From the Guidelines
Insulin resistance develops through a complex interplay of genetic predisposition, lifestyle factors, and metabolic changes, primarily driven by hyperinsulinaemia due to reduced insulin clearance and hypersecretion of insulin, as well as ectopic fat deposition in tissues such as the liver and muscle. The mechanism involves impaired insulin signaling in cells, particularly in muscle, liver, and fat tissues, which is exacerbated by the consumption of a hypercaloric, high-carbohydrate diet 1. When we consume excess calories, especially from refined carbohydrates, fat accumulates in these tissues, leading to increased production of inflammatory cytokines and oxidative stress. These factors interfere with insulin receptor function and downstream signaling pathways, particularly the phosphorylation of insulin receptor substrates and activation of PI3K/Akt pathways.
Some key factors that contribute to the development of insulin resistance include:
- Hyperinsulinaemia, which reduces skeletal muscle insulin sensitivity, creating a negative feedback loop that exacerbates hyperinsulinaemia and obesity 1
- Ectopic fat deposition in tissues such as the liver and muscle, which disrupts normal cellular function and leads to increased production of inflammatory cytokines and oxidative stress
- Chronic inflammation, which activates stress kinases like JNK and IKK, further impairing insulin signaling
- Mitochondrial dysfunction, which reduces cells' ability to properly metabolize glucose
- Genetic factors, sedentary lifestyle, and certain medications, which can exacerbate these processes
The pathogenesis of type 2 diabetes is characterized by hyperinsulinaemia due to reduced insulin clearance and hypersecretion of insulin, which is probably driven by a genetic predisposition and lifestyle factors, in particular the consumption of a hypercaloric, high-carbohydrate diet 1. This leads to a vicious cycle where insulin resistance worsens, forcing the pancreas to produce more insulin, which eventually leads to pancreatic beta-cell exhaustion. Weight loss, regular exercise, and medications like metformin can help reverse insulin resistance by improving cellular insulin sensitivity and reducing inflammation.
From the FDA Drug Label
ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism The mechanism for developing insulin resistance is not directly stated in the provided drug labels. However, the labels do describe how the medications decrease insulin resistance:
- Pioglitazone (2) works by activating PPARγ nuclear receptors, which modulates the transcription of insulin responsive genes involved in glucose and lipid metabolism.
- Metformin (3) improves insulin sensitivity by increasing peripheral glucose uptake and utilization, but the exact mechanism of insulin resistance development is not described.
From the Research
Mechanism of Insulin Resistance
The mechanism of insulin resistance is complex and involves multiple factors, including:
- Ectopic lipid accumulation in liver and skeletal muscle 4
- Endoplasmic reticulum stress 4
- Inflammation 4
- Impaired insulin secretion 5
- Excessive hepatic glucose output 5
- Insulin resistance in skeletal muscle, liver, and adipose tissue 5
Key Factors Contributing to Insulin Resistance
Some key factors that contribute to insulin resistance include:
- Genetic predisposition
- Obesity
- Physical inactivity
- Diet high in sugar and saturated fats
- Certain medications, such as steroids and certain psychiatric medications
Therapeutic Strategies for Insulin Resistance
Several therapeutic strategies have been proposed to address insulin resistance, including:
- Lifestyle modifications, such as diet and exercise 4
- Medications, such as metformin and thiazolidinediones 6, 7, 8
- Combination therapy with multiple medications 6, 7
Effects of Medications on Insulin Resistance
Certain medications, such as metformin and thiazolidinediones, have been shown to improve insulin sensitivity and reduce glucose levels in patients with type 2 diabetes: