Variants this may be helpful for: FTO, IRS1, TCF1L2, ADIPOQ, GLUT4
Insulin resistance is a condition where the body's cells become less responsive to the hormone insulin, leading to higher levels of glucose in the blood. This condition is a key feature of type 2 diabetes and is influenced by both environmental factors (such as diet and physical activity) and genetics - in this article we will delve into how specific genetic variations may predispose you to insulin resistance.
Genetic Factors in Insulin Resistance
The genetic component of insulin resistance is complex and involves the interaction of multiple genes. Research has identified several genes that are linked to insulin sensitivity, including those involved in insulin signalling, fat metabolism, and inflammation. Some of these genes include:
FTO Gene
The FTO gene is associated with increased fat mass and obesity.
- Increased adiposity: FTO variants contribute to a higher risk of obesity, particularly the accumulation of visceral fat. Visceral fat is metabolically active and releases pro-inflammatory cytokines which can impair insulin signalling and lead to insulin resistance.
- Fat distribution: Some FTO gene variants are associated with the accumulation of fat in specific areas, such as the abdominal region. Central obesity has a much stronger link to insulin resistance than fat stored in other areas of the body, like the hips or thighs.
- Disruption of insulin signalling: Research suggests that individuals with FTO gene variants may have altered insulin signalling pathways. This may be due to the combined effects of increased fat mass, inflammation, and possibly altered lipid metabolism, all of which can interfere with insulin’s ability to promote glucose uptake into cells.
- Inflammation: FTO is thought to contribute to low-grade, chronic inflammation seen in obesity. Inflammatory markers, such as interleukin 6 (included on our Ultimate Methylation Report) can disrupt insulin signalling pathways and contribute to insulin resistance.
- Appetite regulation and food intake: FTO variants have been shown to affect appetite and eating behaviours. Increased food intake, particularly the consumption of calorie-dense foods, leads to greater energy imbalance and obesity, which is a known risk factor for insulin resistance.
IRS1 gene
IRS1 (Insulin receptor substrate 1) plays a key role in the body's insulin signalling pathway, which is essential for regulating glucose uptake and metabolism, making cells more sensitive to insulin. Variations in the IRS1 gene can disrupt this insulin signalling pathway leading to higher blood sugar levels and increased insulin production which can worsen inflammation, obesity and visceral fat in several ways:
- Increased Circulating Insulin Levels: When insulin resistance occurs, the body compensates by producing more insulin in an attempt to overcome the reduced effectiveness of the hormone. This results in hyperinsulinemia, which can exacerbate metabolic issues like increased fat storage and obesity which can perpetuate an insulin resistant state.
- Inflammation: IRS1 also has a role in managing inflammation. In the context of obesity or other metabolic disturbances, pro-inflammatory cytokines can impair IRS1 function, further exacerbating insulin resistance. Certain IRS1 gene variants may make this inflammation worse by reducing the gene's ability to counteract the negative signal.
TCF7L2 gene
The TCF7L2 gene (Transcription Factor 7-Like 2) has been strongly associated with insulin resistance and an increased risk of type 2 diabetes. It plays a crucial role in regulating glucose metabolism, insulin signalling, and pancreatic beta-cell function (responsible for insulin production). Variations in the TCF7L2 gene can impair these processes, leading to insulin resistance and an increased risk of developing type 2 diabetes.
- Beta-cell function: TCF7L2 is involved in the regulation of insulin secretion by the pancreas. Impaired TCF7L2 function can lead to beta-cell dysfunction, reducing the pancreas's ability to produce insulin in response to blood glucose levels.
- Insulin signalling: TCF7L2 affects the insulin receptor pathway, which controls the ability of cells (especially in the liver, muscle, and fat) to respond to insulin and remove glucose from the bloodstream.
- Glucose production: TCF7L2 influences how much glucose the liver releases into the bloodstream, especially during periods of fasting. Dysregulation of this process can contribute to elevated blood glucose levels, which is a key feature of insulin resistance.
