What is the First-Phase Insulin Response (FPIR)?

First-Phase Insulin Response (FPIR)

FPIR is the rapid, initial burst of insulin secretion that occurs within 3-10 minutes after glucose stimulation, representing the pancreatic β-cells' immediate response to rising blood glucose levels. 1

Physiological Characteristics

The first-phase insulin response consists of a brief spike lasting approximately 10 minutes following glucose exposure, followed by a slower, sustained second phase lasting 60-120 minutes. 2, 1

Temporal Pattern

• Insulin secretion increases within 3-5 minutes of glucose stimulation and peaks by 10 minutes during the first phase. 1
• After the initial spike, insulin secretion transitions to a second phase that extends over 60-120 minutes, reaching a plateau at 2-3 hours. 2, 3
• Under normal physiological conditions, postprandial insulin secretion increases 3-10 times above basal rates over a 4-hour period before returning to baseline. 1

Mechanism and Function

• FPIR requires rapid changes in glucose concentration to manifest clearly—it is most evident during intravenous glucose challenges rather than oral glucose ingestion. 4
• The first-phase response depends on readily releasable insulin granules that are pre-docked at the β-cell membrane, allowing immediate exocytosis when triggered by glucose-induced calcium influx. 5
• Specific "first responder" β-cells within pancreatic islets initiate the coordinated first-phase calcium response, characterized by high membrane excitability and lower electrical coupling to neighboring cells. 6

Clinical Significance in Diabetes Pathogenesis

Loss of FPIR is one of the earliest detectable abnormalities in β-cell dysfunction and appears in individuals with persistent impaired glucose tolerance before they develop overt type 2 diabetes. 3, 7

Early Detection of β-Cell Dysfunction

• Subjects with persistent impaired glucose tolerance demonstrate significantly reduced first-phase insulin response (measured at 3 minutes post-glucose challenge), while those with transient IGT maintain normal FPIR. 7
• Insulin resistance and impaired first-phase insulin secretion characterize the early stage of type 2 diabetes, causing post-prandial hyperglycemia. 2
• Recent evidence suggests that reductions in both first and second-phase insulin release occur equally early and may precede insulin resistance beyond that caused by obesity alone. 3

Disease-Specific Patterns

• In cystic fibrosis-related diabetes (CFRD), impaired FPIR occurs due to CFTR channel dysfunction in β-cells, which is required for normal insulin exocytosis and membrane potential regulation. 2
• CFTR-deficient animal models (ferrets and pigs) show reduced first-phase insulin secretion and abnormal glucose tolerance from birth, even without pancreatic fibrosis. 2
• Type 1 diabetes results from progressive β-cell destruction leading to absolute insulin deficiency, eliminating both phases of insulin response. 2

Measurement and Assessment

FPIR is most accurately measured using intravenous glucose tolerance testing with frequent blood sampling (at 3,4, and 5 minutes post-glucose administration) rather than oral glucose tolerance tests. 7, 4

Key Methodological Considerations

• A clear biphasic pattern only emerges with rapid intravenous glucose administration; oral glucose produces a gradually rising insulin profile without distinct first-phase morphology. 4
• At the portal vein level, the early insulin response displays pulsatile oscillations that rapidly expose the liver to elevated insulin levels, effectively restraining hepatic glucose production. 4
• Routine testing for insulin levels is not recommended for most patients with diabetes or at risk for diabetes, except in specific scenarios like investigating non-diabetic hypoglycemia or diagnosing insulinomas. 1

Molecular Regulation

Three families of protein kinases (calmodulin-dependent kinase, PKA, and PKC) function as distal amplifiers for stimulus-secretion coupling, with PKA and PKC pathways potentiating fuel-generated signals to produce full biphasic insulin response. 5

Cellular Mechanisms

• PKA activation (via glucagon or GLP-1) produces full biphasic response only in the presence of adequate glucose (≥10 mmol/L), while calcium recruitment alone is insufficient at low fuel levels. 5
• CFTR channels regulate insulin secretion through cAMP-dependent pathways, with CFTR acting upstream of ANO1 (another chloride channel) to control insulin granule exocytosis. 2
• When first responder β-cells are ablated, the first-phase calcium response becomes slowed, diminished, and discoordinated, demonstrating their critical organizational role. 6

Common Pitfalls in Interpretation

The absence of a distinct first-phase peak during oral glucose tolerance testing does not indicate FPIR loss—physiological oral glucose absorption produces a gradually rising insulin profile that masks the biphasic pattern. 4

• Fasting duration affects interpretation: prolonged fasting (≥16 hours) triggers cortisol-mediated hepatic glucose production that can confound glucose and insulin measurements. 8
• Standard diagnostic fasting for glucose testing should be 8-12 hours, not longer, to avoid stress-induced hyperglycemia that may obscure true β-cell function. 8
• The spatial organization of first-phase response within islets remains consistent over approximately 24 hours, meaning timing of testing within a day is less critical than fasting duration. 6