What is GLP1 (Glucagon-Like Peptide-1) and its role in glucose metabolism, particularly in patients with type 2 diabetes and a history of pancreatitis, thyroid C-cell tumors, or impaired renal function?

What is GLP-1 (Glucagon-Like Peptide-1)?

GLP-1 is an incretin hormone secreted primarily from intestinal L-cells in the distal ileum and proximal colon in response to nutrient intake, which regulates glucose homeostasis by stimulating glucose-dependent insulin secretion, suppressing glucagon release, delaying gastric emptying, and promoting satiety. 1, 2

Physiological Origin and Secretion

• GLP-1 is released by L-enteroendocrine cells in the terminal ileum and proximal colon when glucose and triglycerides are detected in the gut lumen 1
• The hormone is also secreted by pancreatic islet cells and neurons in the nucleus tractus solitarius of the brainstem 1
• Natural endogenous GLP-1 has an extremely short half-life of approximately 1.5-2 minutes due to rapid degradation by the enzyme dipeptidyl peptidase-4 (DPP-IV) 1, 3

Mechanism of Action on Glucose Metabolism

Pancreatic Effects

• GLP-1 binds to G-protein coupled receptors (GLP-1R) on pancreatic β-cells, increasing intracellular cyclic AMP and calcium, which triggers insulin secretion only when blood glucose levels are elevated 1, 3
• This glucose-dependent mechanism explains why GLP-1 receptor agonists carry a low risk of hypoglycemia—insulin secretion is significantly attenuated when plasma glucose approaches normal levels 1, 3
• GLP-1 inhibits glucagon secretion from pancreatic α-cells, thereby reducing hepatic glucose production 1, 2
• The hormone may promote β-cell proliferation and protect against apoptosis, potentially preserving pancreatic β-cell mass 1, 2

Gastrointestinal Effects

• GLP-1 delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, which is a primary determinant of postprandial glycemic response 1, 3
• These actions result in reduced gastric contractions, delayed gastric emptying, reduced gastric acid secretion, and increased gastric volumes 1
• The effect on gastric emptying shows tachyphylaxis (diminishing response) with continuous exposure, which is why short-acting GLP-1 receptor agonists maintain their effect on gastric emptying longer than long-acting formulations 1

Central Nervous System Effects

• GLP-1 receptors in the hypothalamus and brainstem nuclei mediate appetite suppression, satiety, and energy expenditure regulation 1, 2
• This central action contributes significantly to the weight loss effects observed with GLP-1 receptor agonist therapy 1

Role in Type 2 Diabetes Pathophysiology

• The incretin effect is reduced in patients with type 2 diabetes, representing a key pathophysiological defect 4
• Abnormalities in the incretin system, including impaired GLP-1 response, contribute to the islet cell dysfunction characteristic of type 2 diabetes 4
• The functional islet incompetence—including disproportionately low insulin production relative to insulin resistance and inappropriate glucagon hypersecretion—is the main quantitative determinant of hyperglycemia in type 2 diabetes 4

Therapeutic Applications

FDA-Approved Indications

• GLP-1 receptor agonists are indicated as adjuncts to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus 5
• They are also indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 5
• GLP-1 receptor agonists are NOT indicated for type 1 diabetes mellitus or treatment of diabetic ketoacidosis 5

Clinical Efficacy

• The American Diabetes Association recommends GLP-1 receptor agonists as a therapeutic option for improving insulin sensitivity, with substantial weight loss effects ranging from 6.1-17.4% in non-diabetic individuals and 4-6.2% in diabetic patients 6
• These agents have good HbA1c-lowering efficacy with an inherently low potential for hypoglycemia 7
• Three GLP-1 receptor agonists have proven cardiovascular benefits, reducing the risk of major adverse cardiovascular events in high-risk patients 7

Available Formulations

• Most GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, beinaglutide, dulaglutide, and semaglutide) require subcutaneous injection 8
• An oral formulation of semaglutide is now available, representing the first oral GLP-1 receptor agonist 7

Critical Safety Considerations

Contraindications

• GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 5
• This is based on rodent studies showing thyroid C-cell tumors, though human relevance remains uncertain 5
• Known hypersensitivity to the medication or its components is also a contraindication 5

Important Warnings

• GLP-1 receptor agonists have not been studied in patients with a history of pancreatitis; consider alternative antidiabetic therapy in these patients 5
• Pancreatitis has been reported in clinical trials and should prompt immediate discontinuation if suspected 5
• Monitor renal function in patients with renal impairment who report severe gastrointestinal adverse reactions, as acute kidney injury has been reported 5

Perioperative Concerns

• There is emerging concern about increased risk of pulmonary aspiration due to retained gastric contents in patients taking GLP-1 receptor agonists 4
• For patients taking GLP-1 receptor agonists for weight management, these drugs should be withheld for at least three half-lives before elective surgical procedures 4
• In patients with type 2 diabetes, prolonged cessation may have detrimental effects on perioperative glycemic control, requiring discussion with an endocrinologist 4

Common Adverse Effects

• The most common adverse reactions (≥5% of patients) include nausea, vomiting, diarrhea, abdominal pain, constipation, dyspepsia, and gastrointestinal reflux 6, 5
• These gastrointestinal effects tend to occur soon after initiation and typically decline over time 7

Drug Interactions

• GLP-1 receptor agonists delay gastric emptying, which may impact the absorption of concomitantly administered oral medications 5
• When used with insulin secretagogues or insulin, consider lowering the dose of these agents to reduce hypoglycemia risk 5

Special Populations

• Discontinue GLP-1 receptor agonists in women at least 2 months before a planned pregnancy due to the long washout period 5