GLP-1 (Semaglutide)
The Blood Sugar Regulator
Control Your Blood Sugar: Support Diabetes Management with Semaglutide
GLP-1, short for Glucagon-Like Peptide-1, is a hormone that plays a crucial role in controlling blood sugar levels after eating. It helps by stimulating insulin release from the pancreas when glucose levels are high, slowing down stomach emptying to make you feel fuller for longer, and reducing the amount of sugar your liver makes. It’s a target for treating diabetes, as enhancing its action can help manage the disease effectively.
Potential Benefits Under Research
- Type 2 diabetes management: GLP-1 stimulates insulin secretion, which helps lower blood glucose levels, and also suppresses glucagon secretion, which prevents the liver from releasing too much glucose.
- Cardiovascular health: It may improve cardiovascular outcomes by reducing blood pressure, improving lipid profiles, and enhancing overall heart function.
- Weight management: GLP-1 helps control appetite and increases feelings of fullness, which can lead to weight loss—a beneficial factor for managing both diabetes and obesity.
- Neuroprotective effects: Studies suggest GLP-1 could protect nerve cells and possibly be beneficial in treating conditions like Alzheimer’s disease and stroke.
- Anti-inflammatory properties: It could potentially reduce systemic inflammation, aiding in the management of autoimmune and chronic inflammatory conditions.
- Gastrointestinal health: Its role in slowing gastric emptying and enhancing satiety could also benefit gastrointestinal disorders such as gastroparesis, commonly seen in people with diabetes.
Dosing Protocol for Research Purposes
Initial Dose Escalation Schedule:
- Weeks 1 through 4: 0.25 mg subcutaneously once a week
- Weeks 5 through 8: 0.5 mg subcutaneously once a week
- Weeks 9 through 12: 1 mg subcutaneously once a week
- Weeks 13 through 16: 1.7 mg subcutaneously once a week
Maintenance Dose:
- Week 17 and onward: 2.4 mg subcutaneously once a week
Dosing Considerations:
- If dose escalation is not tolerated, consider delaying dose escalation for 4 weeks
- If the maintenance dose of 2.4 mg once a week is not tolerated, the dose can be temporarily decreased to 1.7 mg once a week for a maximum of 4 weeks
- After 4 weeks, increase dose back to 2.4 mg once a week; discontinue therapy if the patient cannot tolerate the maintenance dose of 2.4 mg once a week
Overview
GLP-1, short for glucagon-like peptide-1 is a short, naturally occurring peptide hormone just 30-31 amino acids in length. Its primary physiologic function is to lower blood sugar levels by naturally enhancing insulin secretion. It also plays a role in protecting beta cell insulin stores by promoting insulin gene transcription and has been linked with neurotrophic effects in the brain and central nervous system. In the GI system, GLP-1 has been shown to significantly decrease appetite by delaying gastric emptying and reducing intestinal motility. Preliminary research has shown impacts of GLP-1 in the heart, fat, muscles, bones, liver, lungs, and kidneys as well.
The primary focus of GLP-1 research has been in the realm of diabetes treatment/prevention as well as appetite suppression. Secondary research focuses on the potential cardiovascular benefits of the peptide. More recent, and thus less robust, research focuses on the ability of GLP-1 to stave off neurodegenerative disease. Though this latter area of research is newest, it is also the fast-growing area of GLP-1 study now that the peptide has been revealed to slow or prevent the accumulation of amyloid beta plaques in the setting of Alzheimer’s disease.
