neurogenesis{{cite journal | vauthors = Li H, Lee CH, Yoo KY, Choi JH, Park OK, Yan BC, Byun K, Lee B, Hwang IK, Won MH | title = Chronic treatment of exendin-4 affects cell proliferation and neuroblast differentiation in the adult mouse hippocampal dentate gyrus | journal = Neuroscience Letters | volume = 486 | issue = 1 | pages = 38–42 | date = December 2010 | pmid = 20854877 | doi = 10.1016/j.neulet.2010.09.040 | s2cid = 33327108 }}{{cite journal | vauthors = Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, Kortesmaa J, Mercer A, Nielsen E, Rönnholm H, Wikström L | title = Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson's disease | journal = Journal of Neuroscience Research | volume = 86 | issue = 2 | pages = 326–38 | date = February 2008 | pmid = 17803225 | doi = 10.1002/jnr.21483 | s2cid = 40330443 }} and neuroprotective effects including reduced necrotic{{cite journal | vauthors = DellaValle B, Hempel C, Johansen FF, Kurtzhals JA | title = GLP-1 improves neuropathology after murine cold lesion brain trauma | journal = Annals of Clinical and Translational Neurology | volume = 1 | issue = 9 | pages = 721–32 | date = September 2014 | pmid = 25493285 | pmc = 4241798 | doi = 10.1002/acn3.99 }} and apoptotic{{cite journal | vauthors = Wang MD, Huang Y, Zhang GP, Mao L, Xia YP, Mei YW, Hu B | title = Exendin-4 improved rat cortical neuron survival under oxygen/glucose deprivation through PKA pathway | journal = Neuroscience | volume = 226 | pages = 388–96 | date = December 2012 | pmid = 23000625 | doi = 10.1016/j.neuroscience.2012.09.025 | s2cid = 36908739 }} signaling, cell death,{{cite journal | vauthors = Sharma MK, Jalewa J, Hölscher C | title = Neuroprotective and anti-apoptotic effects of liraglutide on SH-SY5Y cells exposed to methylglyoxal stress | journal = Journal of Neurochemistry | volume = 128 | issue = 3 | pages = 459–71 | date = February 2014 | pmid = 24112036 | doi = 10.1111/jnc.12469 | doi-access = free }}{{cite journal | vauthors = Perry T, Haughey NJ, Mattson MP, Egan JM, Greig NH | title = Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4 | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 302 | issue = 3 | pages = 881–8 | date = September 2002 | pmid = 12183643 | doi = 10.1124/jpet.102.037481 | s2cid = 43716740 }} and dysfunctions.{{cite journal |last1=Iwai |first1=T |last2=Sawabe |first2=T |last3=Tanimitsu |first3=K |last4=Suzuki |first4=M |last5=Sasaki-Hamada |first5=S |last6=Oka |first6=J |title=Glucagon-like peptide-1 protects synaptic and learning functions from neuroinflammation in rodents. |journal=Journal of Neuroscience Research |date=April 2014 |volume=92 |issue=4 |pages=446–54 |doi=10.1002/jnr.23335 |pmid=24464856|s2cid=206129862 }} 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,{{cite journal | vauthors = Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, Powers K, Shen H, Egan JM, Sambamurti K, Brossi A, Lahiri DK, Mattson MP, Hoffer BJ, Wang Y, Greig NH | title = GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 4 | pages = 1285–90 | date = January 2009 | pmid = 19164583 | pmc = 2633544 | doi = 10.1073/pnas.0806720106 | bibcode = 2009PNAS..106.1285L | doi-access = free }} Alzheimer's disease,{{cite journal | vauthors = Wang XH, Li L, Hölscher C, Pan YF, Chen XR, Qi JS | title = Val8-glucagon-like peptide-1 protects against Aβ1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats | journal = Neuroscience | volume = 170 | issue = 4 | pages = 1239–48 | date = November 2010 | pmid = 20727946 | doi = 10.1016/j.neuroscience.2010.08.028 | s2cid = 44318394 }}{{cite journal | vauthors = Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan JM, Greig NH | title = Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron | journal = Journal of Neuroscience Research | volume = 72 | issue = 5 | pages = 603–12 | date = June 2003 | pmid = 12749025 | doi = 10.1002/jnr.10611 | s2cid = 83852654 }} stroke, traumatic brain injury, and multiple sclerosis.{{cite journal | vauthors = DellaValle B, Brix GS, Brock B, Gejl M, Landau AM, Møller A, Rungby J, Larsen A | title = Glucagon-Like Peptide-1 Analog, Liraglutide, Delays Onset of Experimental Autoimmune Encephalitis in Lewis Rats | journal = Frontiers in Pharmacology | volume = 7 | pages = 433 | date = 2016 | pmid = 27917122 | pmc = 5114298 | doi = 10.3389/fphar.2016.00433 | doi-access = free }} 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.

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.

