What is Fructosamine

Fructosamine (1-amino-1-deoxy fructose) is a general term which applies to any compound that is formed when glucose combines with protein (glycated protein). Fructosamine is a measure of non-enzymatic glycation resulting in a ketamine linkage to circulating proteins including albumin, globulins and lipoproteins and glycated albumin, is a measure of the percent albumin that is glycated; both provide a measure of glycemia of 2 to 3 weeks duration ¹. Fructosamine is a stable ketoamine formed by the non-enzymatic reaction product of sugar (usually glucose) and the amino group of protein (usually albumin but includes globulins and lipoprotein).  The attachment of the aldehyde group of the carbohydrate with the N terminal amino acid of the protein forms the reversible Schiff base and intermediate. The Schiff base may be converted back to glucose and protein or undergo the Amadori rearrangement to form stable fructosamine. This process is known as non-enzymatic glycation and is also referred to as the Maillard reaction. The Maillard reaction causes the browning phenomenon that occurs in milk and other food products when heated.

Fructosamine is formed by the non-enzymatic reaction of glucose with the a- and e-amino groups of proteins to form intermediate compounds called aldimines. These aldimines may dissociate or undergo an Amadori rearrangement to form stable ketoamines called fructosamines. This nonenzymatic glycation of specific proteins in vivo is proportional to the prevailing glucose concentration during the lifetime of the protein. Therefore, glycated protein measurement in the diabetic patient is felt to be a better monitor of long-term glycemic control than individual or sporadic glucose determinations. The best known of these proteins is glycated hemoglobin which is often measured as hemoglobin A1c, and reflects glycemic control over the past 6 to 8 weeks. In recognition of the need for a measurement that reflects intermediate-term glycemic control and was easily automated, a nonspecific test, termed fructosamine, was developed. Since albumin is the most abundant serum protein, it accounts for 80% of the glycated serum proteins, and thus, a high proportion of the fructosamine. Although a large portion of the color generated in the reaction is contributed by glycated albumin, the method will measure all proteins, each with a different half-life and different levels of glycation.

Glycated albumin refers to the formation of ketoamine specifically involving the major circulating protein albumin (3.5 g/dl to 5 g/dl). Glycated albumin is an example of a fructosamine. Because albumin is the most abundant of the serum proteins, fructosamine is predominantly a measure of glycated albumin. The formation of fructosamine and glycated albumin are post-translational modifications that occur to proteins. This is different from a glycoprotein which is a protein molecule that contains a carbohydrate moiety(group). The formation of a glycoprotein is an enzymatic dependent reaction. The rate of non-enzymatic glycation of albumin is much higher than that of hemoglobin ².

Fructosamine test

Fructosamine test measures the total amount of fructosamine (glycated protein) in your blood. Fructosamine and glycated albumin have a potential role in the diagnoses and management of diabetes ³. In general, fructosamine reflects glycemic control in diabetic patients over the previous 2 to 3 weeks. High values indicate poor control. However, fasting blood glucose and hemoglobin A1c (HbA1c) are the usual and preferred means of monitoring glycemic control in diabetes.

High levels of vitamin C (ascorbic acid) and hyperthyroidism can interfere with fructosamine test results.

Glucose molecules will permanently combine with proteins in the blood in a process called glycation. These proteins include albumin, the principal protein in the fluid portion of blood (serum), as well as other serum proteins and hemoglobin, the major protein found inside red blood cells (RBCs). The more glucose that is present in the blood, the greater the amount of glycated proteins that are formed. These combined molecules persist for as long as the protein or red blood cell is present in the blood and provide a record of the average amount of glucose that has been present in the blood over that time period.

Since the lifespan of red blood cells is about 120 days, glycated hemoglobin (hemoglobin A1c or HbA1C) represents a measurement of the average blood glucose level over the past 2 to 3 months. Serum proteins are present in the blood for a shorter time, about 14 to 21 days, so glycated proteins, and the fructosamine test, reflect average glucose levels over 2 to 3 weeks.

Keeping blood glucose levels as close as possible to normal helps individuals with diabetes to avoid many of the complications and progressive damage associated with elevated glucose levels. Good diabetic control is achieved and maintained by daily (or even more frequent) self-monitoring of glucose levels in people treated with insulin and by occasional monitoring of the effectiveness of treatment using the A1c test or the fructosamine test.

