Why are proinsulin levels normal during fasting and elevated after eating?

Proinsulin Levels During Fasting and After Eating

Proinsulin levels are normal during fasting but increase after eating because proinsulin is released from pancreatic β-cells in response to food intake as part of normal insulin production, with a slower secretion pattern than insulin. 1

Physiological Mechanisms

• During fasting, proinsulin secretion is minimal, maintaining normal baseline levels of approximately 5.8 ± 3.3 pmol/L in healthy individuals 1
• After food intake, proinsulin is released as part of the insulin secretory response but follows a slower release pattern compared to insulin 1
• Proinsulin is the precursor molecule of insulin, produced in pancreatic β-cells and normally cleaved into insulin and C-peptide before secretion 2
• During the fed state, glucose appearance is primarily influenced by gastric emptying time, which triggers insulin (and consequently some proinsulin) secretion 3

Normal Insulin and Proinsulin Secretion Patterns

• Under physiological conditions, basal insulin is continuously produced at a rate of 0.5-1 units per hour, representing approximately 48-52% of total daily insulin production 3
• After meals, insulin secretion increases 3-10 times over a 4-hour postprandial period before returning to basal rate 3
• Insulin is secreted in a biphasic manner with a first rise within 3-5 minutes lasting up to 10 minutes (first phase), followed by a slower extended phase of 60-120 minutes (second phase) 3
• Proinsulin follows a similar but slower pattern, with its postprandial increase lagging behind that of insulin 1

Proinsulin in Metabolic Disorders

• In individuals with impaired glucose tolerance or diabetes, fasting proinsulin levels are elevated (9.5 ± 6.9 pmol/L and 12.6 ± 7.5 pmol/L respectively) compared to healthy individuals 1
• The molar ratio of proinsulin to insulin is increased in subjects with impaired glucose tolerance or diabetes compared to control subjects 1
• Elevated intact proinsulin levels (>10 pmol/L) may indicate insulin resistance, while elevation of total proinsulin (>45 pmol/L) can help identify patients at high cardiovascular risk 2
• Hyperproinsulinemia is not present before the development of hyperglycemia, suggesting that hyperglycemia is the main stimulus for increased proinsulin secretion 4

Clinical Significance

• Routine testing for insulin or proinsulin is not recommended for most people with diabetes or risk for diabetes or cardiovascular disease 3
• These assays are primarily useful for research purposes rather than routine clinical care 3
• A higher proinsulin response to glucose loading may predict deteriorating fasting plasma glucose and progression to diabetes in subjects with impaired glucose tolerance 5
• Proinsulin measurements may be valuable in specific clinical scenarios such as investigating non-diabetic hypoglycemia or diagnosing insulinomas 3, 6

Metabolic Adaptations During Fasting

• During fasting, endogenous glucose production is mediated mainly by hepatic glycogenolysis during the first 8-12 hours, followed by gluconeogenesis 3, 7
• The kidney also plays a role in endogenous glucose production, particularly during prolonged starvation periods 3, 7
• Insulin secretion decreases during fasting, while counter-regulatory hormones (glucagon, cortisol, growth hormone) increase to maintain blood glucose levels 7

Understanding the normal physiological patterns of proinsulin secretion helps in interpreting laboratory findings and can provide insights into β-cell function in various metabolic conditions.