Structure
Sequence: HXEGTFTSDVSSYLEGQAAK
OH.steric diacid-EFIAWLVRGRG
Molecular Formula: C187H291N45O59 Molecular Weight: 4113.64 g/mol
PubChem CID: 56843331
CAS Number: 910463-68-2
Synonyms: Semeglutide, Oxempic, Rybelsus, NN9535
Most Recent Research
GLP-1: anti-inflammatory effects
Gastrointestinal system
GLP-1 is secreted into the distal intestine by enteroendocrine L cells in response to nutrient ingestion. GLP-1 receptors are widely distributed in the gastrointestinal tract, pancreas, heart, lungs, kidneys, and nervous system. These receptors contribute to the wide range of physiological functions. Besides metabolic effects, GLP-1 improves mucosal integrity and diminishes inflammation . Exendin-4, a GLP-1 mimetic peptide, decreases the production of pro-inflammatory cytokines, and diminishes the enteric immune response. GLP-1 decreases production of pro-inflammatory cytokines, mainly by downregulating NF-κB phosphorylation and nuclear translocation.
Several recent studies have suggested that GLP-1 should be considered as a treatment for a wide range of intestinal diseases, including Inflammatory bowel diseases, intestinal mucositis, coeliac disease and short bowel syndrome . GLPs, (including GLP-1, GLP-2 and DPP-4) have recently gained increased attention from researchers studying Inflammatory bowel diseases (IBDs).
IBDs including Crohn’s disease and ulcerative colitis are chronic relapsing-remitting diseases with multifactorial etiologies and complex pathogenesis. The Incidence and prevalence of IBDs are rising globally. GLPs including GLP-1 regulate weight and glycemia. GLP-1 also inhibits gastric emptying, decreases food ingestion, and increases crypt cell proliferation. It also improves intestinal growth and nutrient absorption. GLPs have been proposed to improve tissue healing of injured epithelium, regulate T-cell growth and function, control innate immune cells such as macrophages and dendritic cells, and lower pro-inflammatory cytokines in IBD.
Hepatobiliary system
GLP-1 based therapies have shown promise in liver diseases e.g. non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In recent years, the prevalence of non-alcoholic fatty liver disease (NAFLD) has continued to rise, and 10%-25% of NAFLD cases progress to non-alcoholic steatohepatitis (NASH). 10%-15% of NASH cases will develop into hepatocellular carcinoma, approximately 700,000 people die from the disease each year.
Nonalcoholic steatohepatitis is associated with inflammation of the liver, driven by an aberrant accumulation of fat. In rats fed with a high-fat diet, treatment with liraglutide, a GLP-1R analog, reduced steatosis and lobular inflammation compared to the saline-injected group. Exendin-4, a GLP-1R agonist, was shown in another study to lower hepatic production of the inflammatory markers TNF-, IL-1, and IL-6, as well as macrophage markers cluster of differentiation 68 (CD68), and F4/80 in mice fed a western-type (high fat) diet.
C-reactive-protein (CRP) is produced by the liver and is a marker of inflammation. Liraglutide produced a significant decrease in the mean concentration of CRP in a retrospective investigation of 110 obese patients with type 2 diabetes mellitus, indicating its potential as an anti-inflammatory drug. Exenatide plus metformin caused a significant reduction in baseline CRP and TNF-α. These findings show that GLP-1-based treatments improve fatty liver disease in rats and humans via reducing inflammation.
NAFLD is associated with cell death and fibrosis that ultimately progresses to cirrhosis. In obese patients with NAFLD, Fibroblast growth factor-21 protein (FGF21) and RNA levels are higher in the liver. Treatment with GLP-1R agonists reduced the level of FGF21. This supports its use in cirrhosis. Note that 80% of patients who develop hepatocellular carcinoma had cirrhosis beforehand.
GLP-1RA significantly reduced cell necrosis and apoptosis, the two major forms of liver cell death. Hepatic cell death mainly includes two forms: apoptosis and cell necrosis. Gupta et al. showed that a GLP-1RA significantly reduced cell necrosis and apoptosis. The reduction of abdominal visceral adiposity by GLP-1RAs results in a reduction in liver fat content that can alleviate NAFLD. The ability of GLP-1 to reduce fat is due to its binding to a specific GLP-1R present in adipose tissue. Vendrell et al. confirmed the expression of GLP-1R in mature adipose cells by the detection of the mRNA and protein. A 6-month-long treatment with GLP-1RAs in obese patients with T2DM resulted in significant reductions in intrahepatic lipids (IHL). In addition, the median relative reduction in IHL was 42%.