Fructosamine results must be evaluated in the context of a person’s overall clinical findings. Falsely low fructosamine results may be seen with decreased blood total protein and/or albumin levels, with conditions associated with increased protein loss in the urine or digestive tract, or with changes in the type of protein produced by the body. In this case, there may be a discrepancy between the results obtained from daily glucose monitoring and fructosamine testing. Also, someone whose glucose levels swing erratically from high to low may have normal or near normal fructosamine and A1c levels but still have a condition that requires frequent monitoring. However, most people with such unstable diabetic control do have elevated fructosamine and A1c concentrations.

Can I test for fructosamine at home?

No. Although a home test was available in the past, it was discontinued in 2002.

Do I need to fast for a fructosamine test?

No. Since it measures glycated protein and determines the average glucose over the past 2-3 weeks, the fructosamine test is not affected by food that you have eaten during the day. It can be measured at any time during the day.

What is fructosamine blood test used for?

The clinical utility of fructosamine and glycated albumin includes monitoring of diabetes, diagnosis of pre-diabetes and prediction of both the microvascular and macrovascular complications. They have the advantage of not requiring a fasting sample ¹.

Monitoring of glucose control in diabetes

Fructosamine and glycated albumin can be utilized as short-term markers of glucose control. Both correlate significantly with HBA1c levels. While HbA1c reflects glucose control over a period of the preceding 8 to 12 weeks, fructosamine reflects the average glycemia over the preceding 2 to 3 weeks. This is as a result of the inherent shorter half-life of albumin in comparison to hemoglobin in the erythrocyte.

Fructosamine has largely been used as an alternative to the use of HbA1c monitoring in the presence of certain conditions that preclude the use of HbA1c such as hemoglobin variants and alterations in erythrocyte lifespan. Fructosamine and glycated albumin are not affected by hemoglobin or red blood cell characteristics to which HbA1c is susceptible. This includes conditions such as hemoglobinopathies, sickle cell anemia and anemia related to iron or vitamin B12 deficiency.

Additionally, fructosamine has clinical utility in conditions where information regarding short-term glucose control is important in the management of the patient such as in pregnancy. fructosamine and glycated albumin also useful in monitoring people with diabetes with fluctuating or poorly controlled diabetes.

Diagnosis of diabetes

Recent studies have evaluated the use of the alternate glycemic markers of fructosamine and glycated albumin for the diagnosis of diabetes. It has been reported that in the diagnosis of diabetes, serum glycated albumin measurements can be used to ascertain the need for an oral glucose tolerance test (OGTT). There appears to be a negative correlation between glycated albumin and body mass index (BMI), and hence it could potentially underestimate glycemia in the obese. Currently, no guidelines support the use of glycated albumin or fructosamine for the diagnosis of diabetes or pre-diabetes.

Diabetes prognosis

Previously there was little evidence of the relationship of fructosamine and glycated albumin with diabetes complications and long-term outcomes. Recent studies, for example, the Atherosclerosis Risk in Communities Study (ARIC), have demonstrated that fructosamine and glycated albumin were strongly associated with retinopathy as well as being significantly associated with risk of incident chronic kidney disease and incident diabetes. In addition, both Fructosamine and glycated albumin, even following adjustment for HBA1c, significant prognosticators of cardiovascular outcomes and mortality.

Can a fructosamine test be used to screen for diabetes?

No. Since the fructosamine levels of people with well-controlled diabetes may overlap with those of people who are not diabetic, the fructosamine test is not useful as a screening test for diabetes.

Shouldn’t someone with a family history of diabetes have a fructosamine test?

No. Unlike A1c, this test is not recommended for diabetes screening, even if they have a strong family history.

If I have diabetes, should I have a fructosamine test?

The vast majority of people with diabetes can be monitored using A1c tests that reflect their glycemic control over the previous 2 to 3 months. Fructosamine testing can be useful during pregnancy when the woman has diabetes, when a person’s red blood cells have a shortened lifespan, and in some cases of people with abnormal forms of hemoglobin. Most diabetics will never need to have the test performed.

How is the fructosamine blood test used?

Fructosamine testing may be used to help people with diabetes monitor and control their blood glucose levels in cases where the A1c test cannot be used and/or a shorter-term monitoring window is desired. The level of fructosamine in the blood is a reflection of glucose levels over the previous 2-3 weeks. However, what this translates to in regard to outcomes and prognosis is not as validated as with A1c.