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|date=December 2024}}

Research history

In the early 1980s, Richard Goodman and P. Kay Lund were postdoctoral researchers working in Joel Habener's laboratory at Massachusetts General Hospital.{{cite news |last1=Molteni |first1=Megan |last2=Chen |first2=Elaine |title=GLP-1 drugs are transforming diabetes, obesity and more. Could a Nobel be next? |url=https://www.statnews.com/2023/09/30/weight-loss-ozempic-nobel-prize-science/ |access-date=October 16, 2024 |work=STAT News |date=September 30, 2023}} Starting in 1979, Goodman harvested DNA from 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. In 1982, they published their discovery that the gene for proglucagon actually codes for three peptides, namely glucagon and two novel peptides. 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.

In the 1980s, {{Lang unset italics|mk|Svetlana Mojsov|nocat=y}} worked on the identification of GLP-1 at Massachusetts General Hospital, where she was head of a peptide synthesis facility.{{Cite report |url=https://www.science.org/content/article/her-work-paved-way-blockbuster-obesity-drugs-now-she-s-fighting-recognition |title=Her work paved the way for blockbuster obesity drugs. Now, she's fighting for recognition |date=2023-09-08 |doi=10.1126/science.adk7627 |language=en}} To try to identify whether a specific fragment of GLP-q was an incretin, {{Lang unset italics|mk|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.{{Cite journal |last=Mojsov |first=S. |date=1992 |title=Structural requirements for biological activity of glucagon-like peptide-I |url=https://pubmed.ncbi.nlm.nih.gov/1478791/ |journal=International Journal of Peptide and Protein Research |volume=40 |issue=3–4 |pages=333–343 |doi=10.1111/j.1399-3011.1992.tb00309.x |issn=0367-8377 |pmid=1478791}}{{Cite journal |last1=Mojsov |first1=S |last2=Heinrich |first2=G |last3=Wilson |first3=I B |last4=Ravazzola |first4=M |last5=Orci |first5=L |last6=Habener |first6=J F |date=September 1986 |title=Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing. |journal=Journal of Biological Chemistry |volume=261 |issue=25 |pages=11880–11889 |doi=10.1016/s0021-9258(18)67324-7 |issn=0021-9258 |pmid=3528148|doi-access=free }} {{Lang unset italics|mk|Mojsov}} and her collaborators Daniel J. Drucker and Habener showed that small quantities of laboratory-synthesized GLP-1 could trigger insulin.{{Cite journal |last1=Mojsov |first1=S |last2=Weir |first2=G C |last3=Habener |first3=J F |date=1987-02-01 |title=Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. |url=http://www.jci.org/articles/view/112855 |journal=Journal of Clinical Investigation |language=en |volume=79 |issue=2 |pages=616–619 |doi=10.1172/JCI112855 |issn=0021-9738 |pmc=424143 |pmid=3543057}}{{Cite journal |last1=Drucker |first1=D J |last2=Philippe |first2=J |last3=Mojsov |first3=S |last4=Chick |first4=W L |last5=Habener |first5=J F |date=May 1987 |title=Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=84 |issue=10 |pages=3434–3438 |bibcode=1987PNAS...84.3434D |doi=10.1073/pnas.84.10.3434 |issn=0027-8424 |pmc=304885 |pmid=3033647 |doi-access=free}}{{Cite journal |last=O'Rahilly |first=Stephen |date=2021-04-15 |title=The islet's bridesmaid becomes the bride: Proglucagon-derived peptides deliver transformative therapies |journal=Cell |volume=184 |issue=8 |pages=1945–1948 |doi=10.1016/j.cell.2021.03.019 |issn=0092-8674 |pmid=33831374 |s2cid=233131461|doi-access=free }}

{{Lang unset italics|mk|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.{{Cite report |url=https://www.science.org/content/article/her-work-paved-way-blockbuster-obesity-drugs-now-she-s-fighting-recognition |title=Her work paved the way for blockbuster obesity drugs. Now, she's fighting for recognition |date=2023-09-08 |doi=10.1126/science.adk7627 |language=en}}

The discovery of GLP-1's extremely short half-life meant that it was impossible to develop into a drug.{{cite news |last1=Winkler |first1=Rolfe |last2=Cohen |first2=Ben |title=Monster Diet Drugs Like Ozempic Started With Actual Monsters |url=https://www.wsj.com/articles/ozempic-mounjaro-gila-monster-anglerfish-8c9c1ff2 |access-date=October 16, 2024 |work=The Wall Street Journal |date=June 23, 2023 |url-access=subscription}}{{cite news |last1=Dunaief |first1=Daniel |title=Setauket scientist Andrew Young’s work paves way for drugs like Ozempic |url=https://tbrnewsmedia.com/setauket-scientist-andrew-youngs-work-paves-way-for-drugs-like-ozempic/ |access-date=October 16, 2024 |work=TBR News Media |date=August 31, 2023}} 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.