Stroke
Strokes in the elderly can cause permanent neurological damage and are among the leading causes of death. Patients who have hyperglycemia and diabetes mellitus type 2 (T2DM) have a higher stroke frequency than those who do not have these conditions. Stimulating GLP-1Rs with exendin-4 reduces brain damage and improves stroke outcomes. Exendin-4 suppresses oxidative stress, inducible nitric oxide synthase (iNOS) expression, and cellular apoptosis after ischemia/reperfusion injury.
It is well known that inflammation contributes to the progression of brain damage following ischemia/reperfusion injury, and that COX-2 is a significant mediator of oxidative damage. Activation of GLP-1Rs has anti-inflammatory effects in cerebral ischemia. COX-2 expression in rats was reduced when they were treated with exendin 9-39 (antagonist) after ischemia was induced. There was a reduction in GLP-1R expression in rat brains after cerebral ischemia. Furthermore, administration of the GLP-1R agonist exendin-4 in vivo and in vitro proved protective
GLP-1R elevates cAMP levels and activates protein kinase A (PKA) signaling. Adding GLP-1 to neurons increases cAMP, which indicates receptor activation. In mice with transient focal cerebral ischemia, exendin-4 treatment increased cAMP and activated the cAMP response element-binding protein (CREB) compared with vehicle-treated mice.
GLP-1: obstructive lung disease and asthma
Asthma affects about 25 million people in the US and more than 330 million people worldwide. GLP-1 receptor agonists decreased allergic responses in asthma by preventing the activation of NF-kB leading to decreased release of proinflammatory cytokines (IL-5, IL-13, IL-33) and neutrophils, eosinophils, basophils and CD4+ T cell number. Exendin-4 also relaxes bronchial smooth muscles by acting on the cAMP-PKA pathway.
A recent study demonstrated that GLP-1 agonists improve survival and lung function in mouse models of asthma and COPD. The results showed that GLP-1R agonists have therapeutic potential in the treatment of chronic obstructive pulmonary diseases by decreasing the severity of acute exacerbations. The anti-inflammatory effects of GLP-1 agonists in obstructive disease was evident in studies of female C57BL/6 mice. There was a decrease in CD31+ endothelial cells in lung tissues after agonist treatment. Trials in humans have also shown that liraglutide administration improves forced vital capacity.
GLP-1 causes an increase in cAMP concentration and phosphorylation of endothelial nitric oxide synthase (NOS). Nitric oxide produced as a result may be responsible for the effects of GLP-1 on vasodilation, surfactant production and bronchodilation.
GLP-1 also activates protein kinase A (PKA), which inhibits pro-inflammatory mediators such as nuclear factor kappa light chain enhancer of activated B cells (NF-kB), receptor of advanced glycation end products (RAGE) and asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor. These mediators play a central role in obesity-related asthma by increasing inflammatory cell proliferation and infiltration, airway remodeling, airway hyperreactivity and bronchoconstriction. A recent study showed that bronchodilation caused by GLP-1 analog Exendin-4 was inhibited by GLP-1 receptor blockers. or cAMP-PKA antagonists. Dipeptidyl peptidase-4 (DPP-4), which degrades GLP-1, is expressed in the lungs. Allergens cause upregulation of DPP-4 expression. DPP-4 activates pro-inflammatory pathways (MAPK and NF-kB) and also increases reactive oxygen species, AGE and RAGE gene expression.
GLP-1: acute lung injuries
Acute lung injury is one of the most serious complications of sepsis. LPS administration in mice leads to endotoxemia and sepsis. Inflammation in sepsis can wash out surfactant leading to the development of acute respiratory distress syndrome (ARDS). GLP-1 agonists have a protective effect in acute lung injury and ARDS. GLP-1 promotes the production of surfactants through PKA-dependent and PKC-dependent mechanisms. Following LPS injections in mice, co-administration of GLP-1 diminishes the decline in surfactant levels.
