**Core Concept**
Insulin release is primarily stimulated by agents that enhance glucose-dependent insulin secretion or improve insulin sensitivity. Glucose, incretin hormones, and certain antidiabetic drugs directly or indirectly promote pancreatic beta-cell activity. Thiazolidinediones (TZDs) like rosiglitazone act via insulin sensitization, not direct insulin secretion.

**Why the Correct Answer is Right**
Rosiglitazone is a thiazolidinedione that acts as a PPAR-γ agonist, increasing insulin sensitivity in peripheral tissues (muscle and adipose), thereby lowering blood glucose indirectly. It does **not** stimulate insulin release from beta cells. Instead, it reduces insulin resistance. In contrast, nateglinide, glipizide, and tobutamide are sulfonylurea-like drugs that stimulate insulin secretion by closing K⁺ channels in beta cells, leading to depolarization and insulin release.

**Why Each Wrong Option is Incorrect**
Option B: Nateglinide is a meglitinide analog that stimulates insulin secretion by binding to sulfonylurea receptors on beta cells, causing rapid insulin release.
Option C: Glimipiride is a second-generation sulfonylurea that enhances insulin secretion via similar mechanisms as other sulfonylureas.
Option D: Tobutamide is a sulfonylurea derivative that acts on beta-cell K⁺ channels to trigger insulin release.

**Clinical Pearl / High-Yield Fact**
Always remember: **TZDs (like rosiglitazone) improve insulin sensitivity but do not stimulate insulin secretion**—they are insulin sensitizers, not insulin secretagogues. This distinction is crucial in differentiating drug classes in type 2 diabetes management.

✓ Correct Answer: A. Rosiglitazone