Free Insulin

Insulin, a peptide hormone produced by pancreatic beta cells, is crucial for regulating glucose metabolism in the body. Structurally, it consists of two polypeptide chains connected by disulfide bonds. 

Insulin facilitates glucose uptake into cells, converting glucose into glycogen in the liver and muscle tissues for energy storage, and regulating blood sugar levels to prevent hyperglycemia. It also influences lipid and protein metabolism, playing a key role in maintaining metabolic homeostasis. 

Free insulin, the biologically active form, interacts with insulin receptors on cells, promoting glucose uptake. 

Clinically, measuring both free and total insulin levels is essential for diagnosing and managing conditions like insulin resistance and diabetes, particularly in patients who develop antibodies against insulin. 

Comprehensive biomarker testing, including glycemic control markers like fasting glucose and HbA1c, as well as insulin resistance and beta cell function markers, provides a sensitive approach to detect diabetes risk early and improve glycemic control in clinical practice.

What is Insulin?  [13.] 

Insulin, a peptide hormone, is produced by the beta cells of the pancreas and serves as a fundamental regulator of glucose metabolism in the body. 

Structurally, insulin consists of two polypeptide chains, an A chain comprising 21 amino acids and a longer B chain comprising 30 amino acids, connected by disulfide bonds. 

Insulin plays a central role in the uptake and storage of glucose in cells, promoting the conversion of glucose into glycogen in the liver and muscle tissue for short-term energy storage. 

Additionally, insulin facilitates the uptake of glucose by various tissues, including muscle and fat cells, thereby regulating blood sugar levels and preventing hyperglycemia. 

Beyond glucose metabolism, insulin also influences lipid and protein metabolism, serving as a key orchestrator of metabolic processes essential for maintaining energy balance and overall metabolic homeostasis in the body.

What Does Insulin Do? [13.] 

Insulin has various functions throughout the body, with many implications for health or chronic disease.  Several of insulin’s essential functions in regulating blood sugar levels occur in the liver, in adipocytes or fat cells, in brain cells and in muscles.

Upon secretion from pancreatic beta cells in response to elevated blood glucose levels, insulin binds to specific receptors on target cells, initiating a cascade of cellular events. 

In the liver, insulin promotes the uptake and storage of glucose as glycogen, a process known as glycogenesis. Additionally, insulin inhibits gluconeogenesis, the synthesis of glucose from non-carbohydrate sources, thereby further reducing blood glucose levels.

In peripheral cells like muscle and adipose tissue, insulin facilitates the uptake of glucose from the bloodstream, promoting its utilization for energy production or storage as glycogen and triglycerides. This process helps to lower blood glucose levels and provides cells with the necessary energy for various metabolic functions. 

Furthermore, insulin exerts important effects in the brain, where it contributes to neuronal glucose uptake and metabolism, supporting proper brain function and cognition. Additionally, insulin regulates appetite control in the brain.  

Overall, insulin acts as a key regulator of glucose homeostasis, ensuring that cells receive an adequate supply of glucose for energy production while preventing hyperglycemia.

What is Free Insulin?

Insulin is a hormone produced by the pancreas that plays a crucial role in regulating blood glucose levels by facilitating the uptake of glucose into cells.

It helps move glucose from the bloodstream into cells, where it is used for energy. Insulin levels typically rise after eating and fall as blood glucose levels decrease.

Insulin in the body can exist in two forms: bound and unbound (free).

Free Insulin

Free insulin refers to the portion of total insulin that is not bound to any proteins or antibodies in the bloodstream.

It is considered the biologically active form of insulin because it is available to interact with insulin receptors on cells, facilitating glucose uptake.

Free insulin levels can be measured to assess the amount of active insulin available in the blood. This is particularly important in conditions where insulin antibodies may be present, as these antibodies can bind to insulin and render it inactive.

Total Insulin

In contrast, total insulin includes both free (unbound) insulin and insulin that is bound to proteins or antibodies.

Measuring total insulin provides an overall picture of the insulin present in the blood, but it does not distinguish between active (free) and inactive (bound) forms.