GLP-1: Renal system
Renal inflammation is a primary cause of kidney failure. Repeated kidney injuries ultimately result in end-stage renal disease. Diabetes is one cause of kidney damage. How diabetes causes inflammation is controversial, but it is known to promote the problem in both the organ and the whole body. Inflammatory cells, cytokines, and profibrotic growth factors cause vascular inflammation and fibrosis in diabetic nephropathy (DN). GLP-1, through its anti-inflammatory effects, reduces inflammation and fibrosis in diabetes.
The presence of oxidative stress in diabetic kidneys is a significant element in the inflammatory process. Oxidant/antioxidant imbalances activate NF-kB. GLP-1 receptor knockout mice have increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and PKA activity. These changes lead to renal pathology. Activation of the cyclic adenosine monophosphate–protein kinase A (cAMP–PKA) pathway halts the synthesis of reactive oxygen species. GLP-1 receptor agonists activate cAMP-PKA pathway and protect against oxidative stress. Liraglutide reduced NADPH oxidase activity and increased cAMP-PKA activity in mice. It also enhanced glomerular hyperfiltration by improving glomerular nitric oxide and decreasing mesangial expansion.
Advanced glycation end products are a common pathogenic stimulant in diabetes. They increase production of reactive oxygen species. GLP-1 agonists interfere with the signaling of receptors for advanced glycation end products. This leads to less oxidative stress and promotes protection against diabetic nephropathy.
Reactive oxygen species (ROS) increase the synthesis of monocyte chemotactic protein-1 (MCP-1) in diabetes. Increased NF-kB expression leads to higher levels of MCP-1, IL-1, and TNF-α. Macrophage activation generates a proinflammatory condition that causes structural damage to the kidneys. In the kidneys, prostaglandins serve a protective function. PGE2 synthesis is inhibited when macrophages secrete IL-1 and TNF-α. Reduced PGE2 levels hasten the inflammatory process in the kidneys. In rats with STZ-induced diabetes, exendin-4 decreases proteinuria and serum creatinine levels, and inhibits mesangial matrix expansion. It also protects against glomerular hypertrophy, monocyte infiltration and by reducing TGF-β, ICAM1, and CD14 in the renal cortex. Diabetes caused several histological changes in the renal tissue in another STZ-induced diabetes mouse model, including decreased height and continuity of the tubular brush border, vacuolization of proximal and distal tubular cells, necrosis of tubular and glomerular cells, hemorrhage, and mononuclear cell infiltration. Exendin-4 therapy resulted in a substantial reduction in all these lesions. In another similar mouse model, liraglutide resulted in restoration of catalase and glutathione peroxidase-3 levels, enzymes crucial in tissue protection against oxidative damage in kidneys.
GLP-1 protects diabetic kidneys. It lowers glucose levels and reduces inflammatory responses. GLP-1 receptor levels increase early in sepsis suggesting that it may have a protective role in this disorder as well. The use of recombinant human GLP-1 decreases the albumin content of the urine. In tubular tissue and human proximal tubular cells, it also reduces the production of multiple profibrotic factors including collagen I, alpha smooth muscle actin (SMA), fibronectin, and inflammatory proteins MCP-1 and TNF (HK-2 cells). Furthermore, in both diabetic tubular tissue and HK-2 cells, rhGLP-1 strongly decreased the phosphorylation of NF-kB and MAPK.
Sitagliptin inhibits inflammation and apoptosis. The use of sitagliptin in mice has been shown to decrease urine microalbumin, serum creatinine, blood glucose and blood urea nitrogen. It also decreased TNF-α receptor microRNA levels.
Source: Frontiers
Additional Research
The Incretin Effect of GLP-1
Perhaps the most important effect that GLP-1 has, according to Dr. Holst, is referred to as the “incretin effect.” Incretins are a group of metabolic hormones, released by the GI tract, that cause a decrease in blood glucose (sugar) levels. GLP-1 has been shown to be one of the two most important hormones (the other being GIP) to stimulate the incretin effect in rodent models. Though GIP circulates at levels roughly 10 times higher than that of GLP-1, there is evidence that GLP-1 is the more potent of the two molecules, particularly when levels of blood glucose are quite high.
