What is the appropriate diagnosis and treatment plan for a patient with a fasting plasma glucose of 355 mg/dL and a C‑peptide level of 5.35 ng/mL?

Diagnosis and Management of Hyperglycemia with Preserved C-Peptide

Diagnostic Interpretation

This patient has type 2 diabetes with significant insulin resistance and preserved beta-cell function. The fasting plasma glucose of 355 mg/dL confirms diabetes (diagnostic threshold ≥126 mg/dL), while the C-peptide of 5.35 ng/mL indicates robust endogenous insulin production despite severe hyperglycemia 1. This elevated C-peptide in the setting of marked hyperglycemia reflects insulin resistance rather than insulin deficiency 2, 3.

Key Diagnostic Points

• Fasting glucose ≥126 mg/dL on two occasions establishes diabetes diagnosis, and this patient's value of 355 mg/dL far exceeds this threshold 1.
• C-peptide >0.20 nmol/L (approximately >0.6 ng/mL) indicates preserved beta-cell function and distinguishes type 2 from type 1 diabetes 4.
• The fasting C-peptide/glucose ratio (CGR) helps guide therapeutic decisions—this patient's elevated C-peptide with severe hyperglycemia suggests insulin hypersecretion in response to insulin resistance 2.
• Confirmation requires repeating the same test on a different day unless the patient presents with classic symptoms of hyperglycemia 1.

Immediate Treatment Strategy

Initiate dual therapy with metformin plus basal insulin immediately. At this level of hyperglycemia (fasting glucose 355 mg/dL), monotherapy is insufficient and delays in treatment increase complication risk 5, 6.

Insulin Initiation

• Start basal insulin at 0.3–0.5 units/kg/day given the severity of hyperglycemia (fasting glucose >300 mg/dL) 5, 6.
• Administer 50% as basal insulin once daily (insulin glargine or detemir at bedtime) and 50% as prandial insulin divided among three meals if symptoms suggest marked hyperglycemia 5, 6.
• For less symptomatic patients, begin with basal-only insulin at 10 units once daily or 0.1–0.2 units/kg/day and titrate aggressively 5.
• Increase basal insulin by 4 units every 3 days when fasting glucose remains ≥180 mg/dL until reaching target of 80–130 mg/dL 5, 6.

Metformin Foundation

• Start metformin 500 mg once or twice daily with meals and titrate to 2000 mg daily (1000 mg twice daily) over 2–4 weeks 6.
• Metformin must be continued even when insulin is added because it reduces total insulin requirements by 20–30%, provides cardiovascular benefits, and prevents weight gain 5, 6.
• Metformin is safe when eGFR ≥30 mL/min/1.73 m² and should not be withheld unless contraindicated 6.

Critical Threshold Monitoring

When basal insulin approaches 0.5–1.0 units/kg/day without achieving glycemic targets, add prandial insulin rather than continuing basal escalation. This prevents "overbasalization" with increased hypoglycemia risk 5, 6.

Signs of Overbasalization

• Basal insulin dose >0.5 units/kg/day 5, 6
• Bedtime-to-morning glucose differential ≥50 mg/dL 5
• Hypoglycemia episodes 5
• High glucose variability throughout the day 5

Adding GLP-1 Receptor Agonist

Consider adding a GLP-1 receptor agonist after 3–6 months if HbA1c remains >7% despite optimized basal insulin and metformin. This combination provides superior glycemic control with weight loss rather than weight gain 6, 7.

GLP-1 RA Benefits

• HbA1c reduction of 0.6–0.8% when added to existing therapy 6.
• Proven cardiovascular benefits in patients with established ASCVD or high CV risk 6.
• Minimal hypoglycemia risk when used without sulfonylureas 6.
• Weight loss of 2–5 kg versus weight gain with insulin intensification 6.

Insulin Tapering After GLP-1 RA Initiation

• Begin tapering insulin 2–6 weeks after starting GLP-1 RA once glucose targets are consistently met 7.
• Reduce basal insulin by 10–30% every 2–3 days based on home glucose monitoring 7.
• If hypoglycemia occurs, immediately reduce insulin dose by an additional 10–20% 7.

Monitoring Protocol

Initial Phase (First 3 Months)

• Check fasting glucose daily during insulin titration 5, 6.
• Measure HbA1c every 3 months until target <7% is achieved 6.
• Assess for hypoglycemia (glucose <70 mg/dL) and reduce implicated insulin dose by 10–20% immediately 5, 6.

Glycemic Targets

• Fasting plasma glucose: 80–130 mg/dL 5, 6.
• Postprandial glucose: <180 mg/dL 5, 6.
• HbA1c: <7.0% for most adults to reduce microvascular complications 6.

Common Pitfalls to Avoid

• Never delay insulin initiation when fasting glucose >300 mg/dL—this prolongs hyperglycemia exposure and increases complication risk 5, 6.
• Never discontinue metformin when starting insulin unless contraindicated—this leads to higher insulin requirements and more weight gain 5, 6.
• Never use sliding-scale insulin as monotherapy—major diabetes guidelines condemn this approach as ineffective 5, 6.
• Never continue escalating basal insulin beyond 0.5–1.0 units/kg/day without addressing postprandial hyperglycemia—this causes overbasalization with increased hypoglycemia 5, 6.

Special Considerations

High C-Peptide and Cardiovascular Risk

• Elevated fasting C-peptide at diabetes diagnosis is an independent risk factor for total and cancer mortality 3.
• Treatment should focus not only on normalizing glucose but also on mitigating insulin resistance through metformin, weight loss, and lifestyle modification 3.
• Consider SGLT2 inhibitors for cardiovascular and renal protection independent of glycemic control, especially if cardiovascular risk factors are present 6.

Reversing Glucotoxicity

• Short-term intensive insulin therapy helps reverse glucotoxicity and lipotoxicity while preserving beta-cell function 6, 8.
• Normalization of fasting glucose minimizes glucotoxicity and insulin resistance, profoundly influencing daytime glycemic control 8.
• Even brief periods of hyperglycemia increase complication risk, making prompt treatment essential 8.