Clinical Relevance of High Free Insulin

Hypoglycemia 

High levels of free insulin can lead to hypoglycemia (low blood sugar), which can cause symptoms such as anxiety, trembling, sweating, confusion, nausea, irritability, weakness, and irregular heartbeat.

‍Insulin Resistance and Diabetes 

Measuring free insulin can help in diagnosing and managing conditions like insulin resistance, type 2 diabetes, and other metabolic disorders.

Insulin-Dependent Diabetes Management

Patients receiving insulin therapy may develop antibodies against insulin, necessitating a more thorough examination and assessment.

When Would a Clinician Order Free and Total Insulin Levels? [1., 7.] 

Many patients receiving insulin therapy develop antibodies that bind insulin. These antibodies can affect the measurement and activity of insulin in the body. 

Laboratory tests are used to identify insulin antibodies. The presence of these antibodies can interfere with normal insulin measurements, necessitating tests for both free and total insulin.

Free Insulin Measurement

Free insulin is the portion of total insulin not bound by antibodies in the bloodstream. This fraction represents biologically active insulin and provides an accurate measure of the relationship between insulin dose and blood glucose levels in diabetic patients. 

Free insulin levels correlate with periods of hypoglycemia or hyperglycemia, offering insight into insulin absorption and the effectiveness of subcutaneous injections. 

In cases where insulin-binding antibodies are present, these antibodies can alter insulin pharmacokinetics, causing abnormal periods of hyperglycemia.

Total Insulin Measurement

Total insulin includes both the free (active) insulin and the antibody-bound insulin. 

Measuring total insulin helps assess the insulin-binding capacity of circulating antibodies and the overall insulin dose administered to the patient. 

In patients with significant antibody levels, the bound insulin fraction can account for more than 90% of the total insulin. Despite constant insulin therapy, total insulin levels are typically stable, providing a comprehensive view of insulin availability.

Laboratory Testing for Free Insulin

Test Information, Sample Collection and Preparation

Testing free insulin levels requires a blood draw, typically done via venipuncture.  Special preparation including fasting are often recommended; it is important to consult with the ordering provider prior to sample collection.  

Interpreting Free Insulin Testing

Optimal Levels of Free Insulin

Individuals who do not have an autoimmune response to insulin are expected to have equivalent free and total insulin levels.  

Fasting insulin levels traditionally have a wide variation of acceptable ranges.  However, research points to a reduced risk of metabolic syndrome and diabetes in individuals with a lower fasting insulin level.  One study reports high fasting insulin levels to be >7.9, while moderate fasting insulin levels were 4.9-7.8.  [3.] 

Optimal levels of free insulin equal total insulin, and are below 5.  

One laboratory reports a reference range of 3-25 mcIU/mL of free and total insulin.  [8.] 

Clinical Significance of Elevated Free Insulin

When elevated total and free insulin levels are noted, concern should be raised for insulin resistance, metabolic syndrome, and diabetes.  

Additionally, in insulin-dependent individuals the clinician may reassess insulin dosage to determine whether the individual is receiving excessive insulin therapy, especially in the setting of hypoglycemic symptoms.  

Clinical Significance of Decreased Free Insulin

In the setting of insulin-dependent diabetes, decreased free insulin that is significantly lower than total insulin points to an autoimmune response against insulin.  

Individuals receiving insulin therapy with low free and total insulin may signal to the clinician to reassess their insulin therapy, especially in the setting of hyperglycemia.  

Free Insulin-Related Biomarkers  [10.] 

Biomarkers related to free insulin levels are typically those used to monitor diabetes treatment and adherence.  

Key Biomarkers for Glycemic Control  [2.] 

Fasting Glucose

Fasting blood glucose (FBG) is a simple blood test used to diagnose prediabetes and diabetes and to monitor treatment response and adherence to therapy. 

A fasting blood glucose level of 126 mg/dL (7 mmol/L) or higher on two separate tests indicates diabetes.

