Medicosnext
Prof. Dr. Prabodh Risal
He is a Clinical Biochemist, Professor and Head Department of Biochemistry, Dhulikhel Hospital. He is leading Nepalese Association for Clinical Biochemistry as a President. His research interest includes genetics, hematologic, cardiovascular and liver, diseases. He has more than 30 years of experience in the field of lab medicine.
Biochemistry of GLP-1
Glucagon-like peptide-1 (GLP-1) is a peptide hormone having 30 amino acids, it is involved in the regulation of glucose metabolism, appetite, gastric emptying, and energy balance. The biologically active forms of GLP-1in humans are mainly GLP-1(7–36)NH₂ and GLP-1(7–37). Among these, GLP-1(7–36)NH₂ is mostly found in the circulation. The N-terminal part of the peptide is important for activation of receptor, and the rest of the molecule is responsible for binding with receptor and providing structural stability.
It is produced by the pro-glucagon gene GCG as proglucagon precursors and processed differently in different tissues. In pancreatic α-cells, pro-glucagon is mainly processed by prohormone convertase 2 (PC2), resulting in the formation of glucagon. In the intestinal L-cells it is processed to form GLP-1, GLP-2, and other peptides by the enzyme convertase 1/3.
Mechanism of action and breakdown of GLP-1
Nutrients, along with the neural and endocrine signals associated with food intake, stimulate intestinal cells to release GLP-1. After binding of the hormone to the receptors conformational change occurs that, stimulates G-protein. This stimulates adenylate cyclase, catalyzing the conversion of ATP to cyclic adenosine monophosphate (cAMP). cAMP then activates protein kinase A (PKA) and exchange protein(Epac2).These process activates pancreatic β-cell to secret more insulin upon stimulation by glucose metabolism.
When blood glucose is low, the metabolic stimulus in pancreas becomes weak, resulting reduced insulinotropic effect by the GLP-1. GLP-1 also suppress inappropriate glucagon secretion (during high blood glucose level), contributing blood glucose regulation. Glucagon normally acts on the liver to increase blood glucose by activating glycogenolysis and gluconeogenesis. When glucagon signaling is reduced, hepatic glucose production decreases.
GLP-1 reduces the process of gastric emptying and plays role in neuronal signaling associated with food intake, satiety, and energy homeostasis. When there is a negative energy balance our body begins to mobilize stored fats from the adipose tissues.
GLP-1 is rapidly degraded by dipeptidyl peptidase-4, a serine protease present in the circulation and tissues. Renal and other clearance mechanisms also contribute to the removal of GLP-1 from the circulation. Therefore, endogenous GLP-1 produces only a short-lived physiological signal. To overcome this problem, scientists tried to develop GLP-1 receptor agonists that can reproduce the beneficial actions of GLP-1 while remaining active for much longer time. Most common GLP-1 receptor agonist developed so far includes exenatide, liraglutide, dulaglutide, semaglutide, and lixisenatide.
Glia Monster and its link to GLP-1
In the beginning researchers were interested to know how the Gila monster, a lizard can manages blood glucose for a long time without food. In the early 1990s, researcher John Eng isolated a 39-amino-acid peptide from Gila monster saliva and named it exendin-4. The surprising discovery was that exendin-4 behaved much like human GLP-1: it activated the GLP-1 receptor and augmented insulin secretion.
Exendin-4 is relatively resistant to rapid degradation therefore, provided the basis for the development of first clinically successful GLP-1 receptor agonists used in type 2 diabetes.
Furthermore, structural modifications of the peptide, such as amino-acid substitutions, fatty-acid conjugation, or fusion with larger proteins has increased resistance to enzymatic degradation, improved plasma stability, and reduced renal clearance.
Uses and adverse effects
GLP-1 receptor agonists have rapidly evolved from predominantly diabetes-focused therapies into highly visible chronic weight-management products. Celebrity transformations, online discussions of “Ozempic face” and the increasing availability of lower-cost products have contributed to their public visibility. However, this also raises serious concerns about cosmetic use, and unrealistic expectations of rapid weight loss.
Like all other medicine, GLP-1 receptor agonists can also produce adverse effects. Gastrointestinal symptoms such as nausea, vomiting, diarrhea, constipation, and abdominal discomfort are among the most common. Dehydration may results deterioration of renal function in a susceptible individual. Hypoglycemia is mainly a concern when GLP-1 receptor agonists are combined with insulin or sulfonylureas.
During substantial weight loss, both fat mass and some lean mass may be lost, without adequate protein intake and resistance training. Calorie restriction or prolonged poor oral intake may also promote ketotic states in susceptible individuals, although ketosis is not considered the usual direct effect of GLP-1 receptor agonist therapy.
Laboratory evaluations
From a perspective of laboratory medicine, tests are useful before starting treatment because, it establishes the patient’s baseline status and provides reference values for subsequent monitoring. However, there is no single laboratory panel recommended, commonly requested tests includes:
- Blood sugar test and HbA1c
- Renal function test
- Liver function test
- Lipid profile test
- Thyroid function test
In the patients with diabetes, HbA1c and plasma glucose are important baseline measurements. Serum creatinine and estimated glomerular filtration rate provide useful information about renal function, while urine albumin-to-creatinine ratio is used for screening diabetic kidney disease. Liver function tests are useful, particularly in patients with obesity, diabetes, or suspected fatty liver disease. Cardiovascular risk assessment should be based on the clinical situation and may includes, lipid profile test.
During treatment, laboratory monitoring should be focused mainly toward assessing therapeutic response and investigating clinically relevant adverse effects. Plasma glucose monitoring can be particularly useful during dose escalation or when insulin or sulfonylureas are being used. Renal function test can be done if a patient develops significant vomiting and diarrhea. These conditions can cause dehydration, reduce renal perfusion, and potentially precipitate acute kidney injury. Measurement of amylase or lipase may be recommended in symptomatic patients. Similarly, if gallbladder or biliary disease is suspected, liver biochemical tests and abdominal ultrasonography can be performed according to the clinical presentation. Similarly, calcitonin and thyroid function test can be done if there is relevant clinical findings and personal or family history.
GLP-1 estimation in the blood
GLP-1 measurement is not routinely required for diagnosis or monitoring of diabetes or obesity or before initiating the therapy. The circulating concentration of endogenous GLP-1 does not directly tell us how much GLP-1 receptor signaling is occurring at the tissue level. Similarly, it does not reliably predict an individual’s response to a GLP-1 receptor agonist.
Laboratory estimation is also not convenient because of its short half-life. GLP-1 measurement is mostly done by using immunoassay, such as ELISA but there is no universally accepted clinical “normal range” for endogenous GLP-1.
Conclusion
GLP-1 can be considered an important gut–brain–pancreas signaling hormone that links nutrient intake with glucose regulation and energy balance. The significance of GLP-1 lies not in a single biochemical effect; it integrates glucose regulation, insulin secretion, glucagon suppression, gastrointestinal function, appetite control, and energy balance. This explains why GLP-1 receptor agonists have become important therapeutic agents in both type 2 diabetes and obesity, but caution has to be taken for purely cosmetic purpose, self-medication and unrealistic expectations of rapid weight loss, and it should be taken after careful evaluation and monitoring by the physicians.