ADIPOQ (Adiponectin) Gene
ADIPOQ gene encodes for adiponectin, an anti-inflammatory hormone produced by fat cells (adipocytes) that help improve insulin sensitivity and regulate glucose metabolism. Variants may contribute to increased risk of insulin resistance and metabolic diseases like type 2 diabetes.
- Reduced Adiponectin Levels: People with ADIPOQ gene variants may produce lower amounts of adiponectin, which impairs insulin's ability to regulate blood sugar and promotes fat accumulation. This can lead to insulin resistance, as the body's tissues (muscle, fat, and liver) are unable to respond efficiently to insulin, leading to hyperinsulinemia (elevated insulin levels) and elevated blood glucose.
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Increased Inflammation: Lower adiponectin levels are linked to higher levels of inflammatory cytokines, particularly in visceral fat, which is a central driver of insulin resistance.
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Impaired Fat Metabolism: Adiponectin promotes fat oxidation (fat burning) and helps prevent excessive fat storage, particularly in muscle and liver tissues. When adiponectin levels are low due to genetic variants in ADIPOQ, the body is less able to metabolise fat effectively, leading to increased fat storage and accumulation of fat in areas like the liver (leading to non-alcoholic fatty liver disease). This accumulation of fat worsens insulin resistance.
- Altered Lipid Profiles: Lower adiponectin levels are often associated with dyslipidemia (abnormal lipid levels), including elevated triglycerides and low HDL cholesterol (the "good" cholesterol). These lipid imbalances can further promote insulin resistance by impairing the action of insulin on cells and encouraging fat accumulation.
GLUT4 Gene
GLUT4 is a transporter protein that supports the cellular uptake of glucose in response to insulin. In insulin resistance, the ability of insulin to promote GLUT4 translocation and glucose uptake is impaired. As a result, blood glucose levels remain elevated, and the pancreas compensates by producing more insulin to try to overcome the resistance. Over time, this can lead to hyperinsulinemia (excess insulin in the blood) and type 2 diabetes.
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Obesity and Fat Accumulation: Obesity, particularly visceral fat accumulation, is a major risk factor for insulin resistance and is often associated with decreased GLUT4 expression in adipose tissue and muscle. This reduction in GLUT4 leads to impaired glucose uptake, contributing to higher blood glucose levels.
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Inflammation: Inflammatory cytokines released from adipose tissue, especially in obese individuals, interfere with the insulin signalling pathway, hindering GLUT4 function.
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Physical Inactivity: Sedentary behaviour and lack of exercise can worsen insulin resistance by reducing GLUT4 expression in muscle and adipose tissue.
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High-fat diets: A diet high in fat has been linked to impaired GLUT4 function in tissues, potentially contributing to insulin resistance.
Environmental and Lifestyle Factors
While genetics play a significant role in determining susceptibility to insulin resistance, lifestyle factors such as diet, exercise, and obesity can exacerbate or improve genetic predispositions:
- Obesity: As mentioned above, excess body fat, especially visceral fat, is a major contributor to insulin resistance. Genes influencing fat storage and fat distribution can predispose individuals to gain weight, worsening insulin resistance.
- Physical Activity: Regular exercise increases GLUT4 expression and improves insulin sensitivity, even in individuals with genetic predispositions to insulin resistance.
- Diet: A diet high in refined carbohydrates, saturated fats, and low in fibre can exacerbate insulin resistance, while a balanced diet rich in fibre, healthy fats, and lean proteins can help improve insulin sensitivity.
Genetic factors play a significant role in the development of insulin resistance. Several genes are involved in insulin signalling, glucose metabolism, fat storage, and inflammation, all of which influence the body’s response to insulin.
Genetic Testing at Body Fabulous
ULTIMATE Methylation Test - Ideal for those wanting to optimise their health through personalised supplements and nutrients, providing a comprehensive starting point for your wellness journey. The genes referenced in this article feature in this test.
Metabolics Report - Also features the genes referenced in this article.