It is also used for prediabetes screening: Fasting glucose levels between 100-125 mg/dL (5.6-6.9 mmol/L) suggest prediabetes, indicating an increased risk of developing type 2 diabetes.

For people with diabetes, it is used as routine monitoring to help assess how well their treatment plan is working and whether adjustments are needed.

HbA1c (Hemoglobin A1c)

The HbA1c test measures the percentage of hemoglobin in the blood that is coated with glucose (glycated). Hemoglobin is a protein in red blood cells that carries oxygen. When glucose in the blood binds to hemoglobin, it forms glycated hemoglobin. 

Unlike fasting glucose tests, which measure blood sugar at a single point in time, the HbA1c test provides a long-term view of blood glucose control.

An HbA1c level between 5.7% and 6.4% indicates prediabetes, a condition where blood glucose levels are higher than normal but not yet high enough to be classified as diabetes.

In diabetes, an HbA1c level of 6.5% or higher on two separate tests confirms a diagnosis of diabetes.

Fructosamine [5.] 

The fructosamine test measures the concentration of glycated proteins in the blood, primarily glycated albumin. 

It reflects the average blood glucose levels over the preceding 2-3 weeks, providing a shorter-term view of glycemic control compared to the HbA1c test, which covers approximately 2-3 months.

The fructosamine test is particularly useful for monitoring short-term changes in blood glucose levels. This is beneficial when recent adjustments in diet, exercise, or medication need to be evaluated quickly.

It is also useful for monitoring glycemic control in pregnant women, especially those with gestational diabetes, where rapid changes in glucose levels can occur.

The fructosamine test is advantageous in situations where HbA1c may be unreliable, such as in patients with hemoglobinopathies (e.g., sickle cell disease), hemolytic anemia, or recent blood loss. These conditions can affect red blood cell lifespan and thus HbA1c levels, but do not impact fructosamine levels.

Key Biomarkers for Pancreatic Beta Cell Function

C-Peptide [9.] 

C-peptide is a protein produced by pancreatic beta cells in equal amounts to insulin. It serves as an excellent measure of endogenous insulin production in patients with diabetes. 

C-peptide levels directly reflect the body's ability to produce insulin, making it a valuable marker of beta cell function.

C-peptide testing can also help distinguish between Type 1 and Type 2 diabetes, especially in cases where the diagnosis is unclear. Low or absent C-peptide levels suggest Type 1 diabetes, while detectable levels are more consistent with Type 2 diabetes.

C-peptide levels can help determine if a patient requires insulin therapy. Very low levels (<0.2 nmol/L) typically indicate an absolute need for insulin treatment.

C-peptide measurements can be used to evaluate how well current diabetes management strategies are preserving beta cell function over time.

Even small amounts of C-peptide can indicate some remaining beta cell function, which is associated with better glycemic control and reduced risk of complications.

‍Proinsulin  [11., 12.] 

Proinsulin is the protein precursor to insulin, produced by pancreatic beta cells. It is cleaved to form insulin and C-peptide in equal amounts.

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Proinsulin levels can reflect the state of beta cell function and insulin production capacity, even when C-peptide levels are undetectable.

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Elevated proinsulin levels (>22 pmol/L) at the end of a supervised fast are highly specific for insulinoma diagnosis.

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Proinsulin levels can help distinguish between Type 1 and Type 2 diabetes in unclear cases.

Also, elevated proinsulin-to-C-peptide (PI:C) ratios may indicate beta cell stress or dysfunction. This has been associated with more rapid progression to Type 1 diabetes in high-risk individuals.

Proinsulin levels can be used to assess the impact of interventions aimed at preserving beta cell function in Type 1 diabetes.

Anti-Glutamic Acid Decarboxylase (Anti-GAD) Antibody [4., 6., 14.]

Anti-GAD (glutamic acid decarboxylase) antibody testing has significant clinical utility in assessing beta cell function, particularly in the context of type 1 diabetes diagnosis and management. 

Anti-GAD antibody testing helps distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D), especially in cases where the diagnosis is unclear. The presence of anti-GAD antibodies strongly suggests an autoimmune process characteristic of T1D.