A GLP-1 receptor has been identified on the surface of pancreatic beta cells, making it clear that GLP-1 directly stimulates the exocytosis of insulin from the pancreas. When combined with sulfonylurea drugs, GLP-1 has been shown to boost insulin secretion enough to cause mild hypoglycemia in up to 40% of subjects. Of course, increased insulin secretion is associated with a number of trophic effects including increased protein synthesis, reduction in the breakdown of protein, and increased uptake of amino acids by skeletal muscle.
GLP-1 and Beta Cell Protection
Research in animal models suggests that GLP-1 can stimulate the growth and proliferation of pancreatic beta cells and that it may stimulate the differentiation of new beta cells from progenitors in the pancreatic duct epithelium. Research has also shown that GLP-1 inhibits beta cell apoptosis. Taken In sum, these effects tip the usual balance of beta cell growth and death toward growth, suggesting that the peptide may be useful in treating diabetes and in protecting the pancreas against insults that harms beta cells.
In one particularly compelling trial, GLP-1 was shown to inhibit the death of beta cells caused by enhanced levels of inflammatory cytokines. In fact, mouse models of type 1 diabetes have revealed that GLP-1 protects islet cells from destruction and may, in fact, be a useful means of preventing onset of type 1 diabetes.
GLP-1 and Appetite
Research in mouse models suggests that administration of GLP-1, and its similar cousin GLP-1, into the brains of mice can reduce the drive to eat and inhibit food intake. It appears that GLP-1 may actually enhance feelings of satiety, helping individuals to feel fuller and reducing hunger indirectly. Recent Clinical studies have shown in mice that twice daily administration of GLP-1 receptor agonists cause gradual, linear weight loss. Over a long period, this weight loss is associated with significant improvement in cardiovascular risk factors and a reduction in hemoglobin A1C levels, the latter of these being a proxy marker for the severity of diabetes and the quality of blood sugar control attained via treatment.
Potential Cardiovascular Benefits of GLP-1
It is now known that GLP-1 receptors are distributed throughout the heart and act to improve cardiac function in certain settings by boosting heart rate and reducing left ventricular end-diastolic pressure. The latter may not seem like much, but increased LV end-diastolic pressure is associated with LV hypertrophy, cardiac remodeling, and eventual heart failure.
Recent evidence has even suggested that GLP-1 could play a role in decreasing the overall damage caused by a heart attack. It appears that the peptide improves cardiac muscle glucose uptake, thereby helping struggling ischemic heart muscle cells to get the nutrition they need to continue functioning and avoid programmed cell death. The increase in glucose uptake in these cells appears to be independent of insulin.
Large infusions of GLP-1 into dogs have been shown to improve LV performance and reduce systemic vascular resistance. The latter effect can help to reduce blood pressure and ease strain on the heart as a result. This, in turn, can help to reduce the long-term consequences of high blood pressure such as LV remodeling, vascular thickening, and heart failure. According to Dr. Holst, administration of GLP-1 following cardiac injury has “constantly increased myocardial performance both in experimental animal models and in patients.”
Size of damage in heart in control mice (A), mice given standard vasopressin therapy (B), and mice give GLP-1 (C).Source: Diabetes Journal
GLP-1 and the Brain
There is some evidence to suggest that GLP-1 can improve learning and help to protect neurons against neurodegenerative diseases such as Alzheimer’s Disease. In one study, GLP-1 was shown to enhance associative and spatial learning in mice and even to improve learning deficits in mice with specific gene defects. In rats that over-express the GLP-1 receptor in certain regions of the brain, learning and memory are both significantly better than in their normal controls.
Additional research in mice has shown that GLP-1 can help to protect against excitotoxic neuronal damage, completely protecting rat models of neurodegeneration against glutamate-induced apoptosis. The peptide can even stimulate neurite outgrowth in cultured cells. Researchers are hopeful that additional research on GLP-1 will reveal how it might be used to halt or reverse certain neurodegenerative diseases.
