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DESCRIPTION

• Fructosamine is the common name for 1-amino-1-deoxy-fructose, also called isoglucosamine, and was first synthesized in 1886.  
• Fructosamine is a ketoamine formed from the joining of fructose to protein molecules (mostly albumin) through glycation, a nonenzymatic mechanism involving a labile Schiff base intermediate and the Amadori rearrangement (Armbruster).
• As the half-life of albumin is 14 - 21 days, fructosamine reflects the average blood sugar concentration over the prior two to three weeks (Armbruster, Goldstein, Austin, Baker 1985, Baker 1984).
• 1,5-anhydroglucitol (1,5-AG), the 1-deoxy form of glucose, is a metabolically inert polyol composed of six-carbon chain monosaccharides derived mainly from food and well absorbed by the intestine.
• 1,5-AG competes with glucose for reabsorption into the kidneys. When glucose levels rise (>180 mg/dl), even transiently, urinary loss of 1,5-AG occurs, and circulating levels of 1,5-AG fall.
• GlycoMark is the automated assay for 1,5-AG approved for use in the U.S.
• 1,5-AG has been measured and used clinically in Japan for over a decade to monitor short-term glycemic control.
• 1,5-AG levels more tightly associated with rapid glucose fluctuations and respond within in 24 hours (Buse)

ASSAYS

• Multiple methods have been used to measure fructosamine, including the phenylhydrazine procedure, the furosine procedure, affinity chromatography, the 2-thiobarbituric acid colorimetric procedure, and the nitroblue tetrazolium colorimetric procedure (Armbruster).
• First generation fructosamine assays suffered from lack of specificity, lack of standardization among laboratories, susceptibility to interference by hyperlipidemia, and difficulty in calibrating the assay.
• However, second generation assays are rapid, inexpensive, highly specific, and free from interference by urates and triglycerides (Austin).
• The fructosamine assay commonly used today is the nitroblue tetrazolium colorimetric procedure, which separates glycated from nonglycated species based on differences in chemical reactivity.
• Multiple studies indicate that there is generally good correlation between serum fructosamine and HbA1c values (correlation coefficient, r=0.76). Like HbA1c, fructosamine is a marker of mean glucose. (Gebhart, Negoro).
• Whether fructosamine measurements should be corrected for either total protein or albumin concentrations is debatable; currently, no formal correction method is recommended (Goldstein).
• Fructosamine test results performed on automated instruments are available for same-day clinic visits (Austin, Goldstein)
• GlycoMark^TM is the automated, commercially available assay for 1,5-AG in the USA (Dungan).
• The GlycoMark^TM assay involves two enzymatic steps: the first step uses glucokinase to convert glucose to glucose-6-phophate in order to avoid its interference with the second enzymatic step; in the second step, 1,5-AG is oxidized with pyranose oxidase, and the resulting hydrogen peroxide is detected colorimetrically (Dungan).
• This assay for 1,5-AG is applicable to serum or plasma samples (Dungan)

INDICATIONS

• No definite guideline for using fructosamine or 1,5-AG as an adjunct or alternative to other tests of glycemia, such as HbA1c, fasting serum glucose, or self-monitored blood glucose measures (Goldstein).
• Consider fructosamine in patients with patient visits less than one month apart. Because the half-life of albumin and other serum proteins is shorter than that of hemogloblin, concentrations of fructosamine will change more rapidly than HbA1c. Fructosamine can serve as an index of intermediate-term glycemic control (Armbruster).
• Consider fructosamine in patients with hemoglobinopathies (i.e. thalassemias or hemoglobin variants) that may falsely elevate or lower HbA1c (Saudek).
• Consider fructosamine in patients with comorbidities that may affect erythrocyte life span that may falsely elevate or lower HbA1c (i.e. kidney disease, liver disease, hemolytic anemia, HIV, iron-deficiency anemia, aplastic anemia) (Saudek).
• Fructosamine may be useful in pregnancy to detect short-term changes in glucose.
• Fructosamine and 1,5-AG correlate better with post-load glucose levels compared to fasting values (Herdzik, Dungan), and may be helpful in patients for whom postprandial hyperglycemia is suspected
• 1,5-AG may be most useful when day-to-day glucose changes are being monitored (Yamanouchi) or as an adjunct to self-monitoring of blood glucose to confirm stable glycemic control (Buse).
• 1,5-AG probably superior to HbA1c and fructosamine in detecting near-normoglycemia and glycemic excursions

DIFFERENTIAL DIAGNOSIS

• High fructosamine: hyperglycemia over the preceding 2 to 3 weeks, supported by self-monitored blood glucose measures and/or fasting or random blood glucose measures.
• Low fructosamine: hypoalbuminemia and/or hypoproteinemia from liver failure, protein-losing enteropathy, or nephrotic syndrome (Armbruster, Austin).
• Low 1,5-AG: hyperglycemia within the preceding 24 hours
• 1,5-AG not affected by hypoglycemia and better differentiates patients with extensive glycemic excursions who have similar HbA1c values

INTERPRETATION

• Fructosamine levels depends upon patient's age and sex
• No diabetes, fructosamine range: 175-280 mmol/L
• Controlled diabetes, fructosamine range: 210-421 mmol/L
• Uncontrolled diabetes, fructosamine range: 268-870 mmol/L
• In order to correct for albumin concentration, fructosamine/g albumin: 4.7-6.5 mmol/g of albumin
• The trend of fructosamine levels over time may have greater importance than the absolute value.
• Normal 1,5 AG concentration: women 6.8-29.3 mcg/mL, men 10.7-32.0 mcg/mL (Dungan)

LIMITATIONS OR CONFOUNDERS

• Remains unclear whether serum fructosamine values should be corrected for protein and/or albumin concentration.
• The within subject variation for serum fructosamine is higher than that for HbA1c, which means that fructosamine levels must change much more before a significant difference can be determined (Howey).
• Studies on the clinical usefulness of home fructosamine testing have yielded conflicting results. One study found that mean glycemia over a prior 2-week period was better predicted by HbA1c. Additionally, when used as an adjunct to home blood glucose monitoring, weekly fructosamine did not improve HbA1c levels (Saudek, Goldstein).
• High fructosamine can be due to high levels of glycated immunoglobulins, specifically IgA.
• Simila to HbA1c, fructosamine and 1,5 AG interpretation may be limited in renal disease (Chen).
• 1,5-AG of limited clinical utility in gestational diabetes (Buse)
• Chinese herbal supplement Polygalae Radix is a crude form of 1,5-AG and may artifactually increase levels.

EXPERT COMMENTS

• Several studies recommend cautious interpretation of serum fructosamine values unless they are performed frequently.
• Patients can improve their fructosamine levels by increasing compliance during the week or two prior to their clinic visit (Goldstein).
• The clinical usefulness of intermediate-term measures of glycemia, such as serum fructosamine, remains debatable and may be best applied to specific subsets of diabetic patients, such as those with hemoglobinopathies or abnormal erythrocyte life spans.
• Fructosamine may be particularly suitable, at least in an adjunctive role to other measures of glycemia, for monitoring outpatients with diabetes.
• The low cost and convenience of the fructosamine assay may make it a useful alternative to HbA1c in developing countries (Austin).
• 1,5-AG may be useful as an adjunct to self-monitoring of blood glucose and reflects day-to-day changes in glucose levels.

REFERENCES