The A1c test is much more well-known and widely accepted because there are firm data that a chronically elevated A1c level predicts an increased risk for certain diabetic complications, such as problems with the eyes (diabetic retinopathy), possibly leading to blindness, kidney disease (diabetic nephropathy), and nerve damage (diabetic neuropathy).

The American Diabetes Association recognizes the usefulness of monitoring glucose control and suggests more frequent self-monitoring of blood glucose or changing the timing of continuous glucose monitoring in situations where A1c cannot be reliably measured. The American Diabetes Association states that the prognostic significance of the results of a fructosamine test are not as clear as with A1c.

Instances where fructosamine may be considered over A1c include:

• Rapid changes in diabetes treatment – fructosamine allows the effectiveness of diet or medication adjustments to be evaluated after a few weeks rather than months.
• Diabetic pregnancy – in women with diabetes who become pregnant, good glycemic control is essential during pregnancy, and the needs of the mother frequently change during the pregnancy; fructosamine measurements may be ordered along with glucose levels to help monitor and accommodate shifting glucose, insulin, or other medication requirements.
• Shortened red blood cell life span – an A1c test will not be accurate when a person has a condition that affects the average lifespan of red blood cells (RBCs), such as hemolytic anemia or blood loss. When the lifespan of red blood cells in circulation is shortened, the A1c result is falsely low and is an unreliable measurement of a person’s average glucose over time.
• Abnormal forms of hemoglobin – the presence of some hemoglobin variants, such as hemoglobin S in sickle cell anemia, may affect certain methods for measuring A1c. Furthermore, the National Institute of Diabetes and Digestive and Kidney Diseases recommends against the use of the A1c test in patients with the hemoglobin variants HbSS, HbSC, or HbCC as these patients may suffer from conditions that affect the A1c test, such as anemia, increased red blood cell turn-over, and frequent blood transfusions.

When is fructosamine test ordered?

Although not widely used, the fructosamine test may be ordered whenever a healthcare practitioner wants to monitor a person’s average glucose levels over the past 2 to 3 weeks. Fructosamine test is primarily ordered when a diabetic treatment plan is being started or adjusted in order to monitor the effect of the change in diet, exercise, or medication.

Fructosamine levels also may be ordered periodically when a diabetic woman who has diabetes is pregnant or when a person has an illness that may change their glucose and insulin requirements for a period of time. The fructosamine test may be used when monitoring is required and an A1c test cannot be reliably used, as in cases of a shortened red blood cell life span or in some cases where the person being tested has an abnormal hemoglobin.

Normal fructosamine levels

A normal fructosamine level may indicate good glucose control and that the current treatment plan is effective for the individual. Likewise, a trend from high to normal fructosamine levels may indicate that changes to the treatment regimen have been effective.

• Normal fructosamine level in non-diabetic individuals is generally: 200-285 umol/L

What does high fructosamine mean?

A high fructosamine level means that the average blood glucose over the previous 2 to 3 weeks has been elevated. In general, the higher the fructosamine level, the higher the average blood glucose level. Monitoring the trend of values may be more important than a single high value. A trend from a normal to a high fructosamine level may indicate that glucose control is not adequate. This, however, does not pinpoint the cause. A review and adjustment to diet and/or medication may be required to help get glucose under control. Illness and significant stress can also temporarily raise blood glucose levels so these factors may also be taken into account when interpreting results.

How to lower fructosamine levels

You lower your fructosamine level the same as you lower your blood glucose.

1. Cut back on the carbohydrate foods by focusing on eating the right type of carbohydrates. Or cut down on all carbohydrates go as close to zero as you are able (try under 20g per day)
2. Exercise regularly
3. Live a healthy lifestyle
4. Try intermittent fasting – it will help a lot ⁴
5. Lose weight
6. Use your glucometer to test which acceptable carbohydrates are personal no-nos, and which can be tolerated.

Yes, you probably get sick and tired of hearing that stuff but this is not rocket science, it comes down to commitment, determination, and work (yes work). Eating well does take a little bit of focus but is well worth the effort for the great results you can achieve.

Intermittent fasting helps lower HbA1c in new type 2 diabetes study

Intermittent fasting could be a beneficial option for lowering HbA1c in people with type 2 diabetes, scientists report ⁴.

