Insulin resistance and beta-cell dysfunction

• Insulin resistance and beta-cell dysfunction are primary defects in type 2 diabetes.[1]
• 92% of patients with type 2 diabetes are insulin resistant.[2]
• 50% of beta-cell function is typically lost at the time of diagnosis.[3,4]

The progression of type 2 diabetes[5]

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• In healthy individuals, fasting and postprandial insulin levels are similar and maintained.
• As insulin resistance increases, beta cells compensate by increasing insulin output to keep glucose levels constant.
• Over time, insulin resistance peaks and stabilizes; beta cells are then perpetually functioning at a heightened level to maintain appropriate glucose levels.
• As beta cells begin to fail, postprandial glucose levels become abnormal due to an inefficient insulin response in the body.
• With the onset of beta-cell dysfunction, insulin production can no longer compensate for insulin resistance, and both fasting and postprandial glucose levels continue to rise.

Beta-cell dysfunction occurs for a variety of reasons[6,7]

• The rate of apoptosis may increase as an altered metabolic state, such as hyperglycemia, occurs.
• Typically, beta-cell proliferation equals the rate of apoptosis; however, an increased rate of apoptosis due to elevated glucose levels abolishes the balance of production and destruction.
• Genetically programmed exhaustion of beta cells may occur in response to insulin overproduction.
• Excessive amounts of glucose may cause deleterious modifications in beta cells that cause them to be desensitized to glucose presence.

Hepatic glucose output (HGO) is also a concern when treating
type 2 diabetes[8]

• HGO is a good indicator of fasting glucose levels and is the main cause of fasting hyperglycemia.
• Increased levels of glucagon and free fatty acids, in addition to the recycling of lactate and pyruvate back to the liver, are contributing factors that cause elevated HGO.
• Insulin resistance in hepatic cells is also a serious cause of elevated HGO.

Reducing insulin resistance helps achieve A1C goals and improves beta-cell function

• Treatment with agents that directly reduce insulin resistance can significantly reduce blood glucose levels by targeting an underlying cause of hyperglycemia.[9]
• Agents that directly reduce insulin resistance can decrease circulating insulin levels and have been associated with improvements in beta-cell function, according to HOMA (Homeostasis Model Assessment) calculations.[9,10]

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Insulin resistance is associated with various health conditions[11]

• A wide variety of clinical conditions are associated with insulin resistance.

Treating insulin resistance can have many benefits[12]

• Reductions in blood pressure have been observed with a reduction of insulin resistance.
• Reducing insulin resistance may reduce endothelial dysfunction and hyperplasia, which play a role in the pathogenesis and progression of atherosclerosis.
• Reducing insulin resistance may decrease plasminogen activator inhibitor-1
  (PAI-1) levels to decrease the risk of thrombosis.
• Decreases in vascular inflammation may be seen with reductions in insulin resistance.
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