What is the workup for worsening insulin resistance and deteriorating glucose control?

From the Guidelines

The workup for worsening insulin sensitivity and glucose control should prioritize lifestyle modifications, including a diet low in refined carbohydrates and at least 150 minutes of moderate-intensity exercise weekly, as evidenced by the most recent guidelines 1. The initial step in the workup should involve a comprehensive medical history and physical examination to identify risk factors such as weight gain, medication changes, stress, illness, or decreased physical activity. Key aspects to consider include:

• Laboratory testing: fasting blood glucose, hemoglobin A1C, and a comprehensive metabolic panel to assess current glycemic status.
• Quantifying insulin resistance: consider ordering a fasting insulin level and calculating HOMA-IR (Homeostatic Model Assessment for Insulin Resistance).
• Evaluating secondary causes: thyroid dysfunction (TSH), Cushing's syndrome (morning cortisol), polycystic ovary syndrome in women, and medications like glucocorticoids, atypical antipsychotics, or certain antiretrovirals. Lifestyle modifications are crucial, with recommendations including:
• Weight loss of 5-10% if overweight.
• Exercise regimen: at least 150 minutes of moderate-intensity exercise weekly, with the option for more intense activity if feasible, as suggested by recent standards of care 1.
• Dietary changes: a diet low in refined carbohydrates. Medication adjustments may be necessary, with metformin being first-line therapy for insulin resistance, starting at 500mg daily and increasing to 1000mg twice daily as tolerated. For patients already on medication, intensification of therapy may be required, potentially adding GLP-1 receptor agonists, SGLT-2 inhibitors, or considering insulin therapy if glycemic targets aren't met, as the underlying pathophysiology involves decreased cellular response to insulin, leading to compensatory hyperinsulinemia and eventual beta-cell failure if not addressed, making early intervention critical, as highlighted in earlier recommendations 1.

From the Research

Worsening Insulin Sensitivity and Glucose Control

• Worsening insulin sensitivity and glucose control in patients with type 2 diabetes can be addressed through various therapeutic approaches 2, 3, 4, 5, 6
• The etiology of type 2 diabetes involves a complex interplay between genetics and environmental factors, which can be governed efficiently by lifestyle modifications to achieve better management of diabetes 2
• Resistance to insulin action is the major cause that leads to chronic hyperglycemia in diabetic patients, and activation of multiple pathways and factors involved in insulin resistance and β-cell dysfunction contribute to the development of type 2 diabetes 2

Therapeutic Approaches

• Insulin therapy is very effective in reducing hyperglycemia and may improve β-cell function in patients with type 2 diabetes, but it is associated with weight gain and increased risk of hypoglycemia 3
• Adding other antidiabetes medications to insulin can improve glycemic control and potentially lower the required insulin dose, resulting in less weight gain and lower risk for hypoglycemia 3
• GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when added to insulin and have a low propensity for hypoglycemia and cause no change or a reduction in body weight 3
• Sulfonylureas as add-on therapy to metformin are associated with increased risk of all-cause mortality and major hypoglycemic episodes compared with other OHAs 4

Lifestyle Modifications

• Physical activity is one of the factors that affects glycemic management, and diabetes patients who are physically active have controlled their blood glucose levels by 2.4 times compared to their counterparts 5
• Regular physical activity can help diabetes patients control their blood glucose levels, and patients with diabetes who have had it for a long time should be aware of the need for regular physical activity in maintaining blood glucose control 5

Choice of Therapy

• The choice of therapy in patients with type 2 diabetes inadequately controlled with metformin and a sulphonylurea should be based on a systematic review and mixed-treatment comparison meta-analysis of all available classes of antihyperglycemic therapies 6
• Insulins, DPP-4 inhibitors, GLP-1 analogues, and thiazolidinediones all produced statistically significant reductions in hemoglobin A1c in combination with metformin and a sulphonylurea, whereas meglitinides and alpha-glucosidase inhibitors did not 6