What are the management and treatment options for a patient with elevated insulin and C-peptide (Connecting Peptide) levels and a normal Hemoglobin A1c (HbA1c)?

Elevated Insulin and C-Peptide with Normal HbA1c: Insulin Resistance Syndrome

This clinical presentation—high insulin and C-peptide with normal HbA1c—indicates insulin resistance without overt diabetes, requiring aggressive lifestyle intervention focused on weight loss and physical activity, with consideration of metformin therapy to prevent progression to type 2 diabetes. 1, 2

Understanding the Clinical Picture

This metabolic pattern represents a critical pre-diabetic state where:

• Elevated C-peptide and insulin levels reflect compensatory hyperinsulinemia in response to peripheral insulin resistance, where tissues require higher insulin concentrations to maintain normal glucose homeostasis 1, 2
• Normal HbA1c indicates the pancreatic beta cells are still capable of producing sufficient insulin to overcome the resistance and maintain euglycemia, distinguishing this from established diabetes 3
• High fasting C-peptide in the presence of normoglycemia strongly suggests insulin resistance rather than insulin deficiency, which would be seen in type 1 diabetes or advanced type 2 diabetes 1
• C-peptide correlates significantly with HOMA-IR (homeostatic model assessment of insulin resistance) and serves as a reliable biomarker for screening insulin resistance 2, 4

Primary Management Strategy

Lifestyle Interventions (First-Line Therapy)

• Weight loss is recommended for all overweight or obese individuals who are at risk for diabetes, as this directly addresses the underlying insulin resistance 5
• Either low-carbohydrate, low-fat calorie-restricted, or Mediterranean diets may be effective for weight reduction in the short term (up to 2 years) 5
• Physical activity of at least 150 minutes per week of moderate-intensity aerobic exercise (50-70% of maximum heart rate), spread over at least 3 days with no more than 2 consecutive days without exercise, is essential 5
• Physical activity and behavior modification are most helpful in maintenance of weight loss and improving insulin sensitivity 5

Pharmacologic Consideration

• Metformin therapy should be initiated along with lifestyle interventions for individuals with prediabetes or those at high risk for diabetes progression, as it addresses insulin resistance directly 5
• Metformin provides beneficial effects on cardiovascular mortality beyond glucose control, making it particularly valuable in insulin-resistant states 6
• Metformin dose can be titrated up to 2,000 mg per day as tolerated to maximize efficacy in reducing insulin resistance 6

Monitoring and Follow-Up

Regular Assessment Parameters

• HbA1c should be monitored at least twice yearly in patients meeting treatment goals to detect progression from insulin resistance to overt diabetes 5
• Fasting blood glucose and lipid profiles should be monitored, as insulin resistance is commonly associated with dyslipidemia (low HDL-C and elevated triglycerides) 4
• C-peptide levels show significant positive correlation with triglycerides and negative correlation with HDL-C, making lipid monitoring particularly important 4
• Monitor for vitamin B12 deficiency if metformin is initiated, as its use is associated with reduced B12 levels 6

Progression Risk Assessment

• Individuals with prediabetes should receive individualized medical nutrition therapy to achieve treatment goals, preferably provided by a registered dietitian 5
• Diabetes self-management education should be provided to address behavioral changes and improve long-term outcomes 5
• Reassess and modify the treatment plan regularly (every 3-6 months) to avoid therapeutic inertia and ensure progression to diabetes is prevented 5, 7

Critical Pitfalls to Avoid

• Do not assume normal HbA1c means no metabolic intervention is needed—the elevated insulin and C-peptide indicate active pathology requiring treatment 1, 2
• Do not initiate insulin therapy in this setting, as it would worsen hyperinsulinemia and potentially accelerate weight gain and cardiovascular risk 1
• Do not overlook associated metabolic syndrome components including hypertension, dyslipidemia, and central obesity, which commonly coexist with insulin resistance 4
• Avoid relying solely on HbA1c for metabolic assessment in insulin-resistant patients, as C-peptide and HOMA-IR provide additional valuable information about disease progression risk 2, 4

Special Diagnostic Considerations

• If insulin levels appear disproportionately elevated relative to C-peptide, consider testing for anti-insulin antibodies, as insulin-antibody complexes can cause assay interference and create discordant results 8
• C-peptide measurement is more stable and reliable than insulin measurement for assessing endogenous insulin secretion, making it the preferred biomarker 3
• Persistence of elevated C-peptide distinguishes insulin resistance from insulin deficiency states such as type 1 diabetes or LADA (latent autoimmune diabetes in adults) 1, 3