Alternative markers of glycemia: fructosamine, glycated albumin, 1,5-AG
- 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 .
- As the half-life of albumin is 14 - 21 days, fructosamine reflects the average blood sugar concentration over the prior two to three weeks     .
- Glycated albumin is a ketoamine formed via a non-enzymatic glycation reaction of serum albumin
- Reflects mean glucose over the prior two to three weeks (i.e. extending beyond the half-life of albumin and some other serum proteins) .
- 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 .
- 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 .
- 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 .
- 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  .
- Whether fructosamine measurements should be corrected for either total protein or albumin concentrations is debatable; currently, no formal correction method is recommended .
- Fructosamine test results performed on automated instruments are available for same-day clinic visits  
- Glycated albumin:
- Glycated albumin (GA) measurement involves calculating as a ratio (or %) the GA peak area to the total albumin peak area and can be measured from both serum and plasma samples
- Several methods can be used to quantify GA but have not been uniformly standardized or available including: enzymatic assay, high-performance liquid chromatography and affinity chromatography, immunoassay, (d) enzyme-linked immunosorbent assay, (e) enzyme-linked boronate immunoassay, colorimetry, and electrochemical.
- In the U.S., affinity chromatography is most common followed by enzymatic assay
- GlycoMarkTM is the automated, commercially available assay for 1,5-AG in the USA .
- The GlycoMarkTM 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 .
- This assay for 1,5-AG is applicable to serum or plasma samples .
- No definite guideline for using alternative glycemic biomarkers as an adjunct or alternative to other tests of glycemia, such as HbA1c, fasting serum glucose, or self-monitored blood glucose measures .
- Consider 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 and glycated albumin will change more rapidly than HbA1c and can serve as an index of intermediate-term glycemic control .
- Consider alternative glycemic biomarkers in patients with hemoglobinopathies (i.e. thalassemias or hemoglobin variants) that may falsely elevate or lower HbA1c .
- Consider alternative glycemic biomarkers 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) .
- Fructosamine and GA be useful in pregnancy to detect short-term changes in glucose.
- May correlate better with post-load glucose levels compared to fasting values  , and 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  or as an adjunct to self-monitoring of blood glucose to confirm stable glycemic control .
- 1,5-AG probably superior to HbA1c and fructosamine in detecting near-normoglycemia and glycemic excursions
- High fructosamine or GA: 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 or GA: hypoalbuminemia and/or hypoproteinemia from liver failure, protein-losing enteropathy, or nephrotic syndrome  .
- 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
- 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.
- Glycated albumin:
- Normal 1,5-AG concentration: women 6.8-29.3 mcg/mL, men 10.7-32.0 mcg/mL 
LIMITATIONS OR CONFOUNDERS
- Remains unclear whether serum fructosamine or GA 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 .
- 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  .
- High fructosamine can be due to high levels of glycated immunoglobulins, specifically IgA.
- Fructosamine and GA lower in conditions where albumin metabolism increased (nephrotic syndrome, hyperthyroidism, and glucocorticoid administration); higher when albumin metabolism decreased (liver cirrhosis, hypothyroidism). Also lower in smokers, hyperuricemic patients, patients with hypertriglyceridemia, and men with nonalcoholic fatty liver disease with high ALT levels .
- Similar to HbA1c, fructosamine and 1,5 AG interpretation may be limited in renal disease .
- 1,5-AG of limited clinical utility in gestational diabetes 
- Chinese herbal supplement Polygalae Radix is a crude form of 1,5-AG and may artifactually increase levels.
- Several studies recommend cautious interpretation of serum fructosamine and GA values unless they are performed frequently.
- Patients can improve their fructosamine and GA levels by increasing compliance during the week or two prior to their clinic visit .
- The clinical usefulness of intermediate-term measures of glycemia, such as serum fructosamine and GA, remains debatable and may be best applied to specific subsets of diabetic patients, such as those with iron deficiency anemia, pregnancy, chronic liver disease, chronic renal failure, and variant hemoglobin.
- Alternative markers of glycemia can be used adjunctively to HbA1c in practice
- The low cost and convenience of the fructosamine assay may make it a useful alternative to HbA1c in developing countries .
- 1,5-AG may be useful as an adjunct to self-monitoring of blood glucose and reflects day-to-day changes in glucose levels.
- Alternative markers of glycemia have been described in relationship with long-term microvascular complications of diabetes but more studies are needed 
- Furusyo N, Hayashi J: Glycated albumin and diabetes mellitus. Biochim Biophys Acta May 12 [PMID:23673238]
- Kohzuma T et al: Basic performance of an enzymatic method for glycated albumin and reference range determination. J Diabetes Sci Technol 5:1455, 2011 [PMID:22226265]
- Selvin E et al: Nontraditional markers of glycemia: associations with microvascular conditions. Diabetes Care 34:960, 2011 [PMID:21335368]
- Chen HS et al: Hemoglobin A(1c) and fructosamine for assessing glycemic control in diabetic patients with CKD stages 3 and 4. Am J Kidney Dis 55:867, 2010 [PMID:20202728]
Comment: This study suggests that estimated average glucose calculated from HbA1c and fructosamine underestimates mean blood glucose in patients with CKD stages 3-4.
