The pancreas is a glandular approximately 15 to 20 centimeters in length, situated behind the stomach and adjacent to the duodenum.

However, its endocrine function, though limited in volume, is essential for life-sustaining glucose regulation.

The islets of Langerhans, scattered throughout the pancreatic parenchyma, contain five distinct cell types. Beta (β) cells, which comprise around 60–70% of the islet population, produce insulin.

Alpha (α) cells secrete glucagon, delta (δ) cells produce somatostatin, PP cells generate pancreatic polypeptide, and epsilon (ε) cells synthesize ghrelin. This cellular diversity allows for fine-tuned regulation of carbohydrate metabolism and reflects the complexity in endocrine disorders such as diabetes.

Insulin Dynamics and Glucose Homeostasis

Insulin, secreted in response to elevated blood glucose levels, binds to insulin receptors on muscle, and liver cells, promoting glucose uptake and glycogenesis. In the absence of insulin or in the case of insulin resistance, glucose accumulates in the bloodstream, resulting in hyperglycemia—a hallmark of diabetes mellitus.

Importantly, insulin is secreted in a biphasic pattern. The first phase involves the rapid release of pre-stored insulin granules, and the second phase represents sustained synthesis and secretion. Both phases are often impaired early in the pathogenesis of type 2 diabetes. Studies published in Diabetes Care (2024) highlight that first-phase insulin secretion may be diminished up to 10 years before clinical diagnosis, underscoring the significance of early pancreatic involvement.

Autoimmune Destruction in Type 1 Diabetes

Type 1 diabetes is primarily characterized by autoimmune-mediated β-cell destruction. This process is gradual and often asymptomatic until 80–90% of the β-cell population is destroyed. Auto-antibodies against insulin, GAD65, IA-2, and ZnT8 are commonly detected during the early stages. These auto-antibodies serve as biomarkers for identifying at-risk individuals, even years before symptom onset.

Recent findings from the TrialNet Pathway to Prevention Study (2023) have shown that immune dysregulation involving T helper 1 (Th1) and cytotoxic T lymphocytes plays a critical role in β-cell apoptosis. Moreover, regulatory T-cell (Treg) dysfunction has been implicated in the failure to suppress this autoimmune response.

Dr. Mark Atkinson, a leading researcher at the University of Florida, emphasizes the role of pancreatic-resident memory T cells in perpetuating islet inflammation even after systemic immune suppression.

Metabolic Stress and β-Cell Exhaustion in Type 2 Diabetes

Type 2 diabetes is driven by a complex interplay between insulin resistance and β-cell dysfunction. In response to peripheral insulin resistance, β-cells initially compensate by increasing insulin production. However, chronic metabolic overload leads to lipotoxicity, glucotoxicity, and oxidative stress, culminating in β-cell dysfunction and eventual apoptosis.

The 2024 ADA Scientific Sessions highlighted that chronic hyperglycemia induces UPR (unfolded protein response) dysregulation in the endoplasmic reticulum of β-cells, leading to impaired insulin folding and increased apoptosis. Furthermore, free fatty acids, especially saturated fatty acids like palmitate, activate the NF-κB pathway, exacerbating pro-inflammatory gene expression within islets.

Pancreatic islets in T2D patients often exhibit amyloid deposits composed of islet amyloid polypeptide (IAPP), contributing to local cytotoxicity and disruption of islet architecture. A 2023 article in Cell Metabolism reported that targeting amyloidogenesis through pharmacological inhibitors may preserve islet function in early T2D.

Inflammation, Fibrosis, and the Pancreatic Microenvironment

Chronic islet inflammation, known as insulitis, plays a pathophysiological role in both T1D and T2D, albeit through different immune mechanisms. In T1D, lymphocytic infiltration leads to direct β-cell lysis. In T2D, low-grade inflammation—primarily involving macrophages and innate immune pathways—impairs β-cell survival.

A pivotal study published in The Journal of Clinical Investigation (2025) by Dr. Francesca Dotta demonstrated that inflammatory chemokines such as CXCL10 and MCP-1 disrupt β-cell signaling and enhance local immune cell recruitment. Moreover, fibrotic changes, including collagen deposition and pancreatic stellate cell activation, are increasingly recognized in the diabetic pancreas. These changes compromise islet oxygenation and capillary perfusion, further aggravating cellular stress.

Imaging, Biomarkers, and Functional Assessment of the Pancreas

Recent technological advances allow for non-invasive visualization of pancreatic β-cell mass and function. PET imaging using radiolabeled dihydrotetrabenazine analogs ([¹⁸F]FP-(+)-DTBZ) targets the vesicular monoamine transporter type 2 (VMAT2), a protein selectively expressed in β-cells. MRI, combined with manganese-enhanced contrast, has also been applied to assess islet density in vivo.

Current and Future Therapeutic Strategies Targeting the Pancreas

The pancreas is not just the site of damage in diabetes—it is increasingly becoming the target of therapeutic intervention.

- Teplizumab (Tzield), approved in the U.S. in 2022, is a CD3-directed monoclonal antibody shown to delay the onset of T1D in high-risk individuals. It modulates the autoimmune response without broadly suppressing immunity.

- Incretin-based therapies, such as GLP-1 receptor agonists and DPP-4 inhibitors, not only stimulate glucose-dependent insulin secretion but also exert anti-inflammatory and anti-apoptotic effects on β-cells.

- SGLT2 inhibitors, while acting on the kidney, provide indirect β-cell benefits by lowering glucotoxicity. Some evidence also suggests they reduce islet inflammation through modulation of macrophage phenotypes.

- Stem cell–derived β-cell replacement offers hope for T1D reversal. Ongoing trials using VX-880 and VX-264 (Vertex Pharmaceuticals) have reported positive outcomes, including insulin independence in some recipients. Researchers emphasize the need for encapsulation technology to protect transplanted cells from immune attack without lifelong immunosuppression.

Decades of research have transformed our understanding of diabetes from a mere metabolic disorder to a complex, immune-metabolic disease centered around the pancreas. Whether via autoimmune destruction, chronic metabolic injury, or fibrosis-driven dysfunction, the pancreas remains the fulcrum of pathogenesis and therapy in both major types of diabetes.

Future clinical strategies will likely involve personalized assessment of pancreatic function, targeted immunomodulation, and regenerative interventions to restore endogenous insulin production. As the field advances, preserving pancreatic health is no longer just a goal—it is a clinical imperative in the fight against diabetes.