What are the implications of elevated total insulin and C-peptide (Connecting Peptide) levels?

From the Guidelines

Elevated total insulin and C-peptide levels typically indicate hyperinsulinemia, which may be caused by insulin resistance, insulinoma, or exogenous insulin administration, and prompt consultation with an endocrinologist is recommended for proper evaluation and management to prevent complications such as type 2 diabetes, cardiovascular disease, and metabolic syndrome. The initial management of hyperinsulinemia often includes lifestyle modifications such as adopting a low-carbohydrate diet, regular exercise (30 minutes daily), and weight loss if overweight, as these interventions can improve insulin sensitivity and reduce the risk of developing related conditions 1. Further testing will likely include a fasting glucose test, hemoglobin A1C, C-peptide measurement, and possibly imaging studies if insulinoma is suspected, to determine the underlying cause of hyperinsulinemia and guide treatment decisions 1. The concern with persistently elevated insulin levels is the increased risk of developing type 2 diabetes, cardiovascular disease, and metabolic syndrome, and regular monitoring of glucose levels and insulin function through follow-up appointments is essential for effective management 1. Some key points to consider in the management of hyperinsulinemia include:

• The use of metformin, which is effective and safe, and reduces risks of microvascular complications, cardiovascular events, and death, and is often recommended as first-line therapy for type 2 diabetes 1
• The potential benefits and risks of other glucose-lowering agents, such as SGLT2 inhibitors, GLP-1 receptor agonists, and insulin, which may be considered as part of a combination therapy plan or for individuals with severe hyperglycemia 1
• The importance of weight management, as it has multifaceted benefits, including reduction of A1C, reduction in hepatic steatosis, and improvement in cardiovascular risk factors 1
• The need for regular monitoring of kidney function, as metformin may be safely used in people with estimated glomerular filtration rate ≥30 mL/min/1.73 m², but the risk of lactic acidosis increases with decreasing kidney function 1.

From the Research

Implications of Elevated Total Insulin and C-peptide Levels

• Elevated total insulin and C-peptide levels are associated with an increased risk of cardiovascular disease in patients with type 2 diabetes, as proinsulin, the precursor of insulin, stimulates PAI-1 secretion and blocks fibrinolysis 2.
• The appearance of intact proinsulin in the peripheral blood is a good laboratory marker for beta-cell dysfunction and insulin resistance, and elevated levels of intact proinsulin (> 10 pmol/L) indicate insulin resistance 2.
• Elevated total proinsulin levels (> 45 pmol/L) may help identify patients with a high cardiovascular risk profile 2.
• Restoration of an early rise in plasma insulin levels after glucose ingestion improves glucose tolerance in type 2 diabetic patients by suppressing endogenous glucose production 3.
• Elevated C-peptide levels are associated with insulin hypersecretion, and a fasting C-peptide/glucose ratio (CGR) can be used to estimate insulin secretion and guide therapeutic decisions in diabetes treatment 4.
• In patients with hyperinsulinemic hypoglycemia, elevated insulin and C-peptide levels are characteristic of the condition, and C-peptide levels < 9.6 ng/ml and insulin levels < 75 μU/ml exhibit high sensitivity and specificity for insulinoma diagnosis 5.
• Exogenous insulin therapy does not have a direct effect on C-peptide levels in type 2 diabetic subjects, and the decrease in C-peptide levels during insulin therapy is due to blood glucose reduction 6.