Department: CLINICAL QUERIES
How does exogenous insulin decrease hyperglycemia in patients with type 2 diabetes with insulin resistance?—D.B., IDAHO
Martha Mitchell Funnell, MS, RN, CDE, replies: To answer this question, I'll first explain the pathophysiology of type 2 diabetes. Type 2 diabetes is a heterogeneous group of conditions that constitutes 90% of all diabetes cases in the United States.1,2 Although type 1 diabetes results from absolute insulin deficiency, type 2 diabetes results from both insulin resistance and relative insulin deficiency with increased hepatic glucose production.1,2 In other words, patients with type 1 diabetes have almost a complete lack of insulin production. Patients with type 2 diabetes are resistant to the insulin produced by the pancreatic beta cells, and these cells also produce less insulin.1–4
Insulin resistance is thought to occur before insulin deficiency in most patients with type 2 diabetes.1 Initially, the body can produce additional insulin to compensate, which is why patients with prediabetes and those in the early stages of diabetes often have hyperinsulinemia.2 Over time, the beta cells become less and less able to meet insulin demands, and type 2 diabetes develops even though the patient continues to be hyperinsulinemic for a time.4 Some patients with type 2 diabetes have primarily insulin resistance and others, insulin deficiency. However, insulin resistance alone doesn't cause diabetes without a subsequent decline in insulin production.1,2,4
Although its causes are complex and not well understood, insulin resistance is thought to be the result of both genetic and environmental factors. Patients with prediabetes and both overweight and lean patients with type 2 diabetes have decreased beta-cell mass as a result of increased beta-cell apoptosis.4 Beta-cell apoptosis is associated with glucose toxicity caused by hyperglycemia, elevated free fatty acid levels, inflammation, and deficient incretin hormone levels in the gut.4
The loss of beta-cell function can be reversed early in the course of diabetes. Overweight, obesity, and a sedentary lifestyle are all associated with increased insulin resistance.2,3 The Diabetes Prevention Program showed that a modest amount of weight loss (5% to 10% of body weight) and a moderate amount of exercise (150 minutes of brisk walking/week) among patients with prediabetes could prevent or delay the onset of type 2 diabetes.5,6 Medications to improve insulin sensitivity (thiazolidinediones), to reduce hepatic glucose production (biguanides), and to preserve beta-cell mass (incretin hormones; dipeptidyl peptidase-4 inhibitors) may also be effective.4
Now back to your question. Exogenous insulin works because the dose can be adjusted to provide enough insulin to compensate for the decline in insulin production and overcome the insulin resistance. Because insulin production continues to decline throughout the course of type 2 diabetes, the therapy, including the dose of insulin, will generally need to be increased over time.2 Relatively large doses of insulin (greater than 200 units/day) may be needed to reach blood glucose target levels. U-500 insulin may be used for large doses, but analogue formulations of this insulin aren't currently available. One of the key lessons about insulin resistance is the need to act early in the course of diabetes, particularly during prediabetes. Although the loss of beta-cell mass and insulin production is progressive, both can be delayed through early and consistent intervention.
This work utilized the Behavioral, Clinical and Health Services Research Core of the Michigan Diabetes Research and Training Center funded by DK020572 from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.
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4. Bardsley JK, Magee MF. Pathophysiology of the metabolic disorder. In: Mensing C, ed. The Art and Science of Diabetes Self-Management Education
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5. Delahanty LM, Nathan DM. Implications of the diabetes prevention program and Look AHEAD clinical trials for lifestyle interventions. J Am Diet Assoc
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6. Diabetes Prevention Program (DPP) Research Group. The Diabetes Prevention Program: description of lifestyle intervention. Diabetes Care