Fasting was compared to continuous calorie restriction in a new Australian study ⁴ and researchers are buoyant fasting could return health benefits.

Improved HbA1c was the standout benefit, with a two-day per week fast shown to be comparable to a diet where participants restricted their calorie intake. Additionally, there were similar weight reductions between groups.

A total of 137 adults with type 2 diabetes were recruited for the study. Participants were then randomly assigned to either an intermittent calorie restriction diet consisting of 500-600 kcal per day for two non-consecutive days per week and increased intake for five days, or continuous calorie restriction consisting of 1,200-1,500 calories per day for 12 months.

The University of South Australia researchers primarily analyzed HbA1c, with weight loss a secondary outcome. Medications that could cause hypoglycemia were lowered at the beginning of the study.

The results showed that the intermittent fasting method was as effective as continuous calorie restriction in reducing HbA1c. This not only provides reassurance that intermittent fasting is effective for reducing HbA1c in a safe manner, but suggests that intermittent fasting may represent an effective alternative to daily calorie restriction.

There were similar differences for blood sugar levels, total medication effect score and step count at the study’s end. No differences were observed for low or high blood sugar within the first two weeks, which affected 35% of participants using sulphonylurea and/or insulin.

The researchers stressed that because only people with diabetes who had good blood sugar control were involved, adjustments for medication could interfere with interpretations of HbA1c. Another limitation was that participants had regular access with a dietitian than would be expected outside of a clinical setting.

The researchers concluded: “Intermittent energy restriction is a useful strategy for weight loss in type 2 diabetes and may be superior to continuous energy restriction. However, careful medication management is required to avoid hypoglycemia” ⁴.

Fructosamine testing procedures

The most common assays available for fructosamine involve a colorimetric methodology. The reaction occurs in an alkaline buffer where fructosamine as a reducing agent and involves a color change of the substrate which is measured spectrophotometrically ⁵.

These assays are widely available, can be automated and fairly inexpensive. However, unlike HbA1c there is a serious lack of standardization across the different fructosamine assays.

Glycated Albumin

There are several different assay methodologies available for the analysis of glycated albumin. These include:

• Enzymatic assay
• High-performance liquid chromatography (HPLC) and affinity chromatography
• Immunoassay, including quantification by radioimmunoassay
• Enzyme-linked immunosorbent assay (ELISA)
• Enzyme-linked boronate immunoassay (ELBIA)
• Colorimetry
• Electrochemical

Interfering Factors

Fructosamine assays are affected by changes in temperature and by the increased presence of reducing substances in serum, for example, vitamin C and bilirubin. Fructosamine and glycated albumin are both not standardized assays. Additionally, both fructosamine and glycated albumin are affected by the presence of any conditions that influence serum albumin concentrations. However, this is minimized for glycated albumin since glycated albumin is expressed as a percentage of total albumin. Fructosamine will be unreliable when serum albumin is less than 3.0 g/dl. This will include conditions where there is decreased albumin synthesis, for example, liver cirrhosis or albumin/protein loss such as nephrotic syndrome and protein-losing enteropathies. Fructosamine levels may also be affected by conditions with raised total protein levels such as in multiple myeloma (due to increased immunoglobulins) and polyclonal gammopathies.

References

1. Gounden V, Jialal I. Fructosamine. [Updated 2019 Jan 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470185
2. Muñoz-Prieto A, Escribano D, Cerón JJ, Martínez-Subiela S, Tvarijonaviciute A. Glucose, fructosamine, and insulin measurements in saliva of dogs: variations after an experimental glucose administration. Domest. Anim. Endocrinol. 2019 Jan;66:64-71
3. Neelofar K, Ahmad J. A comparative analysis of fructosamine with other risk factors for kidney dysfunction in diabetic patients with or without chronic kidney disease. Diabetes Metab Syndr. 2019 Jan – Feb;13(1):240-244
4. Carter S, Clifton PM, Keogh JB. Effect of Intermittent Compared With Continuous Energy Restricted Diet on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Noninferiority Trial. JAMA Netw Open. Published online July 20, 20181(3):e180756. doi:10.1001/jamanetworkopen.2018.0756
5. Rivera-Velez SM, Hwang J, Navas J, Villarino NF. Identification of differences in the formation of plasma glycated proteins between dogs and humans under diabetes-like glucose concentration conditions. Int. J. Biol. Macromol. 2019 Feb 15;123:1197-1203