In an overweight adult with a family history of type 2 diabetes, hypertension, dyslipidemia, and acanthosis nigricans, how should I diagnose insulin resistance (which laboratory tests) and what is the recommended management?

Diagnosis of Insulin Resistance

In an overweight adult with family history of type 2 diabetes, hypertension, dyslipidemia, and acanthosis nigricans, diagnose insulin resistance using fasting plasma glucose (FPG), hemoglobin A1C, or 2-hour plasma glucose during 75-g oral glucose tolerance test (OGTT), and manage with intensive lifestyle modification (weight loss and exercise) as first-line therapy, with metformin as pharmacologic adjunct when lifestyle measures are insufficient. 1, 2

Laboratory Testing for Diagnosis

Standard Screening Tests

The American Diabetes Association recommends three equally appropriate tests for screening and diagnosis 1, 2:

• Fasting plasma glucose (FPG) is the preferred initial test because it is faster, easier to perform, more convenient, less expensive, and more reproducible 2, 3

  • Prediabetes (insulin resistance): 100-125 mg/dL 1
  • Diabetes: ≥126 mg/dL 2

• Hemoglobin A1C is equally appropriate as an alternative or complementary test 1, 2

  • Prediabetes (insulin resistance): 5.7-6.4% 1
  • Diabetes: ≥6.5% 2

• 2-hour plasma glucose during 75-g OGTT 1, 2

  • Prediabetes (insulin resistance): 140-199 mg/dL 1
  • Diabetes: ≥200 mg/dL 2
  • Ensure adequate carbohydrate intake (at least 150 g/day) for 3 days prior to testing 1

Why Fasting Insulin Is NOT Recommended

Fasting insulin should not be ordered as a first-line screening test because fasting plasma glucose, A1C, and OGTT are better validated for predicting diabetes risk and cardiovascular outcomes 2. Fasting insulin assays lack standardization across laboratories, which limits their clinical utility 2. The American Diabetes Association does not include fasting insulin in standard diabetes screening guidelines 2.

Additional Cardiovascular Risk Assessment

Given the presence of hypertension and dyslipidemia, obtain a complete lipid profile 4, 3:

• Total cholesterol, LDL, HDL, and triglycerides 4
• This patient meets criteria for screening based on HDL <35 mg/dL and/or triglycerides >250 mg/dL as additional risk factors 1, 2

Clinical Significance of Acanthosis Nigricans

Acanthosis nigricans is a reliable clinical marker of hyperinsulinemia and insulin resistance 5, 6, 7. This skin finding is directly associated with hyperinsulinemia and appears early in the disease process, often before glucose intolerance develops 6, 7. The presence of acanthosis nigricans in this patient provides strong clinical evidence of insulin resistance and identifies them as high-risk for type 2 diabetes 6, 7, 8.

Testing Frequency

• If initial tests are normal, repeat screening at minimum 3-year intervals 1
• If prediabetes is identified (A1C 5.7-6.4%, IFG, or IGT), test yearly 1, 4, 2
• Consider more frequent testing if BMI is increasing or risk factor profile is deteriorating 1

Management of Insulin Resistance

First-Line: Intensive Lifestyle Modification

Weight loss and regular physical activity are the primary interventions that reduce insulin resistance 5, 6. Control of obesity contributes largely to reversing the entire process by reducing both insulin resistance and compensatory hyperinsulinemia 5.

Specific interventions include:

• Weight reduction through caloric restriction 5, 6
• Regular physical activity and exercise 5, 6
• These interventions can lead to diabetes remission in some cases 1

Pharmacologic Management

Metformin is beneficial for treating insulin resistance and clearing acanthosis nigricans 5. Several drugs have shown benefit, including:

• Metformin (primary pharmacologic option) 5
• Octreotide 5
• Retinoids 5
• Topical vitamin D3 analogs for acanthosis nigricans 5

Treatment of Comorbidities

Aggressive management of associated conditions is essential 1:

• Hypertension control 1
• Dyslipidemia management 1
• These interventions decrease cardiovascular events 1

Common Pitfalls to Avoid

• Do not delay screening until symptoms develop - most patients with prediabetes and early type 2 diabetes are asymptomatic 2
• Do not use A1C in conditions with altered red blood cell turnover (pregnancy, hemoglobinopathies, recent blood loss) - use only glucose-based criteria in these situations 4, 3
• Do not order fasting insulin as a screening test when standard tests (FPG, A1C, OGTT) are guideline-recommended and more appropriate 2
• Confirm abnormal results with repeat testing on a separate day in the absence of unequivocal hyperglycemia to establish a diagnosis of diabetes 3

Risk Stratification

This patient has multiple high-risk features that warrant immediate testing 1:

• Overweight/obesity 1
• First-degree relative with diabetes 1
• Hypertension 1
• Dyslipidemia 1
• Acanthosis nigricans (clinical sign of insulin resistance) 1, 5

The presence of acanthosis nigricans with obesity represents a well-defined syndrome with autosomal dominant inheritance patterns, progressing from truncal obesity in childhood to hypertension and ischemic heart disease in young adulthood, and ultimately to type 2 diabetes in late adulthood 9. This patient should be followed as an "at-risk" group and would benefit from intensive weight reduction to prevent later manifestations of the syndrome 9.