Anti-GAD antibodies are crucial for identifying Latent Autoimmune Diabetes in Adults (LADA), a slow-progressing form of autoimmune diabetes often initially misdiagnosed as T2D.

Positive anti-GAD antibodies in newly diagnosed diabetes patients can predict a more rapid progression to insulin dependency. This information is valuable for treatment planning and patient education.

The presence and levels of anti-GAD antibodies can provide insights into the extent of ongoing autoimmune attack on beta cells, indirectly indicating the degree of remaining beta cell function.

FAQ: Free Insulin

What is Free Insulin?

Free insulin refers to the unbound form of insulin that is circulating in the bloodstream; it is biologically active and available to help regulate blood glucose levels. 

Insulin is a hormone produced by the pancreas that plays a crucial role in controlling blood sugar levels by facilitating the uptake of glucose into cells.

What is the Function of Free Insulin in the Body?

Free insulin helps to:

• Regulate blood glucose levels by promoting the uptake of glucose into cells, especially muscle and fat cells.

• Stimulate the liver to store glucose in the form of glycogen.

• Inhibit the breakdown of fat and protein.

• Facilitate cellular uptake of amino acids and potassium.

How is Free Insulin Measured?

Free insulin levels are measured through blood tests. These tests can help determine how much insulin is circulating freely in the blood and are often used to assess insulin sensitivity, insulin resistance, and beta-cell function in the pancreas.

What is a Normal Free Insulin Level?

A normal range for fasting free insulin levels is typically between 2 to 25 microU/mL (micro-international units per milliliter). However, these ranges can vary slightly depending on the laboratory and the methods used. 

It is important to consult with a healthcare provider to interpret test results accurately.

What Do Elevated Levels of Free Insulin Indicate?

Elevated levels of free insulin, a condition known as hyperinsulinemia, can indicate:

• Insulin resistance: The body's cells are less responsive to insulin, often seen in conditions like type 2 diabetes and metabolic syndrome.

• Polycystic ovary syndrome (PCOS): A hormonal disorder common among women of reproductive age.

• Cushing's syndrome: A condition caused by prolonged exposure to high levels of cortisol.

• Certain tumors: Insulinomas are rare tumors of the pancreas that produce excess insulin.

What Do Low Levels of Free Insulin Indicate?

Low levels of free insulin can indicate:

• Type 1 diabetes: An autoimmune condition where the pancreas produces little or no insulin.

• Advanced type 2 diabetes: In some cases, prolonged insulin resistance can lead to beta-cell dysfunction, resulting in lower insulin production.

• Pancreatic disorders: Conditions that affect the pancreas, such as chronic pancreatitis or pancreatic cancer, can reduce insulin production.

How are Abnormal Free Insulin Levels Managed?

Management of abnormal free insulin levels depends on the underlying cause:

• Elevated levels (hyperinsulinemia):

• Lifestyle changes such as diet and exercise to improve insulin sensitivity.

• Medications to improve insulin sensitivity (e.g., metformin) or address underlying conditions.

• Low levels (hypoinsulinemia):

• Insulin therapy for type 1 diabetes and advanced type 2 diabetes.

• Managing underlying pancreatic disorders or other health conditions.

Can Lifestyle Changes Affect Free Insulin Levels?

Yes, lifestyle changes can significantly affect free insulin levels:

• Diet: Eating a balanced diet low in refined sugars and high in fiber can improve insulin sensitivity.

• Exercise: Regular physical activity helps the body use insulin more effectively.

• Weight management: Maintaining a healthy weight can reduce insulin resistance.

• Stress management: Reducing stress can help regulate insulin levels.

Where Can I Find More Information About Free Insulin and Related Conditions?

For more information about free insulin and related conditions, consider consulting:

• Healthcare providers: Medical professionals can provide personalized advice and diagnosis.

• Scientific literature: Research articles and reviews on insulin and its roles in the body.

• Reputable health organizations: Websites of organizations such as the American Diabetes Association, National Institutes of Health (NIH), and Centers for Disease Control and Prevention (CDC).

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