- Roohk HV, Zaidi AR: A review of glycated albumin as an intermediate glycation index for controlling diabetes. J Diabetes Sci Technol 2:1114, 2008 [PMID:19885300]
- Dungan KM: 1,5-anhydroglucitol (GlycoMark) as a marker of short-term glycemic control and glycemic excursions. Expert Rev Mol Diagn 8:9, 2008 [PMID:18088226]
Comment: Comprehensive review of 1,5-AG as a marker of short term glycemia
- Dungan KM et al: 1,5-anhydroglucitol and postprandial hyperglycemia as measured by continuous glucose monitoring system in moderately controlled patients with diabetes. Diabetes Care 29:1214, 2006 [PMID:16731998]
Comment: Describes utility of 1,5-AG in assessing post-prandial hyperglycemia in patients with diabetes
- Saudek CD, Derr RL, Kalyani RR: Assessing glycemia in diabetes using self-monitoring blood glucose and hemoglobin A1c. JAMA 295:1688, 2006 [PMID:16609091]
Comment: Literature review assessing the evidence underlying the use of self-monitored blood glucose and hemoglobin A1c.
- Goldstein DE et al: Tests of glycemia in diabetes. Diabetes Care 27:1761, 2004 [PMID:15220264]
Comment: Technical review of the tests most widely used in monitoring blood glucose control by the National Academy of Clinical Biochemistry and published as a position statement by the American Diabetes Association.
- Buse JB et al: Serum 1,5-anhydroglucitol (GlycoMark ): a short-term glycemic marker. Diabetes Technol Ther 5:355, 2003 [PMID:12828817]
Comment: Describes clinical utility of 1,5-AG.
- Herdzik E, Safranow K, Ciechanowski K: Diagnostic value of fasting capillary glucose, fructosamine and glycosylated haemoglobin in detecting diabetes and other glucose tolerance abnormalities compared to oral glucose tolerance test. Acta Diabetol 39:15, 2002 [PMID:12043934]
Comment: This study found that fructosamine correlated better with 2h-post-load glucose than fasting glucose values.
- Austin GE et al: Usefulness of fructosamine for monitoring outpatients with diabetes. Am J Med Sci 318:316, 1999 [PMID:10555094]
Comment: Prospective case-control study evaluating impact of same-day serum fructosamine levels on clinical decision making.
- Yamanouchi T, Akanuma Y: Serum 1,5-anhydroglucitol (1,5 AG): new clinical marker for glycemic control. Diabetes Res Clin Pract 24 Suppl:S261, 1994 [PMID:7859616]
Comment: Good review of 1,5-AG
- Gebhart SS et al: A comparison of home glucose monitoring with determinations of hemoglobin A1c, total glycated hemoglobin, fructosamine, and random serum glucose in diabetic patients. Arch Intern Med 151:1133, 1991 [PMID:2043015]
Comment: Study comparing four objective measures of glycemic control with home glucose monitoring in diabetic patients.
- Howey JE et al: Clinical utility of assays of glycosylated haemoglobin and serum fructosamine compared: use of data on biological variation. Diabet Med 6:793, 1989 [PMID:2533039]
Comment: Describes the relative variation of HbA1c and fructosamine with changes in glycemia.
- Negoro H, Morley JE, Rosenthal MJ: Utility of serum fructosamine as a measure of glycemia in young and old diabetic and non-diabetic subjects. Am J Med 85:360, 1988 [PMID:3414731]
Comment: Comparison of fructosamine levels with other measures of glycemia in young and old diabetic and non-diabetic subjects.
- Armbruster DA: Fructosamine: structure, analysis, and clinical usefulness. Clin Chem 33:2153, 1987 [PMID:3319287]
Comment: Details the mechanisms,usefulness, and limitations of available fructosamine assays.
- Baker JR et al: Serum fructosamine concentration as measure of blood glucose control in type I (insulin dependent) diabetes mellitus. Br Med J (Clin Res Ed) 290:352, 1985 [PMID:3917816]
Comment: Evaluation of fructosamine as a measure of glycemia in type 1 diabetics.
- Baker JR, Johnson RN, Scott DJ: Serum fructosamine concentrations in patients with type II (non-insulin-dependent) diabetes mellitus during changes in management. Br Med J (Clin Res Ed) 288:1484, 1984 [PMID:6426612]
Comment: Prospective study evaluating usefulness of fructosamine in monitoring metabolic control in non-insulin dependent diabetics during changes in management.
- Lorena Alarcon-Casas Wright and Irl B. Hirsch The Challenge of the Use of Glycemic Biomarkers in Diabetes: Reflecting on Hemoglobin A1C, 1,5-Anhydroglucitol, and the Glycated Proteins Fructosamine and Glycated Albumin Diabetes Spectrum August 2012 25:141-148; doi:10.2337/diaspect.25.3.141
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