What Do GLP-1 and GIP Do? Hormone Functions Explained

What do GLP-1 and GIP do in the body? Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released by the gut after eating. These hormones regulate blood sugar by enhancing insulin secretion and suppressing glucagon release in a glucose-dependent manner, minimizing hypoglycemia risk. GLP-1 also slows gastric emptying and reduces appetite through central nervous system pathways. Understanding these mechanisms has revolutionized diabetes and obesity treatment, with GLP-1 receptor agonists and dual GLP-1/GIP agonists now representing cornerstone therapies. This article explores the distinct physiological roles of these incretins, their clinical applications, and their impact on metabolic health.

What Are GLP-1 and GIP Hormones?

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted by specialized cells in the gastrointestinal tract in response to nutrient intake. GLP-1 is primarily produced by L-cells located predominantly in the distal small intestine and colon, while GIP is secreted by K-cells found mainly in the proximal small intestine, particularly the duodenum and jejunum. These hormones are released within minutes of food consumption, with concentrations typically peaking approximately 30 to 60 minutes after meals, though timing varies based on meal composition and individual factors.

These incretins play a fundamental role in glucose homeostasis through what is known as the incretin effect—the phenomenon whereby oral glucose administration produces a greater insulin response than intravenous glucose delivery at equivalent blood glucose concentrations. In healthy individuals, the incretin effect is estimated to account for approximately 50 to 70 percent of total insulin secretion following oral glucose intake. This physiological mechanism helps ensure efficient nutrient processing and metabolic regulation.

Both GLP-1 and GIP are rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), resulting in plasma half-lives of only about 2 to 3 minutes for GLP-1 and approximately 7 minutes for GIP. This rapid degradation initially posed challenges for therapeutic development but ultimately led to the creation of DPP-4-resistant analogs and DPP-4 inhibitors. Understanding the distinct and overlapping functions of these hormones has significantly advanced diabetes management and obesity treatment approaches, with GLP-1 and dual GLP-1/GIP receptor agonists now representing important therapies in metabolic medicine.

Effects of GLP-1 and GIP on Appetite and Weight

GLP-1 exerts potent effects on appetite regulation and body weight through multiple mechanisms involving both peripheral and central nervous system pathways. The hormone acts on GLP-1 receptors located in the hypothalamus and brainstem, particularly in the arcuate nucleus and area postrema, to promote satiety and reduce food intake. Additionally, GLP-1 slows gastric emptying by inhibiting gastric motility, which prolongs the sensation of fullness after meals and contributes to reduced caloric consumption. Clinical trials demonstrate that GLP-1 receptor agonists consistently produce dose-dependent weight loss, with reductions typically ranging from 5 to 15 percent of baseline body weight depending on the specific agent and dosage. It's worth noting that long-acting GLP-1 receptor agonists may exhibit some tachyphylaxis of the gastric emptying effect over time.

The role of GIP in weight regulation is more complex and has been subject to evolving understanding. Native GIP was historically thought to promote weight gain through effects on adipose tissue, including enhanced lipid storage and adipocyte differentiation. However, recent evidence from dual GLP-1/GIP receptor agonist trials has challenged this paradigm. Tirzepatide, which activates both GLP-1 and GIP receptors, produces greater weight loss than selective GLP-1 agonists, suggesting that GIP receptor activation in the context of concurrent GLP-1 signaling may enhance weight reduction rather than oppose it.

The synergistic effects observed with dual agonism may potentially involve improved insulin sensitivity, enhanced energy expenditure, and complementary actions on appetite centers, though these mechanisms remain hypothetical and require further research. GIP may also modulate GLP-1's effects on gastric emptying and satiety signaling. These findings have important implications for obesity pharmacotherapy, as combination incretin-based approaches appear to offer superior metabolic benefits compared to single-hormone targeting. Patient counseling should emphasize that weight loss with these medications requires ongoing treatment, as discontinuation typically results in weight regain.