Interestingly, GLP-1 and its analogue exendin-4 have been shown in mouse models to reduce levels of amyloid-beta in the brain as well as the beta-amyloid precursor protein found in neurons. Amyloid beta is the primary component of the plaques observed in Alzheimer’s disease, plaques which, while not necessarily known to be causative, are associated with the severity of the disease. It remains to be seen if preventing amyloid beta accumulation can protect against the effects of Alzheimer’s disease, but this research is, at the very least, a tantalizing clue as to how scientists may intervene in the progression of mild cognitive impairment to full Alzheimer’s disease.
GLP-1 exhibits minimal to moderate side effects, low oral and excellent subcutaneous bioavailability in mice. Per kg dosage in mice does not scale to humans.
Initial Dose Escalation Schedule:
- Weeks 1 through 4: 0.25 mg subcutaneously once a week
- Weeks 5 through 8: 0.5 mg subcutaneously once a week
- Weeks 9 through 12: 1 mg subcutaneously once a week
- Weeks 13 through 16: 1.7 mg subcutaneously once a week
Maintenance Dose:
Week 17 and onward: 2.4 mg subcutaneously once a week
Dosing Considerations:
If dose escalation is not tolerated, consider delaying dose escalation for 4 weeks
If the maintenance dose of 2.4 mg once a week is not tolerated, the dose can be temporarily decreased to 1.7 mg once a week for a maximum of 4 weeks
After 4 weeks, increase dose back to 2.4 mg once a week; discontinue therapy if the patient cannot tolerate the maintenance dose of 2.4 mg once a week
About The Author
The above literature was researched, edited and organized by Dr. Logan, M.D. Dr. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.
Scientific Journal Author
In 1986 Professor Jens Juul Holst discovered the GLP-1 hormone in connection with his work on stomach ulcer surgery. Since the discovery, Novo Nordisk Have used the research to successfully develop products to treat diabetes and obesity. The hormone GLP-1 can be used to regulate blood sugar levels and satiety. Not only has it made treatment of obesity and diabetes possible, it has also proven useful preventatively through early diagnosis for citizens who are at risk of developing diabetes and obesity. In 2015, Jens Juul Holst received the prestigious international Fernström prize for his research on GLP-1. He is one of the most cited researchers in Europe, with over 1,200 published articles and citations in over 3,500 articles annually.
Professor Jens Juul Holst is being referenced as one of the leading scientists involved in the research and development of GLP-1. In no way is this doctor/scientist endorsing or advocating the purchase, sale, or use of this product for any reason. There is no affiliation or relationship, implied or otherwise, between Guide to Peptide and this doctor. The purpose of citing the doctor is to acknowledge, recognize, and credit the exhaustive research and development efforts conducted by the scientists studying this peptide. Professor Jens Juul Holst is listed in referenced citations.
Referenced Citations
- “The Physiology of Glucagon-like Peptide 1 | Physiological Reviews.” [Online].
- “Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes. – PubMed – NCBI.” [Online].
- “The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake. – PubMed – NCBI.”[Online].
- “Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with…- PubMed – NCBI.” [Online].
- “Cardiac function in mice lacking the glucagon-like peptide-1 receptor. – PubMed – NCBI.” [Online].
- “Glucagon-like Peptide 1 Can Directly Protect the Heart Against Ischemia/Reperfusion Injury | Diabetes.” [Online].
- “Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-ind… – PubMed – NCBI.” [Online].
- “Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. – PubMed – NCBI.” [Online].
- “Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. – PubMed – NCBI.” [Online].
- “A new Alzheimer’s disease interventive strategy: GLP-1. – PubMed – NCBI.” [Online].
Holst JJ. From the Incretin Concept and the Discovery of GLP-1 to Today’s Diabetes Therapy. Front Endocrinol (Lausanne). 2019;10:260. Published2019 Apr 26. doi:10.3389/fendo.2019.00260 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497767/