Clinical Uses of GLP-1 and GIP-Based Medications

GLP-1 receptor agonists have become established as effective therapies for type 2 diabetes mellitus and obesity. FDA-approved GLP-1-based medications include short-acting agents such as exenatide (administered twice daily) and longer-acting formulations including liraglutide, dulaglutide, semaglutide, and once-weekly exenatide. Semaglutide is available in both subcutaneous (0.5 mg, 1 mg, or 2 mg weekly for diabetes; 2.4 mg weekly for weight management) and oral formulations (7 mg or 14 mg daily). According to the American Diabetes Association (ADA) Standards of Care, GLP-1 receptor agonists are recommended for patients with established atherosclerotic cardiovascular disease (ASCVD), while SGLT2 inhibitors are preferred for heart failure (HF) or chronic kidney disease (CKD). These agents may be initiated independent of metformin based on comorbidities and patient factors.

The first dual GLP-1/GIP receptor agonist, tirzepatide, received FDA approval in 2022 for type 2 diabetes (Mounjaro) and in 2023 for chronic weight management (Zepbound). Clinical trials have shown tirzepatide produces superior glycemic control and weight reduction compared to selective GLP-1 agonists, with hemoglobin A1c reductions of 1.9 to 2.4 percent and weight loss averaging 15 to 22 percent of baseline body weight at the highest doses. These medications are administered via subcutaneous injection, typically in the abdomen, thigh, or upper arm, and require gradual dose titration per FDA labeling.

Common adverse effects include gastrointestinal symptoms—nausea, vomiting, diarrhea, and constipation—which are usually transient. More serious but rare complications include pancreatitis, gallbladder disease, and potential thyroid C-cell tumors (observed in rodent studies but not conclusively demonstrated in humans). These medications are contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. They should be used with caution in patients with severe gastrointestinal disease or gastroparesis. Exenatide should be avoided in severe renal impairment (eGFR <30 mL/min/1.73 m²). Semaglutide carries a warning about potential worsening of diabetic retinopathy, particularly in patients with pre-existing retinopathy. When combined with insulin or sulfonylureas, dose reductions of these agents should be considered to reduce hypoglycemia risk. Weight management formulations are contraindicated during pregnancy.

DPP-4 inhibitors (sitagliptin, linagliptin, saxagliptin, alogliptin) represent an alternative incretin-based approach, working by preventing the degradation of endogenous GLP-1 and GIP. They produce more modest glycemic improvements and no significant weight loss. Saxagliptin and alogliptin have been associated with increased risk of heart failure hospitalization. Combining GLP-1 receptor agonists with DPP-4 inhibitors is not recommended due to limited additional benefit.

How GLP-1 and GIP Regulate Blood Sugar

GLP-1 and GIP regulate blood glucose through complementary mechanisms that enhance insulin secretion while suppressing inappropriate glucagon release. Both hormones bind to G-protein-coupled receptors on pancreatic beta cells, triggering intracellular signaling cascades that amplify glucose-stimulated insulin secretion. Critically, this insulinotropic effect is glucose-dependent—insulin release is enhanced only when blood glucose concentrations are elevated, which substantially reduces hypoglycemia risk compared to insulin secretagogues like sulfonylureas. When glucose levels normalize, incretin-mediated insulin secretion diminishes accordingly, providing an inherent safety mechanism.

GLP-1 additionally suppresses glucagon secretion from pancreatic alpha cells, particularly in hyperglycemic states. Since glucagon promotes hepatic glucose production, its suppression reduces excessive glucose output from the liver. This dual action—enhanced insulin secretion and reduced glucagon release—creates a coordinated response that effectively lowers blood glucose. GIP's effects on glucagon are more nuanced; while it can stimulate glucagon secretion in hypoglycemic conditions (potentially serving a counter-regulatory function), this effect appears attenuated in hyperglycemic states, particularly when GIP receptor activation occurs alongside GLP-1 signaling.

Beyond direct pancreatic effects, GLP-1 may improve beta-cell function and survival through anti-apoptotic mechanisms and promotion of beta-cell proliferation, though the clinical significance of these effects in humans remains under investigation. The slowing of gastric emptying induced by GLP-1 also contributes to glycemic control by moderating the rate of glucose absorption from the intestine, thereby blunting postprandial glucose excursions. In patients with type 2 diabetes, where the incretin effect is markedly diminished, pharmacological incretin-based therapies effectively help restore this deficient physiological mechanism, resulting in meaningful improvements in both fasting and postprandial glucose control without significant hypoglycemia risk when used as monotherapy